Migraine and Other Headache Disorders

NEUROLOGICAL DISEASE AND THERAPY Advisory Board Gordon H. Baltuch, M.D., Ph.D. Department of Neurosurgery University of Pennsylvania Philadelphia, Pennsylvania, U.S.A. Louis R. Caplan, M.D. Professor of Neurology Harvard University School of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A. Mark A. Stacy, M.D. Movement Disorder Center Duke University Medical Center Durham, North Carolina, U.S.A. Mark H. Tuszynski, M.D., Ph.D. Professor of Neurosciences Director, Center for Neural Repair University of CaliforniaSan Diego La Jolla, California, U.S.A.

1. Handbook of Parkinsons Disease, edited by William C. Koller 2. Medical Therapy of Acute Stroke, edited by Mark Fisher 3. Familial Alzheimers Disease: Molecular Genetics and Clinical Perspectives, edited by Gary D. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine, and Linda A. Winters-Miner 4. Alzheimers Disease: Treatment and Long-Term Management, edited by Jeffrey L. Cummings and Bruce L. Miller 5. Therapy of Parkinsons Disease, edited by William C. Koller and George Paulson 6. Handbook of Sleep Disorders, edited by Michael J. Thorpy 7. Epilepsy and Sudden Death, edited by Claire M. Lathers and Paul L. Schraeder 8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook 9. Memory Disorders: Research and Clinical Practice, edited by Takehiko Yanagihara and Ronald C. Petersen 10. The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and Henn Kutt 11. Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J. Thal, Walter H. Moos, and Elkan R. Gamzu 12. Handbook of Amyotrophic Lateral Sclerosis, edited by Richard Alan Smith 13. Handbook of Parkinsons Disease: Second Edition, Revised and Expanded, edited by William C. Koller 14. Handbook of Pediatric Epilepsy, edited by Jerome V. Murphy and Fereydoun Dehkharghani 15. Handbook of Tourettes Syndrome and Related Tic and Behavioral Disorders, edited by Roger Kurlan 16. Handbook of Cerebellar Diseases, edited by Richard Lechtenberg 17. Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr. 18. Parkinsonian Syndromes, edited by Matthew B. Stern and William C. Koller 19. Handbook of Head and Spine Trauma, edited by Jonathan Greenberg 20. Brain Tumors: A Comprehensive Text, edited by Robert A. Morantz and John W. Walsh 21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. Warren Olanow, Moussa B. H. Youdim, and Keith Tipton 22. Handbook of Dementing Illnesses, edited by John C. Morris 23. Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robert P. Lisak 24. Handbook of Neurorehabilitation, edited by David C. Good and James R. Couch, Jr. 25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark Hallett 26. Principles of Neurotoxicology, edited by Louis W. Chang 27. Handbook of Neurovirology, edited by Robert R. McKendall and William G. Stroop 28. Handbook of Neuro-Urology, edited by David N. Rushton 29. Handbook of Neuroepidemiology, edited by Philip B. Gorelick and Milton Alter 30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William C. Koller 31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up and Management, edited by Ronald J. Tusa and Steven A. Newman 32. Handbook of Olfaction and Gustation, edited by Richard L. Doty 33. Handbook of Neurological Speech and Language Disorders, edited by Howard S. Kirshner 34. Therapy of Parkinsons Disease: Second Edition, Revised and Expanded, edited by William C. Koller and George Paulson 35. Evaluation and Management of Gait Disorders, edited by Barney S. Spivack 36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robert S. Dyer 37. Neurological Complications of Cancer, edited by Ronald G. Wiley

38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. Korczyn 39. Handbook of Dystonia, edited by Joseph King Ching Tsui and Donald B. Calne 40. Etiology of Parkinsons Disease, edited by Jonas H. Ellenberg, William C. Koller and J. William Langston 41. Practical Neurology of the Elderly, edited by Jacob I. Sage and Margery H. Mark 42. Handbook of Muscle Disease, edited by Russell J. M. Lane 43. Handbook of Multiple Sclerosis: Second Edition, Revised and Expanded, edited by Stuart D. Cook 44. Central Nervous System Infectious Diseases and Therapy, edited by Karen L. Roos 45. Subarachnoid Hemorrhage: Clinical Management, edited by Takehiko Yanagihara, David G. Piepgras, and John L. D. Atkinson 46. Neurology Practice Guidelines, edited by Richard Lechtenberg and Henry S. Schutta 47. Spinal Cord Diseases: Diagnosis and Treatment, edited by Gordon L. Engler, Jonathan Cole, and W. Louis Merton 48. Management of Acute Stroke, edited by Ashfaq Shuaib and Larry B. Goldstein 49. Sleep Disorders and Neurological Disease, edited by Antonio Culebras 50. Handbook of Ataxia Disorders, edited by Thomas Klockgether 51. The Autonomic Nervous System in Health and Disease, David S. Goldstein 52. Axonal Regeneration in the Central Nervous System, edited by Nicholas A. Ingoglia and Marion Murray 53. Handbook of Multiple Sclerosis: Third Edition, edited by Stuart D. Cook 54. Long-Term Effects of Stroke, edited by Julien Bogousslavsky 55. Handbook of the Autonomic Nervous System in Health and Disease, edited by C. Liana Bolis, Julio Licinio, and Stefano Govoni 56. Dopamine Receptors and Transporters: Function, Imaging, and Clinical Implication, Second Edition, edited by Anita Sidhu, Marc Laruelle, and Philippe Vernier 57. Handbook of Olfaction and Gustation: Second Edition, Revised and Expanded, edited by Richard L. Doty 58. Handbook of Stereotactic and Functional Neurosurgery, edited by Michael Schulder 59. Handbook of Parkinsons Disease: Third Edition, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 60. Clinical Neurovirology, edited by Avindra Nath and Joseph R. Berger 61. Neuromuscular Junction Disorders: Diagnosis and Treatment, Matthew N. Meriggioli, James F. Howard, Jr., and C. Michel Harper 62. Drug-Induced Movement Disorders, edited by Kapil D. Sethi 63. Therapy of Parkinsons Disease: Third Edition, Revised and Expanded, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 64. Epilepsy: Scientific Foundations of Clinical Practice, edited by Jong M. Rho, Raman Sankar, and Jos E. Cavazos 65. Handbook of Tourettes Syndrome and Related Tic and Behavioral Disorders: Second Edition, edited by Roger Kurlan 66. Handbook of Cerebrovascular Diseases: Second Edition, Revised and Expanded, edited by Harold P. Adams, Jr. 67. Emerging Neurological Infections, edited by Christopher Power and Richard T. Johnson 68. Treatment of Pediatric Neurologic Disorders, edited by Harvey S. Singer, Eric H. Kossoff, Adam L. Hartman, and Thomas O. Crawford 69. Synaptic Plasticity : Basic Mechanisms to Clinical Applications, edited by Michel Baudry, Xiaoning Bi, and Steven S. Schreiber

70. Handbook of Essential Tremor and Other Tremor Disorders, edited by Kelly E. Lyons and Rajesh Pahwa 71. Handbook of Peripheral Neuropathy, edited by Mark B. Bromberg and A. Gordon Smith 72. Carotid Artery Stenosis: Current and Emerging Treatments, edited by Seemant Chaturvedi and Peter M. Rothwell 73. Gait Disorders: Evaluation and Management, edited by Jeffrey M. Hausdorff and Neil B. Alexander 74. Surgical Management of Movement Disorders (HBK), edited by Gordon H. Baltuch and Matthew B. Stern 75. Neurogenetics: Scientific and Clinical Advances, edited by David R. Lynch 76. Epilepsy Surgery: Principles and Controversies, edited by John W. Miller and Daniel L. Silbergeld 77. Clinician's Guide To Sleep Disorders, edited by Nathaniel F. Watson and Bradley Vaughn 78. Amyotrophic Lateral Sclerosis, edited by Hiroshi Mitsumoto, Serge Przedborski, and Paul H. Gordon 79. Duchenne Muscular Dystrophy: Advances in Therapeutics, edited by Jeffrey S. Chamberlain and Thomas A. Rando 80. Handbook of Multiple Sclerosis, Fourth Edition, edited by Stuart D. Cook 81. Brain Embolism, edited by Louis R. Caplan and Warren J. Manning 82. Handbook of Secondary Dementias, edited by Roger Kurlan 83. Parkinson's Disease: Genetics and Pathogenesis, edited by Ted M. Dawson 84. Migraine, Russell Lane and Paul Davies 85. Migraine and Other Headache Disorders, edited by Richard B. Lipton and Marcelo E. Bigal

Migraine and Other Headache Disorders

Richard B. Lipton
Albert Einstein College of Medicine New York, New York, U.S.A.

Marcelo E. Bigal
Albert Einstein College of Medicine New York, New York, U.S.A.

New York London

Published in 2006 by Taylor & Francis Group 270 Madison Avenue New York, NY 10016 2006 by Taylor & Francis Group, LLC No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3695-3 (Hardcover) International Standard Book Number-13: 978-0-8493-3695-9 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress

Taylor & Francis Group is the Academic Division of Informa plc.

Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com

Preface

With this rst edition of Migraine and Other Headache Disorders, we celebrate the remarkable progress in the art and science of headache during the last decade. With 32 chapters by 54 leaders in the eld, the book provides health care professionals with practical approaches to patient care and reviews the scientic foundations of headache. We emphasize migraine because of its high prevalence, enormous burden, and the increasing availability of effective management strategies. At the same time, we provide broad coverage of all the primary headache disorders. Finally, although not focusing on specic subtypes of secondary headaches, we discuss strategies for diagnosing and excluding the ominous causes of headache, based both on clinical evaluation and, when appropriate, the use of diagnostic testing. Our understanding of headache and the approach to treatment have been transformed by insights from many places. Based on the Second Edition of the International Classication of Headache Disorders, the book provides a series of diagnostic algorithms intended to simplify clinical practice. We also present up-to-date epidemiologic information on the primary headache disorders. Epidemiologic studies show that the overwhelming majority of headache sufferers who seek treatment in primary care settings have migraine. Diagnosis becomes more efcient when that fact is taken into account. Doctors should avoid oversimplifying the differential diagnosis of the primary headaches, however. Our understanding of migraine as a disorder has signicantly evolved over the past decade, based on genetic, epidemiologic, and translational studies. Once considered an episodic pain problem, treating the pain seemed like a sensible strategy. In the past few years, many lines of evidence have suggested that migraine and other headache disorders are best understood as chronic disorders with episodic manifestations. Painful episodes are the most prominent manifestation of migraine. Nonetheless, between attacks, there is an enduring predisposition to headache that characterizes the migraine brain. Furthermore, migraine is not only a chronic disorder with episodic manifestations, it is sometimes a disorder that progresses in several ways. Progression may be clinical, as attacks increase in frequency until chronic or transformed migraine develops. This clinical progression is sometimes accompanied by the development of allodynia with sensitization as its presumed substrate. In addition, in some individuals, morphological progression takes the form of deep white matter lesion or posterior circulation strokes that increase with migraine attack frequency, probably reecting neuroplastic changes in the brain. Herein we highlight the emerging data on progression and on the modiable risk factors for migraine progression. Progress in treatment has also taken several forms. Since 1990, ten new acute treatments with a multiplicity of formulations and two preventive drugs have been
iii

iv

Preface

approved. Many studies show that acute treatments work best if given early in the attack. Combining acute treatments may improve treatment response in some individuals. In addition, recent epidemiologic data shows that, based on frequency and disability criteria, preventive treatment should be offered or considered in about 40% of migraine sufferers. The same studies show that only 12% currently receive preventive therapy. Preventive treatment decreases attack frequency and severity and possibly prevents migraine progression. The use of specic acute agents that act on the neural pathways of migraine pain, such as the triptans, dramatically improve patient outcomes. Migraine and Other Headache Disorders highlights the treatment approaches developed at some of the best headache clinics in the world. It also reects many of the strategies adopted at The Monteore Headache Center. The Monteore Headache Center was the rst headache specialty care center in the world, founded in 1945 by Dr. Arnold Friedman, and it is where we are both proud to be. We are extremely grateful to our mentors. Among them, Dr. Lipton wants to thank Dr. Seymour Solomon, who directed The Monteore Headache Center for a quarter of a century, for being a wonderful mentor and teacher. Hed also like to thank his mentors and collaborators in research, particularly Drs. Philip Holzman, W. Allen Hauser, and Walter F. Stewart. Dr. Bigal wants to acknowledge Drs. Speciali and Bordini, from Brazil, and the teams at The New England Center for Headache (Rapoport, Sheftell, and Tepper) and at Monteore (Lipton and Solomon) for their help and direction. We also want to thank the authors of the chapters in this book for their excellent work. Finally, we owe special thanks to our families, particularly our wives (Amy Natkins Lipton and Janana Maciel Bigal) and children (Lianna Lipton, Justin Lipton, Lusa Bigal, and Hanna Bigal) for supporting us through evenings and weekends spent writing and editing as we prepared this book. Finally, to our readers, we hope this book furthers your efforts to improve the lives of headache sufferers. These common and disabling disorders are tremendously gratifying to treat. In a eld where cures are rare, we can nonetheless help patients by empowering them with tools that relieve pain, restore their ability to function, and, perhaps, prevent disease progression. Richard B. Lipton Marcelo E. Bigal

Contents

Preface . . . . iii Contributors . . . . xv 1. HeadacheClassication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Marcelo E. Bigal and Richard B. Lipton Introduction . . . . 1 An Overview of the ICHD-2 . . . . 1 Classication of the Primary Headaches . . . . 5 Secondary Headaches . . . . 14 Headache Attributed to Head and/or Neck Trauma . . . . 14 Headache Attributed to Cranial or Cervical Vascular Disorders . . . . 14 Headache Attributed to Nonvascular Intracranial Disorders . . . . 15 Headache Attributed to a Substance or Its Withdrawal . . . . 15 Headache Attributed to Infection . . . . 15 Headache Attributed to Disorders of Homeostasis . . . . 15 Headache or Facial Pain Attributed to Disorders of Cranium, Neck, Eyes, Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial or Cranial Structures . . . . 16 Headache Attributed to Psychiatric Disorders . . . . 16 Cranial Neuralgias and Central Causes of Facial Pain . . . . 16 Controversies in the Classication of Primary Chronic Daily Headaches of Long Duration . . . . 16 References . . . . 17 2. The Epidemiology and Impact of Migraine . . . . . . . . . . . . . . . . . . . 23 Richard B. Lipton and Marcelo E. Bigal Introduction . . . . 23 The Epidemiology of Migraine . . . . 23 The Burden of Migraine . . . . 31 Probable MigraineAn Important Migraine Subtype . . . . 32 Conclusions . . . . 33 References . . . . 34
v

vi

Contents

3. Progressive Headache: Epidemiology, Natural History, and Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Ann I. Scher Introduction . . . . 37 Classication . . . . 37 Chronic Daily Headache Epidemiology and Natural History . . . . 38 Demographic Factors Associated with Chronic Daily Headache . . . . 38 Other Factors Associated with Chronic Daily Headache Prevalence or Incidence . . . . 39 Conclusion . . . . 42 References . . . . 42 4. Comorbidity of Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Nancy C. P. Low and Kathleen Ries Merikangas Introduction . . . . 45 Methodology of Comorbidity Studies . . . . 45 Evidence for Migraine Comorbidity . . . . 46 Conclusion . . . . 53 References . . . . 54 5. Pain Sensitivity: Intracranial and Extracranial Structures Todd D. Rozen Anatomy of Head Pain . . . . 61 References . . . . 65 . . . . . . . . 61

6. Pathophysiology of Aura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 M. Sanchez del Rio and U. Reuter Introduction . . . . 67 Neurophysiological Mechanisms . . . . 67 Imaging Studies . . . . 72 Molecular Mechanisms . . . . 72 Occipital Cortex Excitability . . . . 74 Genetics . . . . 75 Conclusions . . . . 76 References . . . . 77 7. Pathophysiology of Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Peter J. Goadsby Introduction . . . . 81 MigraineExplaining the Clinical Features . . . . 81 Genetics of Migraine . . . . 82 Familial Hemiplegic Migraine (FHM) . . . . 82 Migraine Aura . . . . 83 HeadacheAnatomy . . . . 83 Headache PhysiologyPeripheral Connections . . . . 84

Contents

vii

Headache PhysiologyCentral Connections . . . . 86 Central Modulation of Trigeminal Pain . . . . 88 What Is Migraine? . . . . 89 References . . . . 90 8. Allodynia and Sensitization in Migraine . . . . . . . . . . . . . . . . . . . . . 99 William B. Young, Avi Ashkenazi, and Michael L. Oshinsky Introduction . . . . 99 Sensory Processing by the Nervous System . . . . 100 Sensitization of the Dorsal Horn . . . . 100 Rat Model of Migraine Headache and Allodynia . . . . 102 Human Studies of Allodynia in Pain Disorders Other Than Migraine . . . . 103 Human Studies of Allodynia in Migraine . . . . 104 Time Course of Sensitization in Migraine . . . . 106 The Effect of Allodynia on Treatment Outcome . . . . 106 The Effect of Treatment on Allodynia . . . . 107 Allodynia in Headache Disorders Other Than Migraine . . . . 107 Conclusion . . . . 108 References . . . . 108 9. Genetics of Migraine and Other Primary Headaches . . . . . . . . . . . 113 Gisela M. Terwindt, Esther E. Kors, Joost Haan, Kaate R. J. Vanmolkot, Rune R. Frants, Arn M. J. M. van den Maagdenberg, and Michel D. Ferrari IntroductionGenetic Studies on Headache . . . . 113 The Clinical Spectrum of the CACNA1A Gene Mutations . . . . 114 The Clinical Spectrum of the ATP1A2 Gene . . . . 118 Sporadic Hemiplegic Migraine . . . . 120 Genetic Susceptibility in Migraine . . . . 120 Cluster Headache . . . . 123 Tension-Type Headache . . . . 123 Concluding Remarks . . . . 123 References . . . . 124 10. Identication or Exclusion of Secondary Headaches . . . . . . . . . . 131 Randolph W. Evans and R. Allan Purdy Introduction . . . . 131 General Indications for Neuroimaging for Headaches . . . . 132 Neuroimaging for Headaches with a Normal Neurological Examination . . . . 132 Neuroimaging for Migraine . . . . 133 Evaluation of the Acute Severe New-Onset Headache (First or Worst Headaches) . . . . 135 Headaches Over the Age of 50 Years . . . . 138 New Daily Headaches . . . . 140 References . . . . 141

viii

Contents

11. Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach . . . . . . . . . . . . . . . . . . . . . . . . . 145 Richard B. Lipton and Marcelo E. Bigal Introduction . . . . 145 Approaching a Patient with Headache . . . . 145 Conclusions . . . . 152 References . . . . 152 12. Diagnostic and Severity Tools for Migraine . Marcelo E. Bigal and Richard B. Lipton Introduction . . . . 155 Screening for Migraine . . . . 156 Assessing Migraine-Related Disability . . . . Assessing Psychological Comorbidity . . . . Assessing Ongoing Treatment . . . . 163 Conclusion . . . . 165 References . . . . 165 Appendix: The PRIME-MD Questionnaire . . . . . . . . . . . . . . . . 155

159 163

. . . 167

13. Migraine Without Aura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Fred Sheftell and Roger Cady IntroductionMigraine Without Aura: An Underdiagnosed and Undertreated Disorder . . . . 173 The ICHD-2 Criteria for Migraine Without Aura . . . . 174 Migraine in Clinical Practice . . . . 177 The Convergence Hypothesis . . . . 181 Menstrually Related Migraine . . . . 182 Conclusion . . . . 183 Illustrative Case History . . . . 184 References . . . . 184 14. Migraine with Aura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Malene Kirchmann Eriksen and Jes Olesen Introduction . . . . 189 Classication . . . . 189 Migraine with Typical Aura . . . . 192 Familial and Sporadic Hemiplegic Migraine . . . . 197 Basilar-Type Migraine . . . . 198 Differential Diagnoses . . . . 199 References . . . . 199 15. Childhood Periodic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . 203 Vincenzo Guidetti, Federica Galli, Azzurra Alesini, and Federico Dazzi Introduction . . . . 203 Cyclical Vomiting . . . . 204 RAP and Abdominal Migraine . . . . 206 BPV of Childhood . . . . 207

Contents

ix

Benign Paroxysmal Torticollis . . . . 208 Alternating Hemiplegia of Childhood . . . . 209 Conclusion . . . . 209 References . . . . 210 16. Retinal, or Monocular, Migraine . . . . . . . . . . . . . . . . . . . . . . 213 Brian M. Grosberg and Seymour Solomon Introduction . . . . 213 Diagnostic Criteria . . . . 213 Clinical Features . . . . 215 Epidemiology and Prognosis . . . . 217 Pathophysiology . . . . 218 Differential Diagnosis . . . . 218 Management . . . . 219 References . . . . 220 17. Status Migrainosus, Persistent Aura, Migraine-Associated Seizures (Migralepsy), and Migrainous Infarction . . . . . . . . . . . . . . . . . 223 Jessica Crowder, Curtis Delplanche, and John F. Rothrock Introduction . . . . 223 Status Migrainosus . . . . 223 Prolonged Aura . . . . 227 Migralepsy . . . . 228 Migraine and Stroke . . . . 232 References . . . . 236 18. Principles of Headache Management . . . . . . . . . . . . . . . . . . . . . 241 Marc S. Husid and Alan M. Rapoport Introduction . . . . 241 Establishing the Diagnosis . . . . 242 Assessing Disability . . . . 252 Educating Patients . . . . 252 Establishing Realistic Expectations . . . . 254 Encouraging Patients to Become Active in Their Own Care . . . . 254 Headache Calendars . . . . 255 Developing an Appropriate, Individualized Treatment Plan . . . . 256 Why Headache Treatment Fails . . . . 256 Conclusion . . . . 257 References . . . . 258 Further Reading (Patient Education Resources) . . . . 258 Appendix 1 . . . . 260 19. Behavioral and Educational Approaches to the Management of Migraine: Clinical and Public Health Applications . . . . . . . . . . . . . . . . . . . 261 Kenneth A. Holroyd Introduction . . . . 261 Behavioral Interventions . . . . 261

Contents

Treatment Delivery . . . . 263 Efcacy . . . . 264 Integrating Drug and Behavioral Treatments . . . . 265 Education for Self-Management . . . . 266 Community Applications . . . . 267 Conclusion . . . . 270 References . . . . 270 20. Nonspecic Migraine Acute Treatment . . . . . . . . . . . . . . . . . . . 273 Abouch Krymchantowski and Stewart J. Tepper Introduction . . . . 273 Simple Analgesics . . . . 274 Medications for the Treatment of Nausea . . . . 277 Combinations of NSAIDs and Triptans . . . . 278 Neuroleptics in the Treatment of Pain . . . . 279 OPIOIDS . . . . 279 Nonspecic vs. Specic Treatments . . . . 280 Conclusions . . . . 282 References . . . . 283 21. Specic Acute Migraine Treatment: Ergotamine and Triptans . . . . 289 Hans-Christoph Diener and Volker Limmroth Introduction . . . . 289 Ergotamine . . . . 289 Ergotamine vs. Oral Triptans . . . . 290 Triptans . . . . 292 Conclusions . . . . 304 References . . . . 304 22. Preventive Treatment for Migraine . . . . . . . . . . . . . . . . . . . . . . 311 Stephen D. Silberstein IntroductionWhy and When to Use Migraine-Preventive Medications . . . . 311 Mechanism of Action of Preventive Medications . . . . 313 Specic Migraine-Preventive Agents . . . . 315 Setting Treatment Priorities . . . . 345 References . . . . 347 23. Herbal Medicines and Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . 363 Jean Schoenen and Delphine Magis Introduction . . . . 363 Riboavin . . . . 363 Coenzyme Q10 . . . . 366 Thioctic Acid (a-Lipoic Acid) . . . . 367 Feverfew (Tanacetum parthenium) . . . . 367 Butterbur (Petasites hybridus) . . . . 369 Magnesium . . . . 370

Contents

xi

Conclusions . . . . 370 References . . . . 371 24. Treatment of Migraine in Children and Adolescents . . . . . . . . . . . 375 Paul Winner Introduction . . . . 375 Acute Treatment . . . . 376 Preventive Therapy . . . . 381 Conclusions . . . . 388 References . . . . 389 25. Inpatient Management and Invasive Treatment Strategies for Migraine and Chronic Daily Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Frederick G. Freitag Introduction . . . . 393 Inpatient Treatment . . . . 393 Invasive Treatment of Migraine and Chronic Daily Headaches . . . . 405 Conclusion . . . . 408 References . . . . 409 26. Migraine in the Emergency Department . . . . . . . . . . . . . . . . . . . 413 Merle Diamond and Benjamin W. Friedman Introduction . . . . 413 How to Approach a Patient with Acute Headache in the ED . . . . 414 Treatment . . . . 417 Specic Situations . . . . 422 Disposition . . . . 423 Status Migrainosus/Intractable Pain . . . . 425 References . . . . 426 27. Progression Forms of Migraine . . . . . . . . . . . . . . . . . . . . . . . . . 431 Marcelo E. Bigal and Richard B. Lipton Introduction . . . . 431 Epidemiology of the CDHS . . . . 432 Transformed Migraine . . . . 432 Prospects for Preventing Headache Progression . . . . 441 References . . . . 442 28. The Future of Migraine Therapies . . . . . . . . . . . . . . . . . . . . . . . 445 Todd Schwedt and David Dodick Introduction . . . . 445 Trigeminal Receptor Targets . . . . 446 Adenosine Receptors . . . . 448 Drugs Targeting the ORL-1 Receptors . . . . 448 Vanilloid Receptors . . . . 449

xii

Contents

Glutamate Receptors . . . . 449 CGRP Receptor Antagonists . . . . 450 NOS Inhibitors . . . . 450 Pharmacogenomics . . . . 451 Summary . . . . 452 References . . . . 453 29. Tension-Type Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 Rigmor Jensen Introduction . . . . 457 The Epidemiology of TTH . . . . 458 The Clinical Presentation of TTH . . . . 460 Physical Examination in Subjects with TTH . . . . 462 Psychological Aspects of TTH . . . . 463 Pathophysiology . . . . 463 Treatment . . . . 464 References . . . . 465 30. Trigeminal Autonomic Cephalgias . . . . . . . . . . . . . . . . . . . . . . . 471 David Dodick Introduction . . . . 471 Pathophysiology . . . . 471 Cluster Headache . . . . 473 Paroxysmal Hemicranias . . . . 484 SUNCT Syndrome . . . . 486 References . . . . 487 31. Other Primary Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Lawrence C. Newman, Susan W. Broner, and Christine L. Lay Introduction . . . . 495 Primary Stabbing Headache (ICHD-2 Code 4.1) . . . . 495 Primary Cough Headache (ICHD-2 Code 4.2) . . . . 496 Primary Exertional Headache (ICHD-2 Code 4.3) . . . . 497 Primary Headaches Associated with Sexual Activity (ICHD-2 Code 4.4) . . . . 498 The Hypnic Headache Syndrome (ICHD-2 Code 4.5) . . . . 499 Primary Thunderclap Headache (ICHD-2 Code 4.6) . . . . 500 Hemicrania Continua (ICHD-2 Code 4.7) . . . . 501 New Daily-Persistent Headache (ICHD-2 Code 4.8) . . . . 503 Conclusion . . . . 505 References . . . . 505 32. When the Treatment of Headache Fails . . . . . . . . . . . . . . . . . . . 509 Richard B. Lipton and Marcelo E. Bigal Introduction . . . . 509 Reason 1: The Diagnosis Is Incomplete or Incorrect . . . . 509

Contents

xiii

Reason 2: Important Exacerbating Factors May Have Been Missed . . . . 514 Reason 3: Pharmacotherapy May Be Inadequate . . . . 515 Reason 4: Nonpharmacologic Treatment May Be Inadequate . . . . 517 Reason 5: Other Reasons for Treatment Failure . . . . 517 Conclusions . . . . 518 References . . . . 518 Index . . . . 523

Contributors

Azzurra Alesini Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Avi Ashkenazi Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Marcelo E. Bigal Department of Neurology, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A. Susan W. Broner The Headache Institute, Roosevelt Hospital Center, New York, New York, U.S.A. Roger Cady Headache Care Center, Primary Care Network, Springeld, Missouri, U.S.A. Jessica Crowder Department of Neurology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A. Federico Dazzi Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Curtis Delplanche Department of Neurology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A. M. Sanchez del Rio Department of Neurology, Headache Program, Hospital Ruber International, Madrid, Spain Merle Diamond Diamond Headache Clinic and Rosalyn Finch School of Medicine, Chicago, Illinois, U.S.A. Hans-Christoph Diener Essen, Germany David Dodick Department of Neurology, University of Duisburg-Essen,

Mayo Clinic College of Medicine, Scottsdale, Arizona, U.S.A.

xv

xvi

Contributors

Malene Kirchmann Eriksen Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark Randolph W. Evans Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, Department of Neurology, The Methodist Hospital, and Baylor College of Medicine, Houston, Texas, U.S.A. Michel D. Ferrari Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Rune R. Frants Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Frederick G. Freitag Diamond Headache Clinic, Chicago and Department of Family Medicine, Chicago College of Osteopathic Medicine, Downers Grove and Department of Family Medicine, Rosalind Franklin University of Medicine and Science/Chicago Medical School, North Chicago, Illinois, U.S.A. Benjamin W. Friedman Department of Emergency Medicine, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, U.S.A. Federica Galli Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Peter J. Goadsby Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, U.K. Brian M. Grosberg Department of Neurology, The Monteore Headache Center, Albert Einstein College of Medicine, New York, New York, U.S.A. Vincenzo Guidetti Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy Joost Haan Department of Neurology, Leiden University Medical Center, Leiden, and Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands Kenneth A. Holroyd Ohio, U.S.A. Psychology Department, Ohio University, Athens,

Marc S. Husid Department of Neurology, Walton Headache Center, Medical College of Georgia, Augusta, Georgia, U.S.A. Rigmor Jensen Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark Esther E. Kors Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

Contributors

xvii

Abouch Krymchantowski Outpatient Headache Unit, Instituto de Neurologia, and Deolindo Couto, Headache Center of Rio, Rio de Janeiro, Brazil Christine L. Lay The Headache Institute, Roosevelt Hospital Center, New York, New York, U.S.A. Volker Limmroth Department of Neurology, Cologne City Hospitals, University of Cologne, Cologne, Germany Richard B. Lipton Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Monteore Headache Center, New York, New York, U.S.A. Nancy C. P. Low Section on Developmental Genetic Epidemiology, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, U.S.A. Delphine Magis Departments of Neuroanatomy and Neurology, Headache ` ` Research Unit, University of Liege, Liege, Belgium Kathleen Ries Merikangas Section on Developmental Genetic Epidemiology, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, U.S.A. Lawrence C. Newman The Headache Institute, Roosevelt Hospital Center, New York, New York, U.S.A. Jes Olesen Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark Michael L. Oshinsky Department of Neurology and Preclinical Research, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. R. Allan Purdy Division of Neurology, Dalhousie University, and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada Alan M. Rapoport The New England Center for Headache, Stamford, Connecticut, and Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, U.S.A. U. Reuter Department of Neurology, Charite, Universitatsmedizin Berlin, Berlin, Germany John F. Rothrock Department of Neurology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A. Todd D. Rozen Department of Neurology, Michigan Head Pain and Neurological Institute, Ann Arbor, Michigan, U.S.A.

xviii

Contributors

Ann I. Scher Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, U.S.A. Jean Schoenen Departments of Neuroanatomy and Neurology, Headache ` ` Research Unit, University of Liege, Liege, Belgium Todd Schwedt Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. Fred Sheftell The New England Center for Headache, Stamford, Connecticut, U.S.A. Stephen D. Silberstein Department of Neurology, Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A. Seymour Solomon Department of Neurology, The Monteore Headache Center, Albert Einstein College of Medicine, New York, New York, U.S.A. Stewart J. Tepper The New England Center for Headache, Stamford, and Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, U.S.A. Gisela M. Terwindt Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Arn M. J. M. van den Maagdenberg Department of Neurology and Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Kaate R. J. Vanmolkot Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Paul Winner Palm Beach Headache Center, and Nova Southeastern University, Fort Lauderdale, Florida, U.S.A. William B. Young Department of Neurology and Inpatient Program, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

1
HeadacheClassication
Marcelo E. Bigal
Department of Neurology, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A.

Richard B. Lipton
Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Monteore Headache Center, New York, New York, U.S.A.

INTRODUCTION Headache is one of the most common symptoms in mankind (1,2). Given the range of disorders that present with headache, a systematic approach to headache classication and diagnosis is essential both for good clinical management and for useful research. The rst edition of the International Classication of Headache Disorders (ICHD-1) (3) was the accepted standard for headache diagnosis, from its publication (1988) to the release of the ICHD-2 (2004) (4). It established uniform terminology and consistent operational diagnostic criteria for the entire range of headache disorders. It was translated into 22 languages, providing the basis for clinical trial guidelines for primary headaches (5). Although the basic structure and most of the original categories are preserved in the ICHD-2, relative to the ICHD-1, there are many changes that will inuence headache care and research. These changes include a restructuring of the criteria for migraine, new subclassication of tension-type headache (TTH), introduction of the concept of trigeminal autonomic cephalalgias (TACs), and addition of several previously unclassied types of primary headache. In this chapter, we present an overview of the ICHD-2, highlighting the primary headache disorders and their diagnostic criteria. This chapter is complemented by Chapter 11, where we offer an algorithmic approach to primary headache diagnosis based on attack frequency and duration, using the ICHD-2. Details on diagnosis and treatment of primary headache disorders are discussed in specic chapters. AN OVERVIEW OF THE ICHD-2 Like its predecessor, the ICHD-2 separates headaches into primary and secondary disorders (Table 1). The criteria for primary headaches are clinical and descriptive
1

2 Table 1 The ICHD-2 Classication: An Overview

Bigal and Lipton

1. Migraine 1.1. Migraine without aura 1.2. Migraine with aura 1.3. Childhood periodic syndromes that are commonly precursors of migraine 1.4. Retinal migraine 1.5. Complications of migraine 1.6. Probable migraine 2. TTH 2.1. Infrequent episodic TTH 2.2. Frequent episodic TTH 2.3. Chronic TTH 2.4. Probable TTH 3. CH and other trigeminal autonomic cephalalgias 3.1. CH 3.2. Paroxysmal hemicrania 3.3. SUNCT 3.4. Probable trigeminal autonomic cephalalgia 4. Other primary headaches 4.1. Primary stabbing headache 4.2. Primary cough headache 4.3. Primary exertional headache 4.4. Primary headache associated with sexual activity 4.5. Hypnic headache 4.6. Primary thunderclap headache 4.7. Hemicrania continua 4.8. NDPH 5. Headache attributed to head and/or neck trauma 5.1. Acute post-traumatic headache 5.2. Chronic post-traumatic headache 5.3. Acute headache attributed to whiplash injury 5.4. Chronic headache attributed to whiplash injury 5.5. Headache attributed to traumatic intracranial hematoma 5.6. Headache attributed to other head and/or neck traumata 5.7. Postcraniotomy headache 6. Headache attributed to cranial or cervical vascular disorders 6.1. Headache attributed to ischemic stroke and transient ischemic attack 6.2. Headache attributed to nontraumatic intracranial hemorrhage 6.3. Headache attributed to unruptured vascular malformations 6.4. Headache attributed to arteritis 6.5. Carotid or vertebral artery pain 6.6. Headache attributed to CVT 6.7. Headache attributed to other intracranial vascular disorders 7. Headache attributed to nonvascular intracranial disorder 7.1. Headache attributed to high cerebrospinal uid pressure 7.2. Headache attributed to low cerebrospinal uid pressure 7.3. Headache attributed to noninfectious inammatory disease 7.4. Headache attributed to intracranial neoplasm 7.5. Headache attributed to intrathecal injection 7.6. Headache attributed to epileptic seizure 7.7. Headache attributed to CM1 (Continued)

HeadacheClassication Table 1 The ICHD-2 Classification: An Overview (Continued )

7.8. Syndrome of transient HaNDL 7.9. Headache attributed to other nonvascular intracranial disorders 8. Headache attributed to a substance or its withdrawal 8.1. Headache induced by acute substance use or exposure 8.2. MOH 8.3. Headache as an adverse event attributed to chronic medication 8.4. Headache attributed to substance withdrawal 9. Headache attributed to infection 9.1. Headache attributed to intracranial infection 9.2. Headache attributed to systemic infection 9.3. Headache attributed to HIV/AIDS 9.4. Chronic postinfection headache 10. Headache attributed to disorder of homoeostasis 10.1. Headache attributed to hypoxia and/or hypercapnia 10.2. Dialysis headache 10.3. Headache attributed to arterial hypertension 10.4. Headache attributed to hypothyroidism 10.5. Headache attributed to fasting 10.6. Cardiac cephalalgia 10.7. Headache attributed to other disorders of homoeostasis 11. Headache or facial pain attributed to disorders of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures 11.1. Headache attributed to disorder of cranial bone 11.2. Headache attributed to disorder of neck 11.3. Headache attributed to disorder of eyes 11.4. Headache attributed to disorder of ears 11.5. Headache attributed to rhinosinusitis 11.6. Headache attributed to disorders of teeth, jaws, or related structures 11.7. Headache or facial pain attributed to TMJ disorder 11.8. Headache attributed to other disorders of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structures 12. Headache attributed to psychiatric disorder 12.1. Headache attributed to somatization disorder 12.2. Headache attributed to psychotic disorder 13. Cranial neuralgias and central causes of facial pain 13.1. Trigeminal neuralgia 13.2. Glossopharyngeal neuralgia 13.3. Nervus intermedius neuralgia 13.4. Superior laryngeal neuralgia 13.5. Nasociliary neuralgia 13.6. Supraorbital neuralgia 13.7. Other terminal branch neuralgias 13.8. Occipital neuralgia 13.9. Necktongue syndrome 13.10. External compression headache 13.11. Cold stimulus headache 13.12. Constant pain caused by compression, irritation, or distortion of cranial nerves or upper cervical roots by structural lesions 13.13. Optic neuritis 13.14. Ocular diabetic neuropathy (Continued)

4 Table 1 The ICHD-2 Classification: An Overview (Continued )

Bigal and Lipton

13.15. Head or facial pain attributable to herpes zoster 13.16. TolosaHunt syndrome 13.17. Ophthalmoplegic migraine 13.18. Central causes of facial pain 13.19. Other cranial neuralgias or other centrally mediated facial pains 14. Other headaches, cranial neuralgias, and central or primary facial pain
Abbreviations: TTH, tension-type headache; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing; NDPH, new daily-persistent headache; CVT, cerebral venous thrombosis; CM1, Chiari malformation type I; HaNDL, headache and neurological decits with cerebrospinal uid lymphocytosis; MOH, medication-overuse headache; TMJ, temporomandibular joint; ICHD, International Classication of Headache Disorders; CH, cluster headache.

and, with a few exceptions [i.e., familial hemiplegic migraine (FHM)], are based on headache features, not etiology. In contrast, secondary headaches are attributed to underlying disorders. The four categories of primary headaches are (i) migraine; (ii) TTH; (iii) cluster headache (CH) and other TACs; and (iv) other primary headaches. There are nine categories of secondary headache (against eight in the ICHD-1). Finally, there is a 14th category that includes headache not classiable elsewhere (Table 1). Key operational rules for the classication are summarized below, quoted or paraphrased from the ICHD-2 (4): 1. The classication is hierarchical, allowing diagnoses with varying degrees of specicity, using up to four digits for coding at subordinate levels. The rst digit species the major diagnostic type, e.g., migraine (1.) The second digit indicates a subtype within the category, e.g., migraine with aura (1.2.). Subsequent digits permit more specic diagnosis for some subtypes of headache, e.g., FHM. 2. Patients should receive a diagnosis for each headache type or subtype they currently have (that is, have experienced within the last year). For example, the same patient may have medication-overuse headache (8.2.), migraine without aura (1.1.), and frequent episodic TTH (2.2.). Multiple diagnostic codes should be listed in their order of importance to the patient. This means that if a patient has four attacks of migraine without aura (1.1.) and eight attacks of frequent episodic TTH (2.2.) per month, but describes the migraine as being more incapacitating, the migraine diagnosis should be listed rst. 3. For headaches that meet all but one of a set of diagnostic criteria, without fullling those of another headache disorder, there are probable subcategories, for example, probable migraine (1.6.) and probable CH (3.4.1.). 4. The diagnosis of any primary headache requires the exclusion, on clinical grounds or using subsidiary investigation, of any other disorder that might be the cause of the headache (i.e., of a secondary headache disorder). 5. Secondary headache diagnoses are applied when the patient develops a new type of headache for the rst time in close temporal relation to onset of another disorder known to cause headache. Diagnosis of secondary headache in a patient with a preexisting primary headache can be challenging. Onset of a secondary headache is more likely when (i) there is a very close temporal relation to onset of the potentially causative disorder; (ii) exacerbation of the headache is marked, or differs in pattern from the preexisting

HeadacheClassication

disorder; (iii) other evidence is strong that the potentially causative disorder can cause headache of the type experienced; or (iv) there is improvement or disappearance of headache, or return to the earlier pattern, after relief from the potentially causative disorder. 6. Although some headache types include frequency in their diagnostic criteria [i.e., chronic migraine (CM) and chronic TTH], the ICHD-2 does not specically code frequency or severity. Frequency and severity may be specied parenthetically, at the discretion of the examiner.

CLASSIFICATION OF THE PRIMARY HEADACHES The ICHD-2 divides the primary headaches into four major categories, which are discussed in sequence below.

Migraine Migraine is subclassied into six major categories, the two most important of which are migraine without aura (1.1.) and migraine with aura (1.2.). This is unchanged from the ICHD-1, but there is a restructuring of the criteria for migraine with aura, and CM (1.5.1.) has been added. Ophthalmoplegic migraine, now considered a cranial neuralgia, has been moved to item 13 (Cranial Neuralgias and Central Causes of Facial Pain) (Table 2).
Table 2 The ICHD-2 Classication of Migraine 1.1. Migraine without aura 1.2. Migraine with aura 1.2.1. Typical aura with migraine headache 1.2.2. Typical aura with nonmigraine headache 1.2.3. Typical aura without headache 1.2.4. FHM 1.2.5. Sporadic hemiplegic migraine 1.2.6. Basilar-type migraine 1.3. Childhood periodic syndromes that are commonly precursors of migraine 1.3.1. Cyclical vomiting 1.3.2. Abdominal migraine 1.3.3. Benign paroxysmal vertigo of childhood 1.4. Retinal migraine 1.5. Complications of migraine 1.5.1 CM 1.5.2 Status migrainosus 1.5.3 Persistent aura without infarction 1.5.4 Migrainous infarction 1.5.5 Migraine-triggered seizures 1.6. Probable migraine 1.6.1. Probable migraine without aura 1.6.2. Probable migraine with aura
Abbreviations: FHM, familial hemiplegic migraine; ICHD, International Headache Society Classication; CM, chronic migraine.

6 Table 3 ICHD-2 Criteria for Migraine Without Aura

Bigal and Lipton

Migraine without aura Diagnostic criteria A. At least ve attacksa fullling BD B. Headache attacks lasting 472 hoursb,c and occurring more than 15 days/mod (untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics: 1. Unilateral locatione,f 2. Pulsating qualityg 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (i.e., walking or climbing stairs) D. During headache, occurrence of at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobiah E. Not attributed to another disorderi
Differentiating between migraine without aura and episodic tension-type headache may be difcult. Therefore, at least ve attacks are required. Individuals who otherwise meet the criteria for migraine without aura but have fewer than ve attacks should be coded 1.6. b If the patient falls asleep during migraine and wakes up without it, duration of the attack is until the time of awakening. c In children, attacks may last 1 to 72 hours. (The evidence for untreated durations less than two hours in children should be corroborated by prospective diary studies.) d If attack frequency is 15 days/mo or more and if there is no medication overuse, code 1.1. and 1.5.1. chronic migraine. e Migraine headache is often bilateral in young children; an adult pattern of unilateral pain often emerges in late adolescence or early adult life. f Migraine headache is usually frontotemporal. Occipital headache in children, whether unilateral or bilateral, is rare and calls for diagnostic caution; many cases are attributable to structural lesions. g Pulsating means throbbing or varying with the heartbeat at rest or with movement. h In young children, photophobia and phonophobia may be inferred from behavior. i History and physical and neurological examinations do not suggest one of the disorders listed in groups 512; history and/or physical and/or neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations; or such disorder is present, but migraine attacks do not occur for the rst time in close temporal relation to the disorder. Abbreviation: ICHD, International Headache Society Classication.
a

Migraine Without Aura Migraine without aura is a clinical syndrome characterized by headache features and associated symptoms (Table 3). According to the ICHD-2, if a patient fullls criteria for more than one type of migraine, each type should be diagnosed. It is important to emphasize that:  Criteria for migraine without aura can be met by various combinations of features, and no single feature is required.  Because two of four pain features are required, a patient with unilateral, throbbing pain may meet the criteria, but so does a patient with bilateral, pressure pain, if the pain is moderate and aggravated by physical activity.  Similarly, only one of two possible associated symptom combinations is required. Patients with nausea but not photophobia or phonophobia ll the requirements as do patients without nausea or vomit, but with photophobia and phonophobia.

HeadacheClassication

 Attacks usually last from 4 to 72 hours if untreated. If the patient falls asleep during migraine and wakes up without it, the duration of the attack is timed until the time of awakening.  In children, attacks may last 1 to 72 hours, and in young children, photophobia and phonophobia may be inferred from behavior. If attack frequency is 15 days/mo or more in a subject not overusing acute medications, the ICHD-2 establishes coding 1.5.1 CM [see also Controversies in the Classication of Primary Chronic Daily Headaches of Long Duration].

Migraine with Aura and Its Subtypes The criteria for migraine with aura (1.2.) have been revised substantially. The typical aura of migraine is characterized by focal neurological features that usually precede migrainous headache, but may accompany it or occur in the absence of the headache (Table 4) (6,7). Typical aura symptoms develop over ve minutes or more and last no more than 60 minutes, and visual aura is overwhelmingly the most common (7). Typical visual aura is homonymous, often having a hemianopic distribution and expanding in the shape of a crescent with a bright, ragged edge, which scintillates. Scotoma, photopsia or phosphenes, and other visual manifestations may occur. Visual distortions such as metamorphopsia, micropsia, and macropsia are more common in children (79). Sensory symptoms occur in about one-third of patients who have migraine with aura (810). Typical sensory aura consists of numbness (negative symptom) and tingling or paresthesia (positive symptoms). The distribution is often cheiro-oral (face and hand). Dysphasia may be part of typical aura, but motor weakness, symptoms of brain stem dysfunction, and changes in level of consciousness, all of which may occur (10), signal particular subtypes of migraine with aura (hemiplegic and basilar-type) that are not characterized by typical aura. Recently, typical migraine aura has been noted to occur with nonmigrainous headache (i.e., headache not fullling the criteria of 1.1.). Such cases are coded Typical aura with nonmigraine headache (1.2.2.). Reports have associated apparently

Table 4 ICHD-2 Diagnosis of Typical Aura Diagnostic criteria A. At least two attacks fullling criteria BE B. Fully reversible visual and/or sensory and/or speech symptoms but no motor weakness C. At least two of the following three: 1. Homonymous visual symptoms including positive features (i.e., ickering lights, spots, and lines) and/or negative features (i.e., loss of vision) and/or unilateral sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness) 2. At least one symptom develops gradually over 5 min or more and/or different symptoms occur in succession 3. Each symptom lasts 5 min or more and 60 min or less D. Headache that meets criteria BD for migraine without aura (1.1.) begins during the aura or follows aura within 60 min E. Not attributed to another disorder
Abbreviation: ICHD, International Headache Society Classication.

Bigal and Lipton

typical aura with CH, chronic paroxysmal hemicrania (CPH), and hemicrania continua (HC) (10,11). These cases are classied according to both disorders [e.g., CH (3.1.) plus Typical aura with nonmigraine headache (1.2.2.)]. Typical aura occurring in the absence of any headache is coded typical aura without headache (1.2.3.), a disorder most often reported by middle-aged men (12). Differentiating this benign disorder from transient ischemic attack (TIA), a medical emergency, may require investigation, especially when it rst occurs after age 40, when negative features (i.e., hemianopia) are predominant, or when the aura is of atypical duration (13). FHM (1.2.4.) is the rst migraine syndrome to be linked to a specic set of genetic polymorphisms (1418). Herein, aura includes some degree of motor weakness (hemiparesis) and may be prolonged for more than 60 minutes (up to 24 hours); additionally, at least one rst-degree relative has had similar attacks (also meeting these criteria). Cerebellar ataxia may occur in 20% of FHM sufferers. The onset of weakness may be abrupt, but usually lasts less than one hour. A person with FHM may develop migraine with aura when adult and migraine without aura later in life. In patients otherwise meeting these criteria but who have no family history of this disorder, the disorder is classied as sporadic hemiplegic migraine (1.2.5.), a disorder new to the revised classication (19). Basilar-type migraine (1.2.6.) is a new term, replacing basilar migraine. The change is intended to remove the implication that the basilar artery, or its territory, is involved. The distinguishing feature of basilar-type migraine is a symptom prole that suggests posterior fossa involvement (19). Diagnosis requires at least two of the following aura symptoms, all fully reversible: dysarthria, vertigo, tinnitus, decreased hearing, double vision, visual symptoms simultaneously in both temporal and nasal elds of both eyes, ataxia, decreased level of consciousness, and simultaneously bilateral paresthesias. Because 60% of patients with FHM have basilar-type symptoms, basilar-type migraine should be diagnosed only when weakness is absent. The headache meets the criteria for (1.1.) migraine without aura. Childhood Periodic Syndromes That Are Commonly Precursors of Migraine A number of more or less well-described disorders are classied under this heading (2023). Cyclical vomiting (1.3.1.) occurs in up to 2.5% of schoolchildren (21). The hallmark of this disorder is recurrent and stereotyped episodes of intense but otherwise unexplained nausea and vomiting, which last one hour to ve days in children free of symptoms interictally. Vomiting occurs at least four times in an hour, and no signs of gastrointestinal disease can be found. Abdominal migraine (1.3.2.) aficts up to 12% of schoolchildren, with recurrent attacks of abdominal pain associated with anorexia, nausea, and sometimes vomiting (22). The abdominal pain has all of the following characteristics: midline location, periumbilical or poorly localized; dull or just sore quality; and moderate or severe intensity. At least two of the following symptoms are present during the episode: anorexia, nausea, vomiting, and/or pallor. Physical examination and investigations exclude other causes of these symptoms. Benign paroxysmal vertigo (1.3.3.) is a disorder characterized by recurrent (at least ve) attacks, each comprising multiple episodes of severe vertigo resolving spontaneously in minutes to hours (23). Neurological examination and audiometric and vestibular functions are all normal between attacks, and the electroencephalogram is also normal.

HeadacheClassication

Retinal Migraine This disorder is rare. Recurrent attacks (at least two) of fully reversible scintillations, scotomata, or blindness, affecting one eye only, are accompanied or followed within one hour by migrainous headache (fullling criteria for 1.1.). Other causes of monocular visual loss, including TIA, optic neuropathy, and retinal detachment, must be ruled out by appropriate investigation (24). A recent study suggests that many patients with retinal migraine experience retinal infarction of migrainous origin (25). This disorder should be coded as Migrainous infarction (1.5.4.). In Chapter 16, Drs. Grosberg and Solomon present a detailed review of retinal migraine. Complications of Migraine The ICHD-2 lists ve complications of migraine: CM (1.5.1.) (see section Controversies in the Classication of Primary Chronic Daily Headaches of Long Duration) when headache is both present and meets criteria for migraine (almost invariably migraine without aura) on 15 days/mo or more for three months or more, in the absence of medication overuse. All cases evolve from episodic migraine, and most from migraine without aura, hence its classication as a complication of migraine. When medication overuse is present (acute antimigraine drugs and/or opioids, combination analgesics taken on 10 days/mos or more, or simple analgesics on 15 days/mo or more), it is a likely cause of chronic headache. Neither CM (1.5.1.) nor medication-overuse headache (8.2.) can be diagnosed with condence until the overused medication has been withdrawn; improvement within two months is expected if the latter diagnosis is correct (and is necessary to conrm it), not if the former is present. Meanwhile, the codes to be assigned are that of the antecedent migraine (usually migraine without aura, 1.1.) plus probable medication-overuse headache (8.2.7.) plus probable CM (1.6.5.). Status migrainosus (1.5.2.) refers to an attack of migraine with a headache phase lasting more than 72 hours (26). The pain is severe (a diagnostic criterion) and debilitating. Nondebilitating attacks lasting for more than 72 hours are coded as probable migraine without aura (1.6.1.). Persistent aura without infarction (1.5.3.) is diagnosed when aura symptoms, otherwise typical of past attacks, persist for more than one week. Investigation shows no evidence of infarction. It is an unusual but well-documented complication of migraine, which is now being introduced into the ICHD-2 (27). Migrainous infarction (1.5.4.) is an uncommon occurrence. One or more otherwise typical aura symptoms persist beyond one hour, and neuroimaging conrms ischemic infarction. Strictly applied, these criteria distinguish this disorder from other causes of stroke, which must be excluded (28); the neurological decit develops during the course of an apparently typical attack of migraine with aura and exactly mimics the aura of previous attacks. Migraine and epilepsy are comorbid disorders (29). Headaches are common in the postictal period, but epilepsy can be triggered by migraine (migralepsy). The criteria for migraine-triggered seizure (1.5.5.) require that a seizure fullling the diagnostic criteria for any type of epileptic attack occurs during or within one hour after a migraine aura. Probable Migraine Between 10% and 45% of patients with features of migraine fail to meet all criteria for migraine (or any of its subtypes) (30). If a single criterion is missing (and the full

10

Bigal and Lipton

set of criteria for another disorder are not met), the applicable code is probable migraine (1.6.). Epidemiologic studies demonstrate that probable migraine is common and associated with temporary disability and reduction in the health-related quality of life (31). Tension-Type Headache TTH is the most common type of primary headache, with one-year period prevalences ranging from 31% to 74% (32,33). The ICHD-1 distinguished two subtypes, episodic TTH (less than 15 attacks per month) and chronic TTH (15 or more attacks per month). The ICHD-2 distinguishes three subtypes: Infrequent episodic TTH (2.1.) (headache episodes on less than 1 day/mo), Frequent episodic TTH (2.2.) (headache episodes on 114 days/mo), and Chronic TTH (2.3.) (headache on 15 or more days/mo, perhaps without recognizable episodes). The diagnostic criteria for TTH are presented in Table 5. In contrast to migraine, the main pain features of TTH are bilateral location, nonpulsating quality, mild-to-moderate intensity, and lack of aggravation by routine physical activity. The pain is not accompanied by nausea, and just one of photo- or phonophobia does not exclude the diagnosis. Chronic TTH invariably evolves from episodic TTH but, like CM, cannot be diagnosed in patients overusing acute medication. Such patients often meet criteria for, and in fact have, medication-overuse headache (8.2.), although withdrawal of the medication is required to conrm this diagnosis. A recently recognized disorder that phenotypically resembles chronic TTH, but is nosologically distinct from it (as far as is known), does not evolve from an episodic headache but is present daily and is
Table 5 ICHD-2 Classication of Tension-Type Headache Diagnostic criteria A. At least 10 episodes fullling criteria BE. Number of days with such headache less than 1 day/mo (episodic infrequent), from 1 to 14 (episodic frequent), or 15 or more (chronic) B. Headache lasting from 30 min to 7 days C. At least two of the following pain characteristics: 1. Pressing/tightening (nonpulsating) quality 2. Mild or moderate intensity (may inhibit, but does not prohibit activities) 3. Bilateral location 4. No aggravation by walking stairs or similar routine physical activity D. Both of the following: a. No nausea or vomiting (anorexia may occur) b. Photophobia and phonophobia are absent, or one but not the other may be present E. Not attributed to another disorder 2.X.1. Associated with pericranial tenderness Diagnostic criteria: A. Fullls criteria for 2.X B. Increased tenderness on pericranial manual palpation 2.X.2. Not associated with pericranial tenderness Diagnostic criteria A. Fullls criteria for 2.X Not associated with increased pericranial tenderness
Note: X means the correspondent digit of infrequent episodic (i), frequent episodic (ii), or chronic (iii). Abbreviation: ICHD, International Headache Society Classication.

HeadacheClassication

11

unremitting from onset or within three days of onset. This condition is separately classied as new daily-persistent headache (4.8.). When a headache fullls all but one of the criteria for TTH and does not fulll the criteria for migraine without aura, the diagnosis should be probable TTH (2.4.). CH and Other TACs The addition of the term TACs to the classication reects the observation that CH is one of a group of primary headache disorders characterized by trigeminal activation coupled with autonomic activation. The ICHD-2 includes several disorders not in the previous edition. Cluster Headache The diagnostic criteria for CH have not substantially changed. This disorder manifests as intermittent, short-lasting, excruciating unilateral head pain accompanied by autonomic dysfunction (34). The pain of CH is described variously as sharp, boring, drilling, knife-like, piercing, or stabbing, in contrast to the pulsating pain of migraine. It usually peaks in 10 to 15 minutes but remains excruciatingly intense for an average of one hour within a duration range of 15 to 180 minutes. During this pain, patients nd it difcult to lie still, exhibiting often marked agitation and restlessness, and autonomic signs are usually obvious. After an attack, the patient remains exhausted for some time. CH is classied into two subtypes (Table 6). Attacks of Episodic CH (3.1.1.) occur in cluster periods lasting from seven days to one year separated by attack-free intervals of one month or more. Approximately 85% of CH patients have the episodic subtype. In chronic CH (3.1.2.), attacks recur for more than one year without remission, or with remissions lasting less than one month. Chronic CH can evolve from episodic CH, or develop de novo, and may revert to episodic CH (35). Patients who have both CH as well as trigeminal neuralgia, and received the denomination of cluster-tic syndrome have been described (36). According to the ICHD-2, they should receive both diagnoses.
Table 6 ICHD-2 Classication of Cluster Headache Diagnostic criteria A. At least ve attacks fullling BD B. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15180 min untreated for more than half of the period (or time if chronic) C. Headache is accompanied by at least one of the following symptoms or signs that have to be present on the side of the pain: 1. Conjunctival injection, lacrimation, or both 2. Nasal congestion, rhinorrhoea, or both 3. Eyelid edema 4. Forehead and facial sweating 5. Miosis, ptosis, or both 6. Headache is associated with a sense of restlessness or agitation D. Frequency of attacks: from one every other day to eight per day for more than half of the period if chronic E. Not attributed to another disorder
Abbreviation: ICHD, International Headache Society Classication.

12

Bigal and Lipton

Paroxysmal Hemicrania As a group, the paroxysmal hemicranias have three main features: (i) at least 20 frequent (more than ve per day) attacks of short-lasting (230 minutes), severe, and strictly unilateral orbital, supraorbital, or temporal pain; (ii) symptoms of parasympathetic activation ipsilateral to the pain (as in CH); and (iii) absolute response to therapeutic doses of indomethacin (3739). The ICHD-1 included CPH only. The ICHD-2 includes episodic paroxysmal hemicrania (3.2.1.) and CPH (3.2.2.). Like CH, these disorders are distinguished by the presence or absence of attack-free intervals lasting one month or more. Some patients with both CPH and trigeminal neuralgia have been described (CPH-tic syndrome); they should receive both diagnoses. Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing The short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome (3.3.) and is a very rare primary headache. The diagnostic criteria require at least 20 high-frequency attacks (3200 per day) of unilateral orbital, supraorbital, or temporal stabbing or pulsating pain, lasting 5 to 240 seconds and accompanied by ipsilateral conjunctival injection and lacrimation. The attacks are characteristically dramatic, with moderately severe pain peaking in intensity within three seconds and prominent tearing (40). Headache attacks believed to be a subtype of TAC but fullling all but one of the diagnostic criteria for it are diagnosed as probable TCA.

Other Primary Headaches This group of miscellaneous primary headache disorders includes some mimics of potentially serious secondary headaches, which need to be carefully evaluated by imaging or other appropriate tests. Some headaches, such as hypnic headache, primary thunderclap headache, HC, and new daily-persistent headache were not included in the ICHD-1. Primary Stabbing Headache Episodic localized stabs of head pain occurring spontaneously in the absence of any structural cause (formerly referred to as jabs and jolts) are diagnosed as primary stabbing headache (4.1.). Pain is exclusively or predominantly in the distribution of the rst division of the trigeminal nerve (orbit, temple, and parietal area). It lasts for up to a few seconds and recurs at irregular intervals with a frequency ranging from one to many per day. Other features such as autonomic signs are lacking (40,41). Primary Cough Headache This headache is brought on suddenly by coughing, straining, or Valsalva maneuver, and not otherwise, in the absence of any underlying disorder such as cerebral aneurysm or, especially, ArnoldChiari malformation (42). Diagnostic neuroimaging, with special attention to the posterior fossa and base of the skull, is mandatory to differentiate secondary and primary forms of cough headache.

HeadacheClassication

13

Primary Exertional Headache This disorder is triggered by physical exercise, and not otherwise, and is distinguished from primary cough headache (4.2.) and headache associated with sexual activity (4.4.). Primary exertional headache is pulsating and lasts from 5 minutes to 48 hours. After the rst occurrence of any exertional headache of sudden onset, appropriate investigations must exclude subarachnoid hemorrhage and arterial dissection (4345). Primary Headache Associated with Sexual Activity Headache precipitated by sexual activity usually begins as a dull bilateral ache as sexual excitement increases and suddenly becomes intense at orgasm (46). Two subtypes are classied: preorgasmic headache (4.4.1.), a dull ache in the head and neck, and orgasmic headache (4.4.2.), explosive and severe, and occurring with orgasm. Diagnosis of the latter requires exclusion of subarachnoid hemorrhage and arterial dissection. Hypnic Headache This primary headache disorder of the elderly is characterized by short-lived attacks (typically 30 minutes) of nocturnal head pain, which awakens the patient at a constant time each night, in many cases on more nights than not. It does not occur outside sleep (47). Hypnic headache is usually bilateral (though unilaterality does not exclude the diagnosis) and mild to moderate, very different from the unilateral orbital or periorbital knife-like intense pain of CH. Autonomic features are absent. Primary Thunderclap Headache Severe headache of abrupt onset, which mimics the pain of a ruptured cerebral aneurysm, is classied as primary thunderclap headache (4.6.), although this code is not applied to thunderclap headache meeting the criteria for 4.2, 4.3, or 4.4. Intensity peaks in less than one minute. Pain lasts from 1 hour to 10 days and may recur within the rst week after onset but not regularly over subsequent weeks or months (48). This diagnosis can be established only after excluding subarachnoid hemorrhage. Hemicrania Continua This daily and continuous strictly unilateral headache is dened by its absolute response to therapeutic doses of indomethacin. Pain is moderate, with exacerbations of severe pain, and autonomic symptoms accompany these exacerbations although less prominently than in CH and CPH (49,50). Some bilateral or alternating-side cases have been reported (51). New Daily-Persistent Headache The essence of this headache, which according to the ICHD-2 but not accepted by all, otherwise resembles chronic TTH (2.3.), is that it is present daily and is unremitting from or very soon (less than three days) after onset. There is no history of evolution from episodic headache. Diagnosis is not conrmed until it has been present for more than three months, and cannot be made if this manner of onset is not clearly

14

Bigal and Lipton

recalled by the patient. Nor can it be made in the presence of medication overuse. NDPH is typically bilateral, pressing or tightening in quality, of mild to moderate intensity, and unaffected by routine physical activity, although the diagnostic criteria require only any two of these features. There may be any but not more than one of photophobia, phonophobia, or mild nausea.

SECONDARY HEADACHES Discussing the classication of the secondary headaches in depth is beyond the scope of this chapter. In brief, the classication of all secondary headaches follows the same format: 1. The secondary disorder known to be able to cause headache has been demonstrated. 2. Headache occurs in close temporal relation to the secondary disorder, and/ or there is other evidence of a causal relationship. 3. Headache is greatly reduced or disappears within three months (this may be shorter for some disorders) after successful treatment or spontaneous remission of the causative disorder. There are exceptions to this general rule. Chronic post-traumatic headache does not disappear three months after the trauma. We will briey discuss their classication.

HEADACHE ATTRIBUTED TO HEAD AND/OR NECK TRAUMA This category includes headaches that occur for the rst time in close temporal relation to a known trauma (52). If there is remission within three months after the trauma, the headache should be classied as acute post-traumatic headache. Otherwise, chronic post-traumatic headache is the diagnosis. The same rule applies to acute and chronic postwhiplash injury headache. The ICHD-2 also classies under this group those headaches secondary to intracranial hematoma and postcraniotomy.

HEADACHE ATTRIBUTED TO CRANIAL OR CERVICAL VASCULAR DISORDERS This category encompasses a large group of headaches that fulll the following criteria: symptoms and/or signs of a vascular disorder; appropriate investigations indicating the vascular disorder; and the headache developing in close relationship with the vascular disorder. This group includes headaches related to (i) ischemic stroke and TIAs; (ii) nontraumatic intracranial hemorrhage; (iii) unruptured vascular malformations; (iv) arteritis (including giant cell arteritis); (v) carotid or vertebral artery pain (including arterial dissection, postendarterectomy headache, etc.); (vi) cerebral venous thrombosis; and (vii) other intracranial vascular disorders, including CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), etc. (5359).

HeadacheClassication

15

In many of these conditions, such as ischemic or hemorrhagic stroke, headache may be unrecognized because of focal signs and/or disorders of consciousness. In others, such as subarachnoid hemorrhage and giant cell arteritis, headache may be the most prominent symptom and an initial warning symptom.

HEADACHE ATTRIBUTED TO NONVASCULAR INTRACRANIAL DISORDERS This category includes an extensive and heterogeneous group of disorders (7). They are: (i) high cerebrospinal uid pressure; (ii) low cerebrospinal uid pressure; (iii) noninfectious inammatory diseases; (iv) intracranial neoplasm; (v) headache related to intrathecal injections; (vi) postseizure headache; (vii) Chiari malformation type I (CM1); and (viii) syndrome of transient headache and neurologic decits with cerebrospinal uid lymphocytosis (6062).

HEADACHE ATTRIBUTED TO A SUBSTANCE OR ITS WITHDRAWAL When new headaches occur in close temporal relation to substance use or withdrawal, they are coded to this group. The ICHD-2 classies in this group those headaches following acute exposure to (63,64) (i) nitric oxide donor substances; (ii) phosphodiesterase inhibitors; (iii) carbon monoxide; (iv) alcohol; (v) food components and additives; (vi) monosodium glutamate; (vii) cocaine; (viii) cannabis; and (ix) other acute substance use. In addition, chronic medication overuse is a risk factor for the development of CDH (65,66). Using the ICHD-2, if a subject has a frequent headache associated with medication overuse and meets otherwise the criteria for CM, a diagnosis of probable CM and probable medication-overuse headache should be assigned. Denite diagnosis of medication-overuse headache requires that headaches remit or improve when the overused medication is withdrawn. Prior to withdrawal, the use of the probable term exemplies the difculty of causal attribution (see section Controversies in the classication of primary chronic daily headaches of long duration).

HEADACHE ATTRIBUTED TO INFECTION This is a very straightforward group where headaches secondary to intracranial and extracranial (systemic) infections are classied. This group also includes headaches related to HIV/AIDS and chronic postinfectious headaches (67).

HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS This group of headaches was formerly referred as headaches associated with metabolic or systemic diseases. They include the following headaches: (i) headache attributed to hypoxia and/or hypercapnia (high altitude, diving, and sleep apnea); (ii) dialysis; (iii) arterial hypertension; (iv) headache attributed to hypothyroidism; (v) headache attributed to fasting; (vi), cardiac cephalgia; and (vii) headache attributed to other disturbances of homeostasis (68,69).

16

Bigal and Lipton

HEADACHE OR FACIAL PAIN ATTRIBUTED TO DISORDERS OF CRANIUM, NECK, EYES, EARS, NOSE, SINUSES, TEETH, MOUTH, OR OTHER FACIAL OR CRANIAL STRUCTURES This is a very heteronegenous group classifying headache and facial pain due to disease of the cranium, the neck, and the facial structures. Cranial neuralgias are not classied under this chapter. The ICHD-2 includes criteria for cervicogenic headache (70).

HEADACHE ATTRIBUTED TO PSYCHIATRIC DISORDERS This group provides a link to classify those extremely rare headaches that are causally attributable to a psychiatric disorder. The headache may be attributed to a somatization disorder or to a psychotic disorder. This should be distinguished from psychiatric comorbidities where a headache disorder (e.g., migraine) and a psychiatric disorder (e.g., depression) occur together in the same person (71).

CRANIAL NEURALGIAS AND CENTRAL CAUSES OF FACIAL PAIN Finally, the last chapter of the ICHD-2 codes the cranial neuralgias and facial pain, including (72,73) (i) trigeminal neuralgia; (ii) glossopharyngeal neuralgia; (iii) nervus intermedius neuralgia; (iv) superior laryngeal neuralgia; (v) nasociliary neuralgia (Charlin); (vi) supraorbital neuralgia; (vii) other terminal branch neuralgias; (viii) occipital neuralgia; (ix) necktongue syndrome; (x) external compression headache; (xi) cold stimulus headache; (xii) constant pain caused by compression, irritation, or distortion of cranial nerves or upper cervical roots by structural lesions; (xiii) optic neuritis; (xiv) ocular diabetic neuropathy; (xv) herpes zoster; (xvi) TolosaHunt syndrome; (xvii) ophthalmoplegic migraine; and (xviii) central causes of facial pain. Criteria for trigeminal neuralgia, the prototype of a cranial neuralgia, are summarized in Table 7.

CONTROVERSIES IN THE CLASSIFICATION OF PRIMARY CHRONIC DAILY HEADACHES OF LONG DURATION Primary CDH is dened as a group of primary headaches that occur more than 15 days a month (or 180 days a year) with a duration of four or more hours per day
Table 7 ICHD-2 Classication of Trigeminal Neuralgia A. Paroxysmal attacks affecting one or more divisions of the trigeminal nerve lasting from a fraction of a second to two minutes B. The pain has at least one of the following characteristics: intense, sharp, supercial, stabbing, precipitated from trigger areas, or by trigger factors C. There is no clinically evident neurological decit D. Attacks are stereotyped in the individual patient E. Not attributed to another disorder
Abbreviation: ICHD, International Headache Society Classication.

HeadacheClassication

17

(see Chapter 27 for the clinical features, diagnosis, and treatment of CDH). Studies reported difculties using the ICHD-1 to classify CDH sufferers (74,75). As a consequence, a few proposals for the classication of these patients have emerged. Of these proposals, the Silberstein and Lipton (S-L) criteria have been most widely used (76). The S-L criteria divide the CDH into four main diagnoses: (i) transformed migraine (TM); (ii) chronic TTH; (iii) new daily-persistent headache; and (iv) HC. The system subclassies these main diagnoses as with medication overuse or without medication overuse. As a syndrome, CDH is addressed neither in the ICHD-1 nor in the ICHD-2, which, however, provides criteria for the CDH subtypes. Controversies exist regarding the differences between CM and TM and the best way to classify NDPH. TM and CM have been used synonymously in the past, but this is no longer appropriate. CM has a specic denition in the ICHD-2, and TM is a headache syndrome not included in the ICHD-2. Patients with TM typically have a past history of migraine, usually migraine without aura. Subjects report a process of transformation (chronication) over months or years, and as headache increases in frequency, associated symptoms become less severe and frequent. The process of transformation frequently ends in a pattern of daily or nearly daily headache that resembles chronic TTH, with some attacks of full migraine superimposed. The SL criteria classify TM in two situations: First, a primary CDH develops in a person with previous history of headaches. Second, one of the three following links with migraine are satised: (i) a prior history of migraine; (ii) a period of escalating headache frequency; or (iii) concurrent superimposed attacks of migraine that fulll the IHS criteria. A revision of the criteria for CM is currently being considered by the International Headache Society Classication Committee. As of the writing criteria for CM would require 15 or more days of headache per month and at least 8 days of migraine. This issue is fully discussed in Chapter 27. NDPH is characterized by the relatively abrupt onset of an unremitting primary CDH, i.e., a patient without a previous headache syndrome develops a chronic headache that does not remit. It is the new onset of this primary daily headache that is the most important feature. According to the S-L criteria, the clinical features of the pain are not considered in making the diagnosis, which only requires absence of history of evolution from migraine or episodic TTH. The S-L classication allows the diagnosis of NDPH in patients with migraine or episodic TTH if these disorders do not increase in frequency to give rise to NDPH. The IHS criteria consider NDPH in those cases where the headaches resemble TTHs (in other words, NDPH with migrainous features or coexisting new-onset migraine does not meet the criteria for this diagnosis according to the ICHD-2) (7780).

REFERENCES
1. Scher AI, Stewart WF, Lipton RB. Migraine and headache: a meta-analytic approach. In: Crombie IK, ed. Epidemiology of Pain. Seattle: IASP Press, 1999:159170. 2. Rasmussen BK. Epidemiology of headache. Cephalalgia 1995; 15(1):4568. 3. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):196.

18

Bigal and Lipton

4. Headache Classication Subcommittee of the International Headache Society. The International Classication of Headache Disorders: 2nd edition. Cephalalgia 2004; 24(suppl 1):9160. 5. Tfelt-Hansen P, Block G, Dahlof C, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000; 20(9):765786. 6. Olesen J, Friberg L, Olsen TS, et al. Timing and topography of cerebral blood ow, aura, and headache during migraine attacks. Ann Neurol 1990; 28:791798. 7. Jensen K, Tfelt-Hansen P, Lauritzen M, Olesen J. Classic migraine, a prospective recording of symptoms. Acta Neurol Scand 1986; 73:359362. 8. Silberstein SD, Young WB. Migraine aura and prodrome. Semin Neurol 1995; 45:175182. 9. Russel MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain 1996; 119:355361. 10. Peres MF, Siow HC, Rozen TD. Hemicrania continua with aura. Cephalalgia 2002; 22:246248. 11. Matharu MJ, Goadsby PJ. Post-traumatic chronic paroxysmal hemicrania (CPH) with aura. Neurology 2001; 56:273275. 12. Lipton RB, Pfeffer D, Newman LC, et al. Headaches in the elderly. J Pain Symptom Manage 1993; 8:8797. 13. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J. Classication of primary headaches. Neurology. 2004; 63(3):427435. 14. Haan J, Terwindt GM, Ferrari MD. Genetics of migraine. Neurol Clin 1997; 15:4360. 15. Carrera P, Stenirri S, Ferrari M, et al. Familial hemiplegic migraine: a ion channel disorder. Brain Res Bull 2001; 56:239241. 16. Staehelin-Jensen T, Olivarius B, Kraft M, Hansen H. Familial hemiplegic migraine. A reappraisal and long-term follow-up study. Cephalalgia 1981; 1:3339. 17. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 channel gene CACNL1A4. Cell 1996; 87:543552. 18. De Fusco M, Marconi R, Silvestri L, et al. Haploinsufciency of ATP1A2 encoding the Na/K pump a2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003; advance online publication. 19. Panayiotopoulos CP. Basilar migraine: a review. In: Panayiotopoulos CP, ed. Benign Childhood Partial Seizures and Related Epileptic Syndromes. London: John Libbey & Company Ltd., 1999:303308. 20. Hosking G. Special forms: variants of migraine in childhood. In: Hockaday JM, ed. Migraine in Childhood. Boston: Butterworths, 1988:3553. 21. Fleisher DR. Cyclic vomiting syndrome and migraine. J Pediatr 1999; 134:533535. 22. Abu-Arafeh I, Russel G. Prevalence and clinical features of abdominal migraine compared with those of migraine headache. Arch Dis Child 1995; 72:413417. 23. Drigo P, Carli G, Laverda AM. Benign paroxysmal vertigo of childhood. Brain Dev 2001; 23:3841. 24. Troost T, Zagami AS. Ophthalmoplegic migraine and retinal migraine. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. Philadelphia: Lippincott Willians & Wilkins, 2000:511516. 25. Grosberg BM, Lipton RB. Retinal Migraine Current pain and headache reports. 2005; 17:1221. 26. Couch JR, Diamond S. Status migrainosus. Causative and therapeutic aspects. Headache 1983; 23:94101. 27. Bento MS, Esperanca P. Migraine with prolonged aura. Headache 2000; 40:5253. 28. Rothrock JF, Walicke P, Swenson MR, et al. Migrainous stroke. Arch Neurol 1988; 45:6367. 29. Bigal ME, Lipton RB, Cohen J, Silberstein SD. Epilepsy and migraine. Epilepsy Behav 2003; 4(suppl 2):S13S24.

HeadacheClassication

19

30. Rains JC, Penzien DB, Lipchik GL, et al. Diagnosis of migraine: empirical analysis of a large clinical sample of atypical migraine (IHS 1.7) patients and proposed revision of the IHS criteria. Cephalalgia 2001; 21:584595. 31. Patel N, Bigal ME, Kolodner K, Lafatta J, Leotta C, Lipton RB. The one-year period prevalence of strict migraine and probable migraine within a health-plan population. Neurology 2004:247251. 32. Rasmussen BK, Jensen R, Olesen J. A population-based analysis of the criteria of the International Headache Society. Cephalalgia 1991; 11:129134. 33. Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998; 279(5):381383. 34. Kudrow L. Diagnosis and treatment of cluster headache. Med Clin North Am 1991; 75:579594. 35. Dodick DW, Rozen TD, Goadsby PJ, Silberstein SD. Cluster headache. Cephalalgia 2000; 20:787803. 36. Monzillo PH, Sanvito WL, Da Costa AR. Cluster-tic syndrome: report of ve new cases. Arq Neuropsiquiatr 2000; 58(2B):518521. 37. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic features, including new cases. Brain 1997; 120:193209. 38. Sjaastad O, Dale I. Evidence for a new (?) treatable headache entity. Headache 1974; 14:105108. 39. Broeske D, Lenn NJ, Cantos E. Chronic paroxysmal hemicrania in a young child: possible relation to ipsilateral occipital infarction. J Child Neurol 1993; 8:235236. 40. Pareja JA, Ruiz J, de Isla C, al-Sabbab H, Espejo J. Idiopathic stabbing headache (jabs and jolts syndrome). Cephalalgia 1996; 16:9396. 41. Dangond F, Spierings EL. Idiopathic stabbing headaches lasting a few seconds. Headache 1993; 33:257258. 42. Sjaastad O, Pettersen H, Bakketeig LS. Extracephalic jabs/idiopathic stabs. Vaga study of headache epidemiology. Cephalalgia 2003; 23(1):5054. 43. Pascual J, Iglesias F, Oterino A, Vazquez-Barquero A, Berciano J. Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic cases. Neurology 1996; 46:15201524. 44. Green MW. A spectrum of exertional headaches. Headache 2001; 4:10851092. 45. Lipton RB, Lowenkopf T, Bajwa ZH, Leckie RS, Ribeiro S, Newman LC, Greenberg MA. Cardiac cephalgia: a treatable form of exertional headache. Neurology 1997; 49:813816. 46. Lance JW. Headaches related to sexual activity. J Neurol Neurosurg Psychiat 1976; 39:12261230. 47. Dodick DW, Mosek AC, Campbell IK. The hypnic (alarm clock) headache syndrome. Cephalalgia 1998; 18:152156. 48. Dodick DW, Brown RD, Britton JW, Huston J. Nonaneurysmal thunderclap headache with diffuse, multifocal, segmental and reversible vasospasm. Cephalalgia 1999; 19: 118123. 49. Sjaastad O, Spierings EL. Hemicrania continua: another headache absolutely responsive to indomethacin. Cephalalgia 1984; 4:6570. 50. Bordini C, Antonaci F, Stovner LJ, Schrader H, Sjaastad O. Hemicrania continua: a clinical review. Headache 1991; 31:2026. 51. Bigal ME, Sheftell FD, Rapoport AM, Lipton RB, Tepper SJ. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002; 22(6):432438. 52. Packard RC. Epidemiology and pathogenesis of posttraumatic headache. J Head Trauma Rehabil 1999; 14:921. 53. Gorelick PB, Hier DB, Caplan LR, Langenberg D. Headache in acute cerebrovascular disease. Neurology 1986; 36:14451450.

20

Bigal and Lipton

54. Schuaib A, Metz L, Hing T. Migraine and intra-cerebral hemorrhage. Cephalalgia 1989; 9:5961. 55. Bassi P, Bandera R, Loiero M, Togoni G, Mangoni. Warning signs in subarachnoid hemorrhage: a cooperative study. Acta Neurol Scand 1991; 84:277281. 56. Solomon S, Cappa KG. The headache of temporal arteritis. J Am Geriatr Soc 1987; 35:163165. 57. Ramadan NM, Tietjen GE, Levine SR, Welch KMA. Scintillating scotomata associated with internal carotid artery dissection: report of three cases. Neurology 1991; 41: 10841087. 58. Bousser MG, Ross Russell R. Cerebral Venous Thrombosis. In: Major Problems in Neurology. London: Saunders 1997:Vol. 1. 59. Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Lancet 1995; 346:934939. 60. Ramadan NM. Headache related to increased intracranial pressure and intracranial hypotension. Curr Opinion Neurol 1996; 9:214218. 61. Wall M, George D. Idiopathic intracranial hypertension: a prospective study of 50 patients. Brain 1991; 114:155180. 62. Bartleson JD, Swanson JW, Whisnant JP. A migrainous syndrome with cerebrospinal uid pleocytosis. Neurology 1981; 31:12571262. 63. Versen HK, Nielsen TM, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 1989; 38:1724. 64. Altura BM, Altura BT, Gebrewold A. Alcohol induced spasm of cerebral blood vessels. J Mental Sci 2000; 104:972999. 65. Diener HC, Tfelt-Hansen P. Headache associated with chronic use of substances. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headache. New York: Raven press Ltd., 1993:721727. 66. Rapoport AM. Analgesic rebound headache. Headache 1988a; 28:662665. 67. Gomez-Arada F, Canadillas F, Marti-Masso FJ, et al. Pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis. Brain 1997; 120:11051113. 68. Antoniazzi AL, Bigal ME, Bordini CA, Speciali JG. Headache associated with dialysis. The IHS criteria revisited. Cephalalgia 2003; 23:146149. 69. Moreau T. Headache in hypothyroidism. Prevalence and outcome under thyroid hormone therapy. Cephalalgia 1988; 18:687689. 70. Sjaastad O, Fredriksen TA, Stolt-Nielsen A, et al. Cervicogenic headache: the importance of sticking to the criteria. Funct Neurol 2002; 17(1):3536. 71. Guidetti V, Galli F, Fabrizi P, et al. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia 1998; 18:455462. 72. Terrence CF, Jensen TS. Trigeminal neuralgia and other facial neuralgias. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:929938. 73. Rushton JG, Stevens JC, Miller RH. Glossopharyngeal (vagoglossopharyngeal) neuralgia. A study of 217 cases. Arch Neurol 1981; 38:201205. 74. Sanin LC, Mathew NT, Bellmyer LR, Ali S. The International Headache Society (IHS) headache classication as applied to a headache clinic population. Cephalalgia 1994; 14:443446. 75. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002; 22:432438. 76. Silberstein SD, Lipton RB, Sliwinski M. Classication of daily and near-daily headaches: eld trial of revised IHS criteria. Neurology 1996; 47(4):871875. 77. Thomsen LL, Ostergaard E, Olesen J, Russell MB. Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine. Neurology 2003; 60:595601.

HeadacheClassication

21

78. Jensen R, Fuglsang-Frederiksen A. Quantitative surface EMG of pericranial muscles. Relation to age and sex in a general population. Electroenceph Clin Neurophysiol 1994; 93:175183. 79. Goadsby PJ, Matharu MS, Boes CJ. SUNCT syndrome or trigeminal neuralgia with lacrimation. Cephalalgia 2001; 21:8283. 80. Newman LC, Lipton RB, Solomon S. The hypnic headache syndrome: a benign headache disorder of the elderly. Neurology 1990; 40(12):19041905.

2
The Epidemiology and Impact of Migraine
Richard B. Lipton
Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Monteore Headache Center, New York, New York, U.S.A.

Marcelo E. Bigal
Department of Neurology, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A.

INTRODUCTION Headache disorders are divided into two major categories. Secondary disorders have an identiable underlying cause such as an infection, a brain tumor, or a stroke. Primary headache disorders have no apparent underlying cause (1,2). Of the primary headache disorders, tension-type headache is the most common in population studies (3), but migraine is most common among patients who seek medical care for headache (4). The most important forms of migraine are migraine with and without aura as well as a condition termed probable migraine (PM) (1). In this chapter we review the epidemiology and risk factors for migraine in population studies, as well as the patterns for health care use. We discuss the burden and the costs of migraine, as well as risk factors for disease progression. We close by linking the epidemiological data to treatment strategies directed to reducing the burden of migraine and preventing disease progression. The epidemiology of the other primary headaches is described in the respective chapters.

THE EPIDEMIOLOGY OF MIGRAINE Efforts to improve the diagnosis and treatment of migraine should begin with epidemiologic data, which helps to describe the prevalence and burden of migraine and its scope and distribution. Epidemiological data can be used to identify the groups at highest risk for migraine, including those in need of medical care among migraine sufferers. It also helps to identify individuals at higher risk to progress to chronic daily headache (see Chapter 27). Finally, epidemiologic data may provide clues to preventive strategies or disease mechanisms.
23

24

Lipton and Bigal

Epidemiological studies focus on the incidence and prevalence of disease in dened populations (5). Incidence refers to the rate of onset of new cases of a disease in a given population over a dened period. Prevalence is dened as the proportion of a given population, which has a disease over a dened period. Prevalence is determined by the average incidence and average duration of disease (6). The Incidence of Migraine The incidence of migraine has been investigated in a limited number of studies. Using the reported age of migraine onset from a prevalence study, Stewart et al. (7) found that, in females, the incidence of migraine with aura peaked between ages 12 and 13 (14.1/1000 person-years); migraine without aura peaked between ages 14 and 17 (18.9/1000 person-years). In males, migraine with aura peaked incidence several years earlier, around ve years of age at 6.6/1000 person-years; the peak for migraine without aura was 10/1000 person-years between 10 and 11 years (Fig. 1). New cases of migraine were uncommon in men in their 20s. From this data, we can conclude that migraine begins earlier in males than in females and that migraine with aura begins earlier than migraine without aura. A study performed in a random sample of young adults (2130 years) found that the incidence of migraine was 5.0 per 1000 person-years in males and 22.0 in females (8), supporting the ndings reported above (9). However, a study using a linked medical records system showed a lower incidence (probably because many people with migraine do not consult doctors or receive a medical diagnosis) (8). In this study, the average annual incidence rate per 1000 person-years was 3.4 (4.8 in women and 1.9 in men). In women, incidence rates were low at the extremes of age and higher for ages 10 to 49, with a striking peak at the age of 20 to 29. In this study, incidence also peaked later than in other studies, because medical diagnosis may occur long after the age of onset.

Figure 1 Incidence of migraine, by age and sex. Source: From Ref. 7.

Epidemiology and Impact of Migraine

25

In the Danish population, the annual incidence of migraine for ages 25 to 64 was of 8/1000, being 15/1000 in males and 3/1000 in females. Prevalence peaked in younger women (20/1000) (10). As shown below, the gap between peak incidence in adolescence and peak prevalence in middle life indicates that migraine is a condition of long duration. The Prevalence of Migraine The published estimates of migraine prevalence have varied broadly, probably because of differences in the methodology (for reviews see 5,1113). A meta-analysis, restricted to studies that used the International Headache Society (IHS) criteria and gender-specic models (females and males were modeled separately), found that age and geography accounted for much of the variation in prevalence (14). Herein, we present primarily studies that used the IHS denition (Table 1). Prevalence by Age Before puberty, migraine prevalence is higher in boys than in girls; as adolescence approaches, incidence and prevalence increase more rapidly in girls than in boys. The prevalence increases throughout childhood and early adult life until approximately age 40, after which it declines (Fig. 2) (14). Overall, prevalence is highest between 25 to 55 years of age, the peak years of economic productivity. These dramatic age effects account for some of the variation in prevalence estimates from previous studies. Although studies suggested that migraine prevalence may be increasing (9,15), the stability of prevalence in studies in the United States over the past decade does not support the view that prevalence is increasing (16,17). It is possible that the demonstrable increases in medical consultation and diagnosis may have caused an apparent rather than a real increase. Prevalence in Children and Adolescents The prevalence of headache in children, as investigated in a number of school- and population-based studies (1824), is summarized in Table 2. By age 3, headache occurs in 3% to 8% of children. At age 5, 19.5% have headache and by age 7, 37% to 51.5% have headaches. In 7- to 15-year-olds, headache prevalence ranges from 57% to 82%. The prevalence increases from ages 3 to 11 in both boys and girls with higher headache prevalence in three- to ve-year-old boys than in three- to ve-yearold girls. Thus, the overall prevalence of headache increases from preschool age to mid-adolescence, when examined using various cross-sectional studies. Two relatively recent studies report the prevalence of pediatric migraine in the Asian Middle East. The rst one, performed in southern Iran, evaluated a random sample of 1868 teen-aged girls (aged 1118) (507 reported headache). Overall prevalence rate for migraine was 6.1% (95% CI, 5.07.2) and for tension-type headache, 12.1% (95% CI, 10.613.6). Migraine and tension-type headache were signicantly associated. The exposure of subjects to sunlight, type of food, and a family history of headache were the most signicant factors associated with migraine and tensiontype headaches (25). The second study evaluated 1400 randomly selected Saudi children in grades 1 through 9. Overall, the headache prevalence was 49.8%. The prevalence of migraine was 7.1%. For both boys and girls, the age-specic prevalence rate for nonmigraine headache rose steadily from around 15% at age 6 to age 7 to nearly 60% after age 15. For migraine, there was a sharp increase in the prevalence rate

26

Table 1 Gender-Specic Prevalence Estimates of Migraine from 25 Population-Based Studies Using IHS Diagnostic Criteria Migraine prevalence (%) Female 11.5 9.7 10.6 Male Total Comments Prevalence is higher in boys prior to age 12 (1.14:1). After age 12, more common in girls (2.0:1) 5.0

Author (year of publication) Method Clin interview 1,754 1 yr 515 Sample size Time frame Age range

Country

Source

Abu-Arefeh (1994)

Scotland

School

al Rajeh (1997) 595 2,257 813 538 1 yr 1 yr 10.3 12.9 7.9 1 yr Lifetime All 2130 1,007 2,723 1 yr 5 All 1580 1018 11.3 12.2 6.7 4.5 9.6 3.4 5.6

Saudi Arabia Community

22,630

All

6.8

3.2

Alders (1996) Arregui (1991) Bank et al. (2000) Barea (1996)

Malaysia Peru Hungary Brazil

Community Community Community School

Face-to-face/ clin interview Face-to-face Clin interview Questionnaire Clin interview

9.0 8.4 9.6 9.9 9.2 6.9

248 hr duration allowed

Breslau (1991)

United States Community

Cruz (1995)

Ecuador

Community

Face-to-face/ telephone Clin interview

Cull (1992) 1,668 1,158 4,061 51,833 1 yr

United Kingdom Sweden Telephone interview Face-to-face Mail SAQ Clin interview

Community

Face-to-face

16,002

16 1874 1 yr Lifetime 1 yr 10 18 20

11.0 16.7 5.6 15.0 16.0

4.3 9.5 4.5 7.0 8.0

7.8 13.2

Community endemic for cysticercosis Without aura only

Community

Dahlof et al. (2003) Deleu et al. (2002) Saudi Arabia Gobel (1994) Germany Hagen et al. Norway (2000)

Lipton and Bigal

Community Community Community

11.0 12.0

Haimanot (1995) 4,204 10,585 5,891 3,246 1,320 7.8 17.1 10.2 2.3 7.9 997 6,491 29,727 11,863 379 9,411 1,610 2,922 1,445 740 3,471 4,029 1 yr 1 yr 1 yr Lifetime 1 yr 18 1114 2564 40 15 3 mo 1 yr 18 All 18.0 6 21.9 3.3 15.0 23.7 12.9 1 yr 2829 32.6 1 yr 1865 17.2 6 16.1 8.0 16.7 7.4 2.7 6.0 11.7 3.6 24.5 13.0 13.5 15.2 3.0 10.0 17.7 8.4 Weighted prevalence 12 15 1865 1 yr 1 yr Lifetime 1 yr 1 yr 15 15 15 15 All 11.9 11.2 4.0 4.0 8.1 7.9 8.0 5.3

Ethiopia

Community

15,000

1 yr

20

4.2

1.7

3.0

France France Saudi Arabia Peru Turkey

Community Community Community Community Community

Face-to-face/ clin interview Face-to-face Face-to-face Face-to-face Clin interview Face-to-face

Sweden Netherlands

Community Community

United States Community Telephone Clin interview Mail SAQ Telephone Telephone Clin interview Clin interview Clin interview Mail SAQ

Face-to-face Questionnaire and telephone Telephone

1 yr Lifetime 1 yr 1 yr

13.8 33 25 18.2

6.1 13.3 7.5 6.5

Epidemiology and Impact of Migraine

United States Community

Switzerland

Community

Henry (1992) Henry et al. (2002) Jabbar (1997) Jaillard (1997) Kececi et al. (2002) Lamp et al. (2003) Lenore et al. (1999) Lipton et al. (2001) Lipton et al. (2002) Merikangas (1993) Michel (1995) Miranda et al. (2003) OBrien (1994) Raieli (1994) Rasmussen (1992) Russell (1995) Sakai (1996) Female:male prevalence ratio 3.6. Regional differences 1 yr 1 yr 1865 1280 14.3 17.6 7.6 5.7 18.3 12.0

France Puerto Rico

Community Community

Canada Italy Denmark Denmark Japan

Community School Community Community Community

Steiner et al. (2003) Stewart (1992) Mail SAQ

England

Community

CATI

4,007 20,468

United States Community

27 (Continued)

28

Table 1 Migraine prevalence (%) Female 19.0 9.1 8.2 2.3 14.7 6 Male Total Comments Racial differences Study done in the rural area of western Japan

Gender-Specific Prevalence Estimates of Migraine from 25 Population-Based Studies Using IHS Diagnostic Criteria (Continued )

Author (year of publication) Method Telephone Questionnaires and telephone Face-to-face Clin interview Telephone Telephone and face-to-face 10,480 1,533 7,356 5,173 1 yr 1 yr 1 yr Lifetime 1 yr 12 65 15 1565 12.0 4.7 1.5 22.9 18 5.0 0.7 0.6 14.8 12.3 9.0 3.0 1.0 19 12,328 5,758 1 yr 1 yr 1865 18 Sample size Time frame Age range

Country

Source

Stewart (1996) Takeshima et al. (2004)

United States Community Japan Community

van Roijen (1995) Wang (1997) Wong (1995) Zivadinov et al. (2001)

Netherlands China Hong Kong Croatia

Community Community Community Community

Abbreviations: CATI, computer assisted telephone interview; IHS, International Headache Society; SAQ, structured administered questionnaire.

Lipton and Bigal

Epidemiology and Impact of Migraine

29

Figure 2 Adjusted prevalence of migraine by age from a meta-analysis of studies using IHS criteria. Abbreviation: IHS, International Headache Society. Source: From Ref. 14.

(from around 2% to around 9%) at age 10 to 11, both in boys and girls. Age-adjusted prevalence for migraine between ages 6 and 15 was 6.2% (26). Another study evaluated the evolution over ve years of juvenile migraine without aura in adolescents. Sixty-four subjects out of 80 previously selected were reevaluated. Thirty-two (50%) had migraine without aura. After four years, migraine without aura persisted in 56.2%, converted to migrainous disorder or nonclassiable headache in 9.4% and 3.1% of cases, respectively, changed to episodic tension-type headache in 12.5%, and remitted in 18.8% (27). Prevalence in the United States In the United States, the American Migraine Study-1 (AMS-1) collected information from 15,000 households representative of the U.S. population in 1989 (16). The AMS-II used virtually identical methodology 10 years later (17). Finally, the American Migraine Prevention and Prevalence (AMPP) study replicated, in its rst research phase, the methods of the AMS-I and AMS-II (28). In these three very large studies, the prevalence of migraine was about 18% in women and 6% in men (Fig. 3). Table 1 summarizes several prevalence studies conducted in the last 12 years. We present the prevalence of migraine in different geographic locations, overall and by gender. Prevalence of Migraine by Socioeconomic Status The relationship between migraine prevalence and socioeconomic status is uncertain. In physician- and clinic-based studies, migraine appears to be associated with high intelligence and social class. In his studies of children, Bille did not nd association between migraine prevalence and intelligence (18,19). Similarly, in adults, epidemiologic studies do not support a relationship between occupation and migraine

30

Table 2 Prevalence of Headache and Migraine by Age in Selected Community and School-Based Studies Age range (years) Males Females 1118 618 515 715 1229 311 1114 3 1 yr NS IHS 19.9 1 yr IHS 40.6a 1 yr 2 of NV/U/VA 90 95 36.9a 28.0 4.3 Lifetime Vahlquist 58.0 59.3 1 yr IHS 38.8a 23.9 3.3 5.3 4.1 2.7 4.4 14 2.9 3.3 NS IHS NS IHS 6.1% Time Frame Migraine denition Headache prevalence Migraine prevalence Overall 7.1% 10.6 3.7 3.0

Author (Y) Country

Sample Type of population size

Overall Males Females

School teenage girls School Children

1,868

1,400

6.4% 7.7%

School Children

1,754

School Children

8,993

Community

10,132

General Practice

1,083

Ayatollahi (2002) Iran Al Jumah M (2002) Saudi Arabia Abu-Arafeh (1994) U.K. Bille (1962) Sweden Linet (1989) USA Mortimer (1992) UK Raielli (1995) Italy Sillanpaa (1976) Finland 7 13 NS 1 yr Vahlquist Vahlquist 79.8 84.2 3.2 8.1

School Children School Children

1,445 4,825

Sillanpaa (1983) Finland

School Children

3,784

3.2 15.1

3.2 Lipton and Bigal

age adjusted denitions: N, nausea; U, unilateral; V, vomiting; VA, visual aura; NS, not specied.

Epidemiology and Impact of Migraine

31

Figure 3 Prevalence of migraine in the AMS-I, AMS-II, and AMPP, overall and by gender. Abbreviations: AMS, American Migraine Study; AMPP, American Migraine Prevention and Prevalence.

prevalence (29). In both the AMS-I and AMS-II and the AMPP, migraine prevalence was inversely related to household income (i.e., migraine prevalence fell as household income increased) (17,18,28). This inverse relationship between migraine and socioeconomic status was conrmed in another U.S. study based on the members of a managed care organization and in the National Health Interview Study (29). Finally, although the genetic epidemiology of migraine study (GEM) failed to demonstrate an association between migraine and socioeconomic status (30), a recent study in England showed this relationship (31). Prevalence of Migraine by Geographic Distribution Migraine prevalence also varies by race and geography. In the United States, it is highest in Caucasians, intermediate in African Americans, and lowest in Asian Americans (5). Similarly, a meta-analysis of prevalence studies suggests that migraine is most common in North and South America and Europe, but lower in Africa, and often lowest in studies from Asia (Fig. 4) (4). The inuence of reporting bias on these ndings cannot be excluded. Nonetheless the data suggest that race-related differences in genetic risk may contribute. If and how these differences apply to the pediatric population (of if these differences have later expression) is still to be determined. THE BURDEN OF MIGRAINE Individual Burden of Migraine Migraine is a public health problem of enormous scope, which has an impact on both the individual sufferer and on society (17,18). Nearly one in four U.S. households have someone with migraine. Twenty-ve percent of women in the United States who have migraine experience four or more severe attacks a month; 35% experience one to four severe attacks a month; 38% experience one, or less than one, severe attack a month. Similar frequency patterns were observed for men (18,28). In the AMS-II, 92% of women and 89% of men with severe migraine had some headache-related disability. Similar ndings were reported by the AMPP. About half were severely disabled or needed bed rest (32). In addition to the attack-related

32

Lipton and Bigal

Figure 4 Adjusted prevalence of migraine by geographic area and gender in a meta-analysis of studies using IHS criteria. Source: From Ref. 5.

disability, many migraineurs live in fear, knowing that at any time an attack could disrupt their ability to work, care for their families, or meet social obligations. Abundant evidence indicates that migraine reduces health-related quality of life (33,34). Societal Impact of Migraine Migraine has an enormous impact on society. Recent U.S. studies have evaluated both the indirect costs of migraine and the direct costs (32,3537). Indirect costs include the aggregate effects of migraine on productivity at work (paid employment), in household work, and in other roles. The largest component of indirect costs is the productivity losses that take the form of absenteeism and reduced productivity while at work. Hu et al. estimated that productivity losses due to migraine cost American employers 13 billion dollars per year (35). These issues have been reviewed in more detail elsewhere (38). Migraines impact on health care utilization is marked as well. The National Ambulatory Medical Care Survey, conducted from 1976 to 1977, found that 4% of all visits to physicians ofces (over 10 million visits a year) were for headaches (39,40). Migraine also results in major utilization of emergency rooms and urgent care centers (41,42). Vast amounts of prescription and over-the-counter (OTC) medications are taken for headache disorders. OTC sales of pain medication (for all conditions) were estimated to be 3.2 billion dollars in 1999 (United States) and headache accounts for about one-third of OTC analgesic use. (Consumer Healthcare Products Association. OTC Sales Statistics1995 to 1999. AC Neilsen, April 2000.) Gross sales for the triptans are about US $1 billion per year in the United States. PROBABLE MIGRAINEAN IMPORTANT MIGRAINE SUBTYPE Most epidemiologic studies focus on the two common forms of migraine, migraine without aura (1.1) and migraine with aura (1.2). Clinic- and some population-based

Epidemiology and Impact of Migraine

33

Figure 5 Prevalence of probable migraine, strict migraine, and all migraine within participants of a health plan. Abbreviations: SM, strict migraine; PM, probable migraine; AM, all migraine.

studies show that a large number of patients with migrainous features fail to fully meet the IHS criteria for these two types of migraine (4346). These patients often fulll all criteria but one for migraine with or without aura. This condition is termed probable migraine in the IHS classication (1). Estimates of the prevalence of PM vary widely. The one-year period prevalence in the AMS-II was 2.6%. In the AMPP, the overall prevalence of PM was 4.5%, being 3.9% in men and 5.1% in women (28). In a French population study, Henry et al. (47) found a prevalence of 9.1% for PM. Interestingly, in their study, PM was more prevalent than migraine with or without aura. The impact of PM is poorly understood. We recently conducted a study assessing the prevalence and impact of PM within a health plan (43). Among 8579 respondents, the one-year prevalence for migraine with and without aura (strict migraine) was 14.7% (19.2% in women and 6.6% in men); for PM it was 14.5% (19.6% in women and 13.1% in men); pooling strict migraine and PM, the prevalence of all migraine was 29.2% (38.8% in women and 19.6% in men) (Fig. 5). The prevalence of strict migraine and PM was higher in females, Caucasians, and those in early middle life relative to controls. Health related quality of life (HRQoL) was reduced in the PM, strict migraine, and all migraine groups, compared to controls (mental health scores 50.2, 48.2, 50.9, and 53.1, respectively, p < 0.0001; physical health scores 46.8, 48.8, 47.8, and 51.2, respectively, p < 0.0001). The proportion of subjects with high disability relative to control was elevated in PM, strict migraine, and all migraine groups [migraine disability assessment (MIDAS) III and IV: 13%, 31%, 22%, and 3.7%, respectivelyp < 0.0001]. Strict migraine and PM were associated with an increased risk of depression. Diagnosis of this large group of headache sufferers is an important issue in clinical practice. Given the overlap of symptom features, the prole of familial aggregation, and treatment response proles, it is likely that PM involves the same pathophysiological process as with strict migraine.

CONCLUSIONS Migraine is a lifelong illness for many sufferers and imposes an enormous and prevalent health care burden on society. Migraine parallels other chronic illnesses such as asthma, hypertension, high blood pressure, and seizure disorder in terms

34

Lipton and Bigal

of the impact of disease and requirement for long-term management. Identication of and screening for migraine, establishment of a disease management plan for the patient, based on a stratied care treatment approach, and ongoing assessment of illness severity and disease impact (using a disability measure such as MIDAS) is likely to improve long-term outcomes, including patient satisfaction and treatment success. This effort must be part of a broader strategy that includes effective assessment and follow-up, patient education, behavioral approaches, and preventive treatments that will be discussed in detail in the following chapters.

REFERENCES
1. Headache Classication Committee of the International Headache Society. Classication and Diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. 2nd ed. Cephalalgia 2004 (suppl 1):1160. 2. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J. The classication of the headaches. Neurology 2004; 63(3):427435. 3. Rasmussen BK. Epidemiology of headache. Cephalalgia 1995; 15:4568. 4. Tepper SJ, Dahlof CG, Dowson A, et al. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. Headache 2004; 44(9):856864. 5. Scher AI, Stewart WF, Lipton RB. Migraine and headache: a meta-analytic approach. In: Crombie IK, ed. Epidemiology of Pain. Seattle, Washington: IASP Press, 1999:159170. 6. Waters WE. Headache (Series in Clinical Epidemiology). Littleton, MA: PSG Co Inc., 1986. 7. Stewart WF, Linet MS, Celentano DD, Van Natta M, Ziegler D. Age and sex-specic incidence rates of migraine with and without visual aura. Am J Epidemiol 1993; 34: 11111120. 8. Lyngberg A, Jensen R, Rasmussen BK, Jorgensen T. Incidence of migraine in a Danish population-based follow-up study [abstr]. Cephalalgia 2003; 23:596. 9. Breslau N, Davis GC, Schultz LR, Peterson EL. Joint 1994 Wolff Award Presentation. Migraine and major depression: a longitudinal study. Headache 1994; 34(7):387393. 10. Stang PE, Yanagihara T, Swanson JW, et al. Incidence of migraine headaches: a population-based study in Olmstead County, Minnesota. Neurology 1992; 42:165762. 11. Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. Headache 2005; 45(suppl 1):S3S13. 12. Bigal ME, Lipton RB, Stewart WF. The epidemiology and impact of migraine. Curr Neurol Neurosci Rep 2004; 4(2):98104. 13. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. JAMA 1992; 267:6469. 14. Stewart WF, Simon D, Shechter A, Lipton RB. Population variation in migraine prevalence: a meta-analysis. J Clin Epidemiol 1995; 48:269280. 15. MMWR. Prevalence of chronic migraine headachesUnited States, 198089. MMWR 1991; 40:331338. 16. Lipton RB, Stewart WF, Simon D. Medical consultation for migraine: results from the American Migraine Study. Headache 1998; 38:8796. 17. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41:646657. 18. Bille B. Migraine in school children (1962). Acta Paediatr Scand 51(suppl 136):1151. 19. Bille B. Migraine in children: prevalence, clinical features, and a 30-year follow-up (1989). In: Ferrari MD, Lataste X, eds. Migraine and Other Headaches. New Jersey: Parthenon, 2001.

Epidemiology and Impact of Migraine

35

20. Sillanpaa M. Prevalence of migraine and other headache in Finnish children starting school. Headache 1976; 15:288290. 21. Sillanpaa M. Prevalence of headache in prepuberty. Headache 1983; 23:1014. 22. Sillanpaa M. Changes in the prevalence of migraine and other headaches during the rst seven school years. Headache 1983; 23:1519. 23. Sillanpaa M, Piekkala P, Kero P. Prevalence of headache at preschool age in an unselected child population. Cephalalgia 1991; 11:239242. 24. Sillanpaa M. Headache in children. In: Olesen J, ed. Headache Classication and Epidemiology. New York: Raven Press, 1994:273281. 25. Ayatollahi SM, Moradi F, Ayatollahi SA. Prevalences of migraine and tensiontype headache in adolescent girls of Shiraz (southern Iran). Headache 2002; 42(4): 287290. 26. Al Jumah M, Awada A, Al Azzam S. Headache syndromes amongst schoolchildren in Riyadh, Saudi Arabia. Headache 2002; 42(4):281286. 27. Ozge A, Bugdayci R, Sasmaz T, et al. The sensitivity and specicity of the case denition criteria in diagnosis of headache: a school-based epidemiological study of 5562 children in Mersin. Cephalalgia 2002; 22(10):791798. 28. Lipton RB, Diamond D, Freitag F, Bigal ME, et al. Migraine prevention patterns in a community sample. Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 2005; 45: 792. 29. Stang PE, Sternfeld B, Sidney S. Migraine headache in a pre-paid health plan: ascertainment, demographics, physiological and behavioral factors. Headache 1996l; 36:6976. 30. Launer LJ, Terwindt GM, Ferrari MD. The prevalence and characteristics of migraine in a population-based cohort: the GEM Study. Neurology 1999; 53:537542. 31. Steiner T, Scher A, Stewart W, Kolodner K, Liberman J, Lipton R. The prevalence and disability burden of adult migraine in England and their relationships to age, gender and ethnicity. Cephalalgia 2003; 23(7):519527. 32. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001; 41:638645. 33. Dahlof C, Bouchard J, Cortelli P, et al. A multinational investigation of the impact of subcutaneous sumatriptan. II: Health-related quality of life. Pharmacoeconomics 1997; 11(suppl 1):2434. 34. Santanello NC, Polis AB, Hartmaier SL, Kramer MS, Block GA, Silberstein SD. Improvement in migraine-specic quality of life in a clinical trial of rizatriptan. Cephalalgia 1997; 17(8):867872. 35. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med 1999; 159:813818. 36. Osterhaus JT, Gutterman DL, Plachetka JR. Health care resources and lost labor costs of migraine headaches in the United States. Pharmacoeconomics 1992; 2:6776. 37. Holmes WF, MacGregor A, Dodick D. Migraine-related disability: impact and implications for sufferers lives and clinical issues. Neurology 2001; 56(suppl 1):S13S19. 38. Lipton RB, Bigal ME, Scher AI, Stewart WF. The global burden of migraine. J Headache Pain 2003; 4(suppl 1):311. 39. National Center for Health Statistics. Vital and Health Statistics of the United States. D.H.E.W., PHS Publication No. 53. Advance data. Hyattsville, MD. National Center for Health Statistics, 1979. 40. Celentano DD, Stewart WF, Lipton RB, Reed ML. Medication use and disability among migraineurs: a national probability sample. Headache 1992; 32:223228. 41. Fry J. Proles of Disease. Edinburgh: Livingstone, 1996. 42. Bigal ME, Bordini CA, Speciali JG. Headache in an emergency room. Sao Paulo Med J 2000; 118(3):5862. 43. Bigal ME, Patel N, Kolodner K, et al. The one-year period prevalence of strict migraine, probable migraine (migrainous headache), and the full spectrum of migraine within a health-plan population. Cephalalgia 2003; 23:594.

36

Lipton and Bigal

44. Rains JC, Penzien DB, Lipchik GL, et al. Diagnosis of migraine: empirical analysis of a large clinical sample of atypical migraine (IHS 1.7) patients and proposed revision of the IHS criteria. Cephalalgia 2001; 21:584595. 45. Russell MB, Olesen J. Migrainous disorder and its relation to migraine without aura and migraine with aura. A genetic epidemiological study. Cephalalgia 1996; 16(6):431435. 46. Lipton RB, Cady R, Dodick D, Diamond M. Demographics of migrainous headache sufferers in the United States: additional data from the American Migraine Study II [abstr]. Headache 2002; 42:440. 47. Henry P, Auray JP, Gaudin AF, et al. Prevalence and clinical characteristics of migraine in France. Neurology 2002; 59:232227.

3
Progressive Headache: Epidemiology, Natural History, and Risk Factors
Ann I. Scher
Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, U.S.A.

INTRODUCTION While most headache sufferers experience attacks once or twice per month, some individuals (about 4% of the adult population) chronically experience attacks on a daily or near daily basis. The term chronic daily headache (CDH) is dened by convention as headache on 15 or more days per month. Despite recent insight from animal models (13), focused clinical studies (410), and epidemiology (1114), the etiology of CDH remains uncertain in most cases. Evidence from placebo-controlled trials of treatment strategies for CDH is limited (1520) and, unfortunately, clinical trials of headache-specic agents often exclude individuals with very frequent headache. In this chapter, we review the epidemiology, natural history, and risk factors for CDH identied in population studies.

CLASSIFICATION CDH can be secondary (attributable to an underlying disorder) or primary (not attributable to an underlying disorder). Primary CDH is further subdivided into the shorter duration headaches (less than four hours, such as chronic cluster headache, chronic paroxysmal hemicrania, and hypnic headache) and long-duration types (21). Long duration types include chronic tension-type and chronic migrainous headache, and, less commonly, hemicrania continua and new daily persistent headache (21). In the population, most CDH sufferers can be classied as either chronic migrainous headache or chronic tension-type headache, with roughly equal prevalences of both (2226). CDH patients in tertiary referral centers primarily have chronic migrainous headaches, presumably due to higher rates of consultation (24). A slightly greater proportion of the migraine population experience CDH than of the non-migraine headache population [8% vs. 5%, odds ratio (OR) 1.6 (1.31.9)] (unpublished data from Ref. 24). Therefore, it is possible that migraine
37

38

Scher

headache is either a risk factor for CDH onset or is associated with a poorer prognosis (longer duration) than nonmigrainous CDH. However, two prospective studies found that individuals with migrainous CDH were no more or less likely to remit by two to four years of follow-up than individuals with chronic tension-type headache (23,26).

CHRONIC DAILY HEADACHE EPIDEMIOLOGY AND NATURAL HISTORY Prevalence CDH affects about 4% of the adult and elderly population 23,2527,28) and about 2% of children or adolescents (11,29,30,30a). This relatively constant prevalence of CDH is in contrast to the pattern seen with episodic migraine and, to a lesser extent, tension-type headache, both of which tend to become less prevalent with age. Incidence In a U.S. based population study of adults aged 18 to 65, the one-year incidence of CDH was approximately 3% among those with episodic headache (14). Incidence rates were much higher (14%) in a German clinic-based study of migraine sufferers (31). This higher incidence rate among consulting headache patients could be due to these patients having more severe disease than the population sample or because such patients have a higher prevalence of comorbid conditions or other exposures that inuence incidence and might inuence rates of physician consultation. Remission Three prospective population-based studies suggest high rates of remission over time periods ranging from one to four years. For example, in the U.S. prospective study, more than half (60%) of CDH cases at baseline had remitted to less than 180 headache days per year at follow-up; remission to less than 1 headache per week was less common (16%) (14). A similar remission rate was reported in Taiwan (65% remitted to fewer than 15 headaches per month after two years) (23), although remission was lower in an elderly Chinese population (33% had remitted over a four-year period) (26).

DEMOGRAPHIC FACTORS ASSOCIATED WITH CHRONIC DAILY HEADACHE Gender CDH affects women more than men by a factor of roughly two to one (27) and this increased prevalence in women is evident even after the age of menopause (23,25,26,30). Socioeconomic Status CDH appears to be more common in individuals of less education or lower income (14,23,24,26,32). In a prospective study in the United States, compared to those with a graduate education, individuals with less than a high-school education were at

Progressive Headache: Epidemiology, Natural History, and Risk Factors

39

increased risk of CDH at baseline [OR 3.35 (2.15.3)] and were at reduced risk for remission at one year [OR 0.2 (0.10.5)] (14). However, educational level was not associated with one-year incidence in this study. In a large prospective population study from Norway, Hagen et al. considered whether the risk of CDH was greater in those with lower educational level, income, or social class (32). Results indicated that the risk of CDH was higher in those with less than 10 years of education relative to those with 13 years of education for both women [relative risk (RR) 2.4 (1.14.9)] and men [RR 1.6 (1.12.1)]. Similar results were seen for low social class for women [RR 2.6 (1.54.6)] and men [RR 1.4 (1.02.0)], and for low income for men [RR 1.8 (1.22.7)] but not for women [RR 0.9 (0.61.4)]. Marital Status In the previously mentioned U.S. prospective study (14), marital status at baseline was considered as a risk factor for CDH prevalence, incidence, and remission. Compared to married individuals, previously married individuals (e.g., divorced, widowed, or separated) were found to be at a higher risk of CDH at baseline [OR 1.5 (1.11.9)] and were less likely to have remission after one year [OR 0.5 (0.30.9)]. However, marital status was not associated with CDH incidence [OR 1.8 (0.65.7)] among the episodic headache controls.

OTHER FACTORS ASSOCIATED WITH CHRONIC DAILY HEADACHE PREVALENCE OR INCIDENCE Obesity Obesity, dened as a body-mass index !30, was predictive of one-year CDH incidence in the U.S. prospective study (14). The reason why obesity would predispose individuals to headache progression is unknown, although obesity is associated with other conditions [e.g., osteoarthritis (see below), diabetes, and cardiovascular disease (33)] that might also inuence headache frequency. Medication Use Medication overuse for headache may be an aggravating or causal factor for headache progression, may be a marker of headache intractability, or both. As medication overuse is obviously a consequence of headache progression, the role or even existence of medication overuse as a cause of headache progression is difcult to demonstrate in observational studies, and will remain uncertain absent evidence from well-designed clinical trials. In population samples, approximately one-third of CDH sufferers overuse medication as dened based on criteria by Silberstein (22,23,25,26,34,35), although a somewhat higher proportion of CDH sufferers (4154%) were found to be overusing medication in a large study from Norway (36). Lu et al.(23) followed a group of 106 CDH sufferers for two years, 36 (34%) of who overused medication at baseline. At follow-up two years later, 19/70 (27%) of the nonoverusers had persistent CDH and 18/36 (50%) of the overusers had persistent CDH, corresponding to a relative risk of 1.8 (1.13.1). In a second study in an elderly population, Wang et al. (26) identied 15 (25%) CDH sufferers, who overused medication. At follow-up at least two years later, 21/37 (57%) of non-overusers

40

Scher

had persistent CDH versus 14/15 (93%) of overusers, corresponding to a relative risk of 1.6 (1.22.3). The previously mentioned German clinic-based study found that medication overuse predicted incidence of CDH in episodic migraine-specialty patients, even after adjusting for baseline headache frequency (31). These studies thus support the hypothesis that medication overuse predicts a worse prognosis, but do not answer the question of whether medication overuse is itself a risk factor or is a marker for headache intractability. Zwart et al. (37) interviewed a large population-based sample of individuals two times over a 10-year period. They found that individuals who used analgesics daily or weekly at baseline were more likely to have chronic pain at follow-up compared to individuals who used analgesics less than weekly. Unfortunately, the reason for medication use at baseline was not known. Therefore, this nding cannot be taken to support the hypothesis that medication overuse predicts CDH incidence, because headache frequency at baseline (and the at-risk population for CDH) was not known. For similar reasons, this nding cannot be taken to support the hypothesis that CDH sufferers with medication overuse have a worse prognosis than CDH sufferers without medication overuse, because individuals with CDH were not identied in the baseline survey. Caffeine Consumption The role of caffeine as a causal or aggravating factor in CDH is of particular interest, as caffeine is the only component of pain medication shown to cause withdrawal headache in placebo-controlled trials (38). In a U.S. case-control study, dietary and medicinal caffeine consumption both before and after CDH onset was compared in CDH cases to episodic headache controls (39). Results showed that the CDH sufferers were more likely to have been high caffeine consumers than the comparison group before CDH onset, although the association was modest. There was no difference in current caffeine consumption between the episodic and chronic headache sufferers. High caffeine consumption appeared to be more important as a risk factors in some subgroups of CDH sufferers, particularly younger women, CDH sufferers with daily episodic (as opposed to daily continuous) headache, CDH sufferers who had not consulted physicians, and CDH of recent (less than two years) onset. The migraine sufferers, whether episodic or chronic, consumed more medicinal or dietary caffeine than the other headache sufferers. Snoring and Sleep-Related Factors Habitual snoring was much more common in a population sample of CDH sufferers compared to episodic headache controls (12). This association was independent of factors known to be associated with snoring and sleep apnea (e.g., male gender, increased age, weight, high blood pressure, alcohol consumption) as well as other headache-related factors that can affect sleep (e.g., use of sedating pain medication, coexisting depression, and caffeine consumption). The nding that CDH sufferers were more likely to snore was evident for both chronic migraine and chronic tension-type headache sufferers, for both men and women, for both younger and older CDH sufferers, and for both married and unmarried CDH sufferers. This suggests that, if the association is causal, the effect of snoring on very frequent headache is from a different mechanism than that from sleep apnea/hypopnea. CDH cases were also more likely to report sleep problems and to be either short or long sleepers (unpublished data from Ref. 12).

Progressive Headache: Epidemiology, Natural History, and Risk Factors

41

Stressful Life Events Certain life changes (moves, job changes, child-related changes, changes in marital status, deaths in the family or of close friends, and ongoing extremely stressful life events) were found to be associated with CDH onset in the case-control study. Overall, cases reported more such events in the same year or year before CDH onset than the controls in an equivalent time period (2.7 vs. 2.0, p < 0.001, ranksum test). No difference was found for post-CDH events, strengthening a causal interpretation. A large study based on adolescent students from Taiwan measured the presence of childhood stressors (e.g., parental divorce and child abuse) using the global family environment scale and compared scores between students with CDH and a control group (11). They found that the CDH students had about a 10% higher score on this scalesuggesting that the presence of these negative life events might be involved in the onset of adolescent CDH.

Comorbid Pain The co-occurrence of different pain syndromes has been noted in a number of studies (29,40,41). Pain conditions might be comorbid because of diagnostic uncertainties [for example, chronic tension-type headache and temporomandibular disorder (TMD)], particularly when there is an overlap in the symptomatology of the pain syndromes or when diagnosis is not based on objective markers. It may also be that one condition directly leads to the development of the second (e.g., neck pain triggering headache). However, there may be shared genetic or nongenetic factors that inuence the development of pain at different sites. In the previously mentioned study from Norway (13), individuals with CDH were more than four times more likely to report musculoskeletal symptoms than those without CDH [RR 4.6 (1.05.3)]. Similarly, in a U.S. study (14), CDH sufferers over age 40 were considerably more likely to report physician-diagnosed arthritis [OR 2.41 (1.83.3)] than individuals with episodic headache. Among the episodic headache controls, physician-diagnosed arthritis was also associated with incident CDH, although results were attenuated after adjusting for obesity. In a study by El-Metwally et al. of 1756 third- and fth-grade Finnish schoolchildren (42), children were examined for the presence of nontraumatic musculoskeletal pain symptoms and were tested for hypermobility. They were reevaluated after one and four years to determine factors related to the prognosis of musculoskeletal pain. Baseline headache once or more a week (not characterized by type) was found to be a negative prognostic factorthat is, the children with comorbid headache were more likely to have persistent musculoskeletal pain at follow-up compared to the children without comorbid headache. von Korff et al. conducted a three-year longitudinal study of 803 adult Group Health enrollees to measure factors that were associated with the onset of chronic pain (43). Participants were assessed at baseline for chronic pain, depression, and other factors. At the three-year follow-up, baseline depression was not associated with incidence of TMD pain, back pain, or abdominal pain although it was associated with severe headache incidence [adjusted odds ratios of 1.7 for moderate depression and 5.0 for severe depression and for chest pain incidence (OR 4.5 for moderate depression and OR 4.6 for severe depression)]. Having a baseline pain condition was a more consistent predictor of a new pain condition than having

42

Scher

baseline depression, with signicant risk for new onset back pain (OR 2.1), headache (OR 4.3), abdominal pain (OR 6.3), and TMD pain (OR 3.7). CONCLUSION CDH affects about 4% of the population. In the general population, CDH often remits over a one- to four-year period. CDH is more common in women than men and is inversely associated with measures of socioeconomic status. Risk factors identied in population studies include stressful life events, habitual snoring, and comorbid pain.

REFERENCES
1. Srikiatkhachorn A, Suwattanasophon C, Ruangpattanatawee U, Phansuwan-Pujito P. 5-HT2A receptor activation and nitric oxide synthesis: a possible mechanism determining migraine attacks. Headache: J Head Face Pain 2002; 42(7):566574. 2. Srikiatkhachorn A, Tarasub N, Govitrapong P. Effect of chronic analgesic exposure on the central serotonin system: a possible mechanism of analgesic abuse headache. Headache 2000; 40(5):343350. 3. Srikiatkhachorn A, Tarasub N, Govitrapong P. Acetaminophen-induced antinociception via central 5-HT(2A) receptors. Neurochem Int 1999; 34(6):491498. 4. Gallai V, Alberti A, Gallai B, Coppola F, Floridi A, Sarchielli P. Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal uid. Cephalalgia 2003; 23(3):166174. 5. Sarchielli P, Alberti A, Russo S, et al. Nitric oxide pathway, Ca2, and serotonin content in platelets from patients suffering from chronic daily headache. Cephalalgia 1999; 19(9):810816. 6. Sarchielli P, Alberti A, Floridi A, Gallai V. L-Arginine/nitric oxide pathway in chronic tension-type headache: relation with serotonin content and secretion and glutamate content. J Neurol Sci 2002; 198(1/2):915. 7. Welch KM, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache: J Head Face Pain 2001; 41(7): 629637. 8. Sarchielli P, Alberti A, Floridi A, Gallai V. Levels of nerve growth factor in cerebrospinal uid of chronic daily headache patients. Neurology 2001; 57(1):132134. 9. Bahra A, Walsh M, Menon S, Goadsby PJ. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache: J Head Face Pain 2003; 43(3):179190. 10. Wilkinson SM, Becker WJ, Heine JA. Opiate use to control bowel motility may induce chronic daily headache in patients with migraine. Headache: J Head Face Pain 2001; 41(3):303309. 11. Juang KD, Wang SJ, Fuh JL, Lu SR, Chen YS. Association between adolescent chronic daily headache and childhood adversity: a community-based study. Cephalalgia 2004; 24:5459. 12. Scher AI, Lipton RB, Stewart WF. Habitual snoring as a risk factor for chronic daily headache. Neurology 2003; 60(8):1366. 13. Hagen K, Einarsen C, Zwart JA, Svebak S, Bovim G. The co-occurrence of headache and musculoskeletal symptoms amongst 51 050 adults in Norway. Eur J Neurol 2002; 9(5):527533. 14. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003; 106(1/2):8189.

Progressive Headache: Epidemiology, Natural History, and Risk Factors

43

15. Saper JR, Lake AE, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache: J Head Face Pain 2002; 42(6):470482. 16. Descombes S, Brefel-Courbon C, et al. Amitriptyline treatment in chronic drug-induced headache: a Double-Blind Comparative Pilot Study. Headache: J Head Face Pain 2001; 41(2):178182. 17. Ondo WG, Vuong KD, Derman HS. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study. Cephalalgia 2004; 24(1):6065. 18. Spira PJ, Beran RG. Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study. Neurology 2003; 61(12):17531759. 19. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache: J Head Face Pain 2005; 45(4):293307. 20. Saper JR, Silberstein SD, Lake AE III, Winters ME. Double-blind trial of uoxetine: chronic daily headache and migraine. Headache: J Head Face Pain 1994; 34(9):497502. 21. Silberstein SD, Lipton RB. Chronic Daily Headache, Including Transformed Migraine, Chronic Tension-Type Headache, and Medication Overuse. Wolffs Headache. Oxford: Oxford University Press, 2001:247282. 22. Castillo J, Munoz P, Guitera V, Pascual J. Kaplan Award 1998: Epidemiology of chronic daily headache in the general population. Headache: J Head Face Pain 1999; 39:190196. 23. Lu SR, Fuh JL, Chen WT, Juang KD, Wang SJ. Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors. Cephalalgia 2001; 21(10):980986. 24. Scher AI, Stewart WF, Liberman J, Lipton RB. Wolff Award 1998: Prevalence of frequent headache in a population sample. Headache: J Head Face Pain 1998; 38:497506. 25. Prencipe M, Casini AR, Ferretti C, et al. Prevalence of headache in an elderly population: attack frequency, disability, and use of medication. J Neurol Neurosurg Psychiat 2001; 70(3):377381. 26. Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in Chinese elderly: prevalence, risk factors, and biannual follow-up. Neurology 2000; 2000(54):314319. 27. Scher AI, Lipton RB, Stewart W. Risk factors for chronic daily headache. Curr Pain Headache Rep 2002; 6(6):486491. 28. Hagen K, Zwart JA, Vatten L, Stovner LJ, Bovim G. Prevalence of migraine and nonmigrainous headachehead-HUNT, a large population-based study. Cephalalgia 2000; 20(10):900906. 29. Wang SJ, Fuh JL, Lu SR, Juang KD. Chronic daily headache in adolescents. Prevalence, impact, and medication overuse. Neurology 2006; 66:193197. 30. Anttila P, Metsahonkala L, Aromaa M, et al. Determinants of tension-type headache in children. Cephalalgia 2002; 22(5):401408. 30a. Laurell K, Larsson B, Eeg-Olofsson O. Prevalence of headache in Swedish school children, with a focus on tension-type headache. Cephalalgia 2004; 24(5):380388. 31. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62(5):788790. 32. Hagen K, Vatten L, Stovner LJ, Zwart JA, Krokstad S, Bovim G. Low socio-economic status is associated with increased risk of frequent headache: a prospective study of 22718 adults in Norway. Cephalalgia 2002; 22(8):672679. 33. Scher AI, Terwindt GM, Picavet HSJ, Verschuren WMM, Ferrari MD, Launer LJ. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 2005; 64(4):614620. 34. Silberstein SD, Lipton RB, Sliwinski M. Classication of daily and near-daily headaches: eld trial of revised IHS criteria. Neurology 1996; 47(4):871875. 35. Colas R, Munoz P, Temprano R, Gomez C, Pascual J. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology 2004; 62(8):13381342.

44

Scher

36. Zwart JA, Dyb G, Hagen K, Svebak S, Stovner LJ, Holmen J. Analgesic overuse among subjects with headache, neck, and low-back pain. Neurology 2004; 62(9):15401544. 37. Zwart JA, Dyb G, Hagen K, Svebak S, Holmen J. Analgesic use: a predictor of chronic pain and medication overuse headache: The Head-HUNT Study. Neurology 2003; 61(2):160. 38. Silverman K, Evans SM, Strain EC, Grifths RR. Withdrawal syndrome after the double-blind cessation of caffeine consumption [see comments]. N Engl J Med 1992; 327(16):11091114. 39. Scher AI, Stewart WF, Lipton RB. Caffeine as a risk factor for chronic daily headache: a population-based study. Neurology 2004; 63(11):20222027. 40. Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med 2001; 134(9 Pt 2):868881. 41. Boardman HF, Thomas E, Millson DS, Croft PR. Psychological, sleep, lifestyle, and comorbid associations with headache. J Head Face Pain 2005; 45:657669. 42. El Metwally A, Salminen JJ, Auvinen A, Kautiainen H, Mikkelsson M. Prognosis of non-specic musculoskeletal pain in preadolescents: a prospective 4-year follow-up study till adolescence. Pain 2004; 110(3):550559. 43. von Korff M, Le Resche L, Dworkin SF. First onset of common pain symptoms: a prospective study of depression as a risk factor. Pain 1993; 55(2):251258.

Comorbidity of Migrainea
Nancy C. P. Low and Kathleen Ries Merikangas
Section on Developmental Genetic Epidemiology, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, U.S.A.

INTRODUCTION The term comorbidity, introduced by Feinstein, refers to the presence of any additional coexisting ailment in a patient with a particular index disease (3). Failure to classify and analyze comorbid diseases can create misleading medical statistics and may cause spurious comparisons during the evaluation and treatment planning for patients. Comorbidity can alter the clinical course of patients with the same diagnosis by affecting the time of detection, prognostic anticipations, therapeutic selection, and post-therapeutic outcome of an index diagnosis (4). In addition, it can also affect the length of hospital stay, response to somatic treatment, and mortality (57). Nonrandom co-occurrence of two conditions may be attributable to several methodologic artifacts including: samples selected from clinical settings that are nonrepresentative of persons with the index disease in the general population (i.e., Berksons Paradox) (8); assessment bias, in which the co-occurrence of two conditions is an artifact of overlap in the diagnostic criteria or in the assessments employed to ascertain the criteria; and the lack of an appropriate comparison (or control) group with which to account for factors that confound the association between the two conditions.

METHODOLOGY OF COMORBIDITY STUDIES Associations between migraine and a variety of somatic and psychiatric conditions have been reported in the literature since it was rst described as a discrete syndrome. Most of the early descriptions of such associations were based on clinical case series, so empirical evidence was lacking. Several factors that complicate the investigation of comorbidity of migraine and other conditions include discrimination from migraine

Adapted in part from Refs. 1 and 2. 45

46

Low and Merikangas

migraine equivalents dened as alternate manifestations of migraine that occur in an attack-like fashion, including abdominal pain, dizziness or vertigo, or visual symptoms; lack of specicity of symptom expression or constellations within individuals over time; and the involvement of several systems including the cardiovascular, gastrointestinal, and sensory organs, as well as both the peripheral and central nervous systems. There is dramatic variability in the methodology of studies of comorbidity and migraine, which limits the conclusiveness of the ndings. Studies of comorbidity require valid denitions and reliable ascertainment of each of the disorders under consideration. The majority of migraine comorbidity studies was conducted prior to the introduction of the International Headache Society criteria and employed idiosyncratic denitions of migraine ranging from recurrent headaches to classical migraine with neurologic prodromes. Moreover, standardized denitions of both disorders were rarely included in clinical or community studies. In general, clinical series and casecontrol studies have employed the most thorough clinical evaluations of subjects. In contrast, community studies tend to apply less rigorous denitions of the disorders because collection of extensive diagnostic information on both conditions was precluded by the sheer magnitude of the studies. Community studies generally have sufcient statistical power to detect associations between migraine and rare diseases. Indeed, the negative associations in the smaller sample sizes of the clinical and casecontrol studies are often the result of b-type errors rather than a true lack of association between migraine and other diseases. Another methodologic limitation of the majority of studies of migraine comorbidity is the failure to incorporate confounding risk factors, which could explain the association between several diseases and migraine. In addition, the inter-relationships between the comorbid disorders themselves are often unaccounted for in multivariate analyses, thereby yielding spurious associations. Finally, as noted above, the samples of both the clinical series and casecontrol studies may be biased with respect to the increased probability that persons with two or more conditions are represented in clinical samples (i.e., Berksons paradox) (8). Thus, population-based studies are necessary to identify such biases in treatment samples. Casecontrol studies and cross-sectional epidemiologic studies mainly generate hypotheses about possible associations, and longitudinal population-based studies are necessary to test the hypotheses and reliably identify patterns of comorbidity. EVIDENCE FOR MIGRAINE COMORBIDITY Comorbidities of migraine and several other disorders have been reported in clinical series, casecontrol studies, and epidemiologic surveys. The most widely implicated are disorders of the cardiovascular, gastrointestinal, neurologic, and psychiatric systems and allergies or asthma. This chapter will focus on associations between migraine and selected medical and psychiatric conditions for which evidence has been presented in the literature. In general, for each condition of interest, community studies will be presented rst, followed by casecontrol studies. Cardiovascular Diseases Hypertension In the classic epidemiologic study by Waters (9), no differences emerged between the levels of systolic and diastolic blood pressure among migraineurs. Similar results

Comorbidity of Migraine

47

were obtained from other large studies of community surveys (1014). However, in a recent epidemiologic survey of 5755 adult participants, a modest association between elevated blood pressure and migraine was observed (15). In contrast to the epidemiologic studies above, nearly all casecontrol studies examining the association between migraine and hypertension have reported a positive association. The rst systematic study was conducted by Gardner et al. (16) in 1940, who found that the mean systolic blood pressure was greater in migraineurs over age 40 than among age-matched controls. Both Featherstone and Markush et al. reported a twofold increase in the rates of hypertension among cases when compared to controls (17,18). Research has also shown that relatives of migraine patients are more likely to be hypertensive (19,20). In summary, in view of the largely negative studies done among large-scale community surveys, and despite the positive though inconsistent results of case control studies, a denite association between migraine and hypertension is yet to be established. Moreover, all ndings should be qualied by the fact that pain may result in higher blood pressure. Whether high blood pressure precedes the onset of migraine or rather is caused by the presence of migraine with recurrent headaches is unknown. Heart Disease Heart diseases including mitral valve prolapse, congenital heart defects (e.g., patent foramen ovale and atrial septal aneurysm), coronary artery disease, ischemic heart disease, angina, and arrhythmias have also been purportedly associated with migraine. There are few large-scale, prospective epidemiologic studies specically examining the association between migraine and the above-named heart diseases; however, there are many casecontrol studies. In the examination of migraine and mitral valve prolapse, inconsistent measures and denitions of mitral valve prolapse and migraine, in addition to insufcient power to test this association adequately, are likely reasons for the discrepant ndings among casecontrol studies (17,21). Findings from casecontrol studies considering the relationship between migraine or recurrent headache and heart disease (heart attacks, coronary heart disease, and angina) after controlling for well-known cardiovascular risk factors (17,2227) have been essentially negative, except one cross-sectional community study, which did nd that those over 45 years old having migraine with aura were more likely to be at risk for coronary heart disease (15). Several family studies reporting on the relative risk/odds ratio among relatives of migraineurs compared to controls (19,20,28,29) with heart disease show an average relative risk/odds ratio of approximately 1.5. Thus, overall, there is little evidence for an association between heart disease and migraine, after considering the effects of the other cardiovascular risk factors including smoking and hypertension. Neurologic Diseases Regarding migraine and neurologic diseases, it is important to note that migraine may be secondary to these disorders, i.e., symptomatic migraine of established disease. This pertains, for example, to migraine after stroke, multiple sclerosis (MS), and tumors. Neurologic disorders may cause both symptomatic migraine

48

Low and Merikangas

and epilepsy, and thus, give a false association. In examining comorbidity, the main interest is on primary migraines. Stroke The association between migraine and stroke has received renewed attention because of a recent paper reporting that persons with migraine have an increased prevalence of cerebellar infarcts (of the posterior circulation) compared to controls (30). In addition, there has been growing interest in subclinical white matter hyperintensities observed in migraineurs (31). Several population-based studies have found an association between migraine and stroke (3238). Among the U.S. studies, Buring et al. (33) reported an association between migraine and stroke in data from the Physicians Health Surveya large-scale, prospective longitudinal study of the efcacy of aspirin in male physicians. When assessed after ve years, men with migraine exhibited an elevated risk of stroke when compared to those without a history of migraine, yielding a risk ratio of 2.0 (95% CI 1.13.6) for ischemic stroke, and 1.8 (95% CI 1.13.2) for all stroke. Kurth et al. (35) used the Womens Health Study collection of 40,000 professional women aged over 45 followed prospectively over nine years and observed a hazard ratio of 1.7 (95% CI 1.12.6). Merikangas et al. (34) examined the association in a large-scale epidemiologic study of 13,380 adults, and found that those with migraine have an increased risk ratio of 1.5. In addition, the risk of stroke, given a history of migraine, decreased with increasing agefor example, at age 60 the risk ratio is 1.7, compared to a risk ratio of 2.8 at 40 years. The majority of casecontrol studies that have included both sexes and a wider age range suggest an association between migraine and stroke. In general, the most striking nding is that the elevation of risk for ischemic stroke is among female migraineurs aged 15 to 45. The results are variable, with the magnitude of association ranging between an odds ratio of 3.0 to 6.2, and classic migraine carrying a larger risk than common migraine (3944). In addition, in their review of the literature between 1995 and 2001, Curtis et al. (45) conrmed that migraine in women using oral contraceptives is a risk factor for stroke. One casecontrol study failed to report an association between stroke and migraine (17). The family studies (19,20,29) cited previously, which compared parents of migraine patients and controls, also examined the rates of stroke. Leviton et al. (20) selected parental mating types in which only one parent had recurrent severe migraine headache and found no increase in the history of stroke in the parent with headache compared to the unaffected parent. In contrast, the family history study of Galiano et al. (28) reported a nearly two-fold increased risk of stroke among the relatives of subjects with migraine compared to controls. Lanzi et al. (29) observed an odds ratio of 1.2 (95% CI 0.71.9) for stroke among relatives of child and adolescent migraineurs compared to age-matched psychiatric/neurological controls. In summary, nearly all the studies, epidemiologic and casecontrol, provide convincing evidence for an association between migraine and stroke, though their ndings vary according to the sex and age group in which the risk of stroke is elevated. Epilepsy Since Paskinds (46) rst study of the relationship between seizures and migraine in 1934, there have been many systematic (4752) and controlled (47,49,5357), but no

Comorbidity of Migraine

49

large-scale community-based population studies of this association. Of the dozen or so controlled studies of adults in clinical samples, only two reported a signicant association between these two conditions (49,53). Likewise, the two controlled studies of sufciently large samples of children found no systematic association between convulsions and migraine (58). In a family study of epilepsy of 1948 adult probands with epilepsy and 1411 of their parents and siblings, Ottman and Lipton (5961) reported a twofold increase in migraine among both epileptic probands and their relatives. In contrast, another family study found no signicant difference in the prevalence of migraine among relatives of patients with epilepsy and controls (62). In another group of studies (6367) on specic types of childhood epilepsy and migraine, ndings have been inconsistent. The variability in the denitions and subtypes of epilepsy investigated across studies precludes accurate risk estimation based on aggregate ndings. Additional studies are necessary to conrm an association between migraine and epilepsy. Multiple Sclerosis Although there have been numerous reports (68,69) of an increased risk of migraine among patients with MS, there is scant evidence for an association in controlled studies. One recent casecontrol study of risk factors for MS found that migraine was both associated with MS and was an independent risk factor for the development of MS (70). Immunologic Diseases Allergies/Asthma The association between migraine and allergic conditions including food allergies, asthma, hay fever, and bronchitis has been nearly as widely investigated as cardiovascular disorders. In a prospective longitudinal study, Strachan et al. (71) examined the incidence of wheezing illness in 18,559 subjects at ages 7, 11, 16, 23, and 33, and found weak, independent associations with the occurrence of wheezing illness with migraine during childhood and adulthood. In a community-based survey of adults in California, Von Behren et al. (72) reported that migraine was associated with asthma among women. In a 1999 U.S. populationbased survey (American Migraine Study II), Diamond (73) observed increased rates of allergies and sinusitis among migraineurs. Earlier studies of adults and children by Chen et al. (11,74) reported relative risks of 1.9 for asthma and 4.1 for allergies. The average magnitude of the association between allergic conditions and migraine across these earlier studies was approximately 2.4. Controlled clinical samples among children and adults have consistently yielded signicantly greater rates of allergies or asthma among migraine subjects compared to controls (10,7578). In his classic study, Bille (58) reported that children with migraine had twice the risk of allergies as those without migraine. Mortimer et al. (79) further observed that in a general practice cross-sectional group of 1077 children aged 3 to 11 years, the prevalence of atopic disease (asthma, eczema, and rhinitis) was increased among children with migraine compared to those without it. In a study of 64,678 matched pairs from the General Practice Research Database of the United Kingdom, Davey et al. (80) found that the relative risk of asthma in patients with migraine was 1.6. The relative risks for chronic obstructive pulmonary disease, respiratory symptoms, eczema, and hay fever were also increased among the

50

Low and Merikangas

migraine patients. The only negative study (54) was an uncontrolled series of asthma patients, in whom there was no increased risk of migraine when compared to rates from the general community. Irrespective of the specic type of allergic condition assessed in the studies, a strong and consistent association between the allergic conditions and migraine has been found in both community and clinical studies of children and adults.

Gastrointestinal Disorders Although various gastrointestinal conditions have also been linked with migraine, it is difcult to discriminate whether these conditions are truly independent or whether they represent manifestations of the gastrointestinal component of migraine. Especially in children, the distinction between recurrent abdominal pain and undiagnosed abdominal migraine often presents problems in examining the relationship between migraine and abdominal pain (81). There is a long history of attempts in epidemiologic studies to address this association (8284). Anttila et al.s prospective, population-based study (85) of 1290 school-aged children found that children with migraine reported more abdominal pain than those without migraine, but Mortimer et al.s (78) casecontrol study of 1104 children registered with a general practice clinic did not. Other studies have examined the association between migraine and other gastrointestinal disorders with variable ndings. The association with gastric ulcers was observed in casecontrol samples (17) from clinical settings and yielded relative risks ranging from 1.9 to 2.5, whereas Chen et al. (11) reported that ulcers were only associated with migraine among smokers. Greater rates of hiatal hernia, colitis, and Helicobacter pylori infection have been reported among migraineurs than among controls, but the ndings have been inconsistent (17,86). It is important to note that some of the associations reported between migraine and some gastrointestinal disorders, especially gastric ulcers, may be due to confounding analgesic (nonsteroidal anti-inammatory drugs) use. In summary, no denitive associations have been established between migraine and specic gastrointestinal disorders.

Psychiatric Disorders There have been numerous writings on the comorbidity of migraine and psychiatric syndromes, ranging from mood, anxiety, and somatoform disorders to problems with personality, impulse control, eating, and substance use (87105). This review will mainly focus on the relation between migraine and mood and anxiety disorders. Depression The vast majority of the literature on the relationship between migraine and mood disorders has centered on migraine and major depression where the association has been well-established in community-based surveys. Table 1 presents the association between migraine and mood and anxiety disorders in numerous prospective, large-scale, community studies using standardized psychiatric assessments. The odds ratio for migraine and depression varies between 2.2 and 4.0. Additional populationbased studies using questionnaires to assess depression (106111) conrm associations in a similar range, and community studies (112,113) (N 772, 1139) reporting

Comorbidity of Migraine Table 1 Psychiatric Disorders Associated with Migraine in Prospective, Large-Scale, Community Studies Psychiatric disorder by migraine diagnoses Depression HIS-based (144) Breslau, 1998 (137)b Migraine with aura Migraine without aura Swartz et al., 2000 (129)a Breslau et al., 2000 (128)b Non-IHS-based Merikangas et al., 1990 (136) McWilliams et al., 2004a (145) Bipolar Disorder IHS-based Breslau, 1998 (137)b Bipolar I Migraine with aura Migraine without aura Bipolar II Migraine with aura Migraine without aura Non-IHS-based Merikangas et al., 1990 (136) Bipolar spectrum Generalized Anxiety Disorder IHS-based Breslau, 1998 (137)b Migraine with aura Migraine without aura Non-IHS-based McWilliams et al., 2004a (145) Panic Disorder IHS-based Breslau, 1998 (137)b Migraine with aura Migraine without aura Swartz et al., 2000 (129)a Breslau et al., 2001 (146)d Non-IHS-based Merikangas et al., 1990 (136) Phobia IHS-based Swartz et al., 2000 (129)a Breslau, 1998 (137)b Migraine with aura Migraine without aura Non-IHS-based Merikangas et al., 1990 (136) Social Phobia Odds ratio

51

95% Condence interval

4.0 2.2 2.3 3.5 2.2 2.4

2.27.2 1.24.0 1.43.5 2.64.6 1.14.8 1.83.1

7.3 2.4 5.2 2.5

2.224.6 0.511.3 1.419.9 0.511.9

2.9

1.18.6

4.1 5.5 3.1

1.411.5 2.313.2 2.04.9

10.4 3.0 3.4 3.7 3.3

4.524.1 1.09.4 1.16.7 2.26.2 0.813.8

1.4 2.9 1.8 2.4

1.11.9 1.75.0 1.03.0 1.11.5 (Continued)

52

Low and Merikangas

Table 1 Psychiatric Disorders Associated with Migraine in Prospective, Large-Scale, Community Studies (Continued ) Psychiatric disorder by migraine diagnoses IHS-based Swartz et al., 2000 (129)a Non-IHS-based Merikangas et al., 1990 (136) Obsessive-Compulsive Disorder IHS-based Swartz et al., 2000 (129)a Breslau, 1998 (137)b Migraine with aura Migraine without aura
a

Odds ratio 1.3 3.4

95% Condence interval 0.91.8 1.110.9

1.3 5.0 4.8

0.62.9 1.814.6 1.812.7

age- and sex-adjusted relative risk sex-adjusted relative risk c age-adjusted relative risk d sex- and major depression-adjusted relative risk
b

only rates show migraine in 19% to 26% of depressed women and 6% to 10% of depressed men. Clinical samples employing standardized diagnostic criteria also reveal consistent associations between the two disorders, irrespective of the index disorder for which the subjects sought treatment. Studies examining the prevalence of depression in migraine patients (N 34500) report rates ranging from 3.8% to 57.0% (19,95,96,98,99,101,114121) compared to general population lifetime rates of 16% (122). Studies looking at the reverse relation, the prevalence of migraine in depressed clinical populations (N 116423), have found that migraine rates vary between 19% and 84% (73,90,123126). The lower value of this range is comparable to general rates of migraine in females (16%), but much higher than that in males (6%) (Ferrari 1998). Breslau et al. reported a bidirectional relationship between the onset of migraine and depression in two prospective studies (127,128). However, Swartz et al. (129) did not conrm the bidirectional association nding in a prospective population-based sample of the Baltimore area. Taken together, these clinical and community studies provide substantial evidence for a positive association between migraine and major depression and suggest their association results from common risk factors that may increase the risk of acquiring either condition rather than a causal relation. Bipolar Disorder To date, the evidence to support an association between bipolar disorder and migraine has not been as rigorously pursued. Clinical bipolar samples (124,130134) with sizes ranging from 21 to 327 have reported migraine rates varying overall from 13% to 49%; among women, the migraine rates range from 27% to 44%; among men, 13.7% to 31.4%; and among bipolar type II subjects, 65% to 78%. The migraine rates in male bipolar subjects are consistently elevated over those in the general population.

Comorbidity of Migraine

53

Female subjects with bipolar disorder also demonstrate higher rates of migraine, but this elevation is not as prominent, especially given some samples reporting migraine rates up to 20%. Methods for diagnosing migraine among the clinical samples vary from administration of a structured diagnostic interview of all migraine criteria to a single yes or no question of a history of migraine. One study (135) has investigated the rate of bipolar spectrum disorders among 1000 clinical migraineurs and found rates of 2.1% for bipolar type I, 2.4% for bipolar type II, 1.3% for cyclothymia, and 2.8% bipolar NOS, making a total of 8.6% for the entire bipolar spectrum disorders. This total was similar to the rate found in Merikangas and Angsts community study (136) of young adults in Zurich, Switzerland, where the rate of bipolar spectrum disorder (as dened by a manic or hypomanic episode) in 61 migraineurs was 8.8% and the odds ratio was 2.8 (1.18.6). The only other community study examining bipolar disorder and migraine was in a Detroit sample of young adults, where the OR for Bipolar I was 7.3 (2.224.6) and 5.2 (1.419.9) for Bipolar II (137). Both studies report a distinct elevation of bipolar illness among migraineurs, in the community and the clinic, compared to the general population where the rate is 1%. The prevalence of migraine is also clearly elevated in individuals with bipolar disorder. In fact, mania or the bipolar subtype of mood disorders is more strongly associated with migraine than any other psychiatric disorder. Anxiety Anxiety disorders are also associated with migraine in both clinical and community studies (93,104,108,111,121,123,136,138143). Table 1 reports the association between generalized anxiety, panic, phobic and obsessive-compulsive disorders, and migraine. Two community studies (136,139) have shown that the onset of anxiety disorders tends to precede that of migraine in about 80% of the cases of migraine with comorbid anxiety or depression, and that the onset of depression followed that of migraine in three three-fourths of the comorbidities. This temporal sequence was also conrmed in an eight-year follow-up of childhood migraine (115). Investigation of comorbidity of migraine and depression or anxiety states in family study data revealed that migraine, anxiety, and depression may result from a partially shared diathesis (93,141). Because disturbances in the same neurochemical systems have been implicated in migraine, depression, and anxiety disorders, perturbation of a particular system or systems may produce symptoms of all three conditions, thereby producing one syndrome rather than three discrete entities. These ndings underscore the importance of systematic assessment of depression and anxiety in persons with migraine. If there is a subtype of migraine associated with anxiety and mood disorders, it is critical to treat the entire syndrome rather than limiting the treatment goal to headache cessation.

CONCLUSION Migraine is most consistently associated with mood and anxiety disorders, stroke, epilepsy, allergies, and asthma (Table 2). The most important implications of this comorbidity include its consideration in the treatment and etiology of both disorders. Single-agent; therapeutic choices that may treat migraine and a specic

54

Low and Merikangas

Table 2 Summary of Medical Disorders Most Strongly Associated with Migraine System Cardiovascular Neurologic Disorders Myocardial infarction Hypertension Stroke Epilepsy Multiple sclerosis Allergies Asthma Ulcers, hernia, colitis Mood disorders Bipolar disorder Major depression Anxiety disorders Strength of evidence 0 0 0

Immunologic Gastrointestinal Psychiatric

Note: , limited; , moderate; , strong.

comorbid disorder can include: a beta- or calcium-channel blocker for hypertension or heart disease, valproic acid or topiramate for epilepsy or bipolar disorder, and tricyclic antidepressants for depression. Aggregation of the ndings of previous studies has been precluded by differences in methodology. The salient methodologic factors included: a lack of standardized diagnostic denitions of both the index and comorbid disorder; sampling differences with respect to gender, age, and source of the sample; lack of statistical power to detect associations with rare conditions; and wide variability in the inclusion of confounders in the analyses of the associations. Therefore, future studies need to focus on the application of standardized diagnostic denitions with reliable methods of assessment of both the index and comorbid conditions. It is particularly critical to formulate the hypotheses regarding the associations in advance in order to avoid the possibility of false-positive errors due to multiple testing, particularly in large samples. Moreover, specic risk factors for each of the conditions need to be identied carefully and their effect on the association investigated systematically. For example, although a weak association between heart disease and migraine was reported, the association was not signicant when smoking, a risk factor for both conditions, was included in the analyses. Indeed, the identication of purported confounding risk factors may be the most important nding with respect to the nature of non-random associations between comorbid disorders. Such extrinsic mechanisms can provide targets of prevention for the development of both conditions or for the secondary disorder as a consequence of the index disease.

REFERENCES
1. Low NC, Merikangas KR. The comorbidity of migraine. CNS Spectr 2003; 8(6):433 434, 437444. 2. Merikangas K, Low N, Rasmussen B. Migraine comorbidity. In: Olesen J, Tfelt-Hansen P, Welch K, eds. The Headaches. In press.

Comorbidity of Migraine

55

3. Feinstein A. The pre-therapeutic classication of co-morbidity in chronic disease. J Chronic Dis 1970; 23:455468. 4. Kaplan MH, Feinstein AR. The importance of classifying initial co-morbidity in evaluation the outcome of diabetes mellitus. J Chronic Dis 1974; 27(78):387404. 5. Pfohl B, Stangl D, Zimmerman M. The implications of DSM-III personality disorders for patients with major depression. J Affect Disord 1984; 7(34):309318. 6. Winokur G, Black DW, Nasrallah A. Depressions secondary to other psychiatric disorders and medical illnesses. Am J Psychiatr 1988; 145(2):233237. 7. Black DW, Winokur G, Nasrallah A. Is death from natural causes still excessive in psychiatric patients? A follow-up of 1593 patients with major affective disorder. J Nerv Ment Dis 1987; 175(11):674680. 8. Berkson J. Limitation of the application of the 4-fold table analysis to hospital data. Biometrics 1946; 2:4753. 9. Waters WE. Headache and blood pressure in the community. Br Med J 1971; 1(741):142143. 10. Schele R, Ahlborg B, Ekbom K. Physical characteristics and allergic history in young men with migraine and other headaches. Headache 1978; 18(2):8086. 11. Chen TC, et al. Migraine and other diseases in women of reproductive age. The inuence of smoking on observed associations. Arch Neurol 1987; 44(10):10241028. 12. Weiss NS. Relation of high blood pressure to headache, epistaxis, and selected other symptoms. The United States Health Examination Survey of Adults. N Engl J Med 1972; 287(13):631633. 13. Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology 1992; 42(6):12251231. 14. Hagen K, et al. Blood pressure and risk of headache: a prospective study of 22 685 adults in Norway. J Neurol Neurosurg Psychiatr 2002; 72(4):463466. 15. Scher AI, et al. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 2005; 64(4):614620. 16. Gardner J, Mountain G, Hinew E. The relationship of migraine to hypertension and to hypertensive headaches. Am J Med Sci 1940; 22:5053. 17. Featherstone HJ. Medical diagnoses and problems in individuals with recurrent idiopathic headaches. Headache 1985; 25(3):136140. 18. Markush RE, et al. Epidemiologic study of migraine symptoms in young women. Neurology 1975; 25(5):430435. 19. Couch JR, Hassanein RS. Headache as a risk factor in atherosclerosis-related diseases. Headache 1989; 29(1):4954. 20. Leviton A, Malvea B, Graham JR. Vascular diseases, mortality, and migraine in the parents of migraine patients. Neurology 1974; 24(7):669672. 21. Gamberini G, et al. Further evidence on the association of mitral valve prolapse and migraine. Headache 1984; 24(1):3940. 22. Findings from the aspirin component of the ongoing Physicians Health Study. N Engl J Med 1988; 318:262264. 23. Buring JE, Hennekens C, f.t.W.s.HSR. Group, The Womens Health Study: Rationale, background and summary of the study design. J Myocardial Ischemia 1992; 4:2729, 3040. 24. Cook NR, et al. Migraine and coronary heart disease in women and men. Headache 2002; 42(8):715727. 25. Manson J, et al. Baseline characteristics of participants in the Physicians Health Study: a randomized trial of aspirin and beta-carotene in US physicians. Am J Prev Med 1991; 7:150154. 26. Rexode KM, et al. Baseline characteristics of participants in the Womens Health Study. J Womens Health Gend Based Med 2000; 9:1927. 27. Rose KM, et al. Migraine and other headaches: associations with Rose angina and coronary heart disease. Neurology 2004; 63(12):22332239.

56

Low and Merikangas

28. Galiano L, et al. A case-control study of the associated factors with migraine. Cephalalgia 1993; 13(suppl 13):9. 29. Lanzi G, et al. Are vascular disorders more prevalent in the relatives of children and adolescents with migraine? Cephalalgia 2003; 23(9):887891. 30. Kruit MC, et al. Migraine as a risk factor for subclinical brain lesions. JAMA 291(4) 2004 427434. 31. Swartz RH, Kern RZ. Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis. Arch Neurol 2004; 61(9):13661368. 32. Stang PE, et al. Incidence of migraine headache: a population-based study in Olmsted County, Minnesota. Neurology 1992; 42(9):16571662. 33. Buring JE, et al. Migraine and subsequent risk of stroke in the Physicians Health Study. Arch Neurol 1995; 52(2):129134. 34. Merikangas KR, et al. Association between migraine and stroke in a large-scale epidemiological study of the United States. Arch Neurol 1997; 54(4):362368. 35. Kurth T, Slomke M, Kase C. Headache, migraine, and the risk of stroke in women. Neurology 2004; 62(suppl 5):A187. 36. Milhaud D, et al. Ischemic stroke and active migraine. Neurology 2001; 57(10): 18051811. 37. Mitchell P, et al. Prevalence and vascular associations with migraine in older Australians. Aust NZ J Med 1998; 28(5):627632. 38. Donaghy M, Chang CL, Poulter N. Duration, frequency, recency, and type of migraine and the risk of ischaemic stroke in women of childbearing age. J Neurol Neurosurg Psychiatr 2002; 73(6):747750. 39. Collaborative, et al. Oral contraceptives and stroke in young women: associated risk factors. J Am Med Assoc 1975; 231(7):718722. 40. Carolei A, Marini C, De Matteis G. History of migraine and risk of cerebral ischaemia in young adults. The Italian National Research Council Study Group on Stroke in the Young. Lancet 1996; 347(9014):15031506. 41. Chang CL, Donaghy M, Poulter N. Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999; 318(7175):1318. 42. Henrich JB, Horwitz RI. A controlled study of ischemic stroke risk in migraine patients. J Clin Epidemiol 1989; 42(8):773780. 43. Tzourio C, et al. Migraine and risk of ischaemic stroke: a case-control study. BMJ 1993; 307(6899):289292. 44. Tzourio C, et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ 1995; 310(6983):830833. 45. Curtis KM, Chrisman CE, Peterson HB. Contraception for women in selected circumstances. Obstet Gynecol 2002; 99(6):11001112. 46. Paskind H. Relationship of migraine, epilepsy and some other neuropsychiatric disorders. Arch Neurol Psychiatr 1934; 32:4550. 47. Andermann E, Andermann F. Migraine-elipepsy relationships: epidemiological and genetic aspects. In: Lugaresi E, ed. Migraine and Epilepsy. Boston: Butterworths, 1987:281291. 48. Barolin GS. Migraines and epilepsiesa relationship? Epilepsia 1966; 7(7):5366. 49. Basser LS. The relation of migraine and epilepsy. Brain 1969; 92(2):285300. 50. Leniger T, et al. Seizure-associated headache in epilepsy. Epilepsia 2001; 42(9):1176 1179. 51. Marks DA, Ehrenberg BL. Migraine-related seizures in adults with epilepsy, with EEG correlation. Neurology 1993; 43(12):24762483. 52. Velioglu SK, Ozmenoglu M. Migraine-related seizures in an epileptic population. Cephalalgia 1999; 19(9):797801; discussion 766. 53. Ely F. Migraine-epilepsy syndrome: statistical study of heredity. Arch Neurol Psychiatr 1930; 24:943949.

Comorbidity of Migraine

57

54. Lance J, Anthony M. Some clinical aspects of migraine. Arch Neurol 1966; 15:356361. 55. Lennox W, Lennox M. Epilepsy and Related Disorders. Boston: Little, Brown and Co., 1960:Vol.1. 56. Matias-Guiu J, et al. A case-control study to evaluate the association of epilepsy and migraine. Neuroepidemiology 1992; 11(46):313314. 57. Dalsgaard-Nielson A. Migraene og epilepsi. Ugesdkr Laeger 1964; 126:185191. 58. Bille B. Migraine in school children. Acta Paediatr Scand 1962; 51(suppl 136):3151. 59. Ottman R, Lipton RB. Comorbidity of migraine and epilepsy. Neurology 1994; 44(11):21052110. 60. Lipton RB, et al. Comorbidity of migraine: the connection between migraine and epilepsy. Neurology 1994; 44(10 suppl 7):S28S32. 61. Ottman R, Lipton RB. Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility? Neurology 1996; 47(4):918924. 62. Kraus D. Migraine and Epilepsy: A Case for Divorce. Montreal: McGill, 1978 (Faculty of Graduate Studies and Research). 63. Baier W, Doose H. Migraine and petit mal absence: familial prevalence of migraine and seizures. In: Lugaresi E, ed. Migraine and Epilepsy. Boston: Butterworths, 1987: 293311. 64. Bladin P. The association of benign rolandic epilepsy with migraine. In: Lugaresi E, ed. Migraine and Epilepsy. Boston: Butterworths, 1987. 65. Kinast M, et al. Benign focal epileptiform discharges in childhood migraine (BFEDC). Neurology 1982; 32(11):13091311. 66. Santucci M, et al. Migraine and benign epilepsy with Rolandic spikes in childhood: a case-control study. Dev Med Child Neurol 1985; 27(1):6062. 67. Septien L, et al. Migraine in patients with history of centro-temporal epilepsy in childhood: a Hm-PAO SPECT study. Cephalalgia 1991; 11(6):281284. 68. DAmico D, et al. Prevalence of primary headaches in people with multiple sclerosis. Cephalalgia 2004; 24(11):980984. 69. DAmico D, et al. Coexistence of migraine and cluster headache: report of 10 cases and possible pathogenetic implications. Headache 1997; 37(1):2125. 70. Zorzon M, et al. Risk factors of multiple sclerosis: a case-control study. Neurol Sci 2003; 24(4):242247. 71. Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. BMJ 1996; 312(7040):11951199. 72. Von Behren J, Kreutzer R, Hernandez A. Self-reported asthma prevalence in adults in California. J Asthma 2002; 39(5):429440. 73. Diamond ML. The role of concomitant headache types and non-headache comorbidities in the underdiagnosis of migraine. Neurology 2002; 58(9 suppl 6):S3S9. 74. Chen TC, Leviton A. Asthma and eczema in children born to women with migraine. Arch Neurol 1990; 47(11):12271230. 75. Mediana JL, Diamond S. Migraine and atopy. Headache 1976; 15(4):271273. 76. Monro J et al. Food allergy in migraine. Study of dietary exclusion and RAST. Lancet 1980; 2(8184):14. 77. Speight JW, Atkinson P. Food allergy in migraine. Lancet 1980; 2(8193):532. 78. Mortimer MJ, Kay J, Jaron A. Clinical epidemiology of childhood abdominal migraine in an urban general practice. Dev Med Child Neurol 1993; 35(3):243248. 79. Mortimer MJ, et al. The prevalence of headache and migraine in atopic children: an epidemiological study in general practice. Headache 1993; 33(8):427431. 80. Davey G, et al. Association between migraine and asthma: matched case-control study. Br J Gen Pract 2002; 52(482):723727. 81. Abu-Arafeh IA, Russell G. Current controversiesabdominal migraine. Cephalalgia 1993; 13(2):138139.

58

Low and Merikangas

82. Apley J, Naish N. Recurrent abdominal pains: a eld survey of 1000 school children. Arch Dis Child 1958; 33:165170. 83. Pringle MLK, Butler NR, Davie R. 11,000 Seven-Year-Olds. London: Longman, 1966. 84. Miller FJW, Court SDM, Knox EG. The School Years in Newcastle upon Tyne. London: Oxford University Press, 1974. 85. Anttila P, et al. Comorbidity of other pains in schoolchildren with migraine or nonmigrainous headache. J Pediatr 2001; 138(2):176180. 86. Gasbarrini A, et al. Association between Helicobacter pylori cytotoxic type I CagApositive strains and migraine with aura. Cephalalgia 2000; 20(6):561565. 87. Breslau N. Migraine, suicidal ideation, and suicide attempts. Neurology 1992; 42(2):392395. 88. Brewerton TD, George MS, Harden RN. Migraine and the eating disorders. Psychiatr Res 1993; 46(2):201202. 89. George MS, Brewerton TD, Harden RN. Bulimia nervosa in outpatients with migraine: a pilot study. J Nerv Ment Dis 1993; 181(11):704706. 90. Fasmer OB. The prevalence of migraine in patients with bipolar and unipolar affective disorders. Cephalalgia 2001; 21(9):894899. 91. Kudrow L, Sutkus BJ. MMPI pattern specicity in primary headache disorders. Headache 1979; 19(1):1824. 92. Lainez MJ, Monzon MJ. Chronic daily headache. Curr Neurol Neurosci Rep 2001; 1(2):118124. 93. Merikangas KR, Merikangas JR, Angst J. Headache syndromes and psychiatric disorders: association and familial transmission. J Psychiatr Res 1993; 27(2):197210. 94. Marazziti D, et al. Prevalence of headache syndromes in panic disorder. Int Clin Psychopharmacol 1999; 14(4):247251. 95. Marazziti D, et al. Headache, panic disorder and depression: comorbidity or a spectrum? Neuropsychobiology 1995; 31(3):125129. 96. Mitsikostas DD, Thomas AM. Comorbidity of headache and depressive disorders. Cephalalgia 1999; 19(4):211217. 97. Moldin SO, et al. Association between major depressive disorder and physical illness. Psychol Med 1993; 23(3):755761. 98. Radat F, et al. Psychiatric comorbidity is related to headache induced by chronic substance use in migraineurs. Headache 1999; 39(7):477480. 99. Juang KD, et al. Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes. Headache 2000; 40(10):818823. 100. Terwindt GM, et al. The impact of migraine on quality of life in the general population: the GEM study. Neurology 2000; 55(5):624629. 101. Verri AP, et al. Psychiatric comorbidity in chronic daily headache. Cephalalgia 1998; 18(suppl 21):4549. 102. Weeks R, et al. A comparison of MMPI personality data and frontalis electromyographic readings in two groups of daily headache sufferers. Headache 1983; 23(2):8385. 103. Bag B, Hacihasanoglu R, Tufekci F. Examination of anxiety, hostility and psychiatric disorders in patients with migraine and tension-type headache. Int J Clin Pract 2005; 59(5):515521. 104. Anttilla P, et al. Psychiatric symptoms in children with primary headache. J Am Acad Child Adolesc Psychiatr 2004; 43(4):412419. 105. Galego J, et al. Depression and migraine. Arq Neuropsiquiatr 2004; 62(3-B):774777. 106. Zwart JA, et al. Depression and anxiety disorders associated with headache frequency. The Nord-Trondelag Health Study. Eur J Neurol 2003; 10(2):147152. 107. Kececi H, Dener S, Analan E. Co-morbidity of migraine and major depression in the Turkish population. Cephalalgia 2003; 23(4):271275. 108. Oedegaard K, et al. Migraine with and without aura: association with depression and anxiety disorder in a population-based study. The HUNT Study. Cephalalgia. In press.

Comorbidity of Migraine

59

109. Lipton RB, et al. Migraine, quality of life, and depression: a population-based casecontrol study. Neurology 2000; 55(5):629635. 110. Wang SJ, et al. Comorbidity of headaches and depression in the elderly. Pain 1999; 82(3):239243. 111. Devlen J. Anxiety and depression in migraine. J Roy Soc Med 1994; 87:338341. 112. Crisp AH, et al. Some clinical, social and psychological characteristics of migraine subjects in the general population. Postgrad Med J 1977; 53(625):691697. 113. Paulin JM, et al. The prevalence of headache in a small New Zealand town. Headache 1985; 25(3):147151. 114. Glover V, Sandler M. The biochemical basis of migraine predisposition. In: Sandler M, Collins GM, eds. Migraine: A Spectrum of Ideas. New York: Oxford University Press, 1990. 115. Guidetti V, et al. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia 1998; 18(7):455462. 116. Kashiwagi T, McClure JN Jr, Wetzel RD. Headache and psychiatric disorders. Dis Nerv Syst 1972; 33(10):659663. 117. Morrison DP, Price WH. The prevalence of psychiatric disorder among female new referrals to a migraine clinic. Psychol Med 1989; 19(4):919925. 118. Selby G, Lance J. Observations on 500 cases of migraine and allied vascular headache. J Neurol Neurosurg Psychiatr 1960; 23:2332. 119. Mongini F, et al. Personality traits, depression and migraine in women: a longitudinal study. Cephalalgia 2003; 23(3):186192. 120. Patel N, Bigal M, Kolodner K. Prevalence and impact of migraine and probable migraine in a health plan. Neurology 2004; 63:14321438. 121. Hung C, et al. Risk factors associated with migraine or chronic daily headache in out-patients with major depressive disorder. Acta Psychiatr Scand 2005; 111:310315. 122. Kessler RC, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289(23):30953105. 123. Garvey MJ, Tollefson GD, Schaffer CB. Migraine headaches and depression. Am J Psychiatr 1984; 141(8):986988. 124. Marchesi C et al. Prevalence of migraine and muscle tension headache in depressive disorders. J Affect Disord 1989; 16(1):3336. 125. Philips C, Hunter M. Headache in a psychiatric population. J Nerv Ment Dis 1982; 170(1):3440. 126. Franchini L, et al. Migraine headache and mood disorders: a descriptive study in an outpatient psychiatric population. J Affect Disord 2004; 81(2):157160. 127. Breslau N, et al. Joint 1994 Wolff Award Presentation. Migraine and major depression: a longitudinal study. Headache 1994; 34(7):387393. 128. Breslau N, et al. Headache and major depression: is the association specic to migraine? Neurology 2000; 54(2):308313. 129. Swartz KL, et al. Mental disorders and the incidence of migraine headaches in a community sample: results from the Baltimore Epidemiologic Catchment area follow-up study. Arch Gen Psychiatr 2000; 57(10):945950. 130. Blehar MC, et al. Women with bipolar disorder: ndings from the NIMH Genetics Initiative sample. Psychopharmacol Bull 1998; 34(3):239243. 131. Cassidy WL, Flanagan NB. Clinical observations in manic-depressive disease. J Am Med Assoc 1957; 164:15351546. 132. Low NC, Du Fort GG, Cervantes P. Prevalence, clinical correlates, and treatment of migraine in bipolar disorder. Headache 2003; 43(9):940949. 133. Mahmood T, Romans S, Silverstone T. Prevalence of migraine in bipolar disorder. J Affect Disord 1999; 52(13):239241. 134. Younes RP, et al. Manic-depressive illness in children: treatment with lithium carbonate. J Child Neurol 1986; 1(4):364368.

60

Low and Merikangas

135. Robbins L, Ludmer C. Headache the bipolar spectrum in migraine patients. Am J Pain Manage 2000; 10:167170. 136. Merikangas KR, Angst J, Isler H. Migraine and psychopathology. Arch Gen Psychiatr 1990; 47:849853. 137. Breslau N. Psychiatric comorbidity in migraine. Cephalalgia 1998; 18(suppl 22):5658; discussion 5861. 138. Breslau N, Davis GC. Migraine, physical health and psychiatric disorder: a prospective epidemiologic study in young adults. J Psychiatr Res 1993; 27(2):211221. 139. Breslau N, Davis GC, Andreski P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. Psychiatr Res 1991; 37(1):1123. 140. Harper M, Roth M. Temporal lobe epilepsy and the phobic anxiety-depersonalization syndrome. I. A comparative study. Compr Psychiatr 1962; 3:129151. 141. Merikangas KM. Sources of genetic complexity of migraine. In: Sandler M, Ferrari MD, Harnett S, eds. Migraine: Genetics. New York: Cambridge University Press, 1996:254281. 142. Stewart W, Breslau N, Keck PE Jr. Comorbidity of migraine and panic disorder. Neurology 1994; 44(10 suppl 7):S23S27. 143. Smoller J, et al. Prevalence and correlates of panic attacks in postmenopausal women: results from an ancillary study to the Womens Health Initiative. Arch Intern Med 2003; 163:20412050. 144. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classication Committee of the International Headache Society. Cephalalgia 1988; 8(suppl 7):196. 145. McWilliams LA, Goodwin RD, Cox BJ. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain 2004; 111(12): 7783. 146. Breslau N, et al. Headache types and panic disorder: directionality and specicity. Neurology 2001; 56(3):350354.

5
Pain Sensitivity: Intracranial and Extracranial Structures
Todd D. Rozen
Department of Neurology, Michigan Head Pain and Neurological Institute, Ann Arbor, Michigan, U.S.A.

Head pain can be generated by a multitude of structures, but the brain parenchyma itself is not one of them. The brain has either no or minimal sensory innervation with pain bers. However, the coverings of the brain (meninges), meningeal blood vessels, and large cerebral arteries and veins all are highly innervated, and thus when stimulated, could cause head pain (Fig. 1). In addition, neck structures and paranasal sinuses can contribute to head pain. This chapter will look at the potential pain sensitive intracranial and extracranial structures.

ANATOMY OF HEAD PAIN The sensory innervation of the head is supplied by the trigeminal nerve and the upper cervical nerve roots. The sensory trigeminal nerve has three main branches, all of which pass information to the trigeminal (gasserian) ganglion. The trigeminal ganglion then relays information centrally, via the sensory root of the trigeminal nerve, to the main sensory nuclei of the trigeminal system termed the trigeminal nucleus caudalis (TNC), which is located in the lower medulla and upper cervical spine region (Fig. 2). The ophthalmic division (V1) provides sensory information from the upper eyelid, orbit, bridge of the nose, and a portion of the scalp. The maxillary division (V2) provides sensory input from the lower eyelid, inferior portion of the nose, upper cheek and lip as well as a portion of the jaw and the palate. The mandibular division (V3) subserves the lower lip, lower jaw, lower face and cheek region, tongue, and the front of the ear (1). The trigeminal sensory system also provides innervation to the sinus cavities, meninges, and cerebral veins and arteries. The brain parenchyma itself has no sensory innervation and thus is insensate. The posterior portion of the head gets its sensory innervation from the greater occipital nerve (cervical dorsal rami 2 and 3), lesser occipital nerve (cervical ventral ramus 2), greater auricular nerve (cervical ventral rami 2 and 3), and the upper cervical nerve roots. As there is a dual convergence of inputs of sensory information into the TNC from both trigeminal and cervical afferents, trigeminal activation
61

62

Rozen

Figure 1 Pain sensitive intracranial structures. Source: From Neurology Ambassador Program of the American Headache Society.

Figure 2 Anatomy of the sensory trigeminal nerve. Source: From Neurology Ambassador Program of the American Headache Society.

Pain Sensitivity: Intracranial and Extracranial Structures

63

can be felt clinically as both head and neck pain whereas cervical nerveroot activation can be sensed as both neck and frontal head pain (2). Blood Vessels For decades, migraine was referred to as the vascular headache. Indeed, blood vessels must play some role in migraine pathogenesis, but it is now believed that cerebral vascular changes are secondary to neuronal activation. The vascular supply to the brain is highly innervated by the trigeminal nerve, and thus cranial arterial manipulation can induce head pain. The pain sensitivity of cranial blood vessels was established by Wolff and colleagues (3). They found that not only would arterial stimulation produce pain in conscious subjects, but also different arteries would produce varying pain referral patterns (4). The intracranial segment of the internal carotid artery and the proximal 2 cm of the middle and anterior cerebral arteries would produce eye pain and forehead and temple discomfort ipsilateral to the side of the stimulated arterial segment. Middle meningeal artery distension produced pain in the ipsilateral retro-orbital and temple region. Irritation of the vertebral artery would produce pain in the occiput region. More recently, cerebral artery pain referral patterns have been demonstrated during procedures of arteriovenous malformation embolization. Nichols et al. (5) noted, with balloon distension of the distal internal carotid artery and proximal middle cerebral artery (MCA), that pain was felt lateral to the eye, whereas distension of the middle portion of the MCA produced pain in a retro-orbital distribution. Pain felt above the eye was noted when the distal one-third of the MCA was dilated. Nichols et al. (6) also noted pain referral patterns with balloon distension of the vertebral and basilar arteries. Distension of the vertebral artery at the level of the foramen magnum produced pain from the ipsilateral occiput region to the shoulder. Distension of the vertebral artery midway between the foramen magnum and the vertebral basilar junction produced pain behind the ipsilateral ear, at the level of the mastoid and in the upper neck. Distention of the upper vertebral artery caused pain in the posterior lateral portion of the neck and posterior auricular region, and even in the cheek, forehead, and the area lateral and inferior to the orbit. After distension of the inferior basilar artery, discomfort was felt at the skull vertex, neck, posterior auricular region, and occiput. Martins et al. (7) documented pain referral patterns during endovascular procedures (embolization or balloon ination). In all patients, the pain was focal and ispilateral to the manipulated vessel. MCA and penetrating subcortical artery stimulation produced pain in the temple or supraorbital region. Pain from the vertebralbasilar circulation was felt in the orbit and in the medial frontal and medial supraciliary regions. This is somewhat incongruous with past studies, which usually noted pain referral to the neck and occiput with distension of the vertebralbasilar arterial system. Manipulation of the pericallosal arteries led to discomfort in the parietal region. Clinically, Fisher (8) noted pain referral patterns in patients with headache along with arterial occlusive syndromes. Internal carotid artery occlusion led to pain in the ispilateral forehead region, whereas pain in the forehead and retro-orbital region occurred with MCA occlusion, and occiput and neck pain occurred with vertebral or basilar artery occlusion. Dissection of cerebral arteries also causes distinct pain referral patterns (9). Internal carotid artery dissections usually present with pain involving the face, neck, or head. Headache, the most common symptom of ICA dissection, occurs in 84% of patients. The headaches are usually one sided and focal, most commonly involving the anterior head region, in the orbit or periorbital region. Facial pain occurs in about 30% of

64

Rozen

internal carotid artery dissections. The most common symptoms of vertebral artery dissection are neck pain and headache. Headache usually occurs at the base of the head (occipital area), often in association with neck pain. Cerebral Veins and Sinuses Wolff described the pain referral pattern of cerebral veins as he described that of cerebral arteries (3). Interestingly, stimulation of the superior saggital sinus produced pain that was less intense than arterial-based pain, and the pain referral pattern over the frontaltemporal region was more diffuse. Clinically, when cerebral vein thrombosis occurs, headache location is variable including holocranial pain or focal pain even with a one-sided thrombosis. Recently, Daugaard et al. (10) wanted to test if cephalic veins played a role in migraine pathogenesis. They hypothesized that if the venous system plays some part in migraine pain genesis, then venous dilation during a migraine attack should be a painful event. Queckenstedts maneuver (compression of jugular veins) will induce dilation in both intra- and extracranial veins. Patients during a headache underwent either the Queckenstedts maneuver or a placebo maneuver (pressure over sternocleidomastoid muscles) for 10 seconds. There was no signicant difference between the Queckenstedts maneuver group and the placebo maneuver group in regard to headache worsening. The authors concluded that the cranial venous system does not play an important role in migraine pathogenesis. Certainly, the venous structures, which are highly innervated by the trigeminal system, could produce head pain when stimulated. At present, the pain referral patterns have not been as well documented as the arterial system. Meninges The meninges are highly innervated by trigeminal afferents. Meningeal irritation from neurovascular extravasation is believed to play a large role in migraine pain. Diffuse meningeal irritation such as occurs with infectious meningitis causes diffuse holocranial head pain. There is little literature that describes pain referral patterns when localized parts of the meningeal system are stimulated. About 30% of patients with primary meningeal tumors have headache, whereas up to 75% of individuals with leptomeningeal metastases have headache (11). Cervical Spine The role of the cervical spine in head pain pathology is gaining increasing acceptance. Stimulation of neck structures including cervical roots and the cutaneous tissue innervated by the greater occipital nerve can result in frontal headache. Neck paraspinal muscles and cervical ligaments and joints are innervated by the upper cervical nerve roots. The cervical roots re centrally to the trigeminocervical complex, which comprises the TNC and the upper C23 cervical segments. The spinal C2 root is the primary afferent to this system and is represented peripherally by the greater occipital nerve. Because both dural and cervical afferents converge into the TNC, clinically neck pathology can be felt as head pain whereas dural pathology or irritation can be felt as neck and subocciput discomfort (typical migraine pain location is in or around the eye and at the occipitonuchal junction) (12). Bogduk (13) states that the sources of cervical spinal pain that refer to the head corresponds to those spinal structures that are innervated by the upper three cervical spinal nerves. These structures include the median and lateral atlantoaxial joints,

Pain Sensitivity: Intracranial and Extracranial Structures

65

the atlanto-occipital joint, the C23 zygapophysial joint, and the suboccipital and upper posterior neck muscles, the upper prevertebral muscles, the C23 disc, and the trapezius and sternocleidomastoid muscles (13). Patients with chronic daily headache who are refractory to standard treatment in many instances have an underlying cervicogenic syndrome. Once the cervical irritation is quelled (occipital nerve blockade and cervical facet rhizolysis), the chronic daily head pain can be alleviated. Some specialists believe that anything causing irritation below C3 will not cause headache, whereas others will argue that even a C5 herniated disc can produce head pain. Nasal and Paranasal Structures In many instances, patients will misinterpret the pain of migraine as sinus-based pain. The reason for this is that the pain of both migraine and sinus cavity inammation is in the same location, and that is because both the migraine pain system and the sinus cavities are innervated by the trigeminal nerve. The sinus cavities include the frontal, ethmoid, maxillary, and sphenoid sinuses. The innervation of the frontal sinus is via V1 (supraorbital and supratrochlear branches), maxillary sinus V2 (greater palatine nerve and branches of the infraorbital nerve), and ethmoid sinus V1 (superior portion of sinus cavity) and V2 (inferior portion of sinus cavity), whereas the sphenoid sinus is innervated by both V1 and V2. In the nasal cavity, the superior portion of the nasal septum is innervated by V1, whereas the middle and inferior parts of the septum are innervated by V2 (14). McAuliffe et al.(15) in the early 1940s noted that pain sensitivity was highest in the nasal turbinates and sinus ostia, whereas the nasal septum was less pain inducing. Stammberger and Wolf (16) noted that when a probe was pressed on the superior portion of the nasal septum, pain would occur in the region of the lateral and medial canthus, whereas pressure on the superior turbinate induced pain in the frontal area of the head, medial canthus, in the orbit, and in the ear. Ethmoid pressure led to pain in the outer and inner canthus region, retro-orbital pain, and associated lacrimation and photophobia. Anything causing inammation in the paranasal sinus cavities can theoretically produce pain referred to the head, including infection, polyps, tumors, and an abnormal contact between the nasal turbinates and the nasal septum. Contact point headaches can resemble migraine and present as intractable one-sided head pain, which is refractory to typical migraine treatment. The current literature states that headache may occur from contact between the nasal septum and the superior and middle nasal turbinates or the nasal septum and the medial wall of the ethmoid sinus (14). REFERENCES
1. Edvinsson L, Dahl E. Anatomy of muscles, tendons, joints, blood vessels, and meninges. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:5576. 2. Piovesan EJ, Kowacs PA, Tatsui CE, Lange MC, Ribas LC, Werneck LC. Referred pain after painful stimulation of the greater occipital nerve in humans: evidence of convergence of cervical afferents on trigeminal nuclei. Cephalalgia 2001; 21:107109. 3. Wolff HG. Headache and Other Head Pain. New York: Oxford University press, 1963. 4. Lance JW. Migraine pain originates from blood vessels. In: Olesen J, Edvinsson L, eds. Frontiers in Headache Research. Headache Pathogenesis: Monoamines, Neuropeptides, Purines, and Nitric Oxide. Philadelphia: Lippincott-Raven, 1997; 7:310.

66

Rozen

5. Nichols FT, Mawad M, Mohr JP, Stein B, Hilal S, Michelsen WJ. Focal headache during balloon ination in the internal carotid and middle cerebral arteries. Stroke 1990; 21: 555559. 6. Nichols FT, Mawad M, Mohr JP, Hilal S, Adams RJ. Focal headache during balloon ination in the vertebral and basilar arteries. Headache 1993; 33:8789. 7. Martins IP, Baeta E, Paiva T, Campos J, Gomes L. Headaches during intracranial endovascular procedures: a possible model of vascular headache. Headache 1993; 33:227233. 8. Fisher CM. Headaches in cerebrovascular disease. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Amsterdam: North Holland, 1968; 5:124151. 9. Mokri B. Headache in spontaneous carotid and vertebral artery dissections. In: Goadsby PJ, Silberstein SD, eds. Headache. Boston: Butterworth-Heinemann, 1997:327354. 10. Daugaard D, Thomsen LL, Olesen J. No relation between cephalic venous dilatation and pain in migraine. J Neurol Neurosurg Psychiat 1998; 65:260262. 11. Balm M, Hammack J. Leptomeningeal-presenting features and prognostic factors. Arch Neurol 1996; 53:626632. 12. Bartsch T, Goadsby PJ. The trigeminocervical complex and migraine: current concepts and synthesis. Curr Headache Rep 2003; 7:371376. 13. Bogduk N. The neck and headaches. In: Evans RW, ed. Neurologic Clinic: Secondary Headache Disorders. Philadelphia: Saunders, 2004:151172. 14. Behin F, Behin B, Behin D, Baredes S. Surgical management of contact point headache. Headache 2005; 45:204210. 15. McAuliffe GW, Mueller GC, Wolff HG. Experimental studies on headache: pain from the nasal and paranasal structures. Res Publ Assoc Res Nerv Ment Dis 1950; 23:185206. 16. Stammberger H, Wolf G. Headaches and sinus disease: the endoscopic approach. Ann Otol Rhino Laryngol 1988; 134(suppl):323.

6
Pathophysiology of Aura
M. Sanchez del Rio
Department of Neurology, Headache Program, Hospital Ruber International, Madrid, Spain

U. Reuter
, Department of Neurology, Charite Universita tsmedizin Berlin, Berlin, Germany

INTRODUCTION Since the initial description of cortical spreading depression (CSD) by Leao, there has been growing evidence that CSD is the underlying pathomechanism of the migraine aura (Table 1). CSD is a slowly propagating wave of neuronal and glial depolarization that spreads across the cortex with a speed of 3 to 5 mm/min. It is accompanied by a short-lasting dramatic increase in regional cerebral blood ow (rCBF) followed by a long-lasting rCBF hypoperfusion. Recent functional magnetic resonance imaging (fMRI) (1) and magnetoencephalography (MEG) (2) studies in men strongly support the occurrence of CSD during visual migraine aura. Assessment of the speed of progression of the visual eld defect during migraine aura, using Humphrey eld chart, conrms the rate of progression of 3.6 mm/min (3). The fact that, among all aura symptoms, the visual aura is the most common (4) may reect the hyperexcitability of the occipital cortex of migraineurs.

NEUROPHYSIOLOGICAL MECHANISMS Spreading depressionlike phenomena have been observed in cerebral ischemia models and experimental trauma. In the injured human brain, Strong et al. recently demonstrated CSD or a CSD-like phenomenon developing in the boundary zone of the lesion by electrocorticography (5). The detailed molecular mechanisms initiating CSD are not understood. In experimental animal studies, potassium, pinprick, glutamate, and electrical stimuli cause CSD, indicating that this phenomenon is triggered by primary neuronalglial homeostasis imbalance. A key transmitter in the initiation and propagation of CSD appears to be glutamate. Glutamate binds to N-methyl-D-aspartate receptor (NMDA) and alpha-amino-3-hydroxy-5-methyl isoxazole-propionic acid receptors on neuronal and glial tissue and by doing so causes depolarization of these cells. The NMDA receptor antagonist MK-801 has
67

68

del Rio and Reuter

Table 1 Comparison Between Imaging Finding During Migraine Visual Aura and Experimental CSD Visual aura Cortical gray matter Hyperemia Hypoperfusion Suppression of activation Rate of spread Terminates at major sulci Amplitude recovery First activated/rst to recovery
Abbreviation: CSD, cortical spreading depression.

CSD 34.5 min 12 h 25 mm/min 1530 min (evoked)

3.3 1.9 min 2h 3.5 1.1 mm/min 15 min (80%)

been demonstrated in several experimental animal studies to inhibit CSD initiation and propagation, indicating the crucial function of glutamate and the NMDA receptor in this neurophysiological event (6). In addition, blockade of the NR2B subunit of the NMDA receptor by ifenopril also abolishes CSD in a murine model, supporting the critical role of glutamate for CSD (7). However, at least to our knowledge NMDA receptor antagonists are not available for clinical use, and no trials have been performed in migraine aura so far. More evidence can be derived from a study in a knock-in mouse model carrying the human pure FHM-1 R192Q mutation (8). This mutation in the CaV2.1 (calcium channel type P/Q) channels that control the release of glutamate from cortical neurons has given multiple gain-of-function effects, leading to enhanced neurotransmission and enhanced CSD. In stroke, NMDA receptor antagonists are not benecial for the clinical outcome, although a CSD-like phenomenon called periinfarct depolarization has been suspected of contributing to tissue damage (9). It remains to be determined whether NMDA receptor antagonists are able to abort the migraine aura. The effect of gamma-aminobutyric acid (GABA) in CSD and migraine aura is not entirely clear. The preventative antimigraine drugs valproate and topiramate are likely to affect nociception by modulating GABA- and/or glutamate-mediated neurotransmission (10). Both antiepileptic substances enhance GABA-mediated inhibition. However, they have no effect on the migraine aura, and at least valproic acid has not been proven so far to affect CSD (11). In addition to neuronal events, cerebral angiography or carotid artery dissection is known to initiate migraine aura in a subset of susceptible patients, pointing to a primary endothelial factor as a trigger for CSD. In fact, topical application of the potent vasoconstrictor endothelin-1 has recently been shown to induce typical CSD in a rat model at concentrations between 10 nM and 1 mM, without causing ischemia (12). Endothelin modulates endothelial cells and smooth muscle cells as well as neurons and astrocytes. Therefore, neuronal and vascular mechanisms may apply. However, the mode of action is supposed to be vascular in this experimental model, because the application of an NO donor requires higher concentrations of endothelin to induce CSD. The role of astrocyctic Ca2 waves with respect to the migraine aura and migraine headache remains elusive. It has been speculated that astrocytes may carry the propagating wave front of CSD. In line, L-type calcium channel mRNA expression is enhanced after CSD (13). Interestingly, CSD determines the velocity of an accompanying astrocytic Ca2 wave. When CSD is terminated, the astrocytic

Pathophysiology of Aura

69

Ca2 wave moves on and propagates as a self-reliant mechanism, which covers a larger territory, but spreads with a lower velocity (14). Together these ndings indicate that neuronal CSD and astrocytic Ca2 waves use different propagation mechanisms. However, calcium waves travel through gap junctions, and astrocytepia arachnoid communication also occurs through these structures. Therefore, gap junctions could serve as a link between CSD and pain sensitive structures in cortical proximity. For a long time, CSD-associated short-lasting cortical hyperperfusion, which is a distinct feature of CSD in the rat and cat, was considered as an epiphenomenona of lesser importance (Fig. 1). Recent fMRI studies of the human migraine aura point to the presence of an initial cortical hyperperfusion followed by a longer-lasting wave of hypoperfusion (Fig. 2) (1). However, CSD hyperperfusion was demonstrated in 2002 in primates (cynomolgus monkey) for the rst time using positron emission tomography (PET) (15). Cortical hypoperfusion was not observed in the aforementioned study. CSD hyperperfusion is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve bers (16). Recent data suggest that blockade of CSD hyperperfusion leads to detrimental consequences. Indeed, high extracellular potassium and blockade of nitric oxide synthases abolish CSD hyperperfusion and cause CSD-induced pronounced hypoperfusion that spreads with a speed of 3.4 0.6 mm/min across the cortex, resulting in cortical infarction (17). A similar phenomenon could account for migrainous strokes or strokes in subarachnoid hemorrhage. In rare cases, the aura in migraineurs occurs without subsequent headaches or even during the headache. In contrast, in more than 90%, there is a striking timely link as the aura is followed by typical migraine

Figure 1 Cortical spreading depression (CSD) is dened as a wave of neuronal and glial depolarisation (A) that slowly spreads along the cortex at a rate from 25 mm/min. Together with the depolarisation, laser blood ow measurements have documented (B) dramatic increases in blood ow lasting 25 minutes followed by a long lasting hypoperfusion. (C) CSD is also associated with changes in ion homeostasis and release of glutamate.

70

del Rio and Reuter

% 250 200 150 MR signal

CBF
100 50

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (minutes)
Figure 2 Blood ow changes in cortical spreading depression (CSD) and migraine. Blood ow changes during CSD (gray line) is superimposed over the MRI-BOLD signal obtained during migraine visual aura. Note that the time scale is the same for both measurements. In both cases an initial hyperemia is followed by a long lasting hypoperfusion. Source: Modied from Ref. 1.

headaches. Moskowitz and colleagues demonstrated a pathophysiological connection between CSD and meningeal events consistent with the notion of headache (Fig. 3) (18). CSD resulted in ipsilateral enhanced c-fos expression within the trigeminal nucleus caudalis (TNC), which was dependent on trigeminal nerve integrity, thereby indicating trigeminal nerve activation during CSD. In line, hippocampal CSD activates the TNC albeit bilaterally with a c-fos staining pattern in TNC that is very similar in both studies (primarily Laminae I and II) (19). This is a remarkable nding with respect to the observation that patients describe memory disturbance before the onset of migraine (20). Surprisingly, electrophysiological studies failed to demonstrate CSD-induced activation of neurons within the TNC (21). CSD leads to plasma protein extravasation (PPE) in the ipsilateral dura mater of rats, which can be blocked by trigeminal nerve transection on the same side and an antagonist at the substance Pbinding site (NK-1 receptor). PPE is a model that has been used to assess the efcacy of antimigraine drugs. Finally, CSD results in delayed blood ow increases selectively in ipsilateral meningeal vessels. Delayed blood ow increase was abolished by ipsilateral acute and chronic trigeminal nerve sectioning and trigeminal rhizotomy. Importantly, sectioning of parasympathetic nerve bers also abolished delayed blood ow increase (18). In summary, CSD is able to activate the ipsilateral trigeminal nerve system as demonstrated by c-fos expression in TNC and meningeal PPE. In addition, delayed meningeal blood ow increase is mediated by a trigeminalparasympathetic brain

Pathophysiology of Aura

71

Figure 3 Link between cortical spreading depression (CSD) and trigeminovascular activation (1). CSD releases potassium, hydrogen ions, nitric oxide, metabolites of arachidonic acid (AA) and glutamate, into the extracellular and perivascular space and causes transient hyperemia and vasodilation in cortex pial vessels and duramater (2). This molecules are able to activate and sensitize the perivascular trigeminal afferents and transmit impulses centrally (3) to trigeminal nucleus caudalis via the trigeminal ganglion. From trigeminal nucleus caudalis the impulses are transmitted centrally for further pain processing (4). Dural trigeminal afferents release CGRP, substance P and NK-1, leading to dural vasodilation and inammation (5). Activation of ipsilateral trigeminal nucleus caudalis in turn, leads to stimulation of the superior salivary nucleus (SSN) (6) and parasympathetic activation (7). This leads to release of VIP and acetilcholine, which in turn favours further dural vasodilatation. Source: From Ref. 18.

stem connection. This work (18) was the rst to demonstrate that intrinsic brain events are able to activate extracerebral meningeal nociceptors. Inhibition of CSD may abort the human migraine aura and may prevent subsequent headache. A novel drug has been proposed for the treatment of migraine aura. Tonabersat, a cis benzopyran, effectively attenuates abnormally high levels of neuronal excitation and is also successful in assays that have been used to determine the efcacy of antimigraine drugs. This substance reduces CSD-induced

72

del Rio and Reuter

nitric oxide release and enhanced cGMP levels in cortex and brainstem (22). While the signicance of these ndings for antimigraine action remains to be determined, stronger evidence is derived from an experimental study in the cat. Here, tonabersat reduced the number of CSDs dose dependently (23). If also successful in men, this drug could be the rst one for the treatment of the migraine aura. In an animal study by Nestini and colleagues, application of an independent component analysis to fMRI has aided in detecting for the rst time delayed nonpropagating cerebrovascular changes following the initiation of CSD in cats (24). Contrary to the well-dened propagating CSD initial waves, these localized waves were suppressed by sumatriptan as well as by tonabersat. This ndings may provide insight into the cerebrovascular changes reported in the headache phase of migraine.

IMAGING STUDIES The initial groundbreaking work using xenon blood ow studies was done by Olesen and Friberg (25). Subsequent functional imaging studies have both corroborated the previous ndings and further elucidated the underlying mechanisms of migraine aura. Today we know that migraine aura is characterized by a short phase of hyperemia that is likely to be the correlate of the ashing, jagged lights described during the visual hallucinations (1,3). Hyperemia is then followed by a wave of hypoperfusion that crosses vascular boundaries of contiguous cortex at a rate of 3.5 1.1 mm/min (Fig. 4) (1). While hyperemia is the response to increased neuronal activation, hypoperfusion reects depressed neuronal function and is still clearly present when the headache starts. These ndings, together with direct evidence that local oxygen supply is more than adequate, and the presence of direct current shifts measured with MEG, support the concept of migraine as a primarily neuronal disorder, whereas vascular changes represent an epiphenomenona (2,26,27).

MOLECULAR MECHANISMS The role of gene expression in headache generation due to CSD is not known. For example, primates and rodents express the COX-2 gene in cortical neurons after CSD (28,29). Prostaglandins, the product of COX-2 activity, contribute to the stimulusinduced CBF increase in the somatosensory cortex (30). One may speculate that increased COX-2 expression and activity after CSD may contribute to the reconstitution of decreased CBF and may therefore participate in the prevention of migraineous infarcts. Alternatively COX-2 could promote inammation. Other proinamatory enzymes that are elevated in CSD are tumor necrosis factor (TNF)a and interleukin (IL)-1b, which are expressed in microglia (31). TNF-a and IL-1b are known to protect neurons in vitro against hypoxic or excitatory injury. Upregulation of these cytokines after CSD may therefore be a protective mechanism or may also be a physiological stress response. In addition, CSD leads to reduced COX-2 gene expression in mice overexpressing the antioxidant enzyme copper/ zinc-superoxide dismutase gene compared to control mice (32). This nding supports the hypothesis that free radicals contribute, in part, to CSD-induced gene expression. It also shows that noninjurious metabolic stimulation increases the concentration of oxygen radicals.

Pathophysiology of Aura

73

Figure 4 Spreading suppression of cortical activation during migraine aura. (A) A drawing showing the progression over 20 min of the scintillations and the visual eld defect affecting the left hemield, as described by the patient. (B) A reconstruction of the same patients brain, based on anatomical magnetic resonance (MR) data. The posterior medial aspect of occipital lobe is shown in an inated cortex format. In this format, the cortical sulci and gyri appear in darker and lighter gray, respectively, on a computationally inated surface. MR signal changes over time are shown to the right. Each time course was recorded from one in a sequence of voxels that were sampled along the calcarine sulcus, in the primary visual cortex (V1), from the posterior pole to more anterior location, as indicated by arrowheads. A similar BOLD response was found within all of the extrastriate areas, differing only in the time of onset of the MR perturbation. The MR perturbations developed earlier in the foveal representation, compared with more eccentric representations of retinotopic visual cortex. This nding was consistent with the progression of the aura from central to peripheral eccentricities in the corresponding visual eld (A and C). (C) The MR maps of retinotopic eccentricity from this same subject, acquired during interictal scans. As shown in the logo in the upper left, voxels that show retinotopically specic activation in the fovea are coded (centered at 1.5 eccentricity). Source: From Ref. 10.

Nestin is expressed in neuronal cells under stress, which indicates the transition of cells to a different cellular state. Enhanced expression of nestin in CSD most likely reects a response to stress. However, this nding may be of critical importance for the differentiation of CNS cells posttrauma or ischemia, but not for migraine headache (33). An increased expression of other genes related to oxidative stress such as PRP, GST-5, and apolipoprotein E was observed by Choudhuri et al., along with changes

74

del Rio and Reuter

of vasoactive peptide mRNA (13). While vasoconstrictor peptide neuropeptide Y mRNA was downregulated, atrial natriuretic peptide (ANP) gene expression was increased. Upregulation of vasoactive peptides is expected, considering that CSD causes short-lasting cortical hyperperfusion and subsequent reduced rCBF. Moreover, vasoactive peptides such as ANP could contribute to vasodilation in dura mater vessels and neurogenic inammation. Alternatively, enhanced ANP expression after CSD could resemble a feature of CSD-induced neuroprotection, probably via effects on cyclic guanosine monophosphate (cGMP) production (34). High cGMP concentrations can be induced by an increase of NO, which is also elevated in CSD. Elevated cGMP levels seem to be neuroprotective. In a similar way, CSD has been shown to upregulate the expression of clusterin mRNA (35). Clusterin is a sulfated glycoprotein produced by neurons and by resting and activated astrocytes, with a protective function in response to brain injury. More recently galanin gene upregulation and peptide release has been observed in cortex ipsilateral to CSD (36). Galanin is involved in the regulation of neuronal excitability of hippocampus and cerebral cortex, and mRNA upregulation rather reects the plasticity of the galanin system. Nevertheless galanin may be of importance in headache because galanin is known to release a variety of neurotransmitters and is involved in nociception (37). Long-lasting activation of cortical neurons in layers II to IV and VI was also demonstrated by c-fos, junB, and MKP-1 mRNAs expression after CSD in experimental trauma, indicating the effects of CSD on a variety of genes. Matrix metalloproteinases (MMP) were also identied to play a role in CSD (38). MMP are extracellular proteinases that are capable of degrading matrix components. Collagen IV and laminin are the targets of MMP-9. MMPs are regulated by gene transcription. In general, upregulation of MMP results in tissue injury and inammation. Moskowitz and colleagues demonstrated striking upregulation of MMP-9 mRNA and protein expression in cortex after CSD. Moreover, enhanced MMP-9 expression was associated with a breach of the bloodbrain barrier (BBB) as demonstrated by evans blue leakage and degradation of ZO-1. This protein is associated with endothelial tight junction formation in the BBB, and degradation is indicative of a BBB breach. These preliminary results on MMP-9 formation offer a valuable explanation for how CSD could affect the BBB and may thereby result in the activation of pain-sensitive meningeal structures and headaches. In summary, CSD causes upregulation of a host of genes, which is expected due to the occurrence of this phenomenon in several disorders such as trauma, stroke, and migraine. Some of these genes are clearly related to CSD propagation, vascular responses, or neuroprotection. Others resemble a response to oxidative stress or indicate the breach of the BBB.

OCCIPITAL CORTEX EXCITABILITY It is unclear what triggers migraine aura, but it is increasingly evident that there seem to be factors that modify neuronal excitability, especially in occipital cortex, reducing the threshold for cortical activation. This abnormal responsiveness of the visual cortex is now a widely appreciated characteristic of the migrainous brain, manifested as an increased sensitivity to various physiologic environmental stimuli, lower thresholds of low-level visual processing in the primary visual cortex, and decient habituation (3942). Although the striate cortex accounts for only 3% of the cerebral

Pathophysiology of Aura

75

surface, approximately 10% of cortical neurons are said to be located here. This dense packing of neurons may hypothetically contribute to the abnormal excitability of the occipital cortex. Genetic factors that lead to calcium channelopathies (FHM), cell-surface receptor dysfunction, (CADASIL) or mitochondrial energy defects [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)] may also contribute to lowering the threshold for neuronal excitation. Other factors such as mitochondrial energy impairment, as seen in MELAS, and even in migraine with and without aura, alone or in combination with magnesium deciency, and environmental factors such as stress and ovarian steroid may also play a relevant role in cortical excitability.

GENETICS In approximately half of the families tested, familial hemiplegic migraine (FMH) is caused by missense mutations in CACNA1A, the gene encoding the pore-forming a1A-subunit of voltage-gated P/Q-type Ca2 (CaV2.1) channels (Fig. 5) (44). These

Figure 5 A pivotal role for glutamate is proposed to explain the susceptibility to cortical spreading depression, implicated in migraine aura. After depolarization, glutamate is released into the synaptic cleft regulated by Cav2.1 gating calcium inux. Synaptic activity is terminated in part by astrocytic uptake of glutamate via transporters (GLAST) driven by sodium gradients. Sodium gradients are maintained by activity of Na, K-ATPase removing sodium from inside cells. Energy is required and achieved by glucose utilization after uptake from blood vessels. Lactate so generated is transported and oxidized within neurons to support the excessive energy needs of synaptic activity. Under basal conditions, direct glucose uptake may occur in neurons as well. Susceptibility to cortical spreading depression is enhanced by gain of function mutation in Cav2.1 (FHM type I) and increased synaptic release of glutamide from neurons. Loss of function mutation in Na, K-ATPase (FHM type II) expressed by astrocytes raise extracellular glutamate and potassium. Source: From Ref. 43.

76

del Rio and Reuter

FMH1 mutations in vitro alter both the single-channel properties and the density of functional channels in the membrane. Overall the mutations lead to (i) an increase in the Ca2 inux through single human CaV2.1 channels by shifting the activation curve of CaV2.1 channels to hyperpolarized voltages, and thus increase their open probability, and (ii) a decrease in the density of functional CaV2.1 channels, which varies according to the cell type (45). Recently a study performed in a CACNA1A knock-in mouse has shown increased susceptibility for CSD, both due to a decrease in the threshold and due to an increase in the speed of progression of CSD, as well as enhanced neurotransmission at the neuromuscular junction (8). This knock-in mouse carrying the human pure FHM-1 R192Q mutation may explain the apparently contradictory ndings observed until now in the knock-out mice with spontaneous CaV2.1a1 mutations (46). In the latter case, a striking elevation of the threshold for initiating CSD in the neocortex was found. These mutations lead to a reduced Ca2 entry through CaV2.1 channels and consequently to a reduced neuronal cortical network excitability, making the cortex more resistant to CSD, demonstrating that those spontaneous mutations were not functionally identical as those found in men. Several mutations in the a1A-subunit cause FHM but may also be responsible for episodic ataxia type 2. The nature of the mutation distinguishes both disorders, whereas missense mutations cause FMH and disrupted reading frames cause EA-2 (44). The presence of cerebellar ataxia as part of the clinical spectrum of FHM is not unusual because the cerebellum is rich in P/Q calcium channels. FHM2 is caused in approximately 15% of cases by recently described mutations in chromosome 1q23, in the gene ATP1A2, which encodes the a2 subunit of the Na/K pump in astrocytes (47). Two mutations lead to two amino acid replacements, leucine to proline and tryptophan to arginine. The functional consequences of these amino acid replacements are a loss of function of the a2 subunit, without precluding the correct incorporation of the mutant, the Na/K pump as integral membrane protein. Consequently the haploinsufciency of the Na/K pump activity in astrocytes provokes an increase in extracellular K due to an impaired clearance of brain K by neurons and glial cells D. This produce a wide cortical depolarization and a local boost of intracellular Na, which promotes an increase in intracellular Ca2 through the Na/Ca2 exchanger. This increase in intracellular Ca2 would mimic the effect of the CACNA1A mutation seen in FHM1. Another possibility is that as a consequence of the increase in extracellular K and Na, the glutamate transporter is slowed or even reversed, causing an increase in extracellular glutamate levels (47), the nal consequence being the facilitation of CSD. CONCLUSIONS CSD is a complex neurovascular event that triggers a cascade of mechanisms leading to upregulation of genes, leakage of the BBB, PPE, sensitization of perivascular nerve bers, and central transmission of pain signal via the brainstem. Genetic conditioning and probably environmental factors render the system excitable, facilitating the appearance of CSD. Based on modern functional imaging, the mechanism underlying the migraine aura resembles the neurovascular changes observed in CSD. Slowly and by a multidisciplinary approach, we are completing the puzzle of the pathogenesis of migraine aura.

Pathophysiology of Aura

77

REFERENCES
1. Hadjikhani N, Sanchez del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 2001; 98:46874692. 2. Bowyer SM, Aurora KS, Moran JE, Tepley N, Welch KM. Magnetoencephalographic elds from patients with spontaneous and induced migraine aura. Ann Neurol 2001; 50:582587. 3. Porooshani H, Porooshani AH, Gannon L, Kyle GM. Speed of progression of migrainous visual aura measured by sequential eld assessment. Neuro-ophtalmology 2003; 28:101105. 4. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain 1996; 119:355361. 5. Strong AJ, Fabricius M, Boutelle MG, et al. Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke 2002; 33:27382743. 6. Marrannes R, Willems R, De Prins E, Wauquier A. Evidence for a role of the N-methylD-aspartate (NMDA) receptor in cortical spreading depression in the rat. Brain Res 1988; 457:226240. 7. Faria LC, Mody I. Protective effect of ifenprodil against spreading depression in the mouse entorhinal cortex. J Neurophysiol 2004; 92:26102614. 8. Van den Maagdenberg AM, Pietrobon D, Pizzorusso T, et al. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004; 41(5):701710. 9. Mies G, Iijima T, Hossmann KA. Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport 1993; 4:709711. 10. Corbo J. The role of anticonvulsants in preventive migraine therapy. Curr Pain Headache Rep 2003; 7:6366. Review. 11. Kaube H, Goasdby PJ. Anti-migraine compounds fail to modulate the propagation of cortical spreading depression in the cat. Eur Neurol 1994; 34:3035. 12. Kleeberg J, Petzold GC, Major S, Dirnagl U, Dreier JP. Endothelin-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. Am J Physiol Heart Circ Physiol 2003; 125:102112. 13. Choudhuri R, Cui L, Yong C, Bowyer S, et al. Cortical spreading depression and gene regulation: relevance to migraine. Ann Neurol 2002; 51:499506. 14. Peters O, Schipke CG, Hashimoto Y, Kettenmann H. Different mechanisms promote astrocyte Ca2 waves and spreading depression in the mouse neocortex. J Neurosci 2003; 23:98889896. 15. Yokota C, Kuge Y, Hasegawa Y, et al. Unique prole of spreading depression in a primate model. J Cereb Blood Flow Metab 2002; 22:835842. 16. Reuter U, Weber JR, Gold L, et al. Perivascular nerves contribute to cortical spreading depression-associated hyperemia in rats. Am J Physiol 1998; 274:H1979H1987. 17. Dreier JP, Korner K, Ebert N, et al. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K is increased in the subarachnoid space. J Cereb Blood Flow Metab 1998; 18:978990. 18. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8:136142. 19. Kunkler PE, Kraig RP. Hippocampal spreading depression bilaterally activates the caudal trigeminal nucleus in rodents. Hippocampus 2003; 13:835844. 20. Gifn NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology 2003; 60:935940. 21. Ebersberger A, Schaible HG, Averbeck B, Richter F. Is there a correlation between spreading depression, neurogenic inammation, and nociception that might cause migraine headache? Ann Neurol 2001; 49:713. 22. Read SJ, Smith MI, Hunter AJ, Upton N, Parsons AA. SB-220453, a potential novel antimigraine agent, inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat. Cephalalgia 2000; 20:9299.

78

del Rio and Reuter

23. Bradley DP, Smith MI, Netsiri C, et al. Diffusion-weighted MRI used to detect in vivo modulation of cortical spreading depression: comparison of sumatriptan and tonabersat. Exp Neurol 2001; 172:342353. 24. Netsiri C, Bradley DP, Takeda T, et al. A delayed class of BOLD waveforms associated with spreading depression in the feline cerebral cortex can be detected and characterised using independent component analysis (ICA). Magn Reson Imaging 2003; 21:10971110. 25. Olesen J, Friberg L. Xenon 133 SPECT studies in migraine with aura. In: Olesen J, ed. Migraine and Other Headaches: The Vascular Mechanisms. New York: Raven Press Ltd., 1991:121130. 26. Cao Y, Welch KM, Aurora S, Vikingstad EM. Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol 1999; 56:548554. 27. Sanchez del Rio M, Bakker D, Wu O, et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19:701707. 28. Yokota C, Inoue H, Kuge Y, et al. Cyclooxygenase-2 expression associated with spreading depression in a primate model. J Cereb Blood Flow Metab 2003; 23:395398. 29. Miettinen S, Fusco FR, Yrjanheikki J, et al. Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci USA 1997; 94:65006505. 30. Niwa K, Araki E, Morham SG, Ross ME, Iadecola C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci 2000; 20:763770. 31. Jander S, Schroeter M, Peters O, Witte OW, Stoll G. Cortical spreading depression induces proinammatory cytokine gene expression in the rat brain. J Cereb Blood Flow Metab 2001; 21:218225. 32. Yrjanheikki J, Koistinaho J, Copin JC, de Crespigny A, Moseley ME, Chan PH. Spreading depression-induced expression of c-fos and cyclooxygenase-2 in transgenic mice that overexpress human copper/zinc-superoxide dismutase. J Neurotrauma 2000; 17:713718. 33. Holmin S, von Gertten C, Sandberg-Nordqvist AC, Lendahl U, Mathiesen T. Induction of astrocytic nestin expression by depolarization in rats. Neurosci Lett 2001; 314: 151155. 34. Wiggins AK, Shen PJ, Gundlach AL. Atrial natriuretic peptide expression is increased in rat cerebral cortex following spreading depression: possible contribution to sd-induced neuroprotection. Neuroscience 2003; 118:715726. 35. Wiggins AK, Shen PJ, Gundlach AL. Delayed, but prolonged increases in astrocytic clusterin (ApoJ) mRNA expression following acute cortical spreading depression in the rat: evidence for a role of clusterin in ischemic tolerance. Brain Res Mol Brain Res 2003; 114:2030. 36. Shen PJ, Larm JA, Gundlach AL. Expression and plasticity of galanin systems in cortical neurons, oligodendrocyte progenitors and proliferative zones in normal brain and after spreading depression. Eur J Neurosci 2003; 18:13621376. 37. Liu HX, Hokfelt T. The participation of galanin in pain processing at the spinal level. Trends Pharmacol Sci 2002; 23:468474. 38. Gursoy-Ozdemir Y, Qiu J, Matsuoka N, et al. Cortical spreading depression activates and upregulates MMP-9. J Clin Invest 2004; 113:14471455. 39. Afra J, Mascia A, Gerard P, Maertens dN, Schoenen J. Interictal cortical excitability in migraine: a study using transcranial magnetic stimulation of motor and visual cortices. Ann Neurol 1998; 44:209215. 40. Bohotin V, Fumal A, Vandenheede M, et al. Effects of repetitive transcranial magnetic stimulation on visual evoked potentials in migraine. Brain 2002; 125:912922. 41. Wray SH, Mijovic-Prelec D, Kosslyn SM. Visual processing in migraineurs. Brain 1995; 118:2535. 42. Aurora SK, Ahmad BK, Welch KM, Bhardhwaj P, Ramadan NM. Transcranial magnetic stimulation conrms hyperexcitability of occipital cortex in migraine. Neurology 1998; 50:11111114.

Pathophysiology of Aura

79

43. Moskowitz MA, Bolay H, Dalkara T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann Neurol 2004; 55:276280. 44. Ophoff RA, Terwindt GM, Frants RR, Ferrari MD. P/Q-type Ca2 channel defects in migraine, ataxia and epilepsy. Trends Pharmacol Sci 1998; 19:121127. 45. Tottene A, Fellin T, Pagnutti S, et al. Familial hemiplegic migraine mutations increase Ca (2) inux through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci USA 2002; 99:1328413289. 46. Ayata C, Shimizu-Sasamata M, Lo EH, Noebels JL, Moskowitz MA. Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels. Neuroscience 2000; 95:639645. 47. De Fusco M, Marconi R, Silvestri L, et al. Haploinsufciency of ATP1A2 encoding the Na/K pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003; 33:192196.

7
Pathophysiology of Migraine
Peter J. Goadsby
Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, U.K.

INTRODUCTION An understanding of the pathophysiology of migraine should be based upon the anatomy and physiology of the pain-producing structures of the cranium integrated with knowledge of central nervous system modulation of these pathways. Headache in general, and in particular migraine (1) and cluster headache (2), is better understood now than the last four millennia (3). This chapter will discuss the current understanding of migraine.

MIGRAINEEXPLAINING THE CLINICAL FEATURES Migraine is, in essence, a familial episodic disorder whose key marker is headache with certain associated features (Table 1). It is these features that give clues to its pathophysiology, and ultimately provide insights that lead to new treatments. The essential elements to be considered are:     genetics of migraine; physiological basis for the aura; anatomy of head pain, particularly that of the trigeminovascular system; physiology and pharmacology of the trigeminal nucleus, in particular its caudal most part, the trigeminocervical complex;  physiology and pharmacology of activation of the peripheral branches of ophthalmic branch of the trigeminal nerve; and  brainstem and diencephalic modulatory systems that inuence trigeminal pain transmission and other sensory modality processing. Migraine is a form of sensory processing disturbance with wide ramications within the central nervous system. Although pain pathways are used as an example, it is important to remember that migraine is not simply a pain problem.

81

82 Table 1 International Headache Society Features of Migraine Repeated episodic headache (472 hrs) with the following features Any two of:  Unilateral  Throbbing  Worsened by movement  Moderate or severe Any one of:  Nausea/vomiting  Photophobia and phonophobia
Source: From Ref. 4.

Goadsby

GENETICS OF MIGRAINE One of the most important aspects of the pathophysiology of migraine is the inherited nature of the disorder. It is clear from clinical practice that many patients have rst-degree relatives who also suffer from migraine (3,5). Transmission of migraine from parents to children has been reported as early as the 17th century (6), and numerous published studies have reported a positive family history (7). Genetic Epidemiology Studies of twin pairs are the classical method to investigate the relative importance of genetic and environmental factors. A Danish study included 1013 monozygotic and 1667 dizygotic twin pairs of the same gender, obtained from a population-based twin register (8). The pairwise concordance rate was signicantly higher among monozygotic twin pairs (P < 0.05). Several studies have attempted to analyze the possible mode of inheritance in migraine families, and conicting results have been obtained (911). Both twin studies and population-based epidemiological surveys strongly suggest that migraine without aura is a multifactorial disorder, caused by a combination of genetic and environmental factors.

FAMILIAL HEMIPLEGIC MIGRAINE (FHM) In approximately 50% of the reported families, familial hemiplegic migraine (FHM) has been assigned to chromosome 19p13 (12,13). Few clinical differences have been found between chromosome 19linked and unlinked FHM families. Indeed, the clinical phenotype does not associate particularly with the known mutations (14). The most striking exception is cerebellar ataxia, which occurs in approximately 50% of the chromosome 19linked, but in none of the unlinked families (12,13,1517). Another less striking difference includes the fact that patients from chromosome 19linked families are more likely to have attacks that can be triggered by minor head trauma or that are associated with coma (18). The biological basis for the linkage to chromosome 19 is mutations (19) involving the Cav2.1 (P/Q)-type voltage-gated calcium channel (20) CACNA1A gene. Now known as FHM-I, this mutation is responsible for about 50% of migraines in identied families. Mutations in the ATP1A2 gene (21,22) have been

Pathophysiology of Migraine

83

identied to be responsible for migraines in about 20% of the FHM families. Interestingly, the phenotype of some FHM-II involves epilepsy (23,24), while it has also been suggested that alternating hemiplegia of childhood can be due to ATP1A2 mutations (25). The latter cases are most unconvincing for migraine. Taken together, the known mutations suggest that migraine, or at least the neurological manifestations currently called the aura, are caused by a channelopathy (26). Linking the channel disturbance for the rst time to the aura process has helped to demonstrate that human mutations expressed in a knock-in mouse produce a reduced threshold for cortical spreading depression (CSD) (27), which has some profound implications for understanding that process (28). MIGRAINE AURA Migraine aura is dened as a focal neurological disturbance that manifests as visual, sensory, or motor symptoms (4). It is seen in about 30% of patients (29), and it is clearly neurally driven (30,31). The case for the aura being the human equivalent of the CSD of Leao (32,33) has been well made (34). In humans, visual aura has been described as affecting the visual eld, suggesting the involvement of the visual cortex, and it starts at the center of the visual eld and propagates to the periphery at a speed of 3 mm/min (35). This is very similar to the spreading depression described in rabbits (33). Blood ow studies in patients have also shown that a focal hyperemia tends to precede the spreading oligemia (36), and again this is similar to what would be expected with spreading depression. After this passage of oligemia, the cerebrovascular response to hypercapnia in patients is blunted while autoregulation remains intact (3739). This pattern is repeated with experimental spreading depression (4042). Human observations have rendered the arguments reasonably sound that CSD in animals is equivalent to human aura (43). An area of controversy surrounds whether aura, in fact, triggers the rest of the attack, and is, indeed, painful (44). Based on the available experimental and clinical data, this author is not convinced that aura is painful per se (45); however, this does not diminish the importance of understanding its role, or potential treatments. Tonabersat is a CSD inhibitor that has entered clinical trials in migraine. Tonabersat (SB-220453) inhibits CSD, CSD-induced nitric oxide (NO) release, and cerebral vasodilation (46,47). Tonabersat does not constrict isolated human blood vessels (48), but does inhibit trigeminally induced craniovascular effects (49). Remarkably, topiramate, a proven preventive agent in migraine (5052), also inhibits CSD in cats and rats (53). Tonabersat is inactive in the human NO model of migraine (54), as is propranolol (55), although valproate showed some activity in that model (56). Topiramate inhibits trigeminal neurons activated by nociceptive intracranial afferents (57), but not by a mechanism local to the trigeminocervical complex (58), and thus CSD inhibition may be a model system to contribute to the development of preventive medicines. HEADACHEANATOMY The Trigeminal Innervation of Pain-Producing Intracranial Structures Surrounding the large cerebral vessels, pial vessels, large venous sinuses, and dura mater is a plexus of largely unmyelinated bers that arise from the ophthalmic division of the trigeminal ganglion (59), and in the posterior fossa, from the upper

84 Table 2 Neuroanatomical Processing of Vascular Head Pain Structure Target innervation:  Cranial vessels  Dura mater 1st 2nd 3rd Ophthalmic branch of trigeminal nerve Trigeminal ganglion Trigeminal nucleus (quintothalamic tract) Thalamus Comments

Goadsby

Modulatory Final

Midbrain Hypothalamus Cortex

Middle cranial fossa Trigeminal n. caudalis and C1/C2 dorsal horns Ventrobasal complex Medial n. of posterior group Intralaminar complex Periaqueductal gray matter Unknown  insulae  frontal cortex  anterior cingulate cortex  basal ganglia

cervical dorsal roots (60). Trigeminal bers innervating cerebral vessels arise from neurons in the trigeminal ganglion, which contains substance P and calcitonin generelated peptide (CGRP) (61), both of which can be released when the trigeminal ganglion is stimulated either in humans or in cats (62). Stimulation of the cranial vessels such as the superior sagittal sinus (SSS) is certainly painful in humans (63,64). Human dural nerves that innervate the cranial vessels largely consist of smalldiameter myelinated and unmyelinated bers (65), which almost certainly subserve a nociceptive function (Table 2).

HEADACHE PHYSIOLOGYPERIPHERAL CONNECTIONS Plasma Protein Extravasation Moskowitz (66) has provided a series of experiments to suggest that the pain of migraine may be a form of sterile neurogenic inammation. Although this seems clinically unlikely, the model system has certainly been helpful in understanding some aspects of trigeminovascular physiology. Neurogenic plasma extravasation can be seen during electrical stimulation of the trigeminal ganglion in the rat (67). Plasma protein extravasation (PPE) can be blocked by ergot alkaloids, indomethacin, acetylsalicylic acid, and the serotonin-5HT1B/1D agonist, sumatriptan (68). The pharmacology of abortive antimigraine drugs has been reviewed in detail (69). In addition, there are structural changes in the dura mater observed after trigeminal ganglion stimulation. These include mast cell degranulation and changes in postcapillary venules including platelet aggregation (70,71). While it is generally accepted that such changes, and particularly the initiation of a sterile inammatory response, may cause pain (72,73), it is not clear whether this is sufcient in itself or requires other stimulators or promoters. Preclinical studies suggest that CSD may be a sufcient stimulus to activate trigeminal neurons (74), although this has been a controversial area (45,7578). Although plasma extravasation in the retina, which is blocked by sumatriptan, can be seen after trigeminal ganglion stimulation in experimental animals, no

Pathophysiology of Migraine

85

changes are seen with retinal angiography during acute attacks of migraine or cluster headache (79). A limitation of this study was the probable sampling of both retina and choroid elements in rats, given that choroidal vessels have fenestrated capillaries (80). Clearly, however, blockade of neurogenic plasma protein extravasation is not completely predictive of antimigraine efcacy in humans as evidenced by the failure, in clinical trials, of substance P, neurokinin-1 antagonists (8184), specic PPE blockers, CP122,288 (85) and 4991w93 (86), an endothelin antagonist (87), and a neurosteroid (88). Sensitization and Migraine While it is highly doubtful that there is any signicant sterile inammatory response in the dura mater during migraine, it is clear that some form of sensitization takes place at this time because allodynia is common. About two-thirds of patients complain of pain from non-noxious stimuli, allodynia (8991). A particularly interesting aspect is the demonstration of allodynia in the upper limbs, ipsilateral and contralateral to the pain. This nding is consistent with at least third-order neuronal sensitization such as sensitization of thalamic neurons and rmly places the pathophysiology within the central nervous system. Sensitization in migraine may be peripheral with local release of inammatory markers, which would certainly activate trigeminal nociceptors (73). More likely in migraine is a form of central sensitization, which may be classical central sensitization (72) or a form of disinhibitory sensitization with dysfunction of descending modulatory pathways (92). Just as dihydroergotamine (DHE) can block trigeminovascular nociceptive transmission (93), probably at least by a local effect in the trigeminocervical complex (94,95), DHE can block central sensitization associated with dural stimulation by an inammatory soup (96). Neuropeptide Studies Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood ow and local release of both CGRP and substance P (62). In cats, trigeminal ganglion stimulation also increases cerebral blood ow by a pathway traversing the greater supercial petrosal branch of the facial nerve (97), again releasing a powerful vasodilator peptide, vasoactive intestinal polypeptide (VIP) (98,99). The VIP-ergic innervation of the cerebral vessels is predominantly anterior rather than posterior (100), and this may contribute in part to this regions vulnerability to spreading depression, explaining why the aura is so very often seen to commence posteriorly. Stimulation of the more specically vascular pain-producing SSS increases cerebral blood ow (101) and jugular vein CGRP levels (102). Human evidence that CGRP is elevated in the headache phase of migraine (103,104), cluster headache (105,106), and chronic paroxysmal hemicrania (107) supports the view that the trigeminovascular system may be activated in a protective role in these conditions. Moreover, NO-donortriggered migraine, which is in essence typical migraine (108,109), also results in increases in CGRP (110), which are blocked by sumatriptan (111), just as in spontaneous migraine (112). Compounds that have not shown activity in migraine (86,113), notably the conformationally restricted analogue of sumatriptan, CP122,288 (114), and the conformationally restricted analogue of zolmitriptan, 4991w93 (115), were both ineffective inhibitors of CGRP release after SSS stimulation in the cat. The recent development of nonpeptide, highly specic CGRP antagonists (116) and the announcement of proof-of-concept for a CGRP antagonist in acute

86

Goadsby

migraine (117) rmly establish CGRP receptor antagonism as a novel and important emerging principle for acute migraine. At the same time, the lack of any effect of CGRP blockers on plasma protein extravasation explains in some part why that model has proved inadequate at translation into human therapeutic approaches.

HEADACHE PHYSIOLOGYCENTRAL CONNECTIONS The Trigeminocervical Complex Fos immunohistochemistry is a method for looking at activated cells by plotting the expression of Fos protein (118). After meningeal irritation with blood, Fos expression is noted in the trigeminal nucleus caudalis (119), while after stimulation of the SSS, Fos-like immunoreactivity is seen in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C2 levels in the cat (120) and monkey (121,122). These latter ndings are in accord with data using 2-deoxyglucose measurements with SSS stimulation (123). Similarly, stimulation of a branch of C2, the greater occipital nerve, increases metabolic activity in the same regions, i.e., trigeminal nucleus caudalis and C1/2 dorsal horn (124). In experimental animals, one can record directly from trigeminal neurons with both supratentorial trigeminal input and input from the greater occipital nerve, a branch of the C2 dorsal root (125). Stimulation of the greater occipital nerve for ve minutes results in substantial increases in responses to supratentorial dural stimulation, which can last for over an hour (125). Conversely, stimulation of the middle meningeal artery dura mater with the C-berirritant mustard oil sensitizes responses to occipital muscle stimulation (126). Taken together, these data suggest convergence of cervical and ophthalmic inputs at the level of the second-order neuron. Moreover, stimulation of a lateralized structure, the middle meningeal artery, produces Fos expression bilaterally in both cat and monkey brain (122). This group of neurons from the supercial laminae of trigeminal nucleus caudalis and C1/2 dorsal horns should be regarded functionally as the trigeminocervical complex. These data demonstrate that trigeminovascular nociceptive information comes by way of the most caudal cells. This concept provides an anatomical explanation for the referral of pain to the back of the head in migraine. Moreover, experimental pharmacological evidence suggests that some abortive antimigraine drugs such as ergot derivatives (93,94), acetylsalicylic acid (127), sumatriptan (128,129), eletriptan (130,131), naratriptan (132,133), rizatriptan (134), and zolmitriptan (135) can have actions at these second-order neurons that reduce cell activity and suggest a further possible site for therapeutic intervention in migraine. This action can be dissected out to involve each of the 5-HT1B, 5-HT1D, and 5-HT1F receptor subtypes (136), and are consistent with the localization of these receptors on peptidergic nociceptors (137). Triptans also inuence the CGRP promoter (138) and regulate CGRP secretion from neurons in culture (139). Furthermore, the demonstration that some part of this action is postsynaptic with either 5-HT1B or 5-HT1D receptors located nonpresynaptically (140,141) offers a prospect of highly anatomically localized treatment options.

Higher Order Processing Following transmission in the caudal brain stem and high cervical spinal cord, information is relayed rostrally.

Pathophysiology of Migraine

87

Thalamus Processing of vascular nociceptive signals in the thalamus occurs in the ventroposteromedial (VPM) thalamus, medial nucleus of the posterior complex, and in the intralaminar thalamus (142). Zagami and Lambert (143) have shown by application of capsaicin to the SSS that trigeminal projections with a high degree of nociceptive input are processed in neurons, particularly in the VPM thalamus and in its ventral periphery. These neurons in the VPM can be modulated by activation of gamma aminobutyric acid (GABA) Ainhibitory receptors (144), and perhaps of more direct clinical relevance by propranolol through a b1-adrenoceptor mechanism (145). Remarkably, triptans through 5-HT1B/1D mechanisms can also inhibit VPM neurons locally, as demonstrated by microiontophoretic application (146), suggesting a hitherto unconsidered locus of action for triptans in acute migraine. Human imaging studies have conrmed activation of thalamus contralateral to pain in acute migraine (147,148) (Fig. 1), cluster headache (149), and in SUNCT, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (150,151).

Figure 1 Illustration of some elements of migraine biology. Patients inherit dysfunctional brain control systems for pain and other afferent stimuli, which can be triggered and are, in turn, capable of activating the trigeminovascular system as the initiating event in a positive feedback of neurally driven vasodilatation. Pain from cervical inputs that terminate in the trigeminocervical complex accounts for the nontrigeminal distribution of pain in many patients. Migraine has thus a pain system for its expression and brain centers and modulatory systems, which dene the associated symptoms and periodicity of the clinical syndrome. Source: Brain stem changes after Bahra et al. 148. Genetic Cartoons Courtesy of Neurology Ambassador Program, American Headache Society.

88

Goadsby

Activation of Modulatory Regions Stimulation of nociceptive afferents by stimulation of the SSS in the cat activates neurons in the ventrolateral periaqueductal gray (PAG) matter (152). PAG activation in turn feeds back to the trigeminocervical complex with an inhibitory inuence (153,154). PAG is clearly included in the area of activation seen in positron emission tomography (PET) studies in migraineurs (155). This typical negative feedback system will be further considered below as a possible mechanism for the symptomatic manifestations of migraine. Another potentially modulatory region activated by stimulation of nociceptive trigeminovascular input is the posterior hypothalamic gray (156). This area is crucially involved in several primary headaches, notably cluster headache (2), SUNCT (151), paroxysmal hemicrania (157), and hemicrania continua (158). Moreover, the clinical features of the premonitory phase (159), and other features of the disorder (160,161), suggest dopamine neuron involvement. Orexinergic neurons in the posterior hypothalamus can be both pro- and antinociceptive (162), offering a further possible region whose dysfunction might involve the perception of head pain.

CENTRAL MODULATION OF TRIGEMINAL PAIN Brain Imaging in Humans Functional brain imaging with PET has demonstrated activation of the dorsal midbrain, including the PAG, and in the dorsal pons, near the locus coeruleus, in studies during migraine without aura (155). Dorsolateral pontine activation is seen with PET in spontaneous episodic (147) and chronic migraine (163), and with nitrogylcerin-triggered attacks (148,164). These areas are active immediately after successful treatment of the headache but are not active interictally. The activation corresponds with the brain region that Raskin et al. (165) initially reported, and Veloso et al. conrmed (166), as causing migraine-like headache when stimulated in patients with electrodes implanted for pain control. Similarly, Welch et al. (167) have noted excess iron in the PAG of patients with episodic and chronic migraine, and chronic migraine can develop after a bleed into a cavernoma in the region of the PAG (168), or with a lesion of the pons (169). What could dysfunction of these brain areas lead to?

Animal Experimental Studies of Sensory Modulation It has been shown in the experimental animal that stimulation of nucleus locus coeruleus, the main central noradrenergic nucleus, reduces cerebral blood ow in a frequency-dependent manner (170) through an a2-adrenoceptorlinked mechanism (171). This reduction is maximal in the occipital cortex (172). While a 25% overall reduction in cerebral blood ow is seen, extracerebral vasodilatation occurs in parallel (170). In addition, the main serotonin-containing nucleus in the brain stem, the midbrain dorsal raphe nucleus, can increase cerebral blood ow when activated (173). Furthermore, stimulation of PAG will inhibit sagittal sinus-evoked trigeminal neuronal activity in cat (154), while blockade of P/Q-type voltage-gated Ca2 channels in the PAG facilitates trigeminovascular nociceptive processing (92), with the local GABAergic system in the PAG still intact (153).

Pathophysiology of Migraine

89

Electrophysiology of Migraine in Humans Studies of evoked potentials and event-related potentials provide some link between animal studies and human functional imaging (174). Authors have shown changes in neurophysiological measures of brain activation, but there is much discussion as to how to interpret such changes (175). Perhaps the most reliable theme is that the migrainous brain does not habituate to signals in a normal way (176179). Similarly, contingent negative variation (CNV), an event related potential, is abnormal in migraineurs compared to controls (180). Changes in CNV predict attacks (181) and preventive therapies alter and normalize such changes (182). Attempts to correlate clinical phenotypes with electrophysiological changes (183) may enhance further studies in this area. WHAT IS MIGRAINE? Migraine is an inherited, episodic disorder involving sensory sensitivity. Patients complain of pain in the head that is throbbing, but there is no reliable relationship between vessel diameter and the pain (31,184), or its treatment (185). They complain of discomfort from normal lights and the unpleasantness of routine sounds. Some mention otherwise pleasant odors to be unpleasant. Normal movement of the head causes pain, and many mention a sense of unsteadiness as if they have just stepped off a boat, although having been nowhere near the water! The anatomical connections of, for example, the pain pathways are clear; the ophthalmic division of the trigeminal nerve subserves sensation within the cranium and explains why its involvement at the top of the head causes headache, and why the involvement of the maxillary division causes facial pain. The convergence of cervical and trigeminal afferents explains why neck stiffness or pain is so common in primary headache. The genetics of channelopathies is opening up a plausible way to think about the episodic nature of migraine. However, where is the lesion, what is actually the pathology? If one considers what patients say, then perhaps they tell us the answer to this question. Migraine aura cannot be the trigger, there is no evidence at all after 4000 years that it occurs in more than 30% of migraine patients; aura can be experienced without pain at all, and is seen in the other primary headaches. There is not a photon of extra light that migraine patients receive over others, so for that symptom, and phonophobia and osmophobia, the basis of the problem must be abnormal central processing of a normal signal. Perhaps electrophysiological changes in the brain have been mislabelled as hyperexcitability whereas dyshabituation might be a simpler explanation. If migraine was basically an attentional problem with changes in cortical synchronization (186), hypersynchronization (187), all its manifestations could be accounted for in a single overarching pathophysiological hypothesis of a disturbance of subcortical sensory modulation systems (188). While it seems likely that the trigeminovascular system, and its cranial autonomic reex connections, the trigeminal-autonomic reex (99), act as a feed-forward system to facilitate the acute attack, the fundamental problem in migraine is in the brain. Unravelling its basis will deliver great benets to patients and considerable understanding of some of the very fundamental neurobiological processes. ACKNOWLEDGMENTS The work of the author has been supported by the Wellcome Trust.

90

Goadsby

REFERENCES
1. Goadsby PJ, Lipton RB, Ferrari MD. Migraine-current understanding and treatment. N Engl J Med 2002; 346:257270. 2. Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalalgia. Lancet Neurol 2002; 1:3743. 3. Lance JW, Goadsby PJ. Mechanism and Management of Headache. New York: Elsevier, 2005. 4. Headache Classication Committee of The International Headache Society. The International Classication of Headache Disorders (2nd ed.). Cephalalgia 2004; 24:1160. 5. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. London: Martin Dunitz, 2002. 6. Willis T. Opera Omnia. Amstelaedami: Henricum Wetstenium, 1682. 7. Russell MB. Genetic epidemiology of migraine and cluster headache. Cephalalgia 1997; 17:683701. 8. Ulrich V, Gervil M, Kyvik KO, Olesen J, Russell MB. Evidence of a genetic factor in migraine with aura: a population based Danish twin study. Ann Neurol 1999; 45:242246. 9. Lalouel JM, Morton NE. Complex segregation analysis with pointers. Hum Hereditary 1981; 31:312321. 10. Mochi M, Sangiorgi S, Cortelli P, et al. Testing models for genetic determination in migraine. Cephalalgia 1993; 13:389394. 11. Russell MB, Iselius L, Olesen J. Investigation of the inheritance of migraine by complex segregation analysis. Hum Genet 1995; 96:726730. 12. Joutel A, Ducros A, Vahedi K, et al. Genetic heterogeneity of familial hemiplegic migraine. Am J Hum Genet 1994; 55:11661172. 13. Ophoff RA, Eijk Rv, Sandkuijl LA, et al. Genetic heterogeneity of familial hemiplegic migraine. Genomics 1994; 22:2126. 14. Ducros A, Denier C, Joutel A, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 2001; 345:1724. 15. Haan J, Terwindt GM, Bos PL, et al. Familial hemiplegic migraine in The Netherlands. Clin Neurol Neurosurg 1994; 96:244249. 16. Joutel A, Bousser MG, Biousse V, et al. A gene for familial hemiplegic migraine maps to chromosome 19. Nat Genet 1993; 5:4045. 17. Teh BT, Silburn P, Lindblad K, et al. Familial cerebellar periodic ataxia without myokymia maps to a 19-cM region on 19p13. Am J Hum Genet 1995; 56:14431449. 18. Terwindt GM, Ophoff RA, Haan J, Ferrari MD, The Dutch Migraine Genetics Research Group. Familial hemiplegic migraine: a clinical comparison of families linked and unlinked to chromosome 19. Cephalalgia 1996; 16:153155. 19. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 channel gene CACNL1A4. Cell 1996; 87:543552. 20. Ertel EA, Campbell KP, Harpold MM, et al. Nomenclature of voltage-gated calcium channels. Neuron 2000; 25:533535. 21. De Fusco M, Marconi R, Silvestri L, et al. Haploinsufciency of ATP1A2 encoding the Na/K pump a2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003; 33:192196. 22. Marconi R, De Fusco M, Aridon P, et al. Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23. Ann Neurol 2003; 53:376381. 23. Jurkat-Rott K, Freilinger T, Dreier JP, et al. Variability of familial hemiplegic migraine with novel A1A2 Na/K-ATPase variants. Neurology 2004; 62:18571861. 24. Vanmolkot KRJ, Kors EE, Hottenga JJ, et al. Novel mutations in the Na,K-ATPase pump gene ATP1A2 associated with Familial Hemiplegic Migraine and Benign Familial Infantile Convulsions. Ann Neurol 2003; 54:360366.

Pathophysiology of Migraine

91

25. Swoboda KJ, Kanavakis E, Xaidara A, et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol 2004; 55: 884887. 26. Goadsby PJ, Ferrari MD. Migraine: a multifactorial, episodic neurovascular channelopathy?. In: Rose MR, Griggs RC, eds. Channelopathies of the Nervous System. Oxford: Butterworth Heinemann, 2001:274292. 27. van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, et al. A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004; 41:701710. 28. Goadsby PJ. Migraine aura: a knock-in mouse with a knock-out message. Neuron 2004; 41:679680. 29. Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 1992; 12:221228. 30. Cutrer FM, Sorensen AG, Weisskoff RM, et al. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann Neurol 1998; 43:2531. 31. Olesen J, Friberg L, Skyhoj-Olsen T, et al. Timing and topography of cerebral blood ow, aura, and headache during migraine attacks. Ann Neurol 1990; 28:791798. 32. Leao AAP. Pial circulation and spreading activity in the cerebral cortex. J Neurophysiol 1944; 7:391396. 33. Leao AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol 1944; 7:359390. 34. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994; 117:199210. 35. Lashley KS. Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psychiatr 1941; 46:331339. 36. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981; 9:344352. 37. Harer C, Kummer Rv. Cerebrovascular CO2 reactivity in migraine: assessment by transcranial Doppler ultrasound. J Neurol 1991; 238:2326. 38. Lauritzen M, Skyhoj-Olsen T, Lassen NA, Paulson OB. The changes of regional cerebral blood ow during the course of classical migraine attacks. Ann Neurol 1983; 13:633641. 39. Sakai F, Meyer JS. Abnormal cerebrovascular reactivity in patients with migraine and cluster headache. Headache 1979; 19:257266. 40. Kaube H, Goadsby PJ. Anti-migraine compounds fail to modulate the propagation of cortical spreading depression in the cat. Eur Neurol 1994; 34:3035. 41. Kaube H, Knight YE, Storer RJ, Hoskin KL, May A, Goadsby PJ. Vasodilator agents and supracollicular transection fail to inhibit cortical spreading depression in the cat. Cephalalgia 1999; 19:592597. 42. Lambert GA, Michalicek J, Storer RJ, Zagami AS. Effect of cortical spreading depression on activity of trigeminovascular sensory neurons. Cephalalgia 1999; 19:631638. 43. Hadjikhani N, Sanchez del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci (USA) 2001; 98: 46874692. 44. Moskowitz MA, Bolay H, Dalkara T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann Neurol 2004; 55:276280. 45. Goadsby PJ. Migraine, aura and cortical spreading depression: why are we still talking about it?. Ann Neurol 2001; 49:46. 46. Read SJ, Smith MI, Hunter AJ, Upton N, Parsons AA. SB-220453, a potential novel antimigraine compound, inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat. Cephalalgia 1999; 20:9299. 47. Smith MI, Read SJ, Chan WN, et al. Repetitive cortical spreading depression in a gyrencephalic feline brain: inhibition by the novel benzoylamino-benzopyran SB-220453. Cephalalgia 2000; 20:546553.

92

Goadsby

48. MaassenVanDenBrink A, van den Broek RW, de Vries R, Upton N, Parsons AA, Saxena PR. The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan. Cephalalgia 2000; 20:538545. 49. Parsons AA, Bingham S, Raval P, Read S, Thompson M, Upton N. Tonabersat (SB-220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve-induced neurovascular reexes. Br J Pharmacol 2001; 132:15491557. 50. Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA 2004; 291:965973. 51. Diener HC, Tfelt-Hansen P, Dahlof C, et al. Topiramate in migraine prophylaxis results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004; 251:943950. 52. Silberstein SD, Neto W, Schmitt J, Jacobs D. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 2004; 61:490495. 53. Akerman S, Goadsby PJ. Topiramate inhibits cortical spreading depression in rat and cat: a possible contribution to its preventive effect in migraine. Cephalalgia 2004; 24:783784. 54. Tvedskov JF, Iversen HK, Olesen J. A double-blind study of SB-220453 (Tonerbasat) in the glyceryltrinitrate (GTN) model of migraine. Cephalalgia 2004; 24:875882. 55. Tvedskov JF, Thomsen LL, Iversen HK, et al. The effect of propranolol on glyceryltrinitrate-induced headache and arterial response. Cephalalgia 2004; 24:10761087. 56. Tvedskov JF, Thomsen LL, Iversen HK, Gibson A, Wiliams P, Olesen J. The prophylactic effect of valproate on glyceryltrinitrate induced migraine. Cephalalgia 2004; 24:576585. 57. Storer RJ, Goadsby PJ. Topiramate inhibits trigeminovascular neurons in the cat. Cephalalgia 2004; 24:10491056. 58. Storer RJ, Goadsby PJ. Topiramate has a locus of action outside of the trigeminocervical complex. Neurology 2005; 64:A150A151. 59. Liu-Chen L-Y, Gillespie SA, Norregaard TV, Moskowitz MA. Co-localization of retrogradely transported wheat germ agglutinin and the putative neurotransmitter substance P within trigeminal ganglion cells projecting to cat middle cerebral. J Comp Neurol 1984; 225:187192. 60. Arbab MA-R, Wiklund L, Svendgaard NA. Origin and distribution of cerebral vascular innervation from superior cervical, trigeminal and spinal ganglia investigated with retrograde and anterograde WGA-HRP tracing in the rat. Neuroscience 1986; 19:695708. 61. Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J. Innervation of the feline cerebral vasculature by nerve bers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 1985; 62:131136. 62. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23:193196. 63. Feindel W, Peneld W, McNaughton F. The tentorial nerves and localization of intracranial pain in man. Neurology 1960; 10:555563. 64. Wolff HG. Headache and Other Head Pain. New York: Oxford University Press, 1948. 65. Peneld W, McNaughton FL. Dural headache and the innervation of the dura mater. Arch Neurol Psychiatr 1940; 44:4375. 66. Moskowitz MA. Basic mechanisms in vascular headache. Neurol Clin 1990; 8:801815. 67. Markowitz S, Saito K, Moskowitz MA. Neurogenically mediated leakage of plasma proteins occurs from blood vessels in dura mater but not brain. J Neurosci 1987; 7:41294136. 68. Moskowitz MA, Cutrer FM. SUMATRIPTAN: a receptor-targeted treatment for migraine. Annu Rev Med 1993; 44:145154. 69. Cutrer FM, Limmroth V, Waeber C, Yu X, Moskowitz MA. New targets for antimigraine drug development. In: Goadsby PJ, Silberstein SD, eds. Headache. Philadelphia: Butterworth-Heinemann, 1997:5972.

Pathophysiology of Migraine

93

70. Dimitriadou V, Buzzi MG, Moskowitz MA, Theoharides TC. Trigeminal sensory ber stimulation induces morphological changes reecting secretion in rat dura mater mast cells. Neuroscience 1991; 44:97112. 71. Dimitriadou V, Buzzi MG, Theoharides TC, Moskowitz MA. Ultrastructural evidence for neurogenically mediated changes in blood vessels of the rat dura mater and tongue following antidromic trigeminal stimulation. Neuroscience 1992; 48:187203. 72. Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 1998; 79:964982. 73. Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996; 384:560563. 74. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8:136142. 75. Ebersberger A, Schaible H-G, Averbeck B, Richter F. Is there a correlation between spreading depression, neurogenic inammation, and nociception that might cause migraine headache? Ann Neurol 2001; 41:713. 76. Ingvardsen BK, Laursen H, Olsen UB, Hansen AJ. Possible mechanism of c-fos expression in trigeminal nucleus caudalis following spreading depression. Pain 1997; 72:407415. 77. Ingvardsen BK, Laursen H, Olsen UB, Hansen AJ. Comment on Ingvardsen et al., PAIN, 72 (1997) 407415reply to Moskowitz et al. Pain 1998; 76:266267. 78. Moskowitz MA, Nozaki K, Kraig RP. Neocortical spreading depression provokes the expression of C-fos protein-like immunoreactivity within the trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci 1993; 13:11671177. 79. May A, Shepheard S, Wessing A, Hargreaves RJ, Goadsby PJ, Diener HC. Retinal plasma extravasation can be evoked by trigeminal stimulation in rat but does not occur during migraine attacks. Brain 1998; 121:12311237. 80. Steuer H, Jaworski A, Stoll D, Schlosshauer B. In vitro model of the outer blood-retina barrier. Brain Res Brain Res Protoc 2004; 13:2636. 81. Connor HE, Bertin L, Gillies S, Beattie DT, Ward P, The GR205171 Clinical Study Group. Clinical evaluation of a novel, potent, CNS penetrating NK1 receptor antagonist in the acute treatment of migraine. Cephalalgia 1998; 18:392. 82. Diener H-C. The RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 2003; 23:183185. 83. Goldstein DJ, Wang O, Saper JR, Stoltz R, Silberstein SD, Mathew NT. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 1997; 17:785790. 84. Norman B, Panebianco D, Block GA. A placebo-controlled, in-clinic study to explore the preliminary safety and efcacy of intravenous L-758,298 (a prodrug of the NK1 receptor antagonist L-754,030) in the acute treatment of migraine. Cephalalgia 1998; 18:407. 85. Roon K, Diener HC, Ellis P, et al. CP-122,288 blocks neurogenic inammation, but is not effective in aborting migraine attacks: results of two controlled clinical studies. Cephalalgia 1997; 17:245. 86. Earl NL, McDonald SA, Lowy MT. 4991W93 Investigator Group. Efcacy and tolerability of the neurogenic inammation inhibitor, 4991W93, in the acute treatment of migraine. Cephalalgia 1999; 19:357. 87. May A, Gijsman HJ, Wallnoefer A, Jones R, Diener HC, Ferrari MD. Endothelin antagonist bosentan blocks neurogenic inammation, but is not effective in aborting migraine attacks. Pain 1996; 67:375378. 88. Data J, Britch K, Westergaard N, et al. A double-blind study of ganaxolone in the acute treatment of migraine headaches with or without an aura in premenopausal females. Headache 1998; 38:380.

94

Goadsby

89. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack. Brain 2000; 123:17031709. 90. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614624. 91. Selby G, Lance JW. Observations on 500 cases of migraine and allied vascular headache. J Neurol, Neurosurg Psychiatr 1960; 23:2332. 92. Knight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q-type calcium channel blockade in the PAG facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci 2002; 22:16. 93. Hoskin KL, Kaube H, Goadsby PJ. Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-Fos and electrophysiology study. Brain 1996; 119:249256. 94. Lambert GA, Lowy AJ, Boers P, Angus-Leppan H, Zagami A. The spinal cord processing of input from the superior sagittal sinus: pathway and modulation by ergot alkaloids. Brain Res 1992; 597:321330. 95. Storer RJ, Goadsby PJ. Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell ring in the cat. Brain 1997; 120:21712177. 96. Pozo-Rosich P, Oshinsky M. Effect of dihydroergotamine (DHE) on central sensitisation of neurons in the trigeminal nucleus caudalis. Neurology 2005; 64:A151. 97. Goadsby PJ, Duckworth JW. Effect of stimulation of trigeminal ganglion on regional cerebral blood ow in cats. Am J Physiol 1987; 253:R270R274. 98. Goadsby PJ, Macdonald GJ. Extracranial vasodilatation mediated by VIP (vasoactive intestinal polypeptide). Brain Res 1985; 329:285288. 99. May A, Goadsby PJ. The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural inuences on the cerebral circulation. J Cereb Blood Flow Metab 1999; 19:115127. 100. Matsuyama T, Shiosaka S, Matsumoto M, et al. Overall distribution of vasoactive intestinal polypeptide-containing nerves on the wall of the cerebral arteries: an immunohistochemical study using whole-mounts. Neuroscience 1983; 10:8996. 101. Lambert GA, Goadsby PJ, Zagami AS, Duckworth JW. Comparative effects of stimulation of the trigeminal ganglion and the superior sagittal sinus on cerebral blood ow and evoked potentials in the cat. Brain Res 1988; 453:143149. 102. Zagami AS, Goadsby PJ, Edvinsson L. Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 1990; 16:6975. 103. Gallai V, Sarchielli P, Floridi A, et al. Vasoactive peptides levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 1995; 15:384390. 104. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28:183187. 105. Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from extracerebral circulation during nitroglycerininduced cluster headache attack. Pain 1995; 60:119123. 106. Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Brain 1994; 117:427434. 107. Goadsby PJ, Edvinsson L. Neuropeptide changes in a case of chronic paroxysmal hemicraniaevidence for trigemino-parasympathetic activation. Cephalalgia 1996; 16: 448450. 108. Afridi S, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain 2004; 110:675680. 109. Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin as an experimental headache model. Basic characteristics. Pain 1989; 38:1724. 110. Juhasz G, Zsombok T, Modos EA, et al. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 2003; 106:461470.

Pathophysiology of Migraine

95

111. Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 2005; 25:179183. 112. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33:4856. 113. Roon KI, Olesen J, Diener HC, et al. No acute antimigraine efcacy of CP-122,288, a highly potent inhibitor of neurogenic inammation: results of two randomized doubleblind placebo-controlled clinical trials. Ann Neurol 2000; 47:238241. 114. Knight YE, Edvinsson L, Goadsby PJ. Blockade of CGRP release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288. Neuropeptides 1999; 33:4146. 115. Knight YE, Edvinsson L, Goadsby PJ. 4991W93 inhibits release of calcitonin generelated peptide in the cat but only at doses with 5HT1B/1D receptor agonist activity. Neuropharmacology 2001; 40:520525. 116. Doods H, Hallermayer G, Wu D, et al. Pharmacological prole of BIBN4096BS, the rst selective small molecule CGRP antagonist. Br J Pharmacol 2000; 129:420423. 117. Olesen J, Diener H-C, Husstedt I-W, et al. Calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS is effective in the treatment of migraine attacks. N Engl J Med 2004; 350:11041110. 118. Morgan JI, Curran T. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci 1991; 14:421451. 119. Nozaki K, Boccalini P, Moskowitz MA. Expression of c-fos-like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space. Neuroscience 1992; 49:669680. 120. Kaube H, Keay KA, Hoskin KL, Bandler R, Goadsby PJ. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical cord following stimulation of the superior sagittal sinus in the cat. Brain Res 1993; 629:95102. 121. Goadsby PJ, Hoskin KL. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat 1997; 190:367375. 122. Hoskin KL, Zagami A, Goadsby PJ. Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat. J Anat 1999; 194:579588. 123. Goadsby PJ, Zagami AS. Stimulation of the superior sagittal sinus increases metabolic activity and blood ow in certain regions of the brainstem and upper cervical spinal cord of the cat. Brain 1991; 114:10011011. 124. Goadsby PJ, Hoskin KL, Knight YE. Stimulation of the greater occipital nerve increases metabolic activity in the trigeminal nucleus caudalis and cervical dorsal horn of the cat. Pain 1997; 73:2328. 125. Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain 2002; 125:14961509. 126. Bartsch T, Goadsby PJ. Increased responses in trigeminocervical nociceptive neurones to cervical input after stimulation of the dura mater. Brain 2003; 126:18011813. 127. Kaube H, Hoskin KL, Goadsby PJ. Intravenous acetylsalicylic acid inhibits central trigeminal neurons in the dorsal horn of the upper cervical spinal cord in the cat. Headache 1993; 33:541550. 128. Kaube H, Hoskin KL, Goadsby PJ. Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption. Br J Pharmacol 1993; 109:788792. 129. Levy D, Jakubowski M, Burstein R. Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists. Proc Natl Acad Sci USA 2004; 101:42744279.

96

Goadsby

130. Goadsby PJ, Hoskin KL. Differential effects of low dose CP122,288 and eletriptan on fos expression due to stimulation of the superior sagittal sinus in cat. Pain 1999; 82:1522. 131. Lambert GA, Boers PM, Hoskin KL, Donaldson C, Zagami AS. Suppression by eletriptan of the activation of trigeminovascular sensory neurons by glyceryl trinitrate. Brain Res 2002; 953:181188. 132. Cumberbatch MJ, Hill RG, Hargreaves RJ. Differential effects of the 5HT1B/1D receptor agonist naratriptan on trigeminal versus spinal nociceptive responses. Cephalalgia 1998; 18:659664. 133. Goadsby PJ, Knight YE. Inhibition of trigeminal neurons after intravenous administration of naratriptan through an action at the serotonin (5HT1B/1D) receptors. Br J Pharmacol 1997; 122:918922. 134. Cumberbatch MJ, Hill RG, Hargreaves RJ. Rizatriptan has central antinociceptive effects against durally evoked responses. Eur J Pharmacol 1997; 328:3740. 135. Goadsby PJ, Hoskin KL. Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites a therapeutic target in migraine? Pain 1996; 67:355359. 136. Goadsby PJ, Classey JD. Evidence for 5-HT1B, 5-HT1Dand 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input. Neuroscience 2003; 122:491498. 137. Potrebic S, Ahan AH, Skinner K, Fields HL, Basbaum AI. Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans. J Neurosci 2003; 23:1098810997. 138. Durham PL, Sharma RV, Russo AF. Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation. J Neurosci 1997; 17:95459553. 139. Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci 1999; 19:34233429. 140. Goadsby PJ, Akerman S, Storer RJ. Evidence for postjunctional serotonin (5-HT1) receptors in the trigeminocervical complex. Ann Neurol 2001; 50:804807. 141. Maneesi S, Akerman S, Lasalandra MP, Classey JD, Goadsby PJ. Electron microscopic demonstration of pre- and postsynaptic 5-HT1D and 5-HT1F receptor immunoreactivity (IR) in the rat trigeminocervical complex (TCC) new therapeutic possibilities for the triptans. Cephalalgia 2004; 24:148. 142. Zagami AS, Goadsby PJ. Stimulation of the superior sagittal sinus increases metabolic activity in cat thalamus. In: Rose FC, ed. New Advances in Headache Research: 2. London: Smith-Gordon and Co Ltd, 1991:169171. 143. Zagami AS, Lambert GA. Craniovascular application of capsaicin activates nociceptive thalamic neurons in the cat. Neurosci Lett 1991; 121:187190. 144. Shields KG, Kaube H, Goadsby PJ. GABA receptors modulate trigeminovascular nociceptive transmission in the ventroposteromedial (VPM) thalamic nucleus of the rat. Cephalalgia 2003; 23:728. 145. Shields KG, Goadsby PJ. Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine? Brain 2005; 128:8697. 146. Shields KG, Goadsby PJ. Naratriptan modulates trigeminovascular nociceptive transmission in the ventroposteromedial (VPM) thalamic nucleus of the rat. Cephalalgia 2004; 24:1098. 147. Afridi S, Gifn NJ, Kaube H, et al. A PET study in spontaneous migraine. Arch Neurol 2005; 62:12701275. 148. Bahra A, Matharu MS, Buchel C, Frackowiak RSJ, Goadsby PJ. Brainstem activation specic to migraine headache. Lancet 2001; 357:10161017. 149. May A, Bahra A, Buchel C, Frackowiak RSJ, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet 1998; 352:275278. 150. Cohen AS, Matharu MS, Kalisch R, Friston K, Goadsby PJ. Functional MRI in SUNCT shows differential hypothalamic activation with increasing pain. Cephalalgia 2004; 24:10981099.

Pathophysiology of Migraine

97

151. May A, Bahra A, Buchel C, Turner R, Goadsby PJ. Functional MRI in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 1999; 46:791793. 152. Hoskin KL, Bulmer DCE, Lasalandra M, Jonkman A, Goadsby PJ. Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation. J Anat 2001; 197:2935. 153. Knight YE, Bartsch T, Goadsby PJ. Trigeminal antinociception induced by bicuculline in the periaqueductal grey (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neurosci Lett 2003; 336:113116. 154. Knight YE, Goadsby PJ. The periaqueductal gray matter modulates trigeminovascular input: a role in migraine? Neuroscience 2001; 106:793800. 155. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1:658660. 156. Benjamin L, Levy MJ, Lasalandra MP, et al. Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Neurobiol Dis 2004; 16:500505. 157. Matharu MS, Cohen AS, Frackowiak RSJ, Goadsby PJ. Posterior hypothalamic activation in paroxysmal hemicrania using PET. Cephalalgia. In press. 158. Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RSJ, Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004; 44:462463. 159. Gifn NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology 2003; 60:935940. 160. Bes A, Geraud A, Guell A, Arne-Bes MC. Dopaminergic hypersensitivity in migraine: a diagnostic test? La Nouvelle Presse Medicale 1982; 11:14751478. 161. Peroutka SJ. Dopamine and migraine. Neurology 1997; 49:650656. 162. Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation of nociceptive dural input to [hypocretin] Orexin A and B receptor activation in the posterior hypothalamic area. Pain 2004; 109:367378. 163. Matharu MS, Bartsch T, Ward N, Frackowiak RSJ, Weiner RL, Goadsby PJ. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 2004; 127:220230. 164. Afridi S, Matharu MS, Lee L, et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 2005; 128:932939. 165. Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache 1987; 27:416420. 166. Veloso F, Kumar K, Toth C. Headache secondary to deep brain implantation. Headache 1998; 38:507515. 167. Welch KM, Nagesh V, Aurora S, Gelman N. Periaqueductal grey matter dysfunction in migraine: cause or the burden of illness? Headache 2001; 41:629637. 168. Goadsby PJ. Neurovascular headache and a midbrain vascular malformation evidence for a role of the brainstem in chronic migraine. Cephalalgia 2002; 22:107111. 169. Afridi S, Goadsby PJ. New onset migraine with a brainstem cavernous angioma. J .Neurol, Neurosurg Psychiatr 2003; 74:680682. 170. Goadsby PJ, Lambert GA, Lance JW. Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res 1982; 249:247254. 171. Goadsby PJ, Lambert GA, Lance JW. The mechanism of cerebrovascular vasoconstriction in response to locus coeruleus stimulation. Brain Res 1985; 326:213217. 172. Goadsby PJ, Duckworth JW. Low frequency stimulation of the locus coeruleus reduces regional cerebral blood ow in the spinalized cat. Brain Res 1989; 476:7177. 173. Goadsby PJ, Zagami AS, Lambert GA. Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Headache 1991; 31:365371. 174. Kaube H, Gifn NJ. The electrophysiology of migraine. Curr Opin Neurol 2002; 15: 303309.

98

Goadsby

175. Schoenen J, Ambrosini A, Sandor PS, Maertens de Noordhout A. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic signicance. Clin Neurophysiol 2003; 114:955972. 176. Afra J, Sandor P, Schoenen J. Habituation of visual and intensity dependence of cortical auditory evoked potentials tend to normalise just before and during migraine attacks. Cephalalgia 2000; 20:347. 177. Proietti-Cecchini A, Afra J, Schoenen J. Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia 1997; 17:849854. 178. Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995; 2:115122. 179. Wang W, Schoenen J. Interictal potentiation of passive oddball auditory eventrelated potentials in migraine. Cephalalgia 1998; 18:261265. 180. Schoenen J, Timsit-Berthier M. Contingent negative variation: methods and potential interest in headache. Cephalalgia 1993; 13:2832. 181. Kropp P, Gerber WD. Prediction of migraine attacks using a slow cortical potential, the contingent negative variation. Neurosci Lett 1998; 257:7376. 182. Maertens de Noordhout A, Timsit-Berthier M, Schoenen J. Contingent negative variation (CNV) in migraineurs before and during prophylactic treatment with beta-blockers. Cephalalgia 1985; 5:3435. 183. Gantenbein A, Goadsby PJ, Kaube H. Introduction of a clinical scoring system for migraine research applied to electrophysiological studies. Cephalalgia 2004; 24: 10951096. 184. Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine can be induced by sildenal without changes in middle cerebral artery diameter. Brain 2003; 126:241247. 185. Limmroth V, May A, Auerbach P, Wosnitza G, Eppe T, Diener HC. Changes in cerebral blood ow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine. J Neurol Sci 1996; 138:6065. 186. Niebur E, Hsiao SS, Johnson KO. Synchrony: a neural mechanism for attentional selection?. Curr Opin Neurobiol 2002; 12:190194. 187. Angelini L, de Tommaso M, Guido M, et al. Steady-state visual evoked potentials and phase synchronization in migraine patients. Phys Rev Lett 2004; 93:038103-1038103-4. 188. Goadsby PJ. Migraine pathophysiology: the brainstem governs the cortex. Cephalalgia 2003; 23:565566.

8
Allodynia and Sensitization in Migraine
William B. Young
Department of Neurology and Inpatient Program, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Avi Ashkenazi
Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Michael L. Oshinsky
Department of Neurology and Preclinical Research, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION Migraine is a common disorder that has been recognized since the earliest recorded times. The rst references to migraine date back to Sumerian times (1). Even during these early times, migraine symptoms were noted to include more than just pain. Cutaneous allodynia accompanying a headache attack was perhaps rst described by Liveing in 1873 (2). In 1960, Selby and Lance (3) noted that 65% of their patients complained of cutaneous allodynia in the form of scalp tenderness. Selby writes: This may be so severe as to prevent the patient from lying on the affected side, or described only as abnormal sensitivity when combing or brushing the hair. Cutaneous allodynia has recently been linked to sensitization of neurons in the trigeminal nucleus caudalis (TNC) in animal models of migraine. Furthermore, allodynia was found to be associated with acute attack refractoriness. Understanding the mechanisms of allodynia, preventing its development, and nding effective treatments have become a priority in current headache research. A number of terms are used to describe different, but related, types of sensory system sensitization. Allodynia is the abnormal experience of pain in response to normally nonpainful stimuli. Hyperalgesia is a heightened pain response to noxious stimuli. In theory and in practice, each of these abnormal sensory responses could be due to changes in the rst-order sensory neuron, or in second or higher order neurons within the central nervous system. Throbbing head pain is probably due to peripheral sensitization of the rst-order trigeminal neuron innervating the meninges or, less likely, the blood vessels. Central sensitization occurs when central

99

100

Young et al.

neurons involved in pain transmission become more readily activated by peripheral sensory stimulation. Cutaneous allodynia is thought to be due to changes in rst- or second-order sensory neurons or in higher order sensory neurons, e.g., in the thalamus.

SENSORY PROCESSING BY THE NERVOUS SYSTEM The anatomic and physiologic relationships of the trigeminovascular system underlie important aspects of migraine symptom generation. Myelinated and unmyelinated bers arising from the ophthalmic division of the trigeminal nerve innervate the large cerebral vessels, the large venous sinuses, the pial vessels, and the dura mater. These afferents have a nociceptive function. Pain signals from these structures are processed in second-order neurons of the caudal trigeminal nucleus and the C1/C2 dorsal horns. These sensory neurons then project rostrally to the thalamus and, nally, to the cerebral cortex. Migraine pain is thought to originate from activation of nociceptors in intracranial structures combined with reduced activity of endogenous pain-control pathways (4). Sensory processing occurs at the dorsal horn and at higher levels. The primary afferent input to the dorsal horn is carried by large, fast-conducting Ab-bers, which transmit non-noxious sensory information, and by smaller, more slowly conducting, thinly myelinated Ad-bers, and unmyelinated C bers, which transmit noxious and thermal information. In a normal state, a low intensity stimulus will produce an innocuous sensation, such as touch, vibration, pressure, warmth, and coolness, whereas a high-intensity stimulus activating a primary afferent nociceptor will result in transient, localized pain. This allows for distinction between damaging and nondamaging stimuli (5). The somatosensory system can be suppressed by descending inhibition from neurons in the brain stem. In this state, a high-intensity stimulus activates nociceptors but fails to cause the sensation of pain, enabling ght-or-ight reactions in the presence of major injury. Alternatively, dorsal horn excitability can be increased. When this occurs, low-intensity stimuli acting via low-threshold afferents produce the sensation of pain (cutaneous allodynia). Peripheral tissue injury, peripheral inammation, and damage to the central or peripheral nervous system may all cause sensitization of the dorsal horn and the transition into this state. The sensitized state functions to protect injured body parts from suffering further tissue injury. Transitions between these three states demonstrate the functional plasticity of the nervous system. The nervous system can, however, undergo structural reorganization. Nerve cells may die, their axons may atrophy, new axon terminals may sprout and form novel connections, and the number and morphology of glial cells can change. These structural alterations result in lasting changes in sensory processing, which are maladaptive and pathological (5).

SENSITIZATION OF THE DORSAL HORN Repeated, brief bursts of nociceptor activity sensitize dorsal horn neurons. This central sensitization causes a state shift in the sensory system, manifested as a reduction in threshold, an increase in responsiveness, and an expansion of the receptive elds of dorsal horn neurons (613). Central sensitization is normally initiated by C-ber input.

Allodynia and Sensitization in Migraine

101

This can be demonstrated by applying C-ber irritants, such as capsaicin or mustard oil, to the skin, producing an Ad-bermediated tactile allodynia (14). Nerve injury and peripheral inammation are able to induce central sensitization through neurochemical changes in the dorsal horn. These changes allow for low-intensity stimuli to produce prolonged excitability in dorsal horn neurons (1517). A centrally mediated, progressive tactile allodynia results, such that repeated tactile stimuli of the inamed skin cause pain sensation of an increased intensity (18,19). Upon recovery from the injury or inammation, the source of central sensitization is removed and the allodynia and hyperalgesia disappear within several hours or days. On the molecular level, the N-methyl-D-aspartate (NMDA) glutamate receptor plays a central role in synaptic efcacy in the dorsal horn. Because central sensitization is considered to reect plasticity at spinal synapses, the spinal cord has been the focus of many of the preclinical studies of central sensitization. Glutamate, acting at a spinal NMDA receptor, is implicated in development of sensitization (allodynia and hyperalgia). Subsequent to NMDA receptor activation, spinal nitric oxide (NO), protein kinase C, and other mediators have been implicated in maintaining hyperalgesia (20). At resting membrane potential, this receptor contributes little to the synaptic current due to the blockage of the channel by a magnesium ion. Upon membrane depolarization, the magnesium ion diffuses out of the channel, allowing calcium and sodium ions to traverse the channel, carrying current with them. Protein kinase C or tyrosine kinase is activated at the postsynaptic NMDA receptor ion channel (21). In addition to the dorsal horn of the spinal cord, supraspinal regions of the brain are implicated in maintaining sensitization in the dorsal horn. In particular, there is a body of evidence that correlates increased activity in the rostral ventral medulla (RVM) with sensitization. Intra-RVM injection of a selective neurotensin receptor antagonist (SR48692) or NMDA receptor antagonist (2-amino5-phosphonovaleric acid) fully and dose dependently prevented mustard oilinduced facilitation of the tail-ick reex (22). Another important modulator involved in sensitization is prostaglandin. Prostaglandin E2 (PGE2) is implicated as a key factor in the generation of exaggerated pain sensations evoked by inammation. It exerts its cellular effects through four different G proteincoupled receptors encoded by separate genes, termed EP1 through EP4. Treatment with cyclooxygenase (COX) inhibitors, such as nonsteroidal anti-inammatory drugs, blocks prostaglandin production and has analgesic, anti-inammatory, and antipyretic effects (23). In addition to short- and long-term processes affecting neuronal activity directly, glial and inammatory cells have a critical role in the development and maintenance of allodynia and central sensitization in animal models of pain. Activated astrocytes coalesce to form a microenvironment with which they modulate local neuronal hyperexcitability. When activated, they release cytokines [amino acids, adenosine triphosphate (ATP), prostaglandins, and NO], which directly inuence neuronal activity (24). They regulate glutamate in the neuronal junction (25). This process is sustained and regulated by astrocyte calcium waves: contiguous astrocytes become sequentially active with an increase in intracellular calcium (26). Progressive activation involves a direct intercellular pathway mediated by gap junctions/connexin macromolecules and the diffusion of inosital triphosphate, and an extracellular signaling pathway mediated by the release of glutamate, tumor necrosis factor (TNF) alpha, PGE2, and ATP in the extracellular environment, in turn activating nearby astrocytes. Microglia also become activated during central sensitization. Local neuronal transmitters (ATP, substance P, glutamate, and fractalkine) and circulating

102

Young et al.

lipopolysaccharides and interleukin (IL)1b signal the microglia to become activated. Toll-like receptors appear to mediate part of this response. The activated microglia in turn release TNF, IL1b, IL6, oxygen radical, NO, peroxynitrite, proteolytic enzymes, arachidonic acid derivatives, and low-molecular-weight toxins. These substances in turn potentiate NMDA receptor functions in neurons. Deleo et al. suggest that microglia initiate the phase of persistent activation, whereas astrocytes are more crucial for maintaining central sensitization. Minocycline, when administered before injury, reduces microglial and astrocytic activation, but it is ineffective postinjury (27). Astrocyte inhibitors, however, attenuate chronic pain states (28).

RAT MODEL OF MIGRAINE HEADACHE AND ALLODYNIA Most studies of somatic hyperalgesic pain involved extratrigeminal injury to the rat followed by observation of rat behavior, as well as physiologic recording of neuronal activity and pathological studies. As a general rule, peripheral injection of a nociceptive substance, such as capsaicin, mustard oil, or formalin, predominantly causes cold or heat allodynia, whereas crush or nerve ligation injuries result in a more prominent mechanical allodynia (29). Strassman modeled head pain by sensitizing the dura mater with inammatory agents, including histamine, serotonin, bradykinin, and PGE2. He recorded the activity of the neurons in the rat trigeminal ganglion that innervate the dural venous sinuses. These neurons developed an increased sensitivity to mechanical stimuli (administrated using von Frey hairs) after chemical stimulation of the dura. This may explain why head pain is aggravated by physical activity during a migraine attack, as well as the pulsating quality of the pain (30). Burstein further explored this animal model by locating neurons in the TNC that receive convergent input from the dura and from the skin. The cutaneous receptive elds of trigeminal neurons included the periorbital, maxillary, and mandibular distributions of the trigeminal nerve, but did not extend further. He recorded the dural receptive elds by mechanically stimulating the dura and the cutaneous receptive elds by mechanically and thermally stimulating the skin. Chemical stimulation of the dura caused an increase in the sensitivity of the corresponding cutaneous receptive eld neurons to both mechanical and thermal stimuli. Both the dural and cutaneous receptive eld size increased. Additionally, cutaneous receptive elds that had previously included only the periorbital regions expanded to include the maxillary and mandibular area after the chemical stimulation (31). Chemical stimulation also enabled the normally non-noxious stimuli to produce neuronal responses and blood pressure increases that were previously evoked only by noxious stimuli, suggesting that innocuous stimuli would be perceived as painful after chemical stimulation of the dura (32). Similarly, dilation of the meningeal blood vessels by rat calcitonin generelated peptide (CGRP) sensitized the second-order TNC neurons (33). These data demonstrate that the noxious inputs from dural inammation or from distended intracranial blood vessels cause sensitization of TNC neurons. This central sensitization may account for the extracranial tenderness and cutaneous allodynia that are often experienced during a migraine attack. Triptans, 5HT1B/1D agonists, are commonly used in the treatment of migraine attacks. These drugs target peripheral nociceptors and are not known to have an effect on second- and third-order neurons. Thus, after central sensitization develops, these drugs are expected to have little effect. Burstein sensitized the rat dura mater

Allodynia and Sensitization in Migraine

103

with an inammatory soup and recorded neuronal activity in the TNC in a similar manner to that used in previous studies (34). He administered intravenous triptans either at the same time as the chemical stimulation (early intervention) or two to four hours after it (late intervention). Early intervention prevented both peripheral sensitization (expansion of dural receptive elds and sensitization of primary afferents to mechanical stimuli) and central sensitization (expansion of cutaneous receptive elds of secondary afferents and sensitization to both mechanical and thermal stimuli) (35). Similarly, Cumberbatch found that a 5HT1B/1D agonist, given immediately after brainstem exposure but before location of a neuron in the TNC or dilation of meningeal blood vessels by CGRP, blocked cutaneous sensitization (33). However, though late intervention decreased the peripheral sensitization, it did not effect the development of central sensitization (35). In the inammatory soup model of head pain, Burstein compared early triptan treatment, dened as triptan administration at the same time as inammatory soup administration, and late triptan treatment, dened as triptan administration two hours after administration (36). Early intervention blocked the development of all aspects of central sensitization. Late intervention resulted in shrinkage of expanded neuronal receptive elds in the dura and normalization of neuronal response to threshold dural indentation. However, it did not reverse spontaneous TNC neuron ring or increased response to skin brushing. Early, but not late, intervention was able to reverse central sensitization.

HUMAN STUDIES OF ALLODYNIA IN PAIN DISORDERS OTHER THAN MIGRAINE Dynamic mechanical (brush) allodynia (BA), pain evoked by gently stroking the skin, is the most common type of allodynia in neuropathic pain patients. Static mechanical (pressure) allodynia (PA), pain evoked by steadily applying light pressure on the skin, is the second most common type, followed by cold and heat allodynia (37). Based on experimental compression nerve blocks, BA is mediated by myelinated nerve bers, whereas PA utilizes unmyelinated bers (38). Additionally, BA can cause a variety of pain sensations and may be accompanied by emotional and vegetative reactions including nausea, dizziness, and sweating (37,39). Functional neuroimaging studies have shown activation of various cortical and subcortical areas in migraine, including the somatosensory cortex, anterior cingulate cortex, insulae, thalamus, hypothalamus, amygdala, basal ganglia, and cerebellum (40). Positron emission tomography (PET) and functional magnetic resonance imaging (MRI) studies of BA in conditions other than migraine have demonstrated activation of a network that includes bilateral SII, insulae, thalamus, and contralateral SI and anterior cingulate cortex (41,42). Peyron studied BA and compared responses to brush stimuli in an allodynic area and the contralateral nonallodynic area in 27 patients with neuropathic pain with a variety of causes (43). Increased activation volumes were found in contralateral SI and primary motor cortex. Ipsilateral responses were greatly magnied in SII, SI, and insula. Other areas activated by allodynic stimuli included motor and premotor areas, posterior parietal areas, and midanterior and cingulate cortex. Taken together, these studies demonstrate a matrix of supratentorial activation occurring during allodynic pain. They do not demonstrate pain processing in brainstem or trigeminal nuclei.

104

Young et al.

HUMAN STUDIES OF ALLODYNIA IN MIGRAINE Migraineurs may have baseline differences in sensory processing compared with nonmigraineurs. WeismanFogel found that migraine patients had a lower pain threshold for mechanical stimulation compared with controls, whereas heat and electrical stimulation pain thresholds were the same for both patients and controls (44). Furthermore, migraineurs had increased temporal summation of pain to mechanical and electrical stimulation compared with controls. Burstein examined the relationship between static mechanical allodynia, tested with von Frey hairs, thermal allodynia, and migraine. He examined 44 patients interictally to determine their thresholds to cold, warm, and pressure stimuli on the periorbital and ventral forearm skin bilaterally. Patients pain thresholds were reexamined three to four hours into a migraine attack. Cutaneous allodynia was dened as a decrease in pain threshold at one or more of the skin locations by one or more standard deviation compared with baseline. Seventy-nine percent of patients experienced allodynia on the facial skin ipsilateral to the headache, with 48% experiencing cold allodynia, 55% experiencing heat allodynia, and 64% experiencing PA (45). Burstein noted that allodynic subjects were on an average 6.5 years older than nonallodynic subjects. Subjects with allodynia were more likely to have aura. There was a trend for allodynic subjects to have a higher attack frequency, but attack duration was similar (46). Similarly, Ashkenazi et al. found that migraine patients who experienced aura were more likely to have BA compared with those who did not have aura (42% vs. 19%) (47). Burstein examined a single patient for the sequential spread of cutaneous allodynia during a migraine attack. After one hour of head pain, the patient experienced cold and PA ipsilateral to the head pain. At two hours into the attack, while allodynia continued to develop ipsilaterally, cold, pressure, and BA also developed contralateral to the head pain and cold allodynia developed on the ipsilateral forearm. At four hours into the attack, heat allodynia appeared ipsilaterally and contralaterally on the head, and ipsilaterally on the forearm. At no time did the patient experience any allodynia on the contralateral forearm. At the onset of head pain, the patient rst experienced aggravation of his head pain by coughing or bending over, a manifestation of sensitization of peripheral nociceptors in intracranial blood vessels and meninges (intracranial hypersensitivity). Extracranial hypersensitivity developed later. Allodynia of the periorbital region was interpreted as a result of central sensitization of TNC neurons, whereas allodynia of the ipsilateral forearm was interpreted as resulting from sensitization of third-order trigeminovascular neurons that receive inputs from both TNC and C27 dorsal horn neurons (34). Ashkenazi et al. studied dynamic BA in a series of 111 patients with episodic migraine (EM) and 89 with transformed migraine (TM) (47). Overall, 54 patients (27%) had BA. BA was more common in patients with TM (42.7%) compared with patients with EM (14.4%). Within the EM group, BA was more common in patients who had an acute headache when tested compared with those who did not (60% vs. 9.9 %). In the TM group, however, there was no signicant difference in BA prevalence between those who had headache exacerbation when tested and those who did not (45.7% vs. 40.7%). BA was more common in patients with migraine with aura compared to those with migraine without aura, both in the whole study population (42.0% vs. 19.1%) and in the EM and TM groups separately (EM: 26.5% vs. 9.1%; TM: 57.1% vs. 33.3%). There was a positive correlation (of 0.37) between the allodynia score (the sum of positive responses to a short list of questions describing various

Allodynia and Sensitization in Migraine

105

types of allodynia) and the headache level at testing time. There was also a correlation between the side of head pain and the side of BA. BA was more common in patients with psychiatric comorbidity compared with those without it (34.6% vs. 19.2%). Young et al. compared the incidence of BA with unilateral and with bilateral headache among a cohort of inpatients with a variety of headache disorders (61/78 had TM) (48). Subjects with unilateral headache were signicantly more likely to have BA than those with bilateral headache. This was not due to headache severity, which was identical in subjects with and without BA. Similarly, Selby and Lance showed that patients with unilateral migraine had more scalp tenderness than patients with bilateral migraine (3). Because Burstein reported only on patients with unilateral headache, these ndings are not conrmed for other types of allodynia. In patients with unilateral headache, BA is generally more severe ipsilateral to the headache, but this was not universal (47). Burstein et al. studied allodynia location in 33 allodynic patients with unilateral headache (45). Four sites were assessed: the head ipsilateral and contralateral to the pain, and the forearm ipsilateral and contralateral to the headache. All subjects had heat, cold, or PA ipsilateral to the headache; of these, 15% had only ipsilateral head allodynia, 21% had allodynia at two sites, 21% had allodynia at three sites, and 42% had allodynia at four sites. BA was not reported. Bove described the location of BA in 39 patients, most of whom had EM or TM (49). These subjects could have bilateral migraine. The results of this study are summarized in Figure 1.

Figure 1 Spatial distribution of allodynia. The illustration shows the prevalence of BA at various anatomic sites across a diverse population of headache patients.

106 Table 1 Allodynia Questionnaire

Young et al.

Do you experience pain or unpleasant sensation on your skin during migraine attack when you engage in ANY of the following activities (Yes, No, N/A)?  Combing your hair  Pulling your hair back (e.g., ponytail)  Shaving your face  Wearing eyeglasses  Wearing contact lenses  Wearing earrings  Wearing necklaces  Wearing tight clothes  Taking a shower (when shower water hits your face)  Resting your face on a pillow on the side of pain  Heat exposure (e.g., cooking and placing heating pads on your face)  Cold exposure (e.g., breathing through your nose on a cold day and placing ice packs on your face)
Source: Burstein R, personal communication.

Ashkenazi et al. reported on a patient with referred BA who had EM and right-sided headache (47). When BA was tested on the left posterior neck and left forehead, pain was referred to the right forehead, although brush at this area did not produce pain or discomfort. This report suggests that a complex pain-processing abnormality may occur in migraine. Lopinto et al. compared BA and PA in 55 migraine patients and in a control group. They dened PA for each lament used as the pain level on the visual analog scale below which 95% of the controls responded (50). PA was slightly more common than BA, and there was an incomplete overlap between these groups. If a patient had allodynia to only one sensory modality, it was more likely to be PA than BA. This suggests that BA and PA may result from sensitization of different neuronal populations. Mathew interviewed 295 consecutive migraine patients for symptoms of allodynia. Fifty-three percent of patients reported allodynia. Among patients with allodynia, 50% had pure cephalic allodynia, 35% had both cephalic and extracephalic allodynia, and 15% had pure extracephalic allodynia. Mathew found a positive correlation between the presence of allodynia and both duration of illness and frequency of attacks. Symptoms that are believed to reect allodynia and central sensitization are listed in Table 1. TIME COURSE OF SENSITIZATION IN MIGRAINE Based on a small number of patients and time points, allodynia appears to develop within several hours of the initiation of throbbing pain in migraine (45). Anecdotally, symptoms of allodynia may persist for hours after headache pain resolution. This is roughly consistent with central sensitization studies in rats. THE EFFECT OF ALLODYNIA ON TREATMENT OUTCOME Burstein studied 31 migraineurs on three separate clinic visits. He obtained baseline interictal data on heat, cold, and pressure pain thresholds. He then studied these

Allodynia and Sensitization in Migraine

107

subjects, and their response to triptan treatment, one and four hours into a migraine attack. When the subjects were nonallodynic, they became headache-free after triptan treatment in 93% of attacks, as opposed to only 15% of the attacks when the subjects were allodynic. For attacks in patients who were not allodynic, triptan treatment was equally effective if given early (within one hour of attack onset) or late (four hours after attack onset). For attacks in patients who were allodynic, triptan treatment was equally ineffective, whether given early or late. The outcome of triptan treatment was linked to the presence of allodynia, not the presence of aura (46). In contrast to Bursteins ndings with temperature and PA, BA did not affect outcome in a group of hospitalized headache patients (48). Sixty-six percent of migraine patients with BA and 70% of patients without BA became headache-free by the end of hospitalization. The duration of hospitalization was similar between the groups. The disparity between these ndings and Bursteins may be due to differences in the duration, type, and intensity of treatments that inpatients receive compared with treatments given to outpatients.

THE EFFECT OF TREATMENT ON ALLODYNIA There is little published data on clinically effective allodynia treatments in migraine. Burstein reported that ketorolac was effective in reversing allodynia in migraine (London Migraine Trust, personal communication, 2004). Young et al. demonstrated that occipital nerve block could relieve migraine pain and BA within minutes of injection, suggesting a descending inhibitory process (51). In animal studies of inammatory and neuropathic pain, COX-2 inhibitors (52) and steroids (53) were effective at decreasing allodynia. Ashkenazi et al. studied the effect of greater occipital nerve (GON) block and trigger point injections on both head pain and BA in 19 migraine patients (54). Twenty minutes after treatment, headache level decreased in 90% of patients and allodynia decreased in all of them. The decrease in allodynia was more pronounced in the trigeminal, compared with the cervical, dermatomes. The allodynia level decreased, to a similar degree, both ipsilateral and contralateral to the side of GON block. Young et al. reported a case of migraine with allodynia in which allodynia in both the trigeminal territory and the midthoracic area was completely relieved within ve minutes of GON block. Because thoracic and trigeminal rst-order neurons are unlikely to converge on the same neuron near the TNC or cervical complex, he suggested that a descending inhibitory process for allodynia may underlie the effectiveness of GON block in migraine (51). In contrast, Linde et al. found that sumatriptan treatment caused a transient increase in BA in migraine patients (55). Sumatriptan treatment also resulted in decreased heat pain thresholds in both migraine patients and controls. These effects were noted 20 minutes after treatment but were no longer signicant 40 minutes after.

ALLODYNIA IN HEADACHE DISORDERS OTHER THAN MIGRAINE Migraine is not the only primary or secondary headache condition in which allodynia can develop. In a cohort of hospitalized headache patients, allodynia was present in all of the four chronic cluster headache (CH) patients, and in one of the two posttraumatic headache patients (48). Ashkenazi and Young studied 10 CH patients

108

Young et al.

for the occurrence of BA (56). They found that four patients had BA. Of the two subjects who were studied during an attack, one had BA that resolved after treatment. Median disease duration was longer in patients with BA (22 years) compared with those without BA (12 years), suggesting that allodynia in CH may be a timedependent process. Rozen et al. have noted transient allodynia in attacks of SUNCT, short unilateral neuralgiform headache with conjunctival injection and tearing (57). This is especially interesting because the allodynia here began in seconds, not one to several hours as in migraine. Piovesan et al. described a patient with a migraine-related disorder in which allodynia appeared to be a cardinal feature (58). This patient developed attacks of extracranial stabbing and burning pain associated with allodynia (ESBA) independent of her migraine attacks. These attacks had the same duration as her migraine attacks and resolved completely after she was treated with a beta-blocker. Allodynia started half an hour into the attack. Discontinuing the beta-blocker led to recurrence of the migraine and ESBA.

CONCLUSION Allodynia is an important clinical feature of migraine and other primary headache disorders. Because treatment outcomes are worse in episodic migraineurs with allodynia, developing treatments for migraine with allodynia is now a priority. In the meantime, treating migraine before allodynia develops will improve treatment outcome. REFERENCES
1. Patterson SM, Silberstein SD. Sometimes Jello helps: perceptions of headache etiology, triggers and treatment in literature. Headache 1993; 33:7681. 2. Liveing E. On Megrim, Sick Headache, and Some Allied Disorders: A Contribution to the Pathology of Nerve-Storms. London: Churchill, 1873. 3. Selby G, Lance JW. Observation on 500 cases of migraine and allied vascular headaches. J Neurol Neurosurg Psychiatr 1960; 23:2332. 4. Goadsby PJ. Pathophysiology of headache. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache Other Head Pain. 7th ed. New York: Oxford University Press, 2001:5772. 5. Doubell T, Mannion R, Woolf C. The dorsal horn: state-dependent sensory processing, plasticity, and the generation of pain. In: Wall P, Melzack R, eds. Textbook of Pain. 4th ed. London: Churchill Livingstone, 1999:165181. 6. Woolf CJ. Evidence for a central component of postinjury pain hypersensitivity. Nature 1983; 306:686688. 7. Cook AJ et al. Dynamic receptive eld plasticity in rat spinal cord dorsal horn following C primary afferent input. Nature 1987; 325:151153. 8. Woolf CJ, King AE. Dynamic alterations in the cutaneous mechanoreceptive elds of dorsal horn neurons in the rat spinal cord. J Neurosci 1990; 10:27172726. 9. Simone D, Sorkins L, Oh U, et al. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 1991; 66:228246. 10. Hu JW et al. Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brainstem neurones. Pain 1992; 48:5360. 11. Hoheisel U, Mense S. Long-term changes in discharge behavior of cat dorsal horn neurones following noxious stimulation of deep tissues. Pain 1989; 36:239247.

Allodynia and Sensitization in Migraine

109

12. Hylden J, Nahin R, Traub R, Dubner R. Expansion of receptive elds of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inammation: the contribution of dorsal horn mechanisms. Pain 1989; 37:239243. 13. Neugebauer V, Schaible HG. Evidence for a central component in the sensitization of spinal neurons with joint input during development of acute arthritis in cats knee. J Neurophysiol 1990; 64:299311. 14. Koltzenburg M, Lundberg LE, Torebjork HE. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain 1992; 51:207219. 15. Noguchi K, Kawai Y, Fukuoka T, Senba E, Miki K. Substance P induced by peripheral nerve injury in primary afferent sensory neurons and its affect on dorsal column nucleus neurons. J Neurosci 1995; 15:76337643. 16. Neumann L, Doubell T, Leslie T, Woolf C. Inammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 1996:360364. 17. Abbadie C, Trafton J, Liu H, Mantyh P, Basbaum A. Inammation increases the distribution of dorsal horn neurons that internalize the neurokinin-1 receptor in response to noxious and nonnoxious stimulation. J Neurosci 1997; 17:80498060. 18. Ma QP, Woolf CJ. Progressive tactile hypersensitivity: an inammation-induced incremental increase in the excitability of the spinal cord. Pain 1996; 67:97106. 19. Ma Q, Woolf C. Morphine, the NMDA receptor antagonist MK901 and the tachykinin NK1 receptor antagonist RP67580 attenuate the development of inammation-induced progressive tactile hypersensitivity. Pain 1998; 77:4957. 20. Urban MO, Gebhart GF. The glutamate synapse: a target in the pharmacological management of hyperalgesic pain states. Prog Brain Res 1998; 116:407420. 21. Chen L, Huang L. Protein kinase C reduces Mg2 block of NMDA-receptor channels as a mechanism of modulation. Nature 1992; 356:521523. 22. Urban MO, Gebhart GF. Supraspinal contributions to hyperalgesia. PNAS 1999; 96:76877692. 23. Reinold H, Ahmadi S, Depner UB, et al. Spinal inammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J Clin Invest 2005. 24. Stuesse SL, Crisp T, McBurney DL, Schechter JB, Lovell JA, Cruce WL. Neuropathic pain in aged rats: behavioral responses and astrocytic activation. Exp Brain Res 2001; 137:219227. 25. Huang YH, Bergles DE. Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol 2004; 14:346352. 26. Rouach N, Glowinski J, Giaume C. Activity-dependent neuronal control of gap-junctional communication in astrocytes. J Cell Biol 2000; 149:15131526. 27. deLeo JA, Tanga FY, Tawk VL. Neuroimmune activation and neuroinammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist 2004; 10:4052. 28. Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 1994; 33:14711478. 29. Yu XM, Sessle BJ, Hu JW. Differential effects of cutaneous and deep application of inammatory irritant on mechanoreceptive eld properties of trigeminal brain stem nociceptive neurons. J Neurophysiol 1993; 70:17041707. 30. Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996; 384:560564. 31. Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brainstem trigeminal neurons. J Neurophysiol 1998; 79:964982. 32. Yamamura H, Malick A, Chamberlin NL, Burstein R. Cardiovascular and neuronal responses to head stimulation reect central sensitization and cutaneous allodynia in a rat model of migraine. J Neurophysiol 1999; 81:479493.

110

Young et al.

33. Cumberbatch M, Williamson D, Mason G, Hargreaves RJ. Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist. Br J Pharmacol 1999; 126:14781486. 34. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614624. 35. Burstein R, Collins B, Bajwa Z, Jakubowski M. Triptan therapy can abort migraine attacks if given before the establishment or in the absence of cutaneous allodynia and central sensitization: clinical and preclinical evidence. Headache 2002; 42:390391 (Abstract). 36. Burstein R, Jakubowski M. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol 2004; 55:2736. 37. Hansson P, Kinnman E. Unmasking mechanisms of peripheral neuropathic pain in a clinical perspective. Pain Rev 1996; 3:272292. 38. Ochoa JL, Yarnitsky D. Mechanical hyperalgesias in neuropathic pain patients: dynamic and static subtypes. Ann Neurol 1993; 33:465472. 39. Hansson P. Possibilities and potentials pitfalls of combined bedside and quantitative somatosensory analysis in pain patients. In: Bovie J, Hansson P, Lindblom U, eds. Touch, Temperature, and Pain in Health and Disease: Mechanisms and Assessments. Seattle: IASP Press, 1994:113132. 40. Sanchez Del Rio M, Alvarez LJ. Functional neuroimaging of headaches. Lancet Neurol 2004; 3:645651. 41. Petrovic P, Ingvar M, Stone-Elander S, Petersson KM, Hansson P. A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Pain 1999; 83:459470. 42. Peyron R, Garcia-Larrea L, Gregoire MC, et al. Parietal and cingulate processes in central pain. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case. Pain 2000; 84:7787. 43. Peyron R, Schneider F, Faillenot I, et al. An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain. Neurology 2004; 63:18381846. 44. Weissman-Fogel I, Sprecher E, Granovsky Y, Yarnitsky D. Repeated noxious stimulation of the skin enhances cutaneous pain perception of migraine patients in-between attacks: clinical evidence for continuous sub-threshold increase in membrane excitability of central trigeminovascular neurons. Pain 2003; 104:693700. 45. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000; 123(Pt 8):17031709. 46. Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the developing allodynia. Ann Neurol 2004; 55:1926. 47. Ashkenazi A, Sholtzow M, Young WB. Prevalence of mechanical (brush) allodynia in migraine. Neurology 2004; 62:A83-A84 (Abstract). 48. Young WB, Richardson ES, Shukla P. Brush allodynia in hospitalized headache patients. Headache 2005; 45:9991003. 49. Bove ME, Anjum MW, Ashkenazi A, Young WB. Brush (dynamic mechanical) allodynia in headache: the mapping study. Neurology 2004; 62:A336 (Abstract). 50. Lopinto C, Ashkenazi A, Young WB. Comparison of dynamic (brush) and static (pressure) mechanical allodynia in migraine. Cephalalgia 2004; 24:1093 (Abstract). 51. Young WB, Mateos V, Ashkenazi A. Occipital nerve block rapidly eliminates allodynia far from the site of headache: a case report. Cephalalgia 2004; 24:906907. 52. Yamamoto T, Sakashita Y, Nozaki-Taguchi N. Antiallodynic effects of oral COX-2 selective inhibitor on postoperative pain in the rat. Can J Anesth 2000; 47:354360. 53. Takeda K, Sawamura S, Sekiyama H, Tamai H, Hanaoka K. Effect of methylprednisolone on neuropathic pain and spinal glial activation in rats. Anesthesiology 2004; 100:12491257.

Allodynia and Sensitization in Migraine

111

54. Ashkenazi A, Young WB. The effects of occipital nerve block and trigger point injection on brush allodynia and pain in migraine. Headache. In press. 55. Linde M, Elam M, Lundblad L, Olausson H, Dahlof CG. Sumatriptan (5-HT1B/ 1D-agonist) causes a transient allodynia. Cephalalgia 2004; 24:10571066. 56. Ashkenazi A, Young WB. Brush allodynia in cluster headache. Headache 2003; 43:543 (Abstract). 57. Rozen TD, Haynes GV, Saper JR, Sheftell FD. Abrupt onset and termination of cutaneous allodynia (central sensitization) during attacks of SUNCT. Headache 2005; 45:153155. 58. Piovesan EJ, Young BW, Werneck LC, Kowacs PA, Oshinsky ML, Silberstein SD. Recurrent extratrigeminal stabbing and burning sensation with allodynia in a migraine patient. Cephalalgia 2003; 23:231234.

9
Genetics of Migraine and Other Primary Headaches
Gisela M. Terwindt and Esther E. Kors
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

Joost Haan
Department of Neurology, Leiden University Medical Center, Leiden, and Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands

Kaate R. J. Vanmolkot and Rune R. Frants

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

Arn M. J. M. van den Maagdenberg

Department of Neurology and Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

Michel D. Ferrari
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

INTRODUCTIONGENETIC STUDIES ON HEADACHE While genetic research in primary headaches has mainly focused on migraine, more recently, genetic susceptibility in cluster headache (CH) and tension-type headache are also receiving attention. Migraine without aura (MO) and migraine with aura (MA), the two most common subtypes of migraine, are genetically complex, due to the combination of genes and environmental factors involved. By investigating familial hemiplegic migraine (FHM), a rare subtype of MA, with an autosomal dominant mode of inheritance, the identication of migraine genes was facilitated. In FHM, aura consists of hemiparesis, in addition to typical (visual) aura symptoms, preceding the headache phase. There must be at least one family member with identical attacks. FHM attacks often resemble those of basilar migraine (1), and the headache and aura symptoms, apart from the hemiparesis, are identical to those of MA (2). Some patients have atypical attacks, either with a prolonged aura lasting up to ve days or with signs of diffuse encephalopathy, expressed as confusion or coma, fever, and sometimes epileptic seizures. Attacks may be triggered by head trauma. Very often an initial diagnosis of epilepsy is made. Patients with FHM and their relatives are at increased risk for nonhemiplegic typical MA, but not
113

114

Terwindt et al.

MO attacks (3). Sporadic cases with FHM symptomatology [sporadic hemiplegic migraine (SHM)] exist, virtually always with other aura symptoms as well (visual, sensory, and aphasic) (4). The rst gene for FHM (FHM1), CACNA1A, was identied in 1996 on the short arm of chromosome 19 (5). With the identication of the second FHM (FHM2) gene (ATP1A2, on the long arm of chromosome 1, identied in 2003) (6) and the results of several genome screens in MO and MA patients, important progress has been made toward elucidating the genetic causes of migraine.

THE CLINICAL SPECTRUM OF THE CACNA1A GENE MUTATIONS The chromosome 19-linked CACNA1A gene encodes the Cav2.1 protein, which is the pore-forming subunit of P/Q-type calcium channels (5). These channels are expressed throughout the brain and are also present at motor nerve terminals in the neuromuscular junction (NMJ). Their main function is to mediate transmitter release from synaptic nerve terminals (7). Mutations in the CACNA1A gene cause FHM1 and also two other neurological disorders with an autosomal dominant inheritance pattern, namely episodic ataxia type 2 (EA-2) and spinocerebellar ataxia type 6 (SCA6). FHM, EA-2 and SCA6 have considerably overlapping phenotypes. The still-expanding clinical spectrum of CACNA1A mutations has a very complex genotypephenotype correlation.

CACNA1A: FHM Over 50% of all FHM families, including all families with additional cerebellar ataxia, have been linked to CACNA1A mutations. The ataxic features are similar to those seen in SCA6, although the initial symptoms seem to be present at a much younger age. So far, exclusively missense mutations are found in FHM (Fig. 1) (5,822). Most mutations have been identied in one or two families only, but two mutations occur more frequently. The T666M mutation has been found in 20 families worldwide (5,1214,1820,22). Patients with this mutation have a high frequency of hemiplegic migraine (98%), atypical attacks with coma (50%), and nystagmus (86%) (12). One T666M patient was diagnosed as EA-2 because of ataxic symptoms during the attacks (16). Patients with the T666M mutation can also show mental retardation (18), or attacks resembling acute confusional migraine. Another recurrent mutation is R583Q described in six families (8,10,13,20). Most patients have hemiplegic attacks with interictal ataxia, but some members of a large Portuguese family showed cerebellar ataxia only (8), suggesting a reduced penetrance for migraine attacks. Affected members of FHM1 families with the S218L mutation (17) had recurrent atypical attacks, often triggered by trivial head trauma. The proband of one of the families hadafter a mild head traumaa symptom-free period of several hours before she went into a coma. She died 10 days later because of severe cerebral edema. She had never experienced attacks of (hemiplegic) migraine, unlike some family members who had FHM. It seems that the S218L (and possibly other) CACNA1A mutations may put persons at risk for cerebral edema and fatal coma after minor head trauma. Pseudomigraine with lymphocytic pleocytosis is characterized by episodic neurologic dysfunction associated with headache and cerebrospinal uid lymphocytic pleocytosis. As cerebrospinal uid lymphocytic pleocytosis can occur in

Genetics of Migraine and Other Primary Headaches

115

Figure 1 The CACNA1A gene with mutations. The Cav2.1 pore-forming subunit of P/Q-type voltage-gated calcium channels is located in the neuron membrane and contains four repeated domains. Each domain includes six membrane-spanning segments and a so-called P-loop between the fth and sixth segments. Positions of mutations identied in this gene are given (CACNA1A ref. seq.: Genbank Ac. nr. X99897).

atypical FHM attacks and both pseudomigraine and FHM can be triggered by angiography, the CACNA1A gene was studied as a candidate gene (23). In the study conducted by Chapman and colleagues, however, no mutations were found in eight patients. CACNA1A: MA and MO Some mutation carriers in FHM1 families have attacks of MA or MO only, suggesting a role of CACNA1A in the more frequent types of migraine (13,24). This is supported by a study with sibling pairs with MA and/or MO, where an excess allele sharing of markers in the CACNA1A region was found in affected sib-pairs, which was almost exclusively derived from sibling pairs affected with MA (25). This study suggests that the CACNA1A gene might be involved in MO and MA, but the contribution to MA seems larger than to MO. No FHM mutations were found in unselected groups of patients with MO and/or MA (2628). A large Australian family showed linkage to the D19S1150 marker that is located in the CACNA1A gene, but no mutation was found in this family either (2630). Other studies found no positive linkage results in migraine families, using DNA markers adjacent to or within the CACNA1A gene, conrming genetic heterogeneity (29,3134). A recent Finnish study aimed to clarify the role of the CACNA1A locus in MA by analyzing 72 multigenerational Finnish MA families, the largest family sample so far (35). Polymorphic microsatellite markers surrounding the CACNA1A gene were genotyped on 757 individuals, but none showed evidence of linkage to MA either under locus homogeneity or under locus heterogeneity.

116

Terwindt et al.

CACNA1A: EA-2 and SCA6 EA-2 patients present with early onset attacks of imbalance and/or vertigo, lasting hours to days (36). The attacks can be provoked by a number of triggers, including physical exercise or emotional stress, and can be prevented by acetazolamide. Like FHM1, patients with EA-2 can have interictal permanent cerebellar ataxia, and the attacks can be associated with symptoms of (basilar-type) migraine (37). In some cases, generalized weakness is reported during ataxic spells; in other patients, episodic weakness can precede the attacks of ataxia (38,39). Three patients with EA-2 had generalized epilepsy (4042). So far, more than 30 missense mutations or mutations resulting in premature stop or affecting alternative splicing have been identied in patients with EA-2 (Fig. 1) (5,16,3953). There are considerable interfamilial differences. In some families with symptoms indistinguishable from EA-2, no CACNA1A mutation was identied, suggesting that mutations can be missed or that other genes causing a similar symptomatology exist (5456). SCA6 is characterized by the late onset of a slowly progressive cerebellar ataxia with oculomotor abnormalities, gait ataxia, mild upper limb ataxia, and dysarthria (57). Eye-movement abnormalities such as saccadic intrusions during smooth pursuit and nystagmus are prominent and consistent early manifestations (58). Some patients have ataxia combined with episodic headache or nausea. The permanent signs can be preceded by episodic manifestations (58). SCA6 is caused by moderate, stabile expansions of a CAG repeat in the CACNA1A gene. CACNA1A: Epilepsy The involvement of the CACNA1A locus in epilepsy in humans is of interest in view of the epileptic phenotype observed in Cacna1a mutant mice (57,59). The rst association was reported in a group of patients with idiopathic generalized epilepsy (60). Of four single-nucleotide polymorphisms (SNPs) and one microsatellite marker located within CACNA1A, one SNP in exon 8 showed a signicant association. A follow-up study showed that two SNPs in the immediate vicinity of exon 8 were responsible for the association with epilepsy (61). The association was not limited to a specic epileptic syndrome or subgroup. An effect on expression or alternative splicing of the protein was suggested, but not investigated further. The presence of (childhood) seizures next to attacks of EA-2 and in a CACNA1A mutation carrier further supports a role for CACNA1A in epilepsy (41). Recently, a new family with absence epilepsy and EA-2 was found with a novel CACNA1A mutation (40). Epileptic seizures or status epilepticus in association with FHM attacks have been described in patients with CACNA1A mutations (21,62,63). Recently, a family was shown with a (novel) CACNA1A mutation, causing childhood epilepsy, that occurred independently of FHM attacks (64). CACNA1A: Functional Studies Several FHM mutations have been analyzed with electrophysiological techniques in neuronal and non-neuronal cells (40,41,6569). While EA-2 truncating and missense mutations all show a dramatic decrease or even complete loss of Ca2 channel electric current, FHM mutations cause different effects on channel conductance, kinetics, and expression. The most consistent change found with FHM mutations seems to be a hyperpolarizing shift of about 10 mV of the activation voltage. Although this effect in theory will lead to easier opening of the channels in neurons,

Genetics of Migraine and Other Primary Headaches

117

the overall change in calcium inux is difcult to predict because it will be determined by a delicate interplay of effects of a particular mutation on the different channel properties and the cellular environment. Some phenomena might contribute to the episodic nature of symptoms, because calcium inux will be altered, especially during high neuronal activity. Mutant T666M and V714A channels have a low conductance mode that sometimes switches to the wild type state. For other FHM mutations, such as R583Q and D715E, accumulation of inactivated channels was observed during repetitive stimulation. CACNA1A: Mouse Models Several mouse Cacna1a mutants with symptoms of ataxia and epilepsy are available. The main effect of tottering, leaner, and rolling Nagoya mutated P/Q-type channels appears to be reduction of calcium current density (7073). Furthermore, leaner and rolling Nagoya channel kinetics are changed (7072). Two Cacna1a-null-mutant (knock-out) mice show a lethal phenotype at a young age (74,75). Total calcium current density in cerebellar cells was found decreased. P/Q-type currents were abolished and partly compensated for by N- and L-type currents. Cerebellar granule cells of heterozygous mice from one of the two null-mutants displayed a 50% reduction in P/Q-type current density whereas no reduction was observed in the other model (74,75). It is now generally accepted that migraine aura is caused by cortical spreading depression (CSD), a depolarization wave associated with temporary disturbance of ion balances (76). Aura symptoms in some FHM patients could be abolished by the glutamate receptor antagonist ketamine (77). CACNA1A mutations might very well inuence CSD, because P/Q-type calcium channels mediate glutamate release, and an altered glutamate was reported in tottering and Cacna1a knock-out mice (75,78,79). Experimentally induced CSD in tottering and leaner mice was found altered, in parallel with a reduced release of cortical glutamate (80). Recently, a knock-in mouse model was generated, carrying the human pure FHM1 R192Q mutation (81). Unlike the other mouse models, R192Q mice exhibit no overt phenotype. Multiple gain-of-function effects were found, including increased Cav2.1 current density in cerebellar neurons and, in the intact animal, a reduced threshold and increased velocity of CSD. It seems that whole-animal studies are necessary to dissect the effects of mutations and understand the integrated physiology of a disease. CACNA1A: The NMJ The neuromuscular junction (NMJ) is a suitable synapse model to study Cacna1a mutations, because motor nerve terminals contain P-type calcium channels responsible for acetylcholine release. Transmitter release in tottering NMJs in vitro was decreased during high-rate nerve stimulation (78). Interestingly, spontaneous quantal transmitter release was doubled. In comparison, the R192Q knock-in mice show enhanced neurotransmission at the NMJ. Neuromuscular transmission in vivo in patients may be compromised as well. Indeed, recent clinical electrophysiological studies showed NMJ malfunction in three EA-2 patients with CACNA1A missense and truncation mutations: single-ber electromyography (SFEMG) demonstrated increased jitter and the occurrence of blockings in these patients (39). While similar ndings were observed in patients with MA (82), SFEMG recordings in FHM patients and patients with SCA6 were unremarkable (39,83).

118

Terwindt et al.

THE CLINICAL SPECTRUM OF THE ATP1A2 GENE In 1997 linkage studies identied the FHM2 locus on chromosome 1; however, it took another six years to identify mutations in the ATP1A2 gene, encoding the alpha2 subunit of sodiumpotassium pumps (6,84).

ATP1A2: FHM First, missense mutations were identied in two Italian families with pure FHM (without ataxia) (6). Since then, several other FHM families with similar mutations have been described (Fig. 2). A novel M731T mutation was identied in a small Dutch family with pure FHM (85), and a T345A mutation caused FHM attacks and coma in a Scandinavian family (86). A screening in 27 FHM families, in which CACNA1A mutations were excluded, revealed six novel ATP1A2 mutations (87). Three other novel mutations (and another three possible mutations) were found in German FHM families (88). In a small family from Italy, patients with an R548H mutation did not have FHM attacks, but basilar migraine or migraine with (visual) aura (89). Another Italian group found a G301R mutation in a family with FHM, seizures, coma, and sensory decits, butimportantlyalso transient and permanent cerebellar signs (90). So, the phenotypic spectrum of FHM2 expands beyond migraine, like that of FHM1.

Figure 2 Predicted transmembrane model of the Na, K-ATPase a2 subunit, which is located in the plasma membrane and contains 10 transmembrane segments. Positions of mutations identied in this gene are given (ATP1A2 ref. seq.: Genbank Ac. nr. NM_000702).

Genetics of Migraine and Other Primary Headaches

119

ATP1A2: MA and MO In a recent study, no ATP1A2 mutations were found in probands of families with common types of migraine (MO and MA) (91). In several of the published families with ATP1A2 mutations, there are, however, mutation carriers with nonhemiplegic migraine [e.g., the Italian families described in the rst publication (6)]. The true contribution of the ATP1A2 gene to MO and MA is still unclear. ATP1A2: Epilepsy Three subjects in the Italian families of the rst publication on ATP1A2 (6) reported a history of epileptic seizures resembling the migraine-triggered seizures observed in FHM1 patients. The association of ATP1A2 mutations and epilepsy was conrmed by the nding of the R689Q mutation, which causes FHM and benign familial infantile convulsions (BFIC) in a large family (85,92). BFIC is a rare, autosomal dominant, benign form of epilepsy, with strictly partial, nonfebrile convulsions that begin between 3 and 12 months of age and disappear after the rst year in all. In the family, all BFIC persons tested had the missense mutation, but BFIC and FHM only partially cosegregated. It seems that, in this family, migraine and epilepsy have partially overlapping mechanisms related to dysfunction of ion transport. A further association between an ATP1A2 mutation (G301R) and epilepsy was found by an Italian group, in a family with FHM, seizures, coma, sensory decits, and transient and permanent cerebellar signs (90). Epileptic seizures were also present in German D719N and P979L mutation carriers (88). ATP1A2: AHC Alternating hemiplegia of childhood (AHC) is a rare brain disorder, characterized by (i) repeated periods of hemiplegia involving either side of the body, at least in some attacks; (ii) episodes of bilateral hemiplegia or quadriplegia, starting either as generalization of a hemiplegic episode or present bilaterally from the start; (iii) other paroxysmal phenomena, including tonic/dystonic attacks, choreoathetotic movements, nystagmus, strabismus, dyspnea, and autonomic phenomena, occurring during hemiplegic attacks or in isolation; (iv) immediate disappearance of all symptoms on going to sleep, with recurrence 10 to 20 minutes after awakening in longlasting attacks; and (v) evidence of developmental delay, mental retardation, and permanent neurologic abnormalities, including choreoathetosis, dystonia, or ataxia. In general age at onset is before 18 months (93). AHC has often been regarded as being related to migraine, but some of its aspects are clearly distinct, including choreoathetosis and dystonic posturing, and a progressive course associated with mental deterioration. Two separate groups found ATP1A2 mutations in (presumed) cases of AHC (94,95). In both studies, it was remarkable that familial cases were studied, because AHC is generally considered a sporadic disease. The clinical description of the patients in both studies could also lead to the diagnosis of FHM. So, these ndings are of importance, because they expand the number of families with ATP1A2 mutations (AHC or not), but only the discovery of ATP1A2 mutations in sporadic AHC patients could conrm the importance of this gene in AHC. However, in our two previous studies, no CACNA1A or ATP1A2 mutations were found in sporadic AHC patients (96,97).

120

Terwindt et al.

ATP1A2: Functional Studies The ATP1A2 gene encodes the alpha2 subunit of an Na, K pump ATPase. This catalytic subunit binds Na, K, and ATP, and utilizes ATP hydrolysis to extrude Na ions. Na pumping provides the steep Na gradient essential for the transport of glutamate and Ca2. The gene is predominantly expressed in neurons at the neonatal age and in glial cells at the adult age. Functional analysis of mutated proteins revealed inhibition of pump activity and decreased afnity for K(6,94,98). Both functional phenotypes t nicely the current concepts of (hemiplegic) migraine pathophysiology; clearance of synaptic glutamate and K is slowed, either because of Na, K ATPase haploin sufciency or reduced K afnity, resulting in increased susceptibility to CSD (99). ATP1A2: Mouse Models Several transgenic mouse Atp1a2-null mutants have been generated (100,101). Selective neuronal apoptosis in the amygdala and piriform cortex in response to neural hyperactivity was revealed in 18.5-day-old Atp1a2-null fetuses (100). Atp1a2null mice died immediately after birth, because of severe motor decits that also abolish respiration (100,101). Interestingly, in line with the observed epilepsy in patients, Atp1a2-null mice on 129sv genetic background display frequent and generalized seizures, but die within 24 hours after birth (102). Heterozygous Atp1a2/ mice are viable, and the heart showed a hypercontractile state with positive inotropic response and resembles what is typically seen after the administration of cardiac glycosides (101). In addition, heterozygous Atp1a2/ mice revealed enhanced fear/anxiety behaviors after conditioned fear stimuli, probably due to the observed neuronal hyperactivity in the amygdala and piriform cortex (100).

SPORADIC HEMIPLEGIC MIGRAINE Hemiplegic migraine patients are not always clustered in families, as sporadic patients, without affected family members, are often seen. It was shown that the clinical symptoms of patients with SHM were more similar to FHM than MA, which resulted in the inclusion of SHM as a separate diagnostic entity in the second edition of the diagnostic criteria, apart from migraine with typical aura (4,103). Some of the sporadic patients are the rst FHM patient in the family, as was shown by the identication of CACNA1A mutations in 2 out of 27 patients undergoing mutation analysis (20). However, the majority seem to have no mutation in any of the known FHM genes, dening SHM as a heterogeneous disease of unknown (genetic) origin. This was conrmed by the observation that rst-degree relatives of SHM probands had an increased risk of both MO and typical MA, whereas rst-degree relatives of probands with exclusively SHM had no increased risk of MO but an increased risk of typical MA. SHM probands had a highly increased risk of typical MA only (104). GENETIC SUSCEPTIBILITY IN MIGRAINE Family and Twin Studies in Migraine Two recent twin studies conrmed the presence of genetic and environmental factors in migraine. Svensson et al. studied a cohort of twins aged 42 to 81 years, including a

Genetics of Migraine and Other Primary Headaches

121

subsample of 314 pairs reared apart and 364-matched control pairs reared together (105). They found no signicant shared rearing environmental inuences on migraine. The heritability of migraine was estimated at 38% for men and 48% for women. Interestingly, among monozygotic twins reared apart, those separated at three years of age or earlier were more similar for lifetime migraine than those separated later, and this was especially true for women. Svensson et al. (105) concluded that family resistance in migraine is mainly due to genetic factors, whereas environmental inuences make family members different, not similar. Mulder et al. (106) compared the prevalence and heritability of migraine across six of the countries that participated in the GenomEUtwin project, including a total of 29,717 twin pairs. The prevalence of migraine ranged from 10% to 13% in Finland to 32% to 34% in Danish and Dutch females. Unlike the results of Svensson et al. (105), the genetic variance or heritability was the same between sexes, ranging from 34% to 57% in the different cohorts. Previous family studies have found an increased relative risk of rst-degree family members of patients with MO and MA of approximately 2 and 4, respectively, as compared to the general population. A small family study of MA probands and their rst-degree family members in a southern Italian town found a similar risk (107). Noble-Topham et al. estimated the genetic load in familial MA, by comparing sibling risk, age at onset, and aura type in 54-MA probands categorized by family history of MA (108). Families with an MA proband were divided into families with MA in three generations (n 15), two generations (n 20), and one generation, only the proband being affected (n 19). The recurrence risk to siblings of probands was 2.7-fold higher in the three-generation compared with the two-generation MA families and 4.8-fold higher in the three-generation compared with the one-generation MA families. MA probands from the three-generation families were signicantly younger than probands with no affected family members. The signicant difference in genetic load and the earlier age at onset in the three-generation families is further evidence for a genetic basis for MA. One of the presumptions in the scientic investigations of the genetics of migraine is that the rare autosomal dominant disease FHM is an extreme form of migraine, belonging to a continuous migraine spectrum, and that study of this rare variant can provide insight into the more common forms. To further investigate the migraine-spectrum, Thomsen et al. studied the prevalence of MO and MA in probands with FHM and in their rst-degree relatives (3). Compared to the general population, FHM probands had virtually no increased risk of MO, but a signicantly increased risk of almost eight times of MA. A similar pattern was seen among their rst-degree relatives, who had no increased risk of MO, whereas the risk of MA was signicantly increased7.6 times in FHM-affected rst-degree relatives and 2.4 times in nonFHM-affected rst-degree relatives. These results suggest that the genetic abnormality resulting in FHM may also cause attacks with the symptomatology of MA. Thus, FHM and MA seem to be part of the same spectrum. Linkage Studies in Migraine The identication of genes responsible for the frequent forms of migraine is a challenging task. Linkage analysis in multifactorial diseases such as migraine is limited by the lack of clear genetic segregation of any DNA variants in multigenerational family material, and by the modest contribution to disease of individual susceptibility mutations (109).

122

Terwindt et al.

Linkage studies in large Australian families with MO and MA revealed linkage on 19p13, 1q31, and Xq24-28 (30,110112). These results await conrmation. Recently, several successful genome-wide linkage studies have been conducted. Wessman et al. showed linkage to chromosome 4q21 in Finnish MA families (34), which was recently conrmed in 103 Icelandic families with 289 MO patients (113). Genome-wide scanning revealed a locus on chromosome 4q21, which shows overlap with the Finnish locus. Interestingly, the LOD score increased when the sample set was reanalyzed using affected females only, and allowing a relaxed denition of MO. This might be explained, according to the researchers, by the higher preponderance in females. In a Canadian linkage study, a genome-wide screen was conducted in 43 families with MA, selected because of an apparent autosomal dominant pattern of transmission (114). A susceptibility locus was identied on chromosome 11q24. In 10 Italian MA families with autosomal dominant inheritance, a locus in the 15q11-q13 region was found (115). In addition to linkage analysis in multifamily studies, two mapping studies were reported in single families. A large Italian MO pedigree revealed signicant evidence of linkage on chromosome 14q22.1 (116). In a large Swedish family with MO and MA, linkage was obtained for a locus on chromosome 6p12.2-p21.1 (117). Like the Icelandic study, they allowed a relaxed denition of MO in about half of the MO patients. The causative gene has not been identied in any of the above-mentioned loci, additional studies should investigate the contribution of these loci to migraine.

Association Studies in Migraine A widely used method to assess the genetic background of complex disorders such as migraine is to study possible associations between migraine patients and polymorphisms in genes with hypothesized function in the migraine pathway. Based on this presumption, dopamine-, serotonin-, and homocysteine-related genes were studied frequently, and associations between migraine and dopamine receptor genes and the MTHFR gene have been reported (118124). The serotonin 5-HT-2C receptor gene, located on chromosome X, revealed no signicant association in a group of 275 migraineurs and 275 controls, and mutation analysis showed no mutation in two migraine families previously reported to be linked to this region (125). Associations between migraine polymorphisms in genes such as the glutathione S-transferase gene (126), the low-density lipoprotein receptor gene (127), the INSR gene (128), the endothelin type A receptor gene, and (129) the tumor necrosis factora gene (130) need conrmation. One should keep in mind that association studies are difcult to perform in a comprehensive and meaningful manner. Potential publication bias, power problems, population admixture, and the issue of linkage disequilibrium within a gene make individual studies of limited importance.

Other Studies on Headache Genetics Migraine and Mitochondria Inherited mitochondrial abnormalities are frequently claimed to be important in migraine (131), but mtDNA mutations have never been found in groups of migraine

Genetics of Migraine and Other Primary Headaches

123

patients, even if they were selected based on matrilinear inheritance, on the presence of a migrainous infarct or on other clinical grounds. A recent description of segregation of familiar cases of migraine in a family with the Leber T14484C mutation (132) adds to a number of previous clinical observations of migraine in patients with various mtDNA mutations. An interesting observation was made in the so-called cyclic vomiting syndrome (CVS), recently included in the second edition of the international classication of headache disorders (103) as one of the childhood periodic syndromes that are commonly precursors of migraine. The origin is thought to be mitochondrial. A survey of parents of 62 children with a severe form of CVS showed that migraine, myopathy, seizures, and dysautonomia-like symptoms were far more common in matrilineal versus nonmatrilineal relatives (133). mtDNA sequence variants are probable risk factors in most children at this severe end of the CVS spectrum, and migraine appears to be part of the phenotype (134).

CLUSTER HEADACHE Since the 1990s, familial occurrence of CH has been repeatedly recognized. Recent clinical investigations gave further evidence of a genetic background of CH, without any attempt to map or identify a putative CH gene (135137). Torelli et al. compared familial and nonfamilial CH cases (137). A lower mean age at onset in women with familial CH was found. There were no signicant differences between the two CH groups in pain location, accompanying symptoms, duration and frequency of attacks, and active periods. Rainero et al. evaluated several polymorphisms of the hypocretin/orexin system genes in 109 CH patients and 211 controls. The 1246 G > A polymorphism of the hypocretin receptor 2 gene was signicantly different between cases and controls (138). Hyporcretin neurons play an important role in regulating the sleepwake cycle and CH attacks often during the night. Further studies are needed to conrm the involvement of the hypocretin receptor 2 gene or other genes in this chromosomal region.

TENSION-TYPE HEADACHE In a genetic epidemiological study, the familial aggregation of chronic tension-type headache was investigated. Compared with the general population, rst-degree relatives had a 3.1-fold increased risk of chronic tension-type headache (CTTH). A complex segregation analysis further emphasized the result by suggesting that chronic tension-type headache has multifactorial inheritance (139).

CONCLUDING REMARKS Investigation of FHM is an important part of migraine genetics research, based on the assumption that FHM is part of the migraine spectrum. This is now supported by several family studies. The identication of the second FHM gene, ATP1A2, conrmed that dysfunction in ion transport is a key factor in the pathophysiology of (familial hemiplegic) migraine. New loci for the common forms of migraine were reported on chromosome 6 (MO and MA), 11 (MA), and 14 (MO), and the

124

Terwindt et al.

previously reported MA locus on chromosome 4 seems to be important in MO as well. These ndings underline the complex genetic nature of MO and MA. Finally, associations between migraine and polymorphisms in the dopamine receptor D4 gene and the MTHFR gene show that these genes and the corresponding metabolic pathways are likely part of the genetic susceptibility in migraine. REFERENCES
1. Haan J, Terwindt GM, Ophoff RA, Bos PL, Frants RR, Ferrari MD. Is familial hemiplegic migraine a hereditary form of basilar migraine? Cephalalgia 1995; 15:477481. 2. Thomsen LL, Eriksen MK, Roemer SF, Andersen I, Olesen J, Russell MB. A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain 2002; 125(Pt 6):13791391. 3. Thomsen LL, Olesen J, Russell MB. Increased risk of migraine with typical aura in probands with familial hemiplegic migraine and their relatives. Eur J Neurol 2003; 10(4):421427. 4. Thomsen LL, Ostergaard E, Olesen J, Russell MB. Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine. Neurology 2003; 60(4):595601. 5. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 channel gene CACNL1A4. Cell 1996; 87:543552. 6. De Fusco M, Marconi R, Silvestri L, et al. Haploinsufciency of ATP1A2 encoding the Na/K pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003; 33(2):192196. 7. Catterall WA. Structure and function of neuronal Ca2 channels and their role in neurotransmitter release. Cell Calcium 1998; 24(56):307323. 8. Alonso I, Barros J, Tuna A, et al. Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. Arch Neurol 2003; 60(4):610614. 9. Alonso I, Barros J, Tuna A, et al. A novel R1347Q mutation in the predicted voltage sensor segment of the P/Q-type calcium-channel alpha-subunit in a family with progressive cerebellar ataxia and hemiplegic migraine. Clin Genet 2004; 65(1):7072. 10. Battistini S, Stenirri S, Piatti M, et al. A new CACNA1A gene mutation in acetazolamideresponsive familial hemiplegic migraine and ataxia. Neurology 1999; 53:3843. 11. Carrera P, Piatti M, Stenirri S, et al. Genetic heterogeneity in Italian families with familial hemiplegic migraine. Neurology 1999; 53(1):2633. 12. Ducros A, Denier C, Joutel A, et al. Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 1999; 64:8998. 13. Ducros A, Denier C, Joutel A, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 2001; 345(1):1724. 14. Friend KL, Crimmins D, Phan TG, et al. Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. Hum Genet 1999; 105(3):261265. 15. Gardner K, Bernal O, Keegan M, et al. A new mutation in the Chr19p calcium channel gene CACNL1A4 causing hemiplegic migraine with ataxia. Neurology 1999; 52(suppl 2): A115A116. 16. Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology 2004; 62(1):1722. 17. Kors EE, Terwindt GM, Vermeulen FL, et al. Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol 2001; 49(6):753760.

Genetics of Migraine and Other Primary Headaches

125

18. Kors EE, Haan J, Gifn NJ, et al. Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine. Arch Neurol 2003; 60(5):684688. 19. Takahashi T, Igarashi S, Kimura T, et al. Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene. J Neurol Neurosurg Psychiatr 2002; 72(5):676677. 20. Terwindt G, Kors E, Haan J, et al. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Arch Neurol 2002; 59(6):10161018. 21. Vahedi K, Denier C, Ducros A, et al. CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy [In Process Citation]. Neurology 2000; 55(7):10401042. 22. Wada T, Kobayashi N, Takahashi Y, Aoki T, Watanabe T, Saitoh S. Wide clinical variability in a family with a CACNA1A T666m mutation: hemiplegic migraine, coma, and progressive ataxia. Pediatr Neurol 2002; 26(1):4750. 23. Chapman KM, Szczygielski BI, Toth C, et al. Pseudomigraine with lymphocytic pleocytosis: a calcium channelopathy? Clinical description of 10 cases and genetic analysis of the familial hemiplegic migraine gene CACNA1A. Headache 2003; 43(8):892895. 24. Terwindt GM, Ophoff RA, Haan J, et al. Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Neurology 1998; 50:11051110. 25. Terwindt GM, Ophoff RA, van Eijk R, et al. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 2001; 56(8):10281032. 26. Brugnoni R, Leone M, Rigamonti A, et al. Is the CACNA1A gene involved in familial migraine with aura? Neurol Sci 2002; 23(1):15. 27. Kim JS, Yue Q, Nelson SF, Baloh RW. Familial migraine with vertigo: no mutations found in CACNA1A. Am J Med Genet 1998; 79:148151. 28. Wieser T, Mueller C, Evers S, Zierz S, Deufel T. Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing. Clin Chem Lab Med 2003; 41(3):272275. 29. Lea RA, Curtain RP, Hutchins RP, Brimage PJ, Grifths LR. Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility. Am J Med Genet 2001; 105:707712. 30. Nyholt DR, Hons BSc, Lea RA, Goadsby PJ, Brimage PJ, Grifths LR. Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology 1998; 50:14281432. 31. Hovatta I, Kallela M, Farkkila M, Peltonen L. Familial migraine: exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p. Genomics 1994; 23:707709. 32. Jones KW, Ehm MG, Pericak-Vance MA, Haines JL, Boyd PR, Peroutka SJ. Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus. Genomics 2001; 78(3):150154. 33. Noble-Topham SE, Dyment DA, Cader MZ, et al. Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13. Neurology 2002; 59(7):10991101. 34. Wessman M, Kallela M, Kaunisto MA, et al. A susceptibility locus for migraine with aura, on chromosome 4q24. Am J Hum Genet 2002; 70(3):652662. 35. Kaunisto MA, Tikka PJ, Kallela M, et al. Chromosome 19p13 loci in Finnish migraine with aura families. Am J Med Genet B Neuropsychiatr Genet 2004; 132B(1):8589. 36. Brandt T, Strupp M. Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo). Audiol Neurotol 1997; 2(6):373383. 37. Baloh RW, Yue Q, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 1997; 41(1):816.

126

Terwindt et al.

38. Jen J, Yue Q, Nelson SF, et al. A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. Neurology 1999; 53:3437. 39. Jen J, Wan J, Graves M, et al. Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology 2001; 57(10):18431848. 40. Imbrici P, Jaffe SL, Eunson LH, et al. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain 2004; 127(Pt 12):26822692. 41. Jouvenceau A, Eunson LH, Spauschus A, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 2001; 358(9284):801807. 42. Strupp M, Kalla R, Dichgans M, Freilinger T, Glasauer S, Brandt T. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 2004; 62(9):16231625. 43. Denier C, Ducros A, Vahedi K, et al. High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology 1999; 52:18161821. 44. Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E. Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol 2001; 58(2):292295. 45. Guida S, Trettel F, Pagnutti S, et al. Complete loss of p/q calcium channel activity caused by a cacna1a missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet 2001; 68(3):759764. 46. Matsuyama Z, Murase M, Shimizu H, et al. A novel insertion mutation of acetazolamideresponsive episodic ataxia in a Japanese family. J Neurol Sci 2003; 210(12):9193. 47. Scoggan KA, Chandra T, Nelson R, Hahn AF, Bulman DE. Identication of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2. J Med Genet 2001; 38(4):249253. 48. Subramony SH, Schott K, Raike RS, et al. Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar decits. Ann Neurol 2003; 54(6):725731. 49. Van den Maagdenberg AM, Kors EE, Brunt ER, et al. Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene. J Neurol 2002; 249(11):15151519. 50. Yue Q, Jen JC, Thwe MM, Nelson SF, Baloh RW. De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia. Am J Med Genet 1998; 77:298301. 51. Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet 1997; 61(5):10781087. 52. Kaunisto MA, Harno H, Kallela M, et al. Novel splice site CACNA1A mutation causing episodic ataxia type 2. Neurogenetics 2004; 5(1):6973. 53. Mantuano E, Veneziano L, Spadaro M, et al. Clusters of non-truncating mutations of P/Q type Ca2 channel subunit Ca(v)2.1 causing episodic ataxia 2. J Med Genet 2004; 41(6):e82. 54. Hirose H, Arayama T, Takita J, Igarashi T, Hayashi Y, Nagao Y. A family of episodic ataxia type 2: no evidence of genetic linkage to the CACNA1A gene. Int J Mol Med 2003; 11(2):187189. 55. Sasaki O, Jen JC, Baloh RW, Kim GW, Isawa M, Usami S. Neurotological ndings in a family with episodic ataxia. J Neurol 2003; 250(3):373375. 56. Mochizuki Y, Kawata A, Mizutani T, et al. Hereditary paroxysmal ataxia with mental retardation: a clinicopathological study in relation to episodic ataxia type 2. Acta Neuropathol (Berl) 2004; 108(4):345349. 57. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the 1A-voltage-dependent calcium channel. Nat Genet 1997:6269. 58. Sinke RJ, Ippel EF, Diepstraten CM, et al. Clinical and molecular correlations in spinocerebellar ataxia type 6: a study of 24 Dutch families. Arch Neurol 2001; 58(11): 18391844. 59. Plomp JJ, Van den Maagdenberg AM, Molenaar PC, Frants RR, Ferrari MD. Mutant P/Q-type calcium channel electrophysiology and migraine. Curr Opin Investig Drugs 2001; 2(9):12501260.

Genetics of Migraine and Other Primary Headaches

127

60. Chioza B, Wilkie H, Nashef L, et al. Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology 2001; 56(9):12451246. 61. Chioza B, Osei-Lah A, Nashef L, et al. Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy. Eur J Hum Genet 2002; 10(12):857864. 62. Kramer U, Lerman-Sagi T, Margalith D, Harel S. A family with hemiplegic migraine and focal seizures. Eur J Paediatr Neurol 1997; 1(1):3538. 63. Beauvais K, Cave-Riant F, De Barace C, Tardieu M, Tournier-Lasserve E, Furby A. New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus. Eur Neurol 2004; 52(1):5861. 64. Kors EE, Melberg A, Vanmolkot KRJ, et al. Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation. Neurology 2004; 63(6):1136. 65. Cao YQ, Piedras-Renteria ES, Smith GB, Chen G, Harata NC, Tsien RW. Presynaptic Ca2 channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2 channelopathy. Neuron 2004; 43(3):387400. 66. Hans M, Luvisetto S, Williams M, et al. Functional consequences of mutations in the human 1A calcium channel subunit linked to familial hemiplegic migraine. J Neurosci 1999; 19(5):16101619. 67. Kraus RL, Sinnegger MJ, Glossmann H, Heringt S, Striessnig J. Familial hemiplegic migraine mutations change alpha 1A Ca2 channel kinetics. J Biol Chem 1998; 273(10): 55865590. 68. Kraus RL, Sinnegger MJ, Koschak A, et al. Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2) channel kinetics. J Biol Chem 2000; 275(13): 92399243. 69. Tottene A, Fellin T, Pagnutti S, et al. Familial hemiplegic migraine mutations increase Ca(2) inux through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci USA 2002; 99(20):1328413289. 70. Dove LS, Abbott LC, Grifth WH. Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. J Neurosci 1998; 18(19):76877699. 71. Lorenzon NM, Lutz CM, Frankel WN, Beam KG. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner. J Neurosci 1998; 18(12): 44824489. 72. Mori Y, Wakamori M, Oda S, et al. Reduced voltage sensitivity of activation of P/Qtype Ca2 channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol)). J Neurosci 2000; 20(15):56545662. 73. Wakamori M, Yamazaki K, Matsunodaira H, et al. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel. J Biol Chem 1998; 273(52):3485734867. 74. Fletcher CF, Tottene A, Lennon VA, et al. Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. FASEB J 2001; 15(7):12881290. 75. Jun K, Piedras-Renteria ES, Smith SM, et al. Ablation of P/Q-type Ca(2) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit. Proc Natl Acad Sci USA 1999; 96(26):1524515250. 76. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994; 117(Pt 1):199210. 77. Kaube H, Herzog J, Kaufer T, Dichgans M, Diener HC. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000; 55(1):139141. 78. Plomp JJ, Vergouwe MN, Van den Maagdenberg AM, Ferrari MD, Frants RR, Molenaar PC. Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca(2) channel mutation. Brain 2000; 123(Pt 3): 463471.

128

Terwindt et al.

79. Obrenovitch TP, Zilkha E. Inhibition of cortical spreading depression by L-701,324, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complex. Br J Pharmacol 1996; 117(5):931937. 80. Ayata C, Shimizu-Sasamata M, Lo EH, Noebels JL, Moskowitz MA. Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels. Neuroscience 2000; 95(3):639645. 81. Van den Maagdenberg AM, Pietrobon D, Pizzorusso T, et al. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004; 41(5):701710. 82. Ambrosini A, Maertens DN, Schoenen J. Neuromuscular transmission in migraine: a single-ber EMG study in clinical subgroups. Neurology 2001; 56(8):10381043. 83. Terwindt GM, Kors EE, Vein AA, Ferrari MD, Van Dijk JG. Single-ber EMG in familial hemiplegic migraine. Neurology 2004; 63(10):19421943. 84. Marconi R, De Fusco M, Aridon P, et al. Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23. Ann Neurol 2003; 53(3):376381. 85. Vanmolkot KR, Kors EE, Hottenga JJ, et al. Novel mutations in the Na, K-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 2003; 54(3):360366. 86. Kaunisto MA, Harno H, Vanmolkot KR, et al. A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2. Neurogenetics 2004; 5(2): 141146. 87. Riant F, Ducros A, Ploton C, et al. ATP1A2 screening in 27 families with hemiplegic migraine. Eur J Neurol 2004; 11(suppl 2):292. 88. Jurkat-Rott K, Freilinger T, Dreier JP, et al. Variability of familial hemiplegic migraine with novel A1A2 Na/K-ATPase variants. Neurology 2004; 62(10):18571861. 89. Ambrosini A, DOnofrio M, Grieco GS. Familial basilar migraine associated with a new mutation in the ATP1A2 gene. Neurology 2005; 65:18261828. 90. Spadaro M, Ursu S, Lehmann-Horn F, et al. A G301R Na()/K()-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. Neurogenetics 2004; 5(3):177185. 91. Jen JC, Kim GW, Dudding KA, Baloh RW. No mutations in CACNA1A and ATP1A2 in probands with common types of migraine. Arch Neurol 2004; 61(6):926928. 92. Terwindt GM, Ophoff RA, Lindhout D, et al. Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome. Epilepsia 1998; 38(9):915921. 93. Bourgeois M, Aicardi J, Goutieres F. Alternating hemiplegia of childhood. J Pediatr 1993; 122(5 Pt 1):673679. 94. Bassi MT, Bresolin N, Tonelli A, et al. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet 2004; 41(8):621628. 95. Swoboda KJ, Kanavakis E, Xaidara A, et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol 2004; 55(6): 884887. 96. Haan J, Kors EE, Terwindt GM, et al. Alternating hemiplegia of childhood: no mutations in the familial hemiplegic migraine CACNA1A gene. Cephalalgia 2000; 20(8): 696700. 97. Kors EE, Vanmolkot KR, Haan J, et al. Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2. Neuropediatrics 2004; 35(5):293296. 98. Segall L, Scanzano R, Kaunisto MA, et al. Kinetic alterations due to a missense mutation in the Na, K-ATPase alpha2 subunit cause familial hemiplegic migraine type 2. J Biol Chem 2004; 279(42):4369243696. 99. Moskowitz MA, Bolay H, Dalkara T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann Neurol 2004; 55(2):276280.

Genetics of Migraine and Other Primary Headaches

129

100. Ikeda K, Onaka T, Yamakado M, et al. Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (Atp1a2)-decient mice. J Neurosci 2003; 23(11):46674676. 101. James PF, Grupp IL, Grupp G, et al. Identication of a specic role for the Na, K-ATPase alpha2 isoform as a regulator of calcium in the heart. Mol Cell 1999; 3(5): 555563. 102. Ikeda K, Onimaru H, Yamada J, et al. Malfunction of respiratory-related neuronal activity in Na, K-ATPase alpha2 subunit-decient mice is attributable to abnormal Cl-homeostasis in brainstem neurons. J Neurosci 2004; 24(47):1069310701. 103. Headache Classication Subcommittee of the International Headache Society. The International Classication of Headache Disorders. 2nd ed. Cephalalgia 2004; 24(suppl 1): 1160. 104. Thomsen LL, Ostergaard E, Romer SF, et al. Sporadic hemiplegic migraine is an aetiologically heterogeneous disorder. Cephalalgia 2003; 23(9):921928. 105. Svensson DA, Larsson B, Waldenlind E, Pedersen NL. Shared rearing environment in migraine: results from twins reared apart and twins reared together. Headache 2003; 43(3):235244. 106. Mulder EJ, van Baal C, Gaistz D, et al. Genetic and environmental inuences on migraine: a twin study across six countries. Twin Res 2003; 6(5):422431. 107. Cologno D, De Pascale A, Manzoni GC. Familial occurrence of migraine with aura in a population-based study. Headache 2003; 43(3):231234. 108. Noble-Topham SE, Cader MZ, Dyment DA, Rice GPA, Brown JD, Ebers GC. Genetic loading in familial migraine with aura. J Neurol Neurosurg Psychiatr 2003; 74(8):1128 1130. 109. Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet 2001; 2(2):9199. 110. Lea RA, Shepherd AG, Curtain RP, et al. A typical migraine susceptibility region localizes to chromosome 1q31. Neurogenetics 2002; 4(1):1722. 111. Nyholt DR, Dawkins JL, Brimage PJ, Goadsby PJ, Nicholson GA, Grifths LR. Evidence for an x-linked genetic component in familial typical migraine. Hum Mol Genet 1998; 7(3):459463. 112. Nyholt DR, Curtain RP, Grifths LR. Familial typical migraine: signicant linkage and localization of a gene to Xq2428. Hum Genet 2000; 107(1):1823. 113. Bjornsson A, Gudmundsson G, Gudnnsson E, et al. Localization of a gene for migraine without aura to chromosome 4q21. Am J Hum Genet 2003; 73(6):986993. 114. Cader ZM, Noble-Topham S, Dyment DA, et al. Signicant linkage to migraine with aura on chromosome 11q24. Hum Mol Genet 2003; 12(19):25112517. 115. Russo L, Mariotti P, Sangiorgi E, et al. A new susceptibility locus for migraine with aura in the 15q11-q13 genomic region containing three GABA-A receptor genes. Am J Hum Genet 2004; 76(2). 116. Soragna D, Vettori A, Carraro G, et al. A locus for migraine without aura maps on chromosome 14q21.2-q22.3. Am J Hum Genet 2003; 72(1):161167. 117. Carlsson A, Forsgren L, Nylander PO, et al. Identication of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1. Neurology 2002; 59(11):18041807. 118. Del Zompo M, Cherchi A, Palmas MA, et al. Association between dopamine receptor genes and migraine without aura in a Sardinian sample. Neurology 1998; 51:781786. 119. Mochi M, Cevoli S, Cortelli P, et al. A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes. Neurol Sci 2003; 23(6):301305. 120. Peroutka SJ, Price SC, Wilhoit TL, Jones KW. Comorbid migraine with aura, anxiety and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles. Mol Med 1998; 4:1421.

130

Terwindt et al.

121. Kowa H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K. The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. Am J Med Genet 2000; 96(6):762764. 122. Kara I, Sazci A, Ergul E, Kaya G, Kilic G. Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk. Brain Res Mol Brain Res 2003; 111(12):8490. 123. Lea RA, Ovcaric M, Sundholm J, Macmillan J, Grifths LR. The methylenetetrahydrofolate reductase gene variant C677T inuences susceptibility to migraine with aura. BMC Med 2004; 2(1):3. 124. Scher AI, Terwindt GM, Verschuren WM. Migraine and MTHFR C677T genotype in a population-based sample. Ann Neurol 2006; 59(2):372375. 125. Johnson MP, Lea RA, Curtain RP, MacMillan JC, Grifths LR. An investigation of the 5-HT2C receptor gene as a migraine candidate gene. Am J Med Genet 2003; 117B(1):8689. 126. Kusumi M, Ishizaki K, Kowa H, et al. Glutathione S-transferase polymorphisms: susceptibility to migraine without aura. Eur Neurol 2003; 49(4):218222. 127. Mochi M, Cevoli S, Cortelli P, et al. Investigation of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura. J Neurol Sci 2003; 213(12):710. 128. McCarthy LC, Hosford DA, Riley JH, et al. Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine. Genomics 2001; 78(3):135149. 129. Tzourio C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alperovitch A. Association between migraine and endothelin type A receptor (ETA-231 A/G) gene polymorphism. Neurology 2001; 56(10):12731277. 130. Rainero I, Grimaldi LM, Salani G, et al. Association between the tumor necrosis factoralpha-308 G/A gene polymorphism and migraine. Neurology 2004; 62(1):141143. 131. Klopstock T, May A, Seibel P, Papagiannuli E, Diener HC, Reichmann H. Mitochondrial DNA in migraine with aura. Neurology 1996; 46(6):17351738. 132. Cupini LM, Massa R, Floris R, et al. Migraine-like disorder segregating with mtDNA 14484 Leber hereditary optic neuropathy mutation. Neurology 2003; 60(4):717719. 133. Boles RG, Adams K, Li BUK. Maternal inheritance in cyclic vomiting syndrome. Pediatr Res 2004; 55(4):273A274A. 134. Cupini LM, Santorelli FM, Iani C, Fariello G, Calabresi P. 135. Schuh-Hofer S, Meisel A, Reuter U, Arnold G. Monozygotic twin sisters suffering from cluster headache and migraine without aura. Neurology 2003; 60(11):18641865. 136. Svensson D, Ekbom K, Pedersen NL, Traff H, Waldenlind E. A note on cluster headache in a population-based twin register. Cephalalgia 2003; 23(5):376380. 137. Torelli P, Manzoni GC. Clinical observations on familial cluster headache. Neurol Sci 2003; 24(2):6164. 138. Rainero I, Gallone S, Valfre W, et al. A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 2004; 63(7):12861288. 139. Ostergaard S, Russell MB, Berndtsen L, Olesen J. Comparison of rst degree relatives and spouses of people with chronic tension headache. BMJ 1998; 314:10921093.

10
Identication or Exclusion of Secondary Headaches
Randolph W. Evans
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, Department of Neurology, The Methodist Hospital, and Baylor College of Medicine, Houston, Texas, U.S.A.

R. Allan Purdy
Division of Neurology, Dalhousie University, and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada

INTRODUCTION Clinical assessment still has a signicant role to play in identifying and excluding secondary headaches. This has been dealt with in previous reviews (1). In essence, a good history and careful neurological and general physical examination remains the basis of such an assessment and, in large part, works best for primary headache disorders. It is important to have an approach to headache and to exclude red ags. However, the only way to truly identify or exclude secondary headaches is to investigate; neuroimaging is the most relevant investigative tool for yielding primary neurological etiologies. Nonneurological testing such as laboratory testing and imaging outside the nervous system still have a role to play, but frequently there are signs and symptoms of a nonneurological etiology. For the most part this chapter will deal with neuroimaging. Neuroimaging is at best however, it is now a surrogate for good clinical assessment, becoming the actual standard to identify and exclude secondary headache etiologies. The other strategies for subsidiary investigation will be discussed when appropriate. Notwithstanding the instances listed above, any of the secondary headache disorders can mimic primary headaches. Therefore, judicious use of testing is essential to distinguish primary from secondary headaches, which includes over 300 different types and causes of headache. This chapter reviews in detail the following topics: general indications for neuroimaging; neuroimaging for headaches with a normal neurological examination; neuroimaging for migraine; evaluation of the acute severe new-onset headache (rst or worst headaches); headaches over the age of 50; and evaluation of new daily headaches.

131

132

Evans and Purdy

GENERAL INDICATIONS FOR NEUROIMAGING FOR HEADACHES There are many reasons why physicians recommend diagnostic testing for headaches: aiming for diagnostic certainty; faulty cognitive reasoning; the medical decision rule that holds that it is better to impute disease than to risk overlooking it; busy practice conditions in which tests are ordered as shortcuts; patient and family expectations; nancial incentives; and medicolegal issues (2). In the era of managed care, equally compelling reasons for not ordering diagnostic studies include physician fears of deselection and at-risk capitation. Lack of funds and underinsurance continue to be barriers for appropriate diagnostic testing for many patients, particularly in the United States, with accessibility to testing being a problem in other countries. Table 1 provides reasons to consider neuroimaging for headaches.

NEUROIMAGING FOR HEADACHES WITH A NORMAL NEUROLOGICAL EXAMINATION The yield of computed tomography (CT) scan or magnetic resonance imaging (MRI) in patients with any headache and a normal neurologic examination is about 2% (3). The U.S. Headache Consortium, which published an evidence-based guideline, concluded that there was not sufcient information to estimate the probability of important intracranial pathology among patients with nonmigrainous headache and a normal neurological examination, and recommended comparative studies between MRI and CT (4). Sempere et al. recently reported a study of 1876 consecutive patients aged 15 years or older, with a mean age of 38 years, who presented to a neurology clinic in Spain with nonacute headache (5). The types of headaches were the following: migraine (49%), tension-type (35.4%), cluster (1.1%), post-traumatic (3.7%), and

Table 1 Reasons to Consider Neuroimaging for Headaches A. Based on the temporal and headache features 1. The rst or worst headache 2. Subacute headaches with increasing frequency or severity 3. A progressive or new daily-persistent headache 4. Chronic daily headache 5. Headaches always on the same side 6. Headaches not responding to treatment B. Based on the demographics 7. New-onset headaches in patients who have cancer or who test positive for HIV infection 8. New-onset headaches after age 50 9. Patients with headaches and seizures C. Based on associated symptoms and signs 10. Headaches associated with symptoms and signs such as fever, stiff neck, nausea, and vomiting 11. Headaches other than migraine with aura associated with focal neurologic symptoms or signs 12. Headaches associated with papilledema, cognitive impairment, or personality change
Source: From Ref. 2.

Identication or Exclusion of Secondary Headaches

133

indeterminate (10.8%). One-third of the patients had new-onset headache, while the other two-thirds reported headaches for more than one year. Neurological examination was normal in 99.2% of patients. All patients underwent either a MRI or a CT scan. Neuroimaging studies detected signicant lesions in 1.2%. Signicant intracranial abnormalities were detected in those with headaches and a normal neurological examination (0.9%, 17 patients). The diagnoses in these 17 patients were pituitary adenoma (3), large arachnoid cyst (2), meningioma (2), hydrocephalus (2), Chiari type I malformation, ischemic stroke, cavernous angioma, arteriovenous malformation (AVM), low-grade astrocytoma, brain stem glioma, colloid cyst, and posterior fossa papilloma (1). Of these 17 patients, 8 were treated surgically. Severe, progressive, and new-onset headaches were not associated with higher rates of signicant intracranial lesions. Among 118 patients with normal neurological examinations and normal CT scans, MRI disclosed only one signicant lesion, a small meningioma that was not treated surgically. There were no saccular aneurysms detected among the 580 patients who underwent MRI scans and there was only one patient with a greater than or equal to 5 mm tonsillar descent, a Chiari I malformation that was asymptomatic. The Sempere et al. study is outstanding and provides valuable information about neuroimaging in a large consecutive series of patients referred to a neurology clinic. Questions still remain about the value of MRI versus CT and MRI, without contrast versus with and without contrast, and selection of use of magnetic resonance angiography (MRA) and magnetic resonance venography (MRV). The low overall detection rate for signicant pathology corresponds to our experience. However, if one concludes that CT is as sensitive as MRI for the evaluation of headache, one can miss signicant pathology at the patients peril and ones own medicolegal risk (Table 2). For example, Evans has reported three types of pathology from his own general neurology practice, detected on MRI, that would have been missed on CT: a hemorrhagic pituitary adenoma mimicking migraine (6), spontaneous low cerebrospinal uid (CSF) pressure syndrome mimicking primary cough headache (which would have been missed without the administration of gadolinium) (7), and a pilocytic astrocytoma of the cerebellar hemisphere with mass effect mimicking migraine status (8). In addition, Evans has found occasional incidental saccular aneurysms on MRI scans in his own practice (7) as contrasted to the 0% reported by Sempere. MRA may detect incidental saccular aneurysms in 2.8% of adults (9). The point is not that Evans is so astute, but that we suspect many experienced neurologists will have similar cases. When available, MRI is the preferred study for the evaluation of headaches with the exception of patients with head trauma, acute headache to rule out subarachnoid hemorrhage (SAH), and contraindications to MRI.

NEUROIMAGING FOR MIGRAINE The U.S. Headache Consortium reported that a meta-analysis of patients with migraine and a normal neurological examination found a rate of signicant intracranial lesions of 0.18% (3). The consortium concluded, Neuroimaging is not usually indicated for patients with migraine and normal neurological examination. Table 3 provides some reasons to consider neuroimaging in patients with migraine. Crash migraines are considered in the next section.

134

Evans and Purdy

Table 2 Causes of Headache That Can Be Missed on CT Scan of the Head A. Vascular disease Saccular aneurysms Arteriovenous malformations (especially in the posterior fossa) Subarachnoid hemorrhage Carotid or vertebral artery dissections Infarcts Cerebral venous thrombosis Vasculitis (white matter abnormalities) Subdural and epidural hematomas B. Neoplastic disease Neoplasms (especially in the posterior fossa) Meningeal carcinomatosis Pituitary tumor and hemorrhage C. Cervicomedullary lesions Chiari malformations Foramen magnum meningioma D. Infections Paranasal sinusitis Meningoencephalitis Cerebritis and brain abscess E. Low cerebrospinal uid pressure syndrome
Abbreviation: CT, computed tomography. Source: From Ref. 2.

There is a question mark after Headaches always on the same side, because 17% of patients with migraine without aura and 15% of those with migraine with aura always have headaches on the same side (side-locked headaches) (11). One potential migraine mimic is an AVM malformation where side-locked headaches are present in up to 95% of cases (12). Migraine-like headaches with and without visual symptoms can be associated with AVMs, especially those in the occipital lobe, which is the predominant location of about 20% of parenchymal AVMs (13). However, a typical migraine due to an AVM is the exception because there are usually distinguishing features (12,14). Bruyn reported the following features in

Table 3 Reasons to Consider Neuroimaging in Migraineurs Unusual, prolonged, or persistent aura Increasing frequency, severity, or change in clinical features First or worst migraine Basilar Confusional Hemiplegic Late-life migraine accompaniments Aura without headache Headaches always on the same side Posttraumatic Request of patient or family and friends
Source: From Ref. 10.

Identication or Exclusion of Secondary Headaches

135

patients with migraine-like symptoms and AVM: unusual associated signs (papilledema, eld cut, and bruit), 65%; short duration of headache attacks, 20%; brief scintillating scotoma, 10%; absent family history, 15%; atypical sequence of aura, headache, and vomiting, 10%; and seizures, 25% (11). Distal internal carotid artery dissection is another rare migraine mimic that may be of concern in patients with either new-onset migraine aura or those with a change in the aura or unusual features. The diagnosis can be more challenging because carotid dissection is more common in migraineurs (49.1% had a history of migraine in one study) (15). Migrainous features may include positive symptoms such as monocular visual scintillations or paresthesias, spread of symptoms within a modality with a gradual march of paresthesias from limb to face or an enlargement of a scotoma and from one modality to another, and prolonged course (16). A severe headache with nausea and vomiting can accompany or follow the other symptoms. Multiple episodes can occur. Internal carotid artery dissection can also cause a scintillating scotoma alone resembling the migraine aura (17). MRA, CT angiography (CTA), carotid ultrasound (less sensitive than the other tests), or catheter angiography can detect the dissection. Vertebral artery dissection can also rarely mimic migraine (18).

EVALUATION OF THE ACUTE SEVERE NEW-ONSET HEADACHE (FIRST OR WORST HEADACHES) There are numerous secondary headaches that have to be excluded as the cause of primary headaches which can present with an acute and severe onset such as crash migraine (maximum intensity shortly after the onset), rst migraine, primary thunderclap headache, primary exertional headache (including weightlifting headache), and primary headache associated with sexual activity. Table 4 provides the extensive list of possible causes of the acute severe new-onset headache (the rst or worst). SAH can present with identical symptoms to these primary headaches. A prospective study of 148 patients with acute severe headaches seen by general practitioners in the Netherlands found SAH to be the cause in 25% (20). There are many causes of SAH (Table 5). About 85% of SAH are due to ruptured intracranial aneurysms (21) and 5% are due to rupture of intracranial AVMs. In about 15% of cases, an arteriogram does not demonstrate the cause of the bleeding. In about 50% of these arteriogram-negative cases, the CT scan reveals blood conned to the cisterns around the midbrain, perimesencephalic hemorrhage that may be caused by a ruptured prepontine or interpeduncular cistern dilated vein or venous malformation. Other causes of arteriogram-negative SAH are listed in Table 5 (20). Over 30,000 people per year in the United States have an SAH from a ruptured saccular aneurysm, resulting in over 18,000 deaths. Based upon a meta-analysis, the prevalence of saccular aneurysms in the general population is about 2% with 93% of aneurysms 10 mm or less in size (22). Perhaps 50% of SAHs will present with a Hunt and Hess grade I (no symptoms or minimal headache, slight nuchal rigidity) or II (moderate to severe headache, no neurologic decit other than cranial nerve palsy). Most patients with headache due to SAH will have the worst headache of their life with maximum intensity within ve minutes and a duration of at least one hour (23,24). In a series of 42 patients with aneurysmal SAH, the onset of headache was as follows: almost instantaneous, 50%; 2 to 60 seconds, 24%; and 1 to 5 minutes, 19% (23). Twelve percent had a feeling of a burst. The headaches were of

136 Table 4 Differential Diagnosis of the Acute Severe New-Onset Headache (First or Worst) A. Primary headache disorders Migraine Cluster Primary exertional headache Primary thunderclap headache Primary headache associated with sexual activity B. Posttraumatic C. Associated with vascular disorders Acute ischemic cerebrovascular disease Subdural and epidural hematomas Parenchymal hemorrhage Unruptured saccular aneurysm Subarachnoid hemorrhage Systemic lupus erythematosis Temporal arteritis Internal carotid and vertebral artery dissection Cerebral venous thrombosis Acute hypertension Pressor response Pheochromocytoma Preeclampsia D. Associated with nonvascular intracranial disorders Intermittent hydrocephalus Benign intracranial hypertension Postlumbar puncture Spontaneous intracranial hypotension Related to intrathecal injections Intracranial neoplasm Pituitary apoplexy E. Acute intoxications F. Associated with noncephalic infection Acute febrile illness Acute pyelonephritis G. Cephalic infection Meningoencephalitis Acute sinusitis H. Acute mountain sickness I. Disorders of eyes Acute optic neuritis Acute glaucoma J. Cervicogenic Greater occipital neuralgia Cervical myositis K. Trigeminal neuralgia
Source: From Ref. 53.

Evans and Purdy

moderate-to-severe intensity. Nineteen percent had a prior headache resembling the acute headache. Transient loss of consciousness lasting for 1 to 10 minutes was reported by 26%. SAH can be easily overlooked (25). Ten percent of patients have no headache at onset and 8% describe a mild, gradually increasing headache (26).

Identication or Exclusion of Secondary Headaches Table 5 Causes of Nontraumatic Subarachnoid Hemorrhage 80% Intracranial saccular aneurysm 5% Intracranial arteriovenous malformation 15% Negative arteriogram 50% Benign perimesencephalic hemorrhage 50% Other causes Occult aneurysm Mycotic aneurysm Vertebral or carotid artery dissection Dural arteriovenous malformation Spinal arteriovenous malformation Sickle cell anemia Coagulation disorders Drug abuse (especially cocaine) Primary or metastatic intracranial tumors Primary or metastatic cervical tumors CNS infection CNS vasculitides
Abbreviation: CNS, central nervous system. Source: From Ref. 2.

137

A stiff neck is absent in 36% of patients (27). When rst primary orgasmic and exertional headaches occur, SAH has to be excluded because one-third of SAHs occur during activities such as bending, lifting, defecation, or sexual intercourse. A CT scan of the brain is the initial imaging study of choice to detect SAH. During the rst 24 hours, aneurysmal SAH is present on 95% of scans but decreases to 50% by the end of the rst week, 30% by the end of the second week, and almost 0% by the end of the third week (28). From more than 3 to 14 days after the hemorrhage, MRI using the uid-attenuated inversion recovery sequence is more sensitive than CT scan in the identication and delineation of SAH. A lumbar puncture should be considered in all patients with a new-onset headache suspicious for SAH, who have normal CT or MRI scans. Red blood cells (RBCs) are present in virtually all cases of SAH and variably clear in about 6 to 30 days. When the CSF obtained from the rst lumbar puncture is bloody, the only certain way to distinguish SAH from a traumatic tap is the presence of a xanthochromia. Although oxyhemoglobin can be detected as early as two hours after the entry of RBCs into CSF, xanthochromia is not present in all cases until after 12 hours. Using spectrophotometry to detect xanthochromia, the probability of detection is 100% through the rst two weeks after the SAH, over 70% after three weeks, and over 40% after four weeks (29). Unfortunately, spectrophotometry is available in only about 0.3% of hospital laboratories in the United States. MRA can detect about 90% of saccular aneurysms with a size of 5 mm or larger (30). Spiral (helical) CTA can detect 93% to 100% (31,32) of intracranial saccular aneurysms. CTA can be very useful instead of or as an alternative to MRA for patients with contraindications to MRI, such as those with pacemakers, intracranial ferromagnetic clips, and severe claustrophobia. However, in addition to contrast allergy, there is additional risk from the intravenous contrast in patients with renal insufciency, dehydration, and diabetes (when used as a screening study instead of MRA). In practice, MRA and CTA are both limited, of course, by the quality of the images and the ability of the interpreting physician. Some centers are using CTA

138

Evans and Purdy

alone preoperatively for most cases, (31) whereas others still consider digital subtraction angiography the gold standard. HEADACHES OVER THE AGE OF 50 YEARS The prevalence of headache decreases with older age. As examples, in females and males, respectively, at the following ages, the prevalence of headaches is as follows: 21 to 34 years, 92% and 74%; 55 to 74 years, 66% and 53%; and over 75 years, 55% and 22% (33). Although 90% of headaches in younger patients are of the primary type, only 66% of those in the elderly are primary (34). There are numerous causes of new-onset headaches in those over 50 years of age (Table 6) (36). Temporal arteritis, hypnic headache, and headache of Parkinsons disease are secondary headaches occurring with much greater frequency in this population. In a study of 193 patients 65 years of age and older with new-onset seen by a neurology service, the most frequent diagnoses were tension-type (43%) and trigeminal neuralgia (19%) (37). Only one patient met the migraine criteria. Fifteen percent had secondary headaches due to conditions such as stroke, temporal arteritis, or intracranial neoplasm. The risk of serious disorders causing headache increased 10 times after the age of 65, compared with younger patients. About 10% of those with tension-type headaches have an onset after 50 years of age (38). When new-onset tension-type headaches occur, the diagnosis is one of exclusion. Primary and metastatic brain tumors should be considered (39). Eight percent of patients with headaches and brain tumors have a normal neurologic examination. Papilledema, which is usually associated with headaches, is present in 40% of patients with brain tumors. The most common location of headaches is bifrontal, although patients may complain of pain in other locations of the head as well as the neck. Unilateral headaches are usually on the same side as the neoplasm. Although the quality of the headache is usually similar to that of the tension type,
Table 6 New-Onset Headaches Occurring Over 50 Years of Age A. Primary headaches Migraine Tension Cluster Hypnic B. Secondary headaches Neoplasms Subdural and epidural hematomas Head trauma Cerebrovascular disease Temporal arteritis Trigeminal neuralgia Postherpetic neuralgia Medication related Systemic disease Diseases of the cranium, neck, eyes, ears, and nose Parkinsons disease Exertional headache due to angina
Source: From Ref. 35.

Identication or Exclusion of Secondary Headaches

139

occasional patients have headaches similar to migraine without aura, and rarely migraine with aura and cluster headaches. Most of the headaches are intermittent with moderate-to-severe intensity, but a signicant minority report only mild headaches relieved by simple analgesics. The classic brain tumor headachesevere, worse in the morning, and associated with nausea and vomitingoccurs in a minority of patients with brain tumors. Only 2% of migraineurs have a new onset after 50 years of age. Late-life migrainous accompaniments are transient visual, sensory, motor, or behavioral neurologic manifestations that are similar or identical to the auras of migraine with aura (40,41). Headache is associated with only 50% of cases and may be mild. These accompaniments occur more often in men than in women, with a prevalence of about 1%. Table 7 provides the features of late-life migrainous accompaniments. The complaints occur as follows, from most to least common: visual symptoms (transient blindness, homonymous hemianopsia, and blurring of vision); paresthesias (numbness, tingling, pins-and-needles sensation, or a heavy feeling of an extremity); brain stem and cerebellar dysfunction (ataxia, clumsiness, hearing loss, tinnitus, vertigo, and syncope); and disturbances of speech (dysarthria or dysphasia). Other causes of transient cerebral ischemia should be considered, especially when the patient is seen after the rst episode or if there are unusual aspects. The usual diagnostic evaluation (such as CT scan, MRI and MRA of the brain, carotid ultrasound, electroencephalography, cardiac evaluation, and blood studies) for transient ischemic attacks (TIAs) or seizures is performed. The following features help to distinguish migraine from TIAs: a gradual buildup of sensory symptoms, a march of sensory paresthesias, serial progression from one accompaniment to another, longer duration (90% of TIAs last for less than 15 minutes), and multiple stereotypical episodes. Cluster headache has an onset over the age of 50 years in only a minority of cases. In a study of 554 episodic and chronic cluster patients, an onset over the age of 50 was reported by 16.7% of females and 8.7% of males (42). Consideration might be given to obtaining an MRI scan in late-onset cluster, especially if atypical features are present, to exclude the rare secondary causes of cluster, including the following: internal carotid artery dissection; pseudoaneurysm of intracavernous carotid artery; aneurysm of the anterior communicating, carotid, or basilar artery;
Table 7 Features of Late-Life Migrainous Accompaniments 1. Gradual appearance of focal neurologic symptoms with spread or worsening over a period of minutes 2. Headache is only present in 50% of cases and may be mild 3. Positive visual symptoms such as scintillating scotoma, and ashing or bright lights 4. A history of similar episodes associated with a more severe headache 5. Serial progression from one accompaniment to another (e.g., from ashing lights to paresthesias, paresis, or dysphasia) 6. Diagnosis facilitated with the occurrence of two or more identical episodes 7. A duration of 1525 min 8. A characteristic urry of accompaniments 9. A usually benign natural history, without permanent sequelae 10. Another cause not shown by diagnostic testing that is performed when indicated
Source: From Ref. 35.

140

Evans and Purdy

AVM of the middle cerebral territory or occipital lobe; high cervical meningioma; unilateral cervical cord or lateral medullary infarction; pituitary adenoma; meningioma of the lesser wing of the sphenoid; maxillary sinus foreign body; orbitosphenoidal aspergillosis; and orbital myositis (43).

NEW DAILY HEADACHES Table 8 lists some primary and secondary causes of new daily headaches (44). According to the IHS second edition, the criteria for new daily-persistent headache (NDPH) are a headache that, within three days of onset, is daily and unremitting for more than three months and has at least two of the following characteristics: bilateral location; pressing/tightening (nonpulsating) quality; mild or moderate intensity; and not aggravated by routine physical activity such as walking or climbing. The criteria require both of the following: no more than one of photophobia, phonophobia, or mild nausea; and neither moderate or severe nausea nor vomiting. Finally, the headache is not attributed to another disorder (45). Some of these secondary disorders may have a thunderclap or sudden onset of severe headache whereas others may develop gradually over one to three days and meet the onset period criteria for NDPH. New-onset daily headaches with a normal neurological examination could also be due to various other causes, particularly when seen within the rst two months after onset, including postmeningitis headache, chronic meningitis, brain tumors, leptomeningeal metastasis, temporal arteritis, chronic subdural hematomas, posttraumatic headaches, sphenoid sinusitis, and hypertension. When the headaches have been present for more than three months with a normal neurological examination, the yield of testing is low. A few additional examples will be discussed.
Table 8 Differential Diagnosis of New Daily Headaches Primary headaches New daily-persistent headache Chronic migraine Chronic tension type Combined features (new daily-persistent headaches with frequent migraine features) Primary thunderclap headache Secondary headaches (new daily-persistent headache mimics) Postmeningitis headache Chronic meningitis Primary with medication rebound Neoplasms Temporal arteritis Chronic subdural hematoma Posttraumatic headaches Sphenoid sinusitis Hypertension Subarachnoid hemorrhage Low cerebrospinal uid pressure syndrome Cervical artery dissections Pseudotumor cerebri Cerebral venous thrombosis

Identication or Exclusion of Secondary Headaches

141

Spontaneous intracranial hypotension can be a difcult clinical diagnosis especially when the orthostatic component is minimal or absent (46). The orthostatic worsening can be absent both early in the clinical course and chronically. MRI abnormalities are usually (perhaps 90% of cases) but not always present. Cervical artery dissections can be a rare cause of new daily headaches (47). Occasionally, the headaches can persist intermittently for months and even years, and can lead to a pattern of chronic daily headaches especially after cervical carotid artery dissection (48). Pseudotumor cerebri (PTC) or idiopathic intracranial hypertension can be a cause of new daily headaches and is easily suspected when papilledema is present. However, PTC without papilledema (49) can rarely occur and should be considered as the cause of NDPH especially in obese females who account for 90% of the cases of pseudotumor. Conversely, PTC can be present with papilledema and normal CSF opening pressure (50). Papilledema can initially be present in PTC and then, rarely, resolve even though the intracranial pressure is still elevated (51). Caution is advisable to avoid misdiagnosis, pseudo-PTC (52). Although the CSF opening pressure can be up to 25 cm of water in obese people, the pressure can be ctitiously elevated if the patient is not relaxed, the legs are exed, and the abdominal muscles are contracted. Cerebral venous thrombosis (CVT) can also be misdiagnosed as PTC when the appropriate neuroimaging study is not obtained. Headache is present in up to 90% of cases of CVT and is often the initial symptom. The headache can be unilateral or bilateral in any location, mild to severe, and intermittent or constant. The onset is usually subacute but can be sudden or thunderclap. In over 95% of cases, the headache is associated with a variety of neurological signs in the following percentages of patients: papilledema, 51%; seizures, 42%; focal decits, 39%; encephalopathy, 31%; multiple cranial nerve palsies, 11%; bilateral cortical signs, 4%; and cerebellar signs, 3% (53). As noted, CVT can be a mimic of PTC. Neuroimaging studies have variable sensitivities in diagnosing CVT. Computed tomography only diagnoses about 20% of cases of CVT when demonstrating the hyperdensity of the thrombosed sinus on plain images and the delta sign seen with superior sagittal sinus thrombosis after contrast administration. Helical CT venography is a very sensitive diagnostic method. CVT may be missed on routine MRI imaging of the brain although echo-planar T2 -weighted MRI may increase the sensitivity (54). MRV increases the sensitivity of MR especially within the rst ve days of onset or after six weeks. CVT can also be demonstrated, of course, on conventional angiography.

REFERENCES
1. Purdy RA. Clinical evaluation of a patient presenting with headache. Med Clin North Am 2001; 85(4):847863. 2. Evans RW. The evaluation of headaches. In: Evans RW, ed. Diagnostic Testing in Neurology. Philadelphia: WB Saunders, 1999:118. 3. American Academy of Neurology. The utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations. Neurology 1994; 44:13531354. 4. Frishberg BM, Rosenberg JH, Matchar DB, et al. Evidenced-based guidelines in the primary care setting: neuroimaging in patients with nonacute headache. http:// www.aan.com.

142

Evans and Purdy

5. Sempere AP, Porta-Etessam J, Medrano V, et al. Neuroimaging in the evaluation of patients with non-acute headache. Cephalalgia OnlineEarly doi:10.1111/j.14682982. Cephalalgia 2005; 25:3035. 6. Evans RW. Migrainelike headaches associated with pituitary hemorrhage. Headache 1997; 37:455456. 7. Evans RW, Boes C. Spontaneous low cerebrospinal uid pressure syndrome can mimic primary cough headache. Headache 2005; 45:374377. 8. Evans RW. Medico-legal headaches: trials and tribulations. In: Purdy RA, Rapoport A, Sheftell F, Tepper S, eds. Advanced Therapy of Headache. 2d ed. Hamilton, ON: BC Decker, 2005. 9. Horikoshi T, Akiyama I, Yamagata Z, Nukui H. Retrospective analysis of the prevalence of asymptomatic cerebral aneurysm in 4518 patients undergoing magnetic resonance angiographywhen does cerebral aneurysm develop? Neurol Med Chir (Tokyo) 2002; 42(3):105112. 10. Leone M, DAmico D, Frediani F, et al. Clinical considerations on side-locked unilaterality in long lasting primary headaches. Headache 1993; 33:381384. 11. Bruyn GW. Intracranial arteriovenous malformation and migraine. Cephalalgia 1984; 4:191207. 12. Kupersmith MJ, Vargas ME, Yashar A, et al. Occipital arteriovenous malformations: visual disturbances and presentation. Neurology 1996; 46:953957. 13. Ghossoub M, Nataf F, Merienne L, et al. Characteristics of headache associated with cerebral arteriovenous malformations. Neurochirurgie 2001; 47:177183. 14. Tzourio C, Benslamia L, Guillon B, et al. Migraine and the risk of cervical artery dissection: a case-control study. Neurology. 2002; 13(59):435437. 15. Silverman IE, Wityk RJ. Transient migraine-like symptoms with internal carotid artery dissection. Clin Neurol Neurosurg 1998; 100(2):116120. 16. Ramadan NM, Tietjen GE, Levine SR, Welch KM. Scintillating scotomata associated with internal carotid artery dissection: report of three cases. Neurology 1991; 41:10841107. 17. Young G, Humphrey P. Vertebral artery dissection mimicking migraine. J Neurol Neurosurg Psychiat 1995; 59:340341. 18. Linn FHH, Wijdicks EFM, van der Graaf Y, Weerdesteyn-van Viiet FAC, Bartelds AIM, van Gijn J. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Lancet 1994; 344:590593. 19. Khajavi K, Chyatte D. Subarachnoid hemorrhage. In: Gilman S, ed. Medlink Neurology. San Diego: MedLink Corporation, 2006. Available at www.medlink.com. 20. Rinkel GJE, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms. A systematic review. Stroke 1998; 29:251256. 21. Davenport R. Acute headache in the emergency department. J Neurol Neurosurg Psychiat 2002; 72(suppl 2):ii33ii37. 22. Linn FHH, Rinkel GJE, Algra A, van Gijn J. Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache. J Neurol Neurosurg Psychiat 1998; 65:791793. 23. Johnston SD, Robinson TJ . Subarchnoid haemorrhage: difculties in diagnosis and treatment. Postgrad Med 1998; 74:743748. 24. Weir B. Headaches from aneurysms. Cephalalgia 1994; 14:7987. 25. Kassell NF, Torner JC, Haley EC, Jane JA, Adams HP, Kongable GL. The international cooperative study on the timing of aneurysm surgery. Part I: Overall management results. J Neurosurg 1990; 73:1836. 26. van der Wee N, Rinkel GJE, Hasan D, van Gijn J. Detection of subarachnoid haemorrhage on early CT: is lumbar puncture still needed after a negative scan? J Neurol Neurosurg Psychiat 1995; 58:357359. 27. Vermeulen M, Hasan D, Blijenberg BG, Hijdra A, Van Gijn J. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiat 1989; 52:826828.

Identication or Exclusion of Secondary Headaches

143

28. Medina LS, DSouza B, Vasconcellos E. Adults and children with headache: evidencebased diagnostic evaluation. Neuroimaging Clin N Am 2003; 13(2):225235. 29. Karamessini MT, Kagadis GC, Petsas T, et al. CT angiography with three-dimensional techniques for the early diagnosis of intracranial aneurysms. Comparison with intraarterial DSA and the surgical ndings. Eur J Radiol 2004; 49:212223. 30. Hoh BL, Cheung AC, Rabinov JD, et al. Results of a prospective protocol of computed tomographic angiography in place of catheter angiography as the only diagnostic and pretreatment planning study for cerebral aneurysms by a combined neurovascular team. Neurosurgery 2004; 54:13291340. 31. Waters WE. The Pontypridd headache survey. Headache 1974; 14:8190. 32. Solomon GD, Kunkel RS, Frame J. Demographics of headache in elderly patients. Headache 1990; 30:273276. 33. Geriatric headache. In: Silberstein SD, Lipton RB, Goadsby PJ. Headache in clinical practice. 2d ed. London: Martin Dunitz, 2002:269283. 34. Pascual J, Berciano J. Experience in the diagnosis of headaches that start in elderly people. J Neurol Neurosurg Psychiat 1994; 57:12551257. 35. Rasmussen BK. Epidemiology of headache. Cephalalgia 2001; 21:774777. 36. Purdy RA, Kirby S. Headaches and brain tumors. Neurol Clin N Am 2004; 22:3953. 37. Fisher CM. Late-life migraine accompaniments: further experience. Stroke 1986; 17:10331042. 38. Purdy RA. Late-life migrainous accompaniments. In: Gilman S, ed. MedLink Neurology. San Diego: Arbor, 2006. Available at www.medlink.com. 39. Ekbom K, Svensson DA, Traff H, Waldenlind E. Age at onset and sex ratio in cluster headache: observations over three decades. Cephalalgia 2002; 22:94100. 40. Goadsby PJ. Cluster headache. In: Gilman S, ed. MedLink Neurology. San Diego: Arbor, 2006. Available at www.medlink.com. 41. Evans RW. New daily persistent headache. Curr Pain Headache Rep 2003; 7:303307. 42. Headache Classication Subcommittee of the International Headache Society. The International Classication of Headache Disorders. 2d ed. Cephalalgia 2004; 24(suppl 1):1232. 43. Mokri B. Low cerebrospinal uid pressure syndromes. Neurol Clin 2004; 22:5574. 44. Mokri B. Headache in cervical artery dissections. Curr Pain Headache Rep 2002; 6: 209216. 45. Silbert PJ, Mokri B, Schievink WI. Headache and neck pain in spontaneous internal carotid and vertebral artery dissections. Neurology 1995; 45:15171522. 46. Mathew NT, Ravishankar K, Sanin LC. Coexistence of migraine and idiopathic intracranial hypertension without papilledema. Neurology 1996; 46:12261230. 47. Green JP, Newman NJ, Stowe ZN, Nemeroff CB. Normal pressure pseudotumor cerebri. J Neuroophthalmol 1996; 16(4):241246. 48. Piovesan EJ, Lange MC, Piovesan LdoR, et al. Long-term evolution of papilledema in idiopathic intracranial hypertension: observations concerning two cases. Arq Neuropsiquiatr 2002; 60(2B):453457. 49. Evans RW, Dulli D. Pseudo-pseudotumor cerebri. Headache 2001; 41(4):416418. 50. Bousser MG, Good J, Kittner SJ, Silberstein SD. Headache associated with vascular disorders. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache Other Head Pain. 7th ed. New York: Oxford, 2001:349392. 51. Selim M, Fink J, Linfante I, et al. Diagnosis of cerebral venous thrombosis with echoplanar T2 -weighted magnetic resonance imaging. Arch Neurol 2002; 59(6):10211026. 52. Evans RW. Diagnosis of headaches and medico-legal aspects. In: Evans RW, Mathew NT, eds. Handbook of Headache. 2d ed. Philadelphia: Lippincott-Williams&Wilkins, 2005 (Chap. 1). 53. Evans RW. First or worst headaches. In: Evans RW, Mathew NT. Handbook of Headache. 2d ed. Philadelphia: Lippincott-Williams&Wilkins, 2005 (Chap. 8). 54. Evans RW. Headaches over the age of 50. In: Evans RW, Mathew NT. Handbook of Headache. 2d ed. Philadelphia: Lippincott-Williams&Wilkins, 2005 (Chap. 12).

11
Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach
Richard B. Lipton
Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Monteore Headache Center, New York, New York, U.S.A.

Marcelo E. Bigal
Department of Neurology, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A.

INTRODUCTION Headache is one of the most common types of recurrent pain (1,2), as well as one of the most frequent reasons for medical consultation (3,4). Although virtually everyone gets occasional headaches, there are well-dened headache disorders that vary in incidence, prevalence, and duration (14). Diagnosis of headache disorders is challenging and is complicated by the fact that one individual may have more than one disorder. An orderly approach is required for the proper diagnosis. Crucial elements include a thorough history taking, supplemented by general medical and neurological examinations, as well as laboratory testing and neuroimaging in selected patients. If multiple headache disorders occur concurrently, the conceptual process needs to be repeated for each headache.

APPROACHING A PATIENT WITH HEADACHE Step 1Distinguishing Primary from Secondary Headaches An important rst step in headache diagnosis is to distinguish primary from secondary headaches. The strategies to identify or exclude secondary headaches are discussed in Chapter 10. In brief, the approach is to spot or exclude red ags, the features that suggest the possibility of a secondary headache (Fig. 1). Once these features are identied, the physician must conduct the workup indicated by the red ag (Table 1) and thereby diagnose or exclude any secondary headache disorder that may be present. In the absence of secondary headaches, the clinician proceeds to diagnosing a primary headache disorder. If the headache is atypical or difcult to classify, the
145

146

Lipton and Bigal

Figure 1 Algorithm for headache diagnosis. Source: Adapted from Ref. 5.

possibility of a secondary headache should be reconsidered, although the modifying effect of any treatment being taken should be kept in mind. The diagnostic criteria of primary headaches are discussed in Chapter 1. The objective of this section is to propose a strategy to approach primary headaches, after excluding secondary disorders. Step 2Divide Primary Headaches into Four Syndrome Categories Based on Duration and Frequency In a patient for which secondary headache syndromes were excluded, either by clinical history or by appropriate investigation, the next step is to divide the primary headaches based on the average duration of the attacks as short-duration headache (<4 hours a day) or long-duration headache (!4 hours) (6). Long-duration headaches are classied on the basis of frequency as those with low-to-moderate frequency (<15 headache days per month) or those with high frequency (!15 headache days per month). Short-duration headaches are divided into those that have specic provocative factors and those that do not (Fig. 2). Step 3Assign a Specic Diagnosis Within the Syndrome Category Low-to-Moderate Frequency Headaches of Long Duration Low-to-moderate frequency headaches of long duration include migraine and episodic tension-type headache (TTH). In contrast to migraine, the main pain features of TTH are bilateral location, nonpulsating quality, mild-to-moderate intensity, and lack of aggravation by routine physical activity. The pain is not accompanied by nausea or vomiting, though either photophobia or phonophobia (but not both) does not exclude

Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach Table 1 Red Flags in the Diagnosis of Headache Red ag Sudden-onset headache Consider Subarachnoid hemorrhage, bleed into a mass or AVM, mass lesion (especially posterior fossa) Mass lesion, subdural hematoma, medication overuse Meningitis, encephalitis, Lyme disease, systemic infection, collagen vascular disease, arteritis Mass lesion, AVM, collagen vascular disease

147

Possible investigation(s) Neuroimaging Lumbar puncture (after neuroimaging evaluation) Neuroimaging

Worsening-pattern headache Headache with cancer, HIV, or other systemic illness (fever, neck stiffness, cutaneous rash) Focal neurologic signs, or symptoms other than typical visual or sensory aura Papilloedema

Neuroimaging Lumbar puncture Biopsy Blood tests Neuroimaging Collagen vascular evaluation Neuroimaging Lumbar puncture (after neuroimaging evaluation) Neuroimaging Considerer lumbar puncture Neuroimaging

Mass lesion, pseudotumor, encephalitis, meningitis Subarachnoid hemorrhage, mass lesion Cortical vein/cranial sinus thrombosis Carotid dissection Pituitary apoplexy

Triggered by cough, exertion, or Valsalva Headache during pregnancy or postpartum

Abbreviation: AVM, arterio venous malformation. Source: Adapted from Ref. 5.

the diagnosis (7,8). Even though episodic TTH is the most prevalent primary headache disorder in the population, it is not a frequent cause of medical visits (Fig. 3) (9). Migraines are more common in the clinic setting. Migraines are frequently of severe intensity, throbbing, and associated with nausea (or vomiting), photophobia, or phonophobia (8). Because the attack may be very severe, patients may be prostrated and pale, sometimes vomiting. Migraine attacks may be unilateral or bilateral, and investigation in a typical attack is not necessary. However, migraine-like attacks not responsive to treatment and requiring prolonged hospitalization (>12 hours) should be investigated. High-Frequency Headaches of Long Duration High-frequency headaches of long duration include transformed migraine (TM), chronic TTH, new daily persistent headache, and hemicrania continua (HC) (10). Medication overuse is common; it is present in more than 80% of TM patients in subspecialty clinics (11,12) but in only 30% of chronic headache sufferers in population studies (13). When a clear history of TM is obtained, investigation is not required (Fig. 4). New daily persistent headache is characterized by a new onset of a CDH (14). It is a primary headache disorder. In patients with acute headache, rst seeking care with this syndrome, investigation is necessary to exclude secondary disorders.

148

Lipton and Bigal

Figure 2 Classication of primary headaches based on frequency and duration.

HC is probably the most frequently unrecognized primary headache. HC is a chronic, unilateral pain, commonly mistaken for TM (15,16). Both disorders are characterized by chronic unilateral pain with superimposed painful exacerbations. In HC, the painful exacerbations are often associated with ipsilateral autonomic features such as conjunctival injection, lacrimation, and ptosis. In TM, exacerbations are more typically accompanied by nausea, photophobia, and phonophobia. In addition, patients with HC usually do not have antecedent history of episodic migraine. In TM, attacks increase in frequency over time. If the headaches are longstanding, the patient may not remember how they began. Although pain uctuates in HC, it does not usually have the morning and end-of-dosing interval pattern of exacerbations typical of TM. It is advisable to offer to patients with unilateral chronic daily headache a therapeutic trial with indomethacin prior to other intervention (doses of up to 225 mg/day for 3 to 4 days).

Shorter-Duration Headaches For shorter-duration headache of low or high frequency, it must be considered whether the headache is triggered by coughing, straining or Valsalva maneuver, exertion, or sexual activity (Fig. 5).

Figure 3 Long-duration headaches with low-to-moderate frequency.

Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach

149

Figure 4 Long-duration headaches with high frequency of attacks.

High-frequency, short-duration headaches not triggered by these factors include the trigeminal autonomic cephalgias (TAC), episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania, short unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome, and hypnic headache.

Figure 5 Short-duration headaches.

150

Lipton and Bigal

The TACs are characterized by unilateral pain in the trigeminal distribution, with ipsilateral autonomic features (1720). The most common disorder in this family is CH. The pain of CH is described variously as sharp, boring, drilling, knifelike, piercing, or stabbing, in contrast to the pulsating pain of migraine. It usually peaks in 10 to 15 minutes but remains excruciatingly intense for an average of one hour within a duration range of 15 to 180 minutes. During this pain, patients nd it difcult to lie still, exhibiting often marked agitation and restlessness, and autonomic features are usually obvious. After an attack, the patient remains exhausted for some time. Like CH, the paroxysmal hemicranias are characterized by unilateral attacks of trigeminal pain and autonomic features. In contrast with CH, the paroxysmal hemicranias have three main features: It is (i) more frequent (more than ve per day); (ii) of a short duration (230 minutes); and (iii) has an absolute response to therapeutic doses of indomethacin. They are rare (19,20). The third TAC, SUNCT, is a very rare primary headache. The diagnostic criteria require at least 20 high-frequency attacks (3200 per day) of unilateral orbital, supraorbital, or temporal stabbing or pulsating pain, lasting 5 to 240 seconds and accompanied by ipsilateral conjunctival injection and lacrimation. The attacks are characteristically dramatic, with moderately severe pain peaking in intensity within three seconds and prominent tearing (20,21). Hypnic headache is a primary headache disorder of the elderly, characterized by short-lived attacks (typically 30 minutes) of nocturnal head pain, which awaken the patient at a constant time each night, in many cases on more nights than not. It does not occur outside sleep (22,23). Hypnic headache is usually bilateral (though unilaterality does not exclude the diagnosis) and usually mild to moderate, very different from the unilateral orbital or periorbital knife-like intense pain of CH. Autonomic features are absent. Headaches triggered by cough, exertion, and sexual activity include the disorders named for these triggers. These headaches may just be diagnosed after exhaustive and methodic search for secondary causes (Table 2) (2428). However, in a patient previously investigated or previously diagnosed, it is usually not necessary to repeat the investigation and the patient should be treated.

Table 2 The Aura in Migraine and Epilepsy Symptom Duration of aura Automatisms Gastrointestinal aura Visual disturbances Paresthesias Altered consciousness Olfactory Aphasia ` Deja vu
Source: Adapted from Ref. 35.

Migraine 1560 min Unusual Abdominal pain (rare); nausea (common) Positive/negative Common (560 min) No Very uncommon Not rare Rare

Epilepsy Brief, often < 1 min Frequent for complex partial seizures Butteriesrising epigastric sensation Complicated visual phenomenon Common (seconds to minutes) Sometimes More common Common Common

Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach

151

Step 4Reconsider Diagnosis It is sometimes difcult to assign a specic headache diagnosis if atypical features are present. This is a good reason to reconsider diagnosis, obtain additional laboratory tests (particularly neuroimaging), or refer to a specialist. Specic diagnosis provides a foundation for treatment. If the patient does not respond as expected, the diagnosis should be revisited. It is also important to remember that patients with one headache disorder sometimes develop another superimposed primary or secondary headache. Thus, the diagnostic process remains part of the ongoing management.

Figure 6 Summary algorithm.

152

Lipton and Bigal

CONCLUSIONS The differential diagnosis of the primary headaches requires a systematic approach. Herein, we have presented an orderly approach to differential diagnosis. The precise criteria for each disorder are presented in the specic chapters of this book. These algorithms should help physicians to move forward quickly and safely, when assessing patients with headaches. It is clear that there is some overlap. For example, although TTH is usually a headache of long duration, attacks may last just around 30 minutes. Figure 6 is a summary algorithm that integrates the information discussed in this chapter.

REFERENCES
1. Scher AI, Stewart WF, Lipton RB. Migraine and headache: a meta-analytic approach. In: Crombie IK, ed. Epidemiology of Pain. Seattle, Washington: IASP Press, 1999: 159170. 2. Rasmussen BK. Epidemiology of headache. Cephalalgia 1995; 15:4568. 3. Linet MS, Celentano DD, Stewart WF. Headache characteristics associated with physician consultation: a population-based survey. Am J Prev Med 1991; 7:4046. 4. Pascual J, Combarros O, Leno C, Polo JM, Rebollo M, Berciano J. Distribution of headache by diagnosis as the reason for neurologic consultation. Med Clin (Barc) 1995; 104(5):161164. 5. Silberstein SD, Lipton RB, Goadsby PJ. Headache in clinical practice. London: Martin Dunitz (Taylor Francis), 2002. 6. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J. The classication of primary headaches. Neurology 2004; 63(3):427435. 7. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):196. 8. Headache Classication Committee of the International Headache Society. The International Classication of Headache Disorders. Cephalalgia 2004; 24:1160. 9. Tepper SJ, Dahlof CG, Dowson A, et al. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. Headache 2004; 44(9):856864. 10. Silberstein SD, Lipton RB, Sliwinski M. Classication of daily and near-daily headaches: eld trial of revised IHS criteria. Neurology 1996; 47(4):871875. 11. Mathew NT. Transformed or evolutional migraine. Headache 1987; 27:305306. 12. Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD. Chronic daily headache in a tertiary care population. Correlation between the International Headache Society Diagnostic Criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002; 22:432438. 13. Scher AI, Lipton RB. Risk factors for chronic daily headache. Curr Pain Headache Rep 2002; 6:486491. 14. Rozen TD. New daily persistent headache. Curr Pain Headache Rep 2003; 7(3):218223. 15. Sjaastad O, Spierings EL. Hemicrania continua: another headache absolutely responsive to indomethacin. Cephalalgia 1984; 4:6570. 16. Bordini C, Antonaci F, Stovner LJ, Schrader H, Sjaastad O. Hemicrania continua: a clinical review. Headache 1991; 31:2026. 17. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic features, including new cases. Brain 1997; 120:193209.

Differential Diagnosis of Primary Headaches: An Algorithm-Based Approach

153

18. Dodick DW, Rozen TD, Goadsby PJ, Silberstein SD. Cluster headache. Cephalalgia 2000; 20:787803. 19. Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache 1989; 29:648656. 20. Sjaastad O, Dale I. Evidence for a new (?) treatable headache entity. Headache 1974; 14:105108. 21. Pareja JA, Sjaastad O. SUNCT syndrome. A clinical review. Headache 1997; 37:195202. 22. Newman LC, Lipton RB, Solomon S. The hypnic headache syndrome: a benign headache disorder of the elderly. Neurology 1990; 40(12):19041905. 23. Dodick DW, Mosek AC, Campbell IK. The hypnic (alarm clock) headache syndrome. Cephalalgia 1998; 18:152156. 24. Calandre L, Hernandez-Lain A, Lopez-Valdes E. Benign Valsalvas maneuver-related headache: an MRI study of six cases. Headache 1996; 36:251253. 25. Ertsey C, Jelencsik I. Cough headache associated with Chiari type-I malformation: responsiveness to indomethacin. Cephalalgia 2000; 20:518520. 26. Green MW. A spectrum of exertional headaches. Headache 2001; 4:10851092. 27. DAndrea G, Granella F, Verdelli F. Migraine with aura triggered by orgasm. Cephalalgia 2002; 22:485486. 28. Pascual J, Iglesias F, Oterino A, Vazquez-Barquero A, Berciano J. Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic cases. Neurology 1996; 46:15201524.

12
Diagnostic and Severity Tools for Migraine
Marcelo E. Bigal
Department of Neurology, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A.

Richard B. Lipton
Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Monteore Headache Center, New York, New York, U.S.A.

INTRODUCTION Migraine remains a substantially underdiagnosed and undertreated condition in the United States (1). Prior reports have identied the following barriers to migraine diagnosis and treatment: (i) under-recognition of migraine by headache sufferers themselves; (ii) underconsultation among migraine sufferers who need medical care; (iii) failure to diagnose all who consult; (iv) failure to initiate appropriate therapy among all who are diagnosed; and (v) lack of ongoing assessment of the benets of treatment (2). Tools that screen for migraine and assess disability have been proposed as strategies for surmounting some of these barriers. Effective application of diagnostic screeners within the population should increase recognition of migraine, encourage consultation, and facilitate appropriate care (3). In the primary care setting, screening tools might increase the speed and efciency of headache diagnosis and help target patients who need treatment. Screening for conditions comorbid with migraine, such as depression and anxiety, might also improve patient outcomes. In primary and specialty care, disability tools may help identify those in need of more aggressive treatment approaches, providing a basis for stratied care. Finally, tools that directly assess the adequacy of acute or preventive treatments might help to improve satisfaction with treatment. Recently, the U.S. Headache Consortium (the Consortium) provided a multispecialty consensus on the diagnosis and treatment of migraine (4). One approach recommended by the Consortium to improving primary care diagnosis is to employ screening or case-nding instruments. The Consortium also recommends that clinicians assess the severity of the patients migraine using measures of headacherelated disability as a prelude to selecting treatment. In this chapter, we present in-depth discussions of the tools we use and recommend to screen for assessing migraine disability and comorbid illnesses. We recognize
155

156

Bigal and Lipton

that in many cases, good alternatives are available and provide references for the options. We start by reviewing the criteria for screening diseases. We then assess migraine to determine how well it meets the criteria for screening, and describe a well-validated migraine-screening test, the ID-migraine. We discuss the assessment of disability and the use of the migraine disability assessment (MIDAS) questionnaire as a prelude for treatment. We then discuss the importance of screening comorbid diseases using a validated screener for this purpose, the PRIME-MD. We close with a discussion of tools for assessing satisfaction with treatment.

SCREENING FOR MIGRAINE Medical screening programs survey a population at risk to identify individuals with asymptomatic or early symptomatic disease (5,6). The primary goal is to alter the natural history of disease through early screening, detection, and treatment (6,7). In migraine screening, the goal is to detect individuals who have established undiagnosed disease, so that current pain and disability can be treated. Because migraine progresses in some individuals, screening programs may also alter future pain and disability and impact disease progression. Primary care providers are called upon to screen for a range of medical problems, to manage the problem and to refer to specialists when necessary. Migraine exemplies the issues in primary care screening. Criteria for Screening Although screening tests have long been an informal part of medical practice, in 1957, the Chronic Disease Commission issued a formal and widely inuential policy statement on screening (7). More recently, the U.S. Task Force on Preventive Health Services (The Task Force) proposed criteria for evaluating policy decisions about screening programs (7). The Task Force also made recommendations regarding screening policies for a large number of disorders (Table 1), but discussed few neurologic diseases. The main recommendations from the Task Force are discussed below.
Table 1 Criteria for Screening Programsa 1. The condition must be a public health problem. A. It has signicant prevalence in the population at risk B. It has signicant short-term or long-term morbidity or mortality A population at risk for the disease must be dened. The disease must have a recognizable latent phase or early symptomatic stage (or must be undetected by the health-care system when fully symptomatic)b. Effective treatment for the disease must be available and cost effective. An effective screening test must be available with appropriate specicity, sensitivity, and reliability for the disease and health-care context. The test must be acceptable to patients and health-care providers, i.e., it must be effective, affordable, and relatively safe. Resources must be available for developing, validating, and distributing the test. The screening and treatment program must be cost effective.

2. 3. 4. 5. 6. 7. 8.
a b

U.S. Preventive Services Task Force 7. This parenthetical statement is a modication of traditional criteria for screening programs.

Diagnostic and Severity Tools for Migraine

157

A Public Health Problem in a Population at Risk (Criteria 1 and 2) According to the Task Force, for any screening program, the condition rst must be a signicant public health problem in a specied population at risk for disease. That is, the condition should affect either the quantity of life (mortality) or the quality of life (morbidity) for some identiable group. In addition, the condition must be detectable and treatable, preferably at an early stage. Cost-effective, workable (i.e., sufciently sensitive and specic) screening tests must be available. Finally, the aggregate benets of detecting and treating the disorder must outweigh the aggregate risks and costs of screening and treatment (Table 1). The public health signicance of any disorder is determined by its prevalence, morbidity, and mortality (8). As the prevalence of a disorder increases, its potential for producing widespread morbidity and mortality also rises. For cancer, the major benets of screening are decreased risk of death, decreased morbidity, and decreased health-care costs. For disorders that affect quality more than quantity of life, the goals of screening may include decreasing disability or symptoms, maintaining functional independence, and improving health-related quality of life (912). For migraine with a peak prevalence in early and mid-adult life, the indirect costs (missed work, disability at work, etc.) often predominate (1315). Migraine is a highly prevalent disorder, affecting 18% of American women and 6% of American men (1). It produces 113 million lost work-day equivalents per year, costing American employers more than 13 billion dollars per year (1315). Although migraine is prevalent at all ages, it is most common in women and in persons between the ages of 25 and 55 (1). Thus, migraine meets the criteria discussed. A Recognizable Latent or Early Symptomatic Stage (or a Disease Undetected by the Health Care System)(Criterion 3) In the United States, about half of migraine sufferers report that they never received a medical diagnosis of migraine (16). Migraine may have an early symptomatic stage that progresses to chronic daily headache in some patients. The argument for screening, therefore, is supported by the low rates of diagnosis and treatment, as well as by the opportunity to interfere and alter natural history. This provides the foundation for effective medical intervention once migraine cases are found (Table 1). Effective Treatment for the Disease Must Be Available and Cost Effective (Criterion 4) There is abundant evidence that supports the effectiveness of numerous acute and preventive treatments for migraine (see Chapters 2024) (17,18). Many studies demonstrate that migraine treatment is cost effective (Table 1) (19,20).

Effective Screening Tools (Criteria 5) Effective screening programs require appropriate screening tests. For a disorder diagnosed largely based on symptoms, such as migraine, questionnaire-based screening is an attractive approach. One advantage of questionnaire-based screening is that it is safe and relatively inexpensive (Table 1). Screening tests are evaluated using a series of statistics based on a 2 2 table (Table 2). One compares disease classication based on the results of the screening test, with disease classication based on the results of the gold-standard assessment.

158 Table 2 Statistics Used in the Evaluation of Screening Tests Gold-standard assessment Screening assessment Screening assessment A C AC Gold-standard assessment B D BD

Bigal and Lipton

AB CD

Note: Sensitivity (true positives) A/A C; Specicity (true negatives) B/B D; PPV A/AB. Abbreviation: PPV, positive predictive value.

The sensitivity (true positives) is the proportion of people with the disease correctly detected by the screening test. If the sensitivity is low, people with the disease will be missed, and opportunities for early treatment will be lost. Specicity (true negatives) refers to the proportion of people without the disease, who are correctly classied by the screening test as being free of disease. If the specicity is low, people who are disease free will be classied into the diseased group. As a consequence, people without disease will be unnecessarily subjected to the risk, discomfort, and anxiety of the more denitive diagnostic procedures. For these reasons, screening tests should have both high sensitivity and high specicity. The positive predictive value (PPV) is the proportion of people actually having the disease of those who screen positive for it, based on the gold-standard assessment. Efcient screening requires a high PPV. The PPV is determined by three factors: the sensitivity of the test, the specicity of the test, and the prevalence of the condition in the population being tested. At a given level of sensitivity and specicity, as disease prevalence rises in the population being screened, PPV also rises. For this reason, it is more efcient to screen populations at a relatively high risk for the disease. The ID-Migraine A number of screening tests for migraine have been proposed (21,22). Herein we focus on ID-migraine, a 3-item migraine screener (Fig. 1), which is a valid and reliable screening instrument for migraine headaches in the primary care (23). The rst phase of development of ID-migraine involved 563 patients presenting for routine appointments at 26 primary care practice sitesthe intended setting for the use of ID-migraine. Eligible subjects were those reporting the occurrence of at least two headaches in the previous three months. Each subject completed a selfadministered screening questionnaire that consisted of nine questions referring to the severity and nature of headache pain, the presence of associated migraine symptoms, and the extent to which the headaches resulted in disability. Study subjects then underwent independent diagnostic evaluations performed by headache specialists. Based on the specialists clinical judgment (that were oriented to follow the criteria proposed by the International Classication of Headache Disorders), a gold-standard diagnosis of migraine was made. Results of the gold-standard diagnostic evaluation were then compared with those of a 9-item screener, and the diagnostic sensitivity and specicity of each item was computed. Logistic regression was used to identify those screener items that were most strongly associated with a gold-standard migraine diagnosis. Three questions were identied (Fig. 1): temporary disability (missing one or more days in the previous three months due to headache), nausea, and photophobia.

Diagnostic and Severity Tools for Migraine

159

Figure 1 The ID-migraine.

Individuals who indicated that they had at least two of three of these features were said to screen positive for migraine. The ID-migraine has a sensitivity of 81%, a specicity of 75%, and a PPV of 93% versus a headache-expert migraine diagnosis. In addition, a testretest reliability was assessed in a study involving 121 patients. Good testretest reliability was demonstrated (kappa coefcient of 0.68). The excellent performance characteristics of the three-item ID-migraine suggest it to be a simple method for increasing the recognition of migraine in the primary care setting (23). Other Criteria (Criteria 6, 7, 8) Screening tests must be acceptable to patients and health-care providers (criterion 6). ID-migraine is effective, affordable, and safe, and therefore meets these criteria. Resources must be available for developing and validating the test (criterion 7)a step that has been accomplished (23). Distribution is inexpensive because the test is available on the Internet and costs almost nothing (Table 1). The nal criterionscreening and treatment must be cost effectiveis the only one that had not been studied for screening, though migraine treatment is cost effective in diagnosed cases (19,20). Table 3 summarizes how migraine ts in the overall criteria for screening. ASSESSING MIGRAINE-RELATED DISABILITY If a patient screens positive, the clinician should exclude secondary headaches, either clinically or using subsidiary tests, and then conrm the migraine diagnosis. After this, the next step is to assess disability as a prelude to developing treatment. Measuring migraine severity is challenging because of the episodic occurrence of attacks and variation in impact of attacks both within and among individuals.

160 Table 3 Does Migraine Meet the Criteria for Screening? Disease characteristics Signicant public health problems Dened population at risk Recognizable latent or early symptomatic phase Or Undetected by the health-care system

Bigal and Lipton

Migraine (Reference) 14 million Americans had migraine with signicant disability in 2001 (1) Risk broadly distributed. Females 2555 at highest risk (1) No

Appropriate screening test available Gold-standard diagnosis

Effective treatment available Benet of screening diagnosis and treatment outweigh the costs

One-third of people with migraine are medically diagnosed, 80% of people with undiagnosed migraine experience disability (13) Self-administered screening developed (23) Clinical assessment using International Headache Society criteria with a semistructured questionnaire and laboratory tests as indicated (23) Yes. Goal of treatment is to prevent current disability and pain (9) High societal cost of disease (24). Effectiveness of screening has not been demonstrated

The World Health Organization (WHO) denes disability in terms of the consequences of illness on ability to work and function in other roles, such as household work and nonwork activities (e.g., recreation, social, and family) (24). Studies conducted in North America, Europe, and Japan consistently show that about 75% of migraine sufferers have a reduced ability to function during attacks (25 27). A population survey of migraine found that half of migraine sufferers discontinued normal activities during their attacks and almost one-third required bed rest (16). In more than 70% of the headache sufferers in this survey, interpersonal relationships were impaired. Other studies have measured disability by estimating lost time due to migraine, including inability to do things as well as reduced effectiveness. Disability is the major determinant of the cost of illness (13,28,29). The MIDAS Questionnaire The most frequently used disability instrument in migraine clinical care and research is the MIDAS questionnaire (Fig. 2) (30). The MIDAS questionnaire consists of ve questions that focus on lost time in three domains: school work or work for pay; household work or chores; and family, social, and leisure activities (31). All questions ask about either days of missed activity or days where productivity was reduced by at least half. If productivity is decreased to 50% or below, the day is considered missed. The MIDAS score is derived as the sum of missed days due to a headache over a three-month period in the three domains. Two additional questions on the MIDAS questionnaire are not included in MIDAS scorethose assessing frequency and intensity of pain. The four-point grading system for the MIDAS questionnaire is as follows:  Grade I (scores ranging from 0 to 5) little or no disability  Grade II (scores ranging from 6 to 10) mild disability

Diagnostic and Severity Tools for Migraine

161

Figure 2 The MIDAS questionnaire. Abbreviation: MIDAS, migraine disability assessment.

 Grade III (scores ranging from 11 to 20) moderate disability  Grade IV (21 or greater) severe disability The Disability Strategies of Care (DISC) study proved that MIDAS is useful for stratifying patients to therapy (32). Attributes of the MIDAS Questionnaire The accuracy of the MIDAS score was evaluated using a 90-day daily headache disability diary as the gold standard (31). A population-based sample of migraine sufferers recorded the occurrence and consequence of their headaches. Study participants were examined by a physician to conrm migraine diagnosis and were then trained in the use of the daily diary. The gold standard for assessing validity of the MIDAS questions and the MIDAS score were equivalent measures derived from the 90-day diary data. The results show that MIDAS can accurately measure the headache-related disability. Internal consistency of the MIDAS score was assessed in two population-based surveys (30,31) performed in the United Kingdom and the United States. The Cronbach alpha was 0.76 in the United States and 0.73 in the United Kingdom. This index ranges from 0 to 1. A score of 0.7 is acceptable, and 0.8 or more indicates that the internal consistency is excellent. The testretest Pearson correlation coefcient for individual items ranged from 0.54 to 0.68 in the United States and from 0.52 to 0.82 in the United Kingdom. Considering the total score, the coefcient was 0.8,

162

Bigal and Lipton

overall. These results indicate that the overall MIDAS score is highly reliable, especially if you consider that there was a three-week interval between both MIDAS assessments. A study was conducted to determine whether MIDAS scores were associated with physicians clinical judgment of pain, disability, and need for medical care (33). Twelve histories from patients with migraine were presented to 49 primary and specialty care physicians unaware of the MIDAS scores. Physicians graded each patient for pain level (mild, moderate, or severe), level of disability (none, mild, moderate, or severe), and need for medical care [from 0 (lowest) to 100 (highest)]. Physicians also identied MIDAS scores they associated with different degrees of disability and with the urgency to prescribe an effective treatment during the rst consultation. The physicians perceptions of the need for medical care based on medical histories correlated with the MIDAS score (r 0.69). Estimates of pain and disability by physicians were directly correlated with increasing MIDAS scores (33). The MIDAS Perceptions Study investigated whether MIDAS scores reect headache severity and the need for medical care, and assessed whether the MIDAS questionnaire is meaningful and relevant to patients and easy to use (34). Satisfaction with current therapy decreased signicantly with increasing MIDAS grade. The MIDAS questionnaire was rated as easy to use by the vast majority of respondents, and ratings of its perceived value increased signicantly as the MIDAS grade increased. Other Disability Tools Other disability measures include the Headache Disability Inventory and the Headache Impact Test. The Headache Disability Inventory is a 25-item questionnaire with good internal consistency, reliability, robust long-term testretest stability, and good construct validity (35). The Headache Impact Test is a 6-item (HIT-6) paper questionnaire that was recently developed and validated (36). An interactive version of HIT-6 is available over the Internet. Stratifying Treatment by Headache Disability The U.S. Headache Consortium Guidelines recommend stratied care based on the level of disability to help physicians target patients who require careful assessment and treatment (4), a concept also supported by the DISC study (32). Figure 3 provides a schematic view of how the MIDAS questionnaire might be used to provide appropriate treatment, based on the patients level of headacherelated disability. All patients require a specic diagnosis, and education about their disorder and self-management strategies. At the time of consultation and diagnosis, the migraine patient completes a MIDAS questionnaire and is categorized into a MIDAS Grade (IIV). A MIDAS score of 0 to 5 (MIDAS Grade I) or 6 to 10 (MIDAS Grade II) indicates relatively low medical need. Simple analgesics are appropriate for rst-line acute treatments for these patients. If simple analgesics are unsuccessful, various combination treatments (e.g., aspirin plus metoclopramide) may be needed. If these treatments fail, further escalation and triptan medication may be necessary. A MIDAS score of 11 or over (MIDAS Grade III/IV) indicates high medical need. Specic acute therapies such as the triptans may be needed by these patients, together with prophylaxis where necessary. Of course, any specic sequence of treatment recommendation requires empirical testing.

Diagnostic and Severity Tools for Migraine

163

Figure 3 Potential utility of the MIDAS Questionnaire in relating migraine severity to treatment choice. Abbreviation: MIDAS, migraine disability assessment.

ASSESSING PSYCHOLOGICAL COMORBIDITY It is clear that comorbid factors are signicant in the development and maintenance of headaches. Originally coined by Feinstein (37), the term comorbidity is used to refer to the greater than coincidental association of two conditions in the same individual. The association between migraine, depression (odds ration ranging from 2.1 to 3.0), and anxiety (from 1.9 to 5.3) is consistently reported (38,39). Additionally, comorbid disorders are often associated to refractoriness to migraine treatment. Therefore, a more sophisticated approach toward the diagnosis and treatment of migraine requires the assessment of comorbid psychiatric diseases. Herein we describe the PRIME-MD questionnaire. The original PRIME-MD was developed by Spitzer et al. (40). The current version is a single, self-administered instrument, the Patient Health Questionnaire (PHQ). It consists of three pages of questions on somatoform disorders, depression, anxiety, alcohol, and eating disorders and takes approximately ve minutes for the patient to complete. An optional fourth page on recent psychosocial stressors and a section for women on problems with menstruation, pregnancy, and childbirth were also added. In validation and utility studies of the self-administered PHQ among 3000 primary care patients (40), the authors found that the diagnostic validity of the instrument was comparable to that of the original clinician-administered instrument, with a sensitivity of 75% and a specicity of 90%. It was also reported to be more efcient to use (Appendix).

ASSESSING ONGOING TREATMENT A large gap continues to exist between evidence-based treatment guidelines and clinical practice. Optimal migraine management would be enhanced if physicians had available a simple decision tool to assist them in determining which patients

164

Bigal and Lipton

are likely to benet from a change in their acute migraine therapy. The systematic evaluation of efcacy and tolerability employed in clinical trials is excessively cumbersome for use in clinical practice settings, where the duration of a patient visit is brief (41). Because satisfaction with therapy is driven in part by patient expectations, satisfaction alone may not fully inform a decision regarding the value of a change in treatment. A validated tool that helped doctors determine whether a change in treatment was necessary would provide broad use. A French group (44) and a collaborative English and American group have developed questionnaires designed to assess satisfaction with acute treatment. The migraine assessment of current therapy (Migraine-ACT) questionnaire assesses four domains with one question for each domain:  Consistency of response: Does your migraine medication work consistently, in the majority of your attacks?  Global assessment of relief: Does the headache pain disappear within two hours?  Impact: Are you able to function normally within two hours?

Figure 4 Summary algorithm.

Diagnostic and Severity Tools for Migraine

165

 Emotional response: Are you comfortable enough with your medication to be able to plan your daily activities? The 4-item Migraine-ACT was shown to be highly reliable (Spearman/Pearson measure r 0.82). The individual questions, and the total 4-item Migraine-ACT score, showed good correlation with items of the SF-36 and MIDAS. A multinational group has developed another Treatment Satisfaction Questionnaire and has recently completed a large multinational study. Although still in its infancy, we anticipate that over the next several years, treatment satisfaction will become an important part of medical practice and that the use of well-validated measures will be incorporated into treatment guidelines.

CONCLUSION Overall, migraine has been found to rank in the top 20 of the worlds most disabling medical illnesses, based on the WHOs global burden of disease survey (44). The U.S. Task Force on Preventive Health Services has established criteria for recommending screening for specic disorders, including those related to (7) (i) signicant prevalence/ disability; (ii) effective treatment; (iii) safe and effective screening tools; and (iv) improving outcomes in a cost-effective manner. The Task Force recently added depression in the list of disorders to be screened. Migraine now meets all criteria except the demonstration that screening and intervention improves outcomes in a cost-effective manner. According to the consortium guidelines (4), after diagnosing migraine, the physician should assess the severity of the patients migraine based on headache-related disability, an approach that captures the economic burden of migraine on society. The guidelines recommend that treatment be individualized for each patient based on disability. Active screening and the use of disability assessment with MIDAS may help address the under-recognition and undertreatment of migraine. Figures 3 and 4 summarize how the tools discussed in this chapter can be used in the rational assessment of migraine. REFERENCES
1. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American United States: data from the American Migraine Study II. Headache 2001; 41:646657. 2. Lipton RB, Amatniek JC, Ferrari MD, Gross M. Migraine. Identifying and removing barriers to care. Neurology 1994; 44(suppl 4):6368. 3. Edmeads J, Lainez JM, Brandes JL, Schoenen J, Freitag F. Potential of the Migraine Disability Assessment (MIDAS) Questionnaire as a public health initiative and in clinical practice. Neurology 2001; 56(Suppl 1):2934. 4. Matchar DB, Young WB, Rosenerg J, et al. Multispecialty consensus on diagnosis and treatment of headache: pharmacological management of acute attacks. Neurology 2000;54:www.aan.com/public/practiceguidelines/03.pdf. 5. Evans MI, Krivchenia EL. Principles of screening. Clin Perinatol 2001; 28:273278. 6. Weiss NS. Application of the case-control method in the evaluation of screening. Epidemiol Rev 1994; 16:102108. 7. Woolf SH, Di Guiseppi CG, Atkins D, et al. Developing evidence-based clinical practice guidelines: lessons learned by the US Preventive Services Task Force. Annu Rev Public Health 1996; 17:511538.

166

Bigal and Lipton

8. Watanabe H. Mass screening program for prostatic cancer in Japan. Int J Clin Oncol 2001; 6:6673. 9. Kattlove H, Liberati A, Keeler E, Brook RH. Benets and costs of screening and treatment for early breast cancer. JAMA 1995; 273:142148. 10. Krahn MD, Mahoney JE, Eckman MH, et al. Screening for prostate cancer. A decision analytic view JAMA 1994; 272:773780. 11. Keil U, Hense HW, Stieber J. Screening for hypertension: results of the Munich Blood Pressure Program. Prev Med 1985; 14:519531. 12. Frame PS. Screening and management of cholesterol levels in children and adolescents. National Cholesterol Education Program. J Am Board Fam Pract 1993; 6:582587. 13. Lipton RB, Stewart WF, Von Korff M. Burden of migraine: societal costs and therapeutic opportunities. Neurology 1997; 48(Suppl 3):S4S9. 14. Hu X, Markson L, Lipton RB, Stewart WF, Berger M. Disability and economic costs of migraine in the United States: a population-based approach. Arch Int Med 1999; 159:813818. 15. Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton RB. Work-related cost of common pain conditions in the US workforce. JAMA 2003; 290(18):24432454. 16. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001; 41:638645. 17. Ferrari MD, Krista RI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT1b/1d agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001: 35816681775. 18. Ramadan NM, Silberstein SD, Freitag FG, et al. Multispecialty consensus on diagnosis and treatment of headache: pharmacological management for prevention of migraine. Neurology [serial online] 2000. Available at: http://www.aan.com/professionals/practice/pdfs/gl0090.pdf Accessed March 20, 2002. 19. Cady RC, Ryan R, Jhingran P, OQuinn S, Pait DG. Sumatriptan injection reduces productivity loss during a migraine attack: results of a double-blind, placebo-controlled trial. Arch Intern Med 1998; 158:10131018. 20. Dasbach EJ, Carides GW, Gerth WC, Santanello NC, Pigeon JG, Kramer. Work and productivity loss in the rizatriptan multiple attack study. Cephalalgia 2000 Nov; 20(9):8304. 21. Cady RK, Borchert LD, Spalding W, Hart CC, Sheftell FD. Simple and efcient recognition of migraine with 3-question headache screen. Headache 2004 Apr; 44(4):323327. 22. Maizels M, Burchette R. Rapid and sensitive paradigm for screening patients with headache in primary care settings. Headache 2003 May; 43(5):44150. 23. Lipton RB, Dodick D, Sadovsky R, Kolodner K, Endicott J, Hettiarachchi J, Harrison W. A self-administered screener for migraine in primary care: The ID Migraine(TM) validation study. Neurology 2003 Aug 12; 61(3):37582. 24. Michaud CM, Murray CJ, Bloom BR. Burden of diseaseimplications for future research. JAMA 2001; 285:535539. 25. Sakai F, Igarashi H. Epidemiology of migraine in Japan. Cephalalgia 1997; 17:1522. 26. Edmeads J, Findlay H, Tugwell P, et al. Impact of migraine and tension-type headache on life-style, consulting behavior, and medication use: a Canadian population survey. Can J Neurol Sci 1993; 20:131137. 27. Michel P, Dartigues JF, Lindousli A, Henry P. Loss of productivity and quality of life in migraine sufferers among French workers: results from the GAZEL cohort. Headache 1997; 37:7178. 28. Lipton RB, Stewart WF, Von Korff M. Burden of migraine: societal costs and therapeutic opportunities. Neurology 1997; 48(Suppl 3):S4S9. 29. Hu X, Markson L, Lipton RB, Stewart WF, Berger M. Disability and economic costs of migraine in the United States: a population-based approach. Arch Int Med 1999; 159:813818.

Diagnostic and Severity Tools for Migraine

167

30. Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton RB. Work-related cost of common pain conditions in the US workforce. JAMA 2003 Nov 12; 290(18):244354. 31. Stewart WF, Lipton RB, Kolodner K, Liberman J, Sawyer J. Reliability of the migraine disability assessment score in a population-based sample of headache sufferers. Cephalalgia 1999; 19:107113. 32. Stewart WF, Lipton RB, Kolodner K, Sawyer J, Lee C, Liberman JN. Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a diary-based measure in a population sample of migraine sufferers. Pain 2000; 88:4152. 33. Lipton RB, Stewart WF, Stone AM Lainez MJA, Sawyer JPC. Stratied care vs step care strategies for migraine: results of the Disability in Strategies of Care (DISC) Study. JAMA 2000; 284:25992605. 34. Lipton RB, Stewart WF, Sawyer J, Edmeads JG. Clinical utility of an instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Headache 2001 Oct; 41(9):85461. 35. Stewart WF, Lipton RB. Need for care and perceptions of MIDAS among headache sufferers study. CNS drugs 2002; 16(Suppl 1):511. 36. Jacobson GP, Ramadan NM, Norris L, Newman CW. Headache disability inventory (HDI): short-term test-retest reliability and spouse perceptions. Headache 1995; 35:534549. 37. Pryse-Phillips W. Evaluating migraine disability: the headache impact test instrument in context. Can J Neurol Sci 2002; 29(suppl 2):1115. 38. Feinstein AR. The pretherapeutic classication of comorbidity in chronic disease. J Chron Dis 1970; 23:455468. 39. Merikangas KR, Stevens DE. Comorbidity of migraine and psychiatric disorders. Neurol Clin 1997 Feb;15(1):11523. 40. Breslau N, Davis GC. Migraine, physical health and psychiatric disorder: a prospective epidemiologic study in young adults. J Psychiatr Res 1993; 27:211221. 41. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA 1999 Nov 10;282(18):173744. 42. Carr-Hill R, Jenkins-Clarke S, Dixon P, et al. Do minutes count? Consultationlengths in general practice. J Health Serv Res Policy 1998;3:207. 43. Dowson AJ, DAmico D, Tepper SJ, Baos V, Baudet F, Kilminster S. Identifying patients who require a change in their current acute migraine treatment: the Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire. Neurol Sci 2004 Oct; 25 Suppl 3:S2768. 44. ANAES. Recommendations for clinical practice. Review of diagnosis and treatment of migraine in the adult and child October 2002. Professional recommendations and references: economic evaluation service. Rev Neurol (Paris) 2003; 159:S515. 45. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990 2020: Global Burden of Disease Study. Lancet 1997; 349:14981504.

APPENDIX: THE PRIME-MD QUESTIONNAIRE Instructions and Items: 1. During the last 4 weeks, how much have you been bothered by any of the following problems? (Scale: Not bothered; Bothered a little; Bothered a lot) a. b. c. d. Stomach pain Back pain Pain in your arms, legs, or joints (knees, hips, etc.) Menstrual cramps or other problems with your periods

168

Bigal and Lipton

e. f. g. h. i. j. k. l. m.

Pain or problems during sexual intercourse Headaches Chest pain Dizziness Fainting spells Feeling your heart pound or race Shortness of breath Constipation, loose bowels, or diarrhea Nausea, gas, or indigestion

2. Over the last 2 weeks, how often have you been bothered by any of the following problems? (Scale: Not at all; Several days; More than half the days; Nearly every day) a. b. c. d. e. f. Little interest or pleasure in doing things Feeling down, depressed, or hopeless Trouble falling or staying asleep, or sleeping too much Feeling tired or having little energy Poor appetite or overeating Feeling bad about yourself or that you are a failure or have let yourself or your family down g. Trouble concentrating on things, such as reading the newspaper or watching television h. Moving or speaking so slowly that other people could have noticed or the oppositebeing so dgety or restless that you have been moving around a lot more than usual i. Thoughts that you would be better off dead or of hurting yourself in some way 3. Questions about anxiety. (No or Yes) a. In the last 4 weeks, have you had an anxiety attacksuddenly feeling fear or panic? If you checked No, go to question #5. b. Has this ever happened before? c. Do some of these attacks come suddenly out of the bluethat is, in situations where you dont expect to be nervous or uncomfortable? d. Do these attacks bother you a lot, or are you worried about having another attack? 4. Think about your last bad anxiety attack. (No or Yes) a. b. c. d. e. f. g. h. i. j. k. Were you short of breath? Did your heart race, pound, or sip? Did you have chest pain or pressure? Did you sweat? Did you feel as if you were choking? Did you have hot ashes or chills? Did you have nausea or an upset stomach or the feeling that you were going to have diarrhea? Did you feel dizzy, unsteady, or faint? Did you have tingling or numbness in parts of your body? Did you tremble or shake? Were you afraid you were dying?

Diagnostic and Severity Tools for Migraine

169

5. Over the last 4 weeks, how often have you been bothered by any of the following problems? (Scale: Not at all; Several days; More than half the days) a. Feeling nervous, anxious, on edge, or worrying a lot about different things If you checked Not at all, go to question #6. b. Feeling restless so that it is hard to sit still c. Getting tired very easily d. Muscle tension, aches, or soreness e. Trouble falling asleep or staying asleep f. Becoming easily annoyed or irritable 6. Questions about eating. (No or Yes) a. Do you often feel that you cant control what or how much you eat? b. Do you often eat, within any 2-hour period, what most people would regard as an unusually large amount of food? If you checked No to either a or b, go to question #9. c. On average, has this been as often as twice a week for the last 3 months? 7. In the last 3 months have you often done any of the following in order to avoid gaining weight? (No or Yes) a. b. c. d. Made yourself vomit? Took more than twice the recommended dose of laxatives? Fastednot eaten anything at all for at least 24 hours? Exercised for more than an hour specically to avoid gaining weight after binge eating?

8. If you checked Yes to any of these ways of avoiding gaining weight, were any as often as twice a week, on average? (Yes or No) 9. Do you ever drink alcohol (including beer or wine)? (No or Yes) If you checked No, go to question #11. 10. Have any of the following happened to you more than once in the last 6 months? (No or Yes) a. You drank alcohol even though a doctor suggested that you stop drinking because of a problem with your health. b. You drank alcohol, were high from alcohol, or were hungover while you were working, going to school, or taking care of children or other responsibilities. c. You missed or were late for work, school, or other activities because you were drinking or hungover. d. You had a problem getting along with other people while you were drinking. e. You drove a car after having several drinks or after drinking too much. 11. If you checked off any problems on this questionnaire, how difcult have these problems made it for you to do your work, take care of things at home, or get along with other people? (Scale: Not difcult at all; Somewhat difcult; Very difcult; Extremely difcult)

170

Bigal and Lipton

12. In the last 4 weeks, how much have you been bothered by any of the following problems? (Scale: Not bothered; Bothered a little; Bothered a lot) a. b. c. d. e. f. g. h. i. j. Worrying about your health Your weight or how you look Little or no sexual desire or pleasure during sex Difculties with husband/wife, partner/lover, or boyfriend/girlfriend The stress of taking care of children, parents, or other family members Stress at work outside of the home or at school Financial problems or worries Having no one to turn to when you have a problem Something bad that happened recently Thinking or dreaming about something terrible that happened to you in the pastlike your house being destroyed, a severe accident, being hit or assaulted, or being forced to commit a sexual act

13. In the last year, have you been hit, slapped, kicked, or otherwise physically hurt by someone, or has anyone forced you to have an unwanted sexual act? (No or Yes) 14. What is the most stressful thing in your life right now? 15. Are you taking any medicine for anxiety, depression, or stress? (No or Yes) 16. FOR WOMEN ONLY: Questions about menstruation, pregnancy, and childbirth. a. Which best describes your menstrual periods? [Scale: Periods are unchanged; No periods because pregnant or recently gave birth; Periods have become irregular or changed in frequency, duration, or amount; No periods for at least a year; Having periods because taking hormone replacement (estrogen) therapy or oral contraceptive.] b. During the week before your period starts, do you have a serious problem with your moodlike depression, anxiety, irritability, anger, or mood swings? (No; Does not apply; Yes) c. If Yes: Do these problems go away by the end of your period? (No; Does not apply; Yes) d. Have you given birth within the last six months? (No; Does not apply; Yes) e. Have you had a miscarriage within the last six months? (No; Does not apply; Yes) f. Are you having difculty getting pregnant? (No; Does not apply; Yes) Scoring. Depression items: Major depressive syndrome is suggested if  Either item #1 or #2 is positivethat is, at least More than half the days AND  Of the 9 items, 5 or more are checked as at least More than half the days. (Count #9 if present at all) Other depressive syndrome is suggested if  Either item #1 or #2 is positivethat is, at least More than half the days AND

Diagnostic and Severity Tools for Migraine

171

 Of the 9 items, 2, 3, or 4 of them are checked as at least More than half the days. (Count #9 if present at all) Note that item #2 (the suicide item) should always be a red ag that further investigation is necessary.

13
Migraine Without Aura
Fred Sheftell
The New England Center for Headache, Stamford, Connecticut, U.S.A.

Roger Cady
Headache Care Center, Primary Care Network, Springeld, Missouri, U.S.A.

INTRODUCTIONMIGRAINE WITHOUT AURA: AN UNDERDIAGNOSED AND UNDERTREATED DISORDER Given its prevalence, impact, and associated disability, migraine remains surprisingly underdiagnosed and under-recognized throughout the world (14). In the United States, 50% or more of sufferers with migraine in the population do not receive proper diagnosis. Because the hallmark of successful treatment is proper diagnosis, sufferers are undertreated as well (5). Some of the reasons for under-recognition relates to the uniqueness of migraine itself. Migraine is both a disease and an episodic disruption of nervous system function. If episodes occur infrequently, are not severe, or are easily self-treated, migraine may not warrant a medical diagnosis and treatment. Over the last two decades, there has been an explosion in the scientic and medical understanding of migraine. Through this time period, migraine, once viewed as a disease of women that resulted from excessive stress and vascular fragility, has emerged as a valid neurobiological disorder. This rapid advance in scientic knowledge of migraine has yet to displace the many myths and misconceptions that surround this important medical condition. Other, more sinister factors may also be partially responsible for the underrecognition and diagnostic confusion that surrounds migraine. For example, the overdiagnosis of sinus headache is a myth continually perpetuated by media in the United States. In direct-to-consumer advertising, migraine is portrayed as sinus in origin (6,7), with unilateral throbbing pain and disability with rapid resolution, which further trivializes the disorder. Patients and physicians often regard headaches as sinus in origin if autonomic symptoms (such as congestion and running nostrils) occur, or if the headache is related to changes in weather. Often, patients direct their own diagnosis by suggesting to a medical provider that their headaches are sinus-, allergy-, or stress-related. Eross et al. showed that one of the most frequent reasons for physicians misidentifying migraine as sinus in origin is the location of the pain (8,9). However, the American Academy of Otolaryngology
173

174

Sheftell and Cady

states that headache is a minor criterion for the diagnosis of acute sinusitis (10), and in fact the Second Edition of the International Classication of Headache Disorders (ICHD-2) does not recognize the sinus headache diagnosis (11). Other issues such as neck involvement may lead to a diagnosis of tension-type headache, delaying diagnosis and appropriate therapy. Kaniecki showed that the vast majority of patients with migraine have neck pain at some point during the attack process (prodrome, the attack, and postdrome) (12). There are few, if any, other common medical complaints that present the magnitude of under- and inaccurate diagnosis associated with migraine. In this chapter, we review the diagnostic criteria for migraine without aura according to the ICHD-2 and then move on to other instruments that may be more practical and less time consuming especially in the primary-care environment or to the nonheadache specialist. We close by presenting an illustrative case that summarizes our discussion on the classication and clinical features of migraine without aura.

THE ICHD-2 CRITERIA FOR MIGRAINE WITHOUT AURA The ICHD-2 criteria for migraine without aura are presented in Box 1. Migraine without aura is an idiopathic, recurring headache disorder manifesting in attacks lasting 4 to 72 hours if not treated. Typical attacks reach moderate or severe intensity, are aggravated by routine physical activity, and are associated with nausea, photophobia, and phonophobia. There is much clinical wisdom behind the required ve episodes necessary to conrm a diagnosis of migraine without aura. Migraine without aura may indeed mimic headache associated with structural pathology (13), arteriovenous malformations (AVM) (14), septic meningitis (15), and headache associated with stroke (16), and each of these is potentially responsive to migraine-specic treatment, such as the triptans (17). A history of ve previous attacks without sequelae and a normal physical and neurological examination should begin to provide a reasonable level of comfort with a primary-headache diagnosis. Although, the differential diagnosis of migraine and other acute headaches is described in detail in Chapter 11. Figure 1 presents red ags that are of concern for the diagnosis of migraine. Some features, including menstrual association, family history, alcohol or other triggers, etc., are presented in Figure 2.

Box 1 ICHD-2 Criteria for Migraine Without Aura A. B. C. At least ve attacks fullling BD Headache attacks lasting 472 hrs (untreated or unsuccessfully treated) Headache has at least two of the following characteristics 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by routine physical activity (i.e., walking or climbing stairs) During headache, occurrence of at least one of the following 1. Nausea and/or vomiting 2. Photophobia and phonophobia Not attributed to another disorder

D.

E.

Migraine Without Aura

175

Figure 1 Worrisome signs and symptoms associated with migraine.

The duration of the typical untreated attack is generally between 4 and 72 hours in adults, but one hour or less in children, where it typically can come on and resolve rapidly. Understanding the nuances of criteria C and D is also critical to assuring accurate diagnosis. Although clinically it has been understood that migraine is characterized by a unilateral throbbing headache (criteria C1 and C2), 40% of attacks are not associated with either unilaterality or throbbing (18). The next two criteria (C3 and C4) dene headache associated with migraine as being of moderate or severe intensity and aggravated by routine physical activity. Headaches associated with at least two of these four criteria are required for an ICHD-2 diagnosis of migraine. However, the attack must also be accompanied by phonophobia and photophobia (D2), nausea, and/or vomiting (D1) for the formal criteria to be met. Thus, a nonthrobbing, bilateral headache with sensitivity to light and sound satises the criteria for the diagnosis of migraine without aura. If the attack is characterized by all but one of the required criteria, the ICHD-2 codes it as probable migraine, previously called migrainous headache, which in the authors opinion is, indeed, migraine and responds to migrainespecic medications (19). While the ICHD-2 criteria remain the gold standard for regulatory studies of migraine, doubts have remained as to the utility of these criteria in the clinical setting, especially in the primary-care environment, given the time constraints and the fact that primary-care providers are responsible for patients with a gamut of diseases, not just headaches. There are a variety of alternative methods that may have greater relevance in clinical practice by which the diagnosis of migraine can be made. The ICHD-2 criteria are based on a consensus of experts and represent the traditional symptombased approach to diagnosis (20).

Figure 2 Comfort signs and symptoms of migraine.

176

Sheftell and Cady

If one examines the criteria for migraine without aura, it is apparent that a minimum of eight questions are necessary to make a diagnosis of migraine without aura. However, those questions do not provide any sense of impact, frequency, disability, change in patterns, response to treatment, and response to medications. This makes the ICHD-2 criteria less clinically relevant because much of the crucial information required for effective decisions about management of migraine patients is lacking in these criteria. A variety of other means of diagnosis are also available (21,22). Pattern-based recognition of migraine is often more clinically valuable for both specialty-based practitioners and primary-care providers. The use of headache calendars may be extremely helpful (23) in revealing patterns such as menstrually associated migraine and migraine triggered by foods, stressful circumstances, weather, or medication overuse. There have been several tools developed over the years targeting temporary impairment related to migraine (see Chapter 12) (2429). Headache-related impact is an essential part of the history and is vital in the diagnosis of migraine and in understanding the effects of headaches on the lives of patients. Lipton et al. have shown that when impact is introduced into the history, physicians are more likely to treat more aggressively and appropriately versus a simple reporting of symptoms (29). For example, in a patient with intermittent migraine who looks perfectly well during the initial visit, hearing Doctor, Im missing two to three days of work every month; I often cant show up at family functions, elicits a better understanding of the impact than, Doctor, my headaches are one-sided, throbbing, and I can be sensitive to light and sound! The use of disability instruments such as Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) can be enormously helpful in accurately diagnosing and understanding the therapeutic needs of the patient. A variety of other instruments, including brief screeners, are also useful as efcient means of considering migraine as a diagnosis. The rst of these is the four-question screener proposed in Patient-Centered Strategies for Effective Management of Migraine (30): 1. How do headaches interfere with your life? A stable pattern of episodic headaches that interfere with work, family, or social functions has a high probability of being migraine. 2. How frequently do you experience headaches of any type? Frequent headaches indicate the need for preventive medication and raise the possibility of medication overuse. 3. Has there been any change in your headache pattern over the last six months? New or unstable headache patterns require complete medical evaluation. 4. How often and how effectively do you use medication to treat headaches? Coping strategies and timing of therapeutic intervention are assessed. As framed, these questions identify patients likely to have migraine, medication overuse, and secondary headaches. A more narrowly focused but well-validated tool is the ID MigraineTM (21). This tool is designed to screen for migraine in the primary-care setting. The validation study found that when two out of three crucial headache features are present, 93% of patients who screen positive receive an ICHD-2based diagnosis when they

Migraine Without Aura

177

see a headache expert. The features include photophobia, inability to function, and nausea, aided by the mnemonic PIN (for a complete description of ID migraine, see Chapter 12). Maizels and Burchette were also among the rst to develop a tool to aid in migraine recognition in the primary-care environment. The Brief Headache Screener (BHS) (31) addresses impact, frequency, patterns of medication use, satisfaction with current therapy, and the need for prophylaxis. They found over a 90% correlation with ICHD-2 criteria for migraine. One study showed that 29% of patients in the waiting room of primary-care practices for any reason screen positive for migraine (20). Moreover, the Landmark Study (32) established that over 90% of patients who seek medical evaluation with a complaint of headache to their primary-care physician, if without obvious signs of secondary headache, will screen positive for migraine. To summarize, recurrent, episodic headache associated with disability, a stable pattern, normal examination, and lack of worrisome features is most likely migraine. Thus, in an outpatient setting where a patient presents with an established pattern of headache rather than a new onset or evolving headache, migraine should be considered the default diagnosis unless there are compelling reasons to the contrary.

MIGRAINE IN CLINICAL PRACTICE Understanding the patient with a primary-headache disorder is more complex than simply applying the academic diagnostic criteria to each primary-headache complaint. By the time patients seek out medical care for a primary headache disorder, they have generally failed for years at self-management and often have developed xed ideas as to the cause and diagnosis of their headaches. Thus, it is critical that providers understand the unique biological and sociological aspects of a headache patient and factors that separate them from the general headache population. Primary headache is nearly a universal human experience and as such can be considered part of human biology. For most people in the general population, headaches are self-diagnosed and self-managed throughout their lifetime. What separates the headache sufferers in the general population from headache patients seen in medical practice is that headache patients have a lower threshold to headaches. They suffer from headaches more frequently, which creates greater impact and disability in their lives. For example, a person in the general population experiencing infrequent severe migraine may seek bed rest for that rare attack, but if they awaken the next morning without headache and can function fully, they are unlikely to consider headache a medical problem. However, the individual who seeks medical care for headaches is likely to be experiencing more frequent disabling headaches that do not always resolve with sleep. Further, the headache patient is likely to believe that they experience more than one type of headache, and headache is generally only one of several physical complaints that they are experiencing (3,33). Consequently, clinicians frequently evaluate primary headaches imbedded amidst other medical concerns and must carefully dissect the relevant symptoms from which a proper diagnosis can be formulated. In addition, they must often overcome the inherent biases the patient has acquired from such sources as the media, well-meaning friends and family, and, at times, poorly informed health-care providers.

178

Sheftell and Cady

Understanding Migraine The episode of migraine is a neurological event that most often begins well before the symptom of headache emerges. The clinical evolution of migraine without aura can be divided into several distinct clinical phases, which not necessarily happen in all patients (Fig. 3) (34,35): (i) premonitory features; (ii) aura; (iii) headache; and (iv) postdromic features. More recently, efforts have been made to link these clinical phases of migraine to its underlying pathophysiology. These observations have important implications for diagnosis and treatment of the migraine process and the patient living with the disorder.

The Phases of Migraine Without Aura Many factors undoubtedly determine an individuals susceptibility to an attack of migraine. Included are genetic factors linked to a more excitable neurological system, biological factors such as age and hormonal status, trauma (both physical and psychological), and environmental factors (36). Clearly, the initiation and susceptibility of the nervous system are determined by the complex interaction of human physiology and environmental factors. This susceptibility to attacks of migraine often changes throughout an individuals lifetime and is quite variable from one individual to another. Premonitory Phase When the nervous system of a person susceptible to migraine is exposed to a risk environment, symptoms that are harbingers of the impending event of headache often emerge. These symptoms are dened in ICHD-2 nomenclature as premonitory symptoms but will often coalesce into a recognizable pattern that allows a migraine sufferer to accurately predict the event of migraine. This

Figure 3 Phases of migraine in clinically observable primary headache diagnoses.

Migraine Without Aura

179

recognizable pattern of premonitory signs and symptoms is commonly referred to as a prodrome. Frequently observed premonitory symptoms include fatigue, mood changes, cognitive dysfunction, muscle pain, nasal congestion, food cravings, and yawning, though many other unique symptoms are also reported in the premonitory phase (37,38). These symptoms can emerge hours to days before the onset of headache. During the premonitory phase, many patients can predict future headache with remarkable accuracy. In an electronic diary study, the patients estimate of the probability of headache corresponded almost exactly to the actual probability of having headache. For example, subjects who reported a 90% chance of having headache developed headache 90% of the time; the use of an electronic diary ensured that the prediction preceded the reported headache onset (37). It is, however, essential to bear in mind that not every premonitory phase evolves into migraine or even headache. At this stage, the pathophysiological process leading to migraine may resolve through natural history or proactive steps such as rest or even medication. Although the premonitory symptoms pale in impact compared to the drama of severe headache, they can and often do create a signicant impact (3739). Consequently, if the premonitory period of migraine persists or occurs frequently without evolving into a migraine headache, these symptoms may not be recognized as a phase of migraine, leading to an erroneous diagnosis. Although the ICHD-2 classication allows a diagnosis of migraine aura without headache, there is no current allowance for premonitory symptoms without headache. Mild Headache The headache associated with migraine often (but not always) begins insidiously; rst as awareness that headache is beginning and then intensifying over minutes to hours to eventually become recognizable as migraine. The early headache is often mild in intensity, diffuse in nature, nonpulsatile in character, and not necessarily aggravated with activity or associated with signicant photophobia or phonophobia. Associated with this headache is often muscle tension or pain in the head and neck or nasal congestion, and pressure in the face (6,10). In many instances, this phase of migraine is considered by patients to be a tension-type headache particularly if it is associated with muscle pain, and sinus headache if it is associated with facial pain and nasal symptoms. The mild headache phase of migraine has relevance both clinically and therapeutically. From a therapeutic standpoint, pharmacological intervention particularly with oral triptans is most efcacious when initiated during this phase of migraine (4042). Although, this therapeutic approach has been described as early intervention, it is more accurate to characterize it as treatment during the mild headache phase of migraine (43,44). Interventions during this time with triptans improve painfree rates by 50% to 100% over interventions initiated during moderate-to-severe headache, and reduce headache recurrence and the occurrence of drug-related adverse events (44). Pharmacoeconomic models also suggest increased value and reduced cost of treatment when this strategy is consistently employed (4547). The clinical relevance of this phase of migraine is also important to understand. Despite the therapeutic value of treatment during this phase of migraine, many patients do not initiate treatment during the mild headache phase of migraine because they are waiting to see if a specic headache will evolve to become a real

180

Sheftell and Cady

migraine (48). In delaying intervention many patients may not achieve optimal therapeutic response and extend the time that migraine disrupts their function. This underscores the need to educate appropriate migraine patients about the value of accurately recognizing this phase of migraine. The mild headache phase, like the premonitory phase, can resolve without evolving into a more severe headache. When this occurs, most people suffering with episodes of severe migraine believe these less severe headaches to be a tensiontype headache. The frequency with which the mild headache resolves without pharmacological intervention is unknown. However, many patients will initiate pharmacological agents (especially over-the-counter drugs) during mild headache, which undoubtedly distort the underlying symptomatology of the evolving migraine. Consequently, they may simply consider these episodes to be of a less severe nonmigraine headache. This underscores some of the diagnostic confusion surrounding migraine recognition.

Moderate-to-Severe Headache Symptoms occurring during the moderate-to-severe headache phase of migraine constitute many of the features required to diagnose migraine by the ICHD-2 criteria. The headache intensies during this phase to the point of being moderate-to-severe in intensity and throbbing, especially with activity, and is frequently associated with nausea, photophobia, and phonophobia. In addition, many of the symptoms observed during the earlier phase of migraine also persist into and through the moderate-to-severe phase of headache, but are not part of the formal diagnostic taxonomy. It is common for patients to describe cognitive difculties, muscle pain in the neck and shoulders, nasal congestion, facial pressure or pain, and mood and affective changes (10,49). In many instances, these symptoms are more frequent and prominent than the symptoms selected as diagnostic criteria for migraine without aura. As this phase of headache reaches its zenith, migraine becomes a signicantly disabling disorder and frequently requires withdrawal from activity and bed rest. Like all previous phases of migraine, the moderate-to-severe headache phase also resolves even if treatment is not initiated. However, without effective intervention, it may produce signicant disability for up to 72 hours and occasionally longer.

Postdrome Following the resolution of the headache phase of migraine, patients frequently experience symptoms described as a postdrome or the hangover of migraine. These symptoms are often a continuation of symptoms similar to those observed during the premonitory phase of migraine. These symptoms may continue for 24 or more hours and may add to the impact and disability associated with an attack of migraine. The Spectrum of Migraine The ICHD-2 diagnostic criteria for migraine include diagnoses of migraine with aura, migraine without aura, and probable migraine. In clinical practice, several

Migraine Without Aura

181

or all of these different presentations may be experienced by the same patient. In addition, the migraine patient often considers some of their headaches to be tension-type headaches. In the American Migraine Study II (3), over 1600 subjects with migraine, as diagnosed by a validated telephone interview and a medical diagnosis of primary headache(s), completed a survey inquiring about the types of headaches they were experiencing. Invariably, these subjects reported multiple types of headache regardless of the medical diagnosis(es) they had received. The most common headache self-diagnoses were migraine, sinus headache, and tension-type headache. The Spectrum Study, published in 2000 (50), explored the relationship of different primary headaches in the patient with migraine. In this study, subjects with a history of migraine were allowed to treat up to 10 moderate-to-severe headaches of any type, with 50 mg of oral sumatriptan. Diaries were used to record the severity and quality of headache, associated symptoms, and treatment response. The diaries records were used to assign an ICHD-2 diagnosis to each treated headache. The results of this study demonstrated that although the subjects experienced some headaches that fullled criteria for migraine with or without aura, they also experienced headaches that fullled criteria for probable migraine and tension-type headache. Thus, there was an observed spectrum of primary headaches in the population with migraine. Analysis of treatment response to sumatriptan suggested statistically signicant efcacy over placebo for all headache presentations as well as similar response rates between these different headache diagnoses. The authors conclude that there were underlying pathophysiological mechanisms shared by these phenotypically different primary headaches at least in the migraine population (19). Subsequently, Cady et al. reported on a population of subjects with self-diagnosed or physician-diagnosed sinus headache (6). Detailed interviews revealed that 98% had enough symptoms to establish a diagnosis of migraine with or without aura (70%) or migrainous headache (28%). When these subjects treated a headache with 50 mg of oral sumatriptan, the efcacy was similar to that observed in treating migraine. A larger placebo-controlled study of over 3000 subjects was reported by Schreiber et al. (51) and conrmed the results seen in the earlier pilot study. Thus, it would appear that most sinus headaches are in reality part of the spectrum of primary headache presentations observed in the migraine population.

THE CONVERGENCE HYPOTHESIS The Convergence Hypothesis (51) is proposed as a clinical model of migraine that attempts to connect clinical diagnosis of common primary headaches with the pathophysiology of migraine and the observed clinical phases of migraine. This model proposes that an episode of migraine is initiated when a vulnerable nervous system is exposed to an environment (internal or external) that puts it at risk for migraine. Placed in this migraine-risk environment, the nervous system undergoes changes in its normal homeostatic mechanisms. These changes are witnessed clinically as premonitory symptoms. Numerous events may individually or in conjunction with other events set the environment for nervous system disruption. These different events may impact on the nervous system in unique ways resulting in different premonitory symptoms.

182

Sheftell and Cady

The rst phase would be followed by cortical spreading depression (CSD). This physiological phenomenon is used to explain the aura associated with 20% of migraine attacks. It remains unknown whether CSD occurs in migraine without aura (52). According to the Convergence Hypothesis, the mild headache phase of migraine results from a net loss of central inhibitory modulation of peripherally generated sensory inputs arising from trigeminal afferents and/or sensory input from the C-2-3 dermatomes. The early perception of headache is often related by patients as secondary to muscle tension and pain, skin sensitivity, or sinus pressure or congestion. These symptoms may be erroneously interpreted as evidence for sinus headache or muscle tension headache. Later, the moderate-to-severe headache phase of migraine primarily would relate to neurovascular activation of trigeminal afferents. The clinical symptoms observed during the moderate-to-severe headache phase of migraine evolve as underlying pathophysiology of migraine progresses. Initially, the headache begins to intensify and may localize. As second-order neurons become sensitized, physical activity aggravates the pain. This is prominent during activities that increase intracranial pressure (and consequently mechanical pressure on the trigeminal afferents innervating meningeal vessels) such as cough or bending forward. As higher orders of the nervous system are sensitized, sensory inputs are registered as unpleasant or painful. During some attacks, patients may develop cutaneous allodynia (53). As is noted with the other phases of migraine, the moderate-to-severe headache phase can be arrested or terminated at any point in its evolution. The diagnostic implications of the Convergence Hypothesis are that a diagnosis of ICHD-2 migraine denes the extent and capability of the nervous system to experience the entire pathophysiological process of migraine. Once this diagnosis is made, the entire spectrum of primary headaches can be understood as arising from the same pathophysiological process, and clinical management can shift to understanding the pattern of headache rather than diagnosing each individual headache.

MENSTRUALLY RELATED MIGRAINE Perhaps the most consistent risk event for migraine in women throughout their reproductive years is menses. Evidence suggests that falling levels of estrogen are involved in the pathophysiology of these migraine attacks (54). This speculation is supported by the observation that 70% of women may experience headache during the week of placebo pills when using oral contraceptive pills (55) and by the frequent exacerbation of migraine observed during the perimenopausal time period. Menstrually related migraine (MRM) is not formally recognized by the ICHD-2 diagnostic criteria as a separate diagnostic category but has been added to the appendix. The classication notes that there are two subtypes of menstrual migraine. In pure menstrual migraine, the attacks are restricted to the menstrual cycle. Although MRMs are clustered in the menstrual period, they also happen unrelated to the cycle. Both pure menstrual migraine and MRM are not associated with aura, suggesting a unique role for estrogen withdrawal in initiating activation of the trigeminal vascular system. There is much folklore surrounding MRM. For example, MRM is often considered a more virulent variant of migraine than those attacks not associated with menses and is described as being more difcult to treat or longer in duration.

Migraine Without Aura

183

However, data are generally lacking to either support or refute these claims. MRM is an important form of migraine to understand for both its clinical importance and theoretical value. MRM is in most instances predictable by both the occurrence of premonitory symptoms and its cyclic nature. In general, data from clinical trials suggest that MRM responds to triptan intervention with about the same efcacy as non-MRM (56,57). However, the study period of the clinical trials was only 24 hours, which limits conclusions on migraine recurrence. Based on the predictable nature of MRM, numerous novel efforts have been made to prevent attacks from occurring. These include efforts to prevent estrogen levels from decreasing, such as with unopposed use of oral contraceptives and the use of oral triptans in a preemptive method. Both strategies appear to have efcacy, though they are not approved by the Food and Drug Administration. Studies with triptans used in a preemptive manner have interesting implications as to the early use and perhaps limited prophylactic use of these drugs in the future (38,5860).

CONCLUSION Migraine without aura is a common, though under-recognized medical condition. Although headache is nearly a universal human experience, the potential of the nervous system to express a fully developed migraine appears to occur in approximately 12% of the adult population. Migraine is a neurological process that is initiated when a susceptible nervous system of a migraineur is exposed to an environment that places that nervous system at risk for migraine. Clinically, migraine often evolves through several recognizable phases before progressing into an attack fullling all the ICHD-2 criteria for migraine without aura. This neurological process can resolve at any point in its evolution, which may in part explain the multiple unique and varied clinical phenotypes of the migraine process. Patients living with a nervous system that has the potential to express migraine often experience multiple clinical presentations of migraine. These unique presentations of headaches can create diagnostic confusion for the patient and provider. However, close analysis reveals that in most instances these headaches do achieve enough symptoms to satisfy the ICHD-2 criteria for migraine. Many patients assume that headache associated with facial pain is sinus in origin and headache associated with muscle pain is tension in origin. Understanding migraine as a neurological process permits a more complete comprehension of these different clinical nuances of migraine. This results a more accurate diagnosis through integration of the pattern and impact of migraine with the associated clinical symptoms. And this provides opportunities to educate patients for a better understanding of the rationale for important therapeutic paradigms such as early intervention. Migraine is a unique medical condition in that it arises from human physiology. Unlike many medical diseases that providers manage, migraine has no obvious catastrophic medical end point nor is there any etiological toxic agent or infection to resolve. However, when migraine is uncontrolled, it can literally destroy decades of a persons quality of life. Medical providers can do much to assist patients living with this disorder to improve their quality of life by providing education, support, and appropriate therapeutic interventions.

184

Sheftell and Cady

ILLUSTRATIVE CASE HISTORY MR is a 35-year-old female with a history of headache going back to adolescence starting around the time of menarche. She experiences several different types of headache. Type I: The ones that occur monthly with her menses are the most severe and characterized by severe bilateral squeezing pain, which affects her ability to function. Climbing stairs making it worse. She denies vomiting, nausea, and sensitivity to sound, but she will avoid bright light. Her mother had sinus headaches, which dissipated after her menopause. Her grandmother had sick headaches. Physical/ neurologic examination is within normal limits. Type II: These are associated with weather changes with moderate pain located above the bridge of her nose between her eyes and involving both infraorbital areas. The pain can throb when severe and she may get mildly nauseated, which she blames on the medication, a combination of a simple analgesic and pseudoephedrine, which takes the edge off the headache. Type III: These start in her neck and involve the occipital region as well. The pain is at least of moderate intensity, sometimes triggered by stress, and may cause her to lie down if she can, with the lights off and sound at a minimum. Going back to the ICHD-2 criteria and the screeners you can see how all of these are migraine! Type I headache incorporates only sensitivity to light and no other Group B symptoms. These episodes formerly called migrainous headache are now called probable migraine according to ICHD-2.

REFERENCES
1. Lipton RB, Stewart WF, Simon D. Medical consultation for migraine: results from the American Migraine Study. Headache 1998; 38(2):8796. 2. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41(7):646657. 3. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001; 41(7):638645. 4. Rasmussen BK. Epidemiology and socio-economic impact of headache. Cephalalgia 1999; 19(suppl 25):2023. 5. Lipton RB, Amatniek JC, Ferrari MD, Gross M. Migraine. identifying and removing barriers to care. Neurology 1994; 44(6 suppl 4):S63S68. 6. Cady RK, Schreiber CP. Sinus headache or migraine? Considerations in making a differential diagnosis. Neurology 2002; 58(9 suppl 6):S10S14. 7. Cady RK, Schreiber CP. Sinus headache: a clinical conundrum. Otolaryngol Clin North Am 2004; 37(2):267288. 8. Eross EJ, Gladstone JP, Dodick DW. Migraine headache misdiagnosed as sinus headache: You can only nd what you are looking for. Headache 2004; 44:479. 9. Eross EJ, Gladstone JP, Dodick DW. Why migraine is misdiagnosed as sinus headache: the patients perspective. Headache 2004; 44:479. 10. National Center for Health Statistics. International Classication of Diseases, Tenth Revision, Clinical Modication. (ICD-10-CM). Available at http://www.cdc.gov/nchs/ search/search.htm. Accessed 12/15/2004. 11. Headache Classication Subcommittee of the International Headache Society. The international classication of headache disorders: 2nd ed. Cephalalgia 2004; 24(suppl 1):9160.

Migraine Without Aura

185

12. Kaniecki RG. Migraine and tension-type headache: an assessment of challenges in diagnosis. Neurology 2002; 58(9 suppl 6):S15S20. 13. Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993; 43(9):16781683. 14. Fung LW, Ganesan V. Arteriovenous malformations presenting with papilloedema. Dev Med Child Neurol 2004; 46(9):626627. 15. La Mantia L, Erbetta A. Headache and inammatory disorders of the central nervous system. Neurol Sci 2004; 25(suppl 3):S148S153. 16. Welch KM. Relationship of stroke and migraine. Neurology 1994; 44(10 suppl 7): S33S36. 17. Hoffmann O, Keilwerth N, Bille MB, et al. Triptans reduce the inammatory response in bacterial meningitis. J Cereb Blood Flow Metab 2002; 22(8):988996. 18. Pryse-Phillips WEM, Dodick DW, Edmeads JG, et al. Guidelines for the diagnosis and management of migraine in clinical practice. Can Med Assoc Mat 1 1997; 156 (9): 12731287. 19. Lipton RB, Cady RK, Stewart WF, Wilks K, Hall C. Diagnostic lessons from the spectrum study. Neurology 2002; 58(9 suppl 6):S27S31. 20. Sheftell FD, Tepper SJ. New paradigms in the recognition and acute treatment of migraine. Headache 2002; 42(1):5869. 21. Lipton RB, Dodick D, Sadovsky R, et al. ID Migraine validation study. A selfadministered screener for migraine in primary care: The ID Migraine validation study. Neurology 2003; 61(3):375382. 22. Cady RK, Borchert LD, Spalding W, Hart CC, Sheftell FD. Simple and efcient recognition of migraine with 3-question headache screen. Headache 2004; 44(4): 323327. 23. Lipton RB, Goadsby PJ, Sawyer JP, Blakeborough P, Stewart WF. Migraine: diagnosis and assessment of disability. Rev Contemp Pharmacother 2000; 11:6373. 24. Ware JE Jr, Bjorner JB, Kosinski M. Practical implications of item response theory and computerized adaptive testing: a brief summary of ongoing studies of widely used headache impact scales. Med Care 2000; 38(suppl):11731182. 25. Kinski M, Bjorner JB, Bayliss MS, Ware JE. Measuring the impact of migraine and severe headache with the headache impact test: using item response theory (IRT) models to score widely-used measures of headache impact and assess disability due to migraine or other severe headaches [abstract]. Neurology 2000; 54(suppl 3):A453. 26. Ware JE, Kosinski M, Diamond M, et al. Validation of the headache impact test using patient-reported symptoms and headache pain severity [abstract]. Cephalalgia 2000; 20:320. 27. Jacobson GP, Ramadan NM, Aggarwal SK, Newman CW. The Henry Ford Hospital Headache Disability Inventory (HDI). Neurology 1994; 44:837842. 28. Jacobson GP, Ramadan NM, Norris L, Newman CW. Headache disability inventory (HDI): short-term test-retest reliability and spouse perceptions. Headache 1995; 35: 534539. 29. Lipton RB, Stewart WF, Sawyer J, Edmeads JG. Clinical utility of an instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Headache 2001; 41(9):854861. 30. Advisory Board of the Primary Care Network. Patient-Centered Strategies for Effective Management of Migraine. Primary Care Network 2000. 31. Maizels M, Burchette R. Rapid and sensitive paradigm for screening patients with headache in primary care settings. Headache 2003; 43(5):441450. 32. Tepper SJ, Dahlof CG, Dowson A, et al. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the landmark study. Headache 2004; 44(9):856864. 33. Cady RK, Farmer KU, Dexter JK, Schreiber CP. Cosensitization of pain and psychiatric comorbidity in chronic daily headache. In press.

186

Sheftell and Cady

34. Blau JN. Adult migraine: the patient observed. In: Blau JN, ed. Migraine Clinical and Research Aspects. Baltimore, MD: Johns Hopkins University Press, 1987:317. 35. Wolff HG. Headache and Other Head Pain. 2nd ed. New York, NY: Oxford University Press. 1963:227301. 36. Cady RK, Farmer KU, Schreiber CP. Understanding the patient with migraine: the evolution from episodic headache to chronic neurological disease. A proposed classication of patients with headache. Headache 2004; 44:110. 37. Gifn NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology 2003; 60:935940. 38. Luciani R, Carter D, Mannix L, et al. Prevention of migraine during prodrome with naratriptan. Cephalalgia 2000; 20(2):122126. 39. Farmer KU, Cady RK, Reeves D. The effect of prodrome on cognitive efciency [abstr]. Headache 2003; 43:518. 40. Cady RK, Lipton RB, Hall C, et al. Treatment of mild headache in disabled headache sufferers: results of the spectrum study. Headache 2000; 40(10):792797. 41. Cady RK, Sheftell F, Lipton RB, et al. Early treatment with sumatriptan enhances pain-free responses: retrospective analysis from three clinical trials. Clin Ther 2000; 22(9): 10351048. 42. Pascual J, Cabarrocas X. Within-patient early versus delayed treatment of migraine attacks with almotriptan: the sooner the better. Headache 2002; 42(1):2831. 43. Brandes JL, Kudrow D, Cadt RK, Tiseo PJ, Sun W, Sikes CR. Eletriptan in the early treatment of migraine; inuence of pain intensity and timing of dosing. Cephalalgia 2005; 25(9):735742. 44. Sheftell F, OQuinn S, Watson C, Pait D, Winter P. Low migraine headache recurrence with naratriptan: clinical parameters related to recurrence. Headache 2000; 40: 103110. 45. Stang P, Cady RK, Batenhorst AS, Hoffman L. Workplace productivity: a review of the impact of migraine and its treatment. Pharmacoeconomics 2001; 19:231244. 46. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States. Arch Intern Med 1999; 159:813818. 47. Halprin MT, Cady RK, Kwong WJ, Mario KO, Batenhorst AS. Costs and outcomes of early versus delayed migraine treatment with sumatriptan. Headache 2002; 42(10): 984999. 48. Foley KA, Cady RK, Martin V, et al. Treating early vs treating mild: timing of migraine prescription medications among patients with diagnosed migraine. Headache. 2005; 45(5):538545. 49. Schreiber CP, Hutchinson S, Webster CJ, et al. Prevalence of migraine among patients with a history of self-reported or physician diagnosed sinus headache. Arch Intern Med 2004; 164:17691772. 50. Lipton RB, Stewart WF, Cady RK, et al. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study. Headache 2000; 40:783791. 51. Cady R, Schreiber C, Farmer K, Sheftell F. Primary headaches: a convergence hypothesis. Headache 2002; 42:204216. 52. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8(2):136142. 53. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614624. 54. Somerville BW. The role of estrogen withdrawal in the etiology of menstrual migraine. Neurology 1972; 22:355. 55. Sulak PJ, Scow RD, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol 2000; 55:15171523. 56. Solbach P, Waymer R. Treatment of menstrually associated headache with subcutaneous sumatriptan. Obstet Gynecol 1993; 82:769772.

Migraine Without Aura

187

57. Silberstein SD, Massiou G, LeJeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol 2000; 96:237242. 58. Sheftell FD, Rappaport AM, Coddon DR. Naratriptan in the prophylaxis of transformed migraine. Headache 1999; 39(7):506510. 59. Newman LC, Lipton RB, Lay CL, Solomon S. A pilot study of oral sumatriptan as intermittent prophylaxis of menstrually-related migraine. Neurology 1998; 52(6): 13011302. 60. Silberstein SD, Elkind AH, Schreiber CP, Keywood C. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology 2004; 63(2): 261269.

14
Migraine with Aura
Malene Kirchmann Eriksen and Jes Olesen
Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark

INTRODUCTION Migraine with aura is characterized by transient focal neurological symptoms called aura. Visual, sensory, and dysphasic aura are the most common symptoms, but other aura variants such as motor aura may occur. The visual and sensory aura are generally characterized by positive symptoms (ickering light, zigzag lines, or prickling paresthesias) followed by negative symptoms (blind spot and numbness). Furthermore, the aura symptoms usually develop gradually, over a few minutes, and often spread over the area of initial clinical manifestation (across the visual eld, from one hand to the lower arm, or across the face). The aura duration is usually less than one hour. The aura symptoms may be followed by headache, nausea, vomiting, or photo- or phonophobia as seen in migraine without aura, but aura attacks may also occur in isolation. This chapter describes the classication and clinical features of migraine with aura.

CLASSIFICATION According to the second edition of The International Classication of Headache Disorders (ICHD-2) (1), certain clinical features must be present and organic diseases must be excluded, either by clinical or by subsidiary investigation (see Chapter 11), to establish a diagnosis of migraine with aura. The diagnosis of migraine with aura requires at least two attacks fullling the ICHD-2 criteria. There are four major subtypes of migraine with aura and more than one subtype may occur in one individual (Table 1). In brief, typical aura (ICHD-2 codes 1.2.13) is characterized by visual, sensory, or dysphasic aura (Table 2) that may be followed by a migraine headache (1.1) or nonmigraine headaches (1.2), or occur without headaches (1.3). Familial hemiplegic migraine (FHM) (1.2.4) is characterized by motor weakness in addition to the typical aura, as well as at least one rst- or second-degree relative with the same disorder (Table 3). Sporadic hemiplegic migraine (1.2.5) is characterized by motor weakness in addition to typical aura, but no rst- or second-degree relative has hemiplegic
189

190

Eriksen and Olesen

Table 1 Classication of Migraine According to the Second Edition of the International Classication of Headache Disorders 1.1 Migraine without aura 1.2 Migraine with aura 1.2.1 Typical aura with migraine headache 1.2.2 Typical aura with nonmigraine headache 1.2.3 Typical aura without headache 1.2.4 Familial hemiplegic migraine 1.2.5 Sporadic hemiplegic migraine 1.2.6 Basilar-type migraine 1.6 Probable migraine 1.6.1 Probable migraine without auraa 1.6.2 Probable migraine with aurab
a b

Attacks fullling all but one of the criteria for migraine without aura. Attacks fullling all but one of the criteria for migraine with aura or any of its subtypes.

migraine (Table 3); basilar-type migraine (1.2.6) is characterized by aura symptoms clearly originating from the brainstem, or both hemispheres simultaneously affected, but no motor weakness (Table 4). Migraine with typical aura is subtyped according to the characteristics of the headache following the aura: typical aura with migraine headache (1.2.1), typical aura with nonmigraine headache (1.2.2), and typical aura without headache (1.2.3) (Table 2). The ICHD-2 criteria for migraine with aura have been improved compared to the ICHD-1 criteria (1988). The ICHD-2 criteria for migraine with typical aura and familial- and sporadic hemiplegic migraine were based on the analysis of empirical
Table 2 Diagnostic Criteria for Migraine with Typical Aura According to the Second Edition of the International Classication of Headache Disorders A. At least two attacks fullling criteria BD B. Aura consisting of at least one of the following, but no motor weakness: 1. Fully reversible visual symptoms including positive features (i.e., ickering lights, spots, and lines) and/or negative features (i.e., scotoma) 2. Fully reversible sensory symptoms including positive features (i.e., pinprick and needle sensation) and/or negative features (i.e., numbness) 3. Fully reversible dysphasic speech disturbance C. At least two of the following: 1. Homonymous visual symptoms and/or unilateral sensory symptoms 2. At least one aura symptom develops gradually over !5 min and/or different symptoms occur in succession over !5 min 3. Each symptom lasts !5 min and 60 min D. This criterion determines the subdiagnosis of migraine with typical aura: 1.2.1 Typical aura with migraine headache: Headache fullling criteria BD for 1.1 Migraine without aura begins during the aura or follows aura within 60 min, or 1.2.2 Typical aura with nonmigraine headache: Headache that does not fulll criteria BD for 1.1 Migraine without aura begins during the aura or follows aura within 60 min, or 1.2.3 Typical aura without headache: Headache does not occur during the aura nor follow aura within 60 min E. Not attributed to another disorder

Migraine with Aura

191

Table 3 Diagnostic Criteria for Familial Hemiplegic Migraine According to the Second Edition of the International Classication of Headache Disorders A. At least two attacks fullling criteria B and C B. Aura consisting of fully reversible motor weakness and at least one of the following: 1. Fully reversible visual symptoms including positive features (i.e., ickering lights, spots, and lines) and/or negative features (i.e., scotoma) 2. Fully reversible sensory symptoms including positive features (i.e., pinprick and needle sensation) and/or negative features (i.e., numbness) 3. Fully reversible dysphasic speech disturbance C. At least two of the following: 1. At least one aura symptom develops gradually over !5 min and/or different symptoms occur in succession over !5 min 2. Each symptom lasts !5 min and 24 hr 3. Headache fullling criteria BD for migraine without aura (1.1) begins during the aura or follows onset of aura within 60 min D. At least one rst- or second-degree relative has attacks fullling criteria AE E. Not attributed to another disorder
Note: The diagnostic criteria for sporadic hemiplegic migraine are identical to the criteria for familial hemiplegic migraine except no rst- or second-degree relative fullls criteria AE.

data (24). New genetic data have allowed a more precise denition of FHM since specic genetic subtypes have been identied: in FHM1 there are mutations in the CACNA1A gene on chromosome 19, and in FHM2, mutations occur in the ATP1A2 gene on chromosome 1 (see Chapter 9). It is likely that further genetic subtypes of FHM will be added.

Table 4 Diagnostic Criteria for Basilar-Type Migraine According to the Second Edition of the International Classication of Headache Disorders A. At least two attacks fullling criteria BD B. Aura consisting of at least two of the following fully reversible symptoms, but no motor weakness: 1. Dysarthria 2. Vertigo 3. Tinnitus 4. Hypacusia 5. Diplopia 6. Visual symptoms simultaneously in both temporal and nasal elds of both eyes 7. Ataxia 8. Decreased level of consciousness 9. Simultaneously bilateral paresthesias C. At least one of the following: 1. At least one aura symptom develops gradually over !5 min and/or different symptoms occur in succession over !5 min 2. Each symptom lasts !5 min and 60 min D. Headache fullling criteria BD for migraine without aura (1.1) begins during the aura or follows aura within 60 min E. Not attributed to another disorder

192

Eriksen and Olesen

MIGRAINE WITH TYPICAL AURA Prevalence and Prognosis Migraine with typical aura is the most prevalent subtype of migraine with aura, affecting 5% to 8% of the population, with a male to female ratio of 1:2.5 (see Chapter 2). The attack frequency varies from few in a lifetime to several per week, and furthermore, the attack frequency shows wide periodicity. Most patients develop typical aura with headache in the rst three decades of life (mean age at onset 21 12 years), while typical aura without headache may develop later in life (mean age at onset 36 15 years) (5). In a 16-year follow-up study of 53 patients, the long-term prognosis for migraine with nonhemiplegic aura was good (6). At the time of followup, attacks had ceased for two years in 36% of patients. Attacks had stopped in 41% of patients with visual aura without other aura symptoms and in 25% of those with sensory or aphasic aura besides their visual aura. In those who continued to have attacks of migraine with aura at follow-up, the headache intensity was improved in 44%, and the frequency was improved in 41% of patients (6). Another study of 80 patients with migraine with aura showed that 35% of patients had been attack free for one year at 10 to 20 years follow-up (7). Patients with a strong familial predisposition to migraine with aura have an earlier age at onset and a later age of cessation of attacks than patients from the general population (5,8). General Symptom Characteristics Migraine with typical aura is characterized by attacks of visual, sensory, or dysphasic aura often followed by a headache (Table 2). In a study of 320 patients with a positive family history of migraine with typical aura (ICHD-2 criteria), 63% of patients had migraine aura with headache in every attack, 32% had attacks of both migraine aura with and without headache, and 6% had exclusively migraine aura without headache (9). In a population-based sample of 163 patients (ICHD-1 criteria), the corresponding gures were 58%, 38%, and 4%, respectively (10). Males have exclusively aura without headache more often than females (6). At onset, many patients experience attacks of typical aura with headache, but later in life aura attacks often appeared without a following headache, especially in men. Visual aura is the overwhelmingly most common aura symptom, occurring in 99% of patients at least in some attacks (5,10). Sensory aura has been reported in 54% (5), 31% (10), 40% (11), and 30% (12) of patients. Dysphasic aura has been reported in 32% (5), 18% (10), 20% (11), and 17% (12) of patients. When more than one aura symptom is observed, they occur in succession in more than 96% of patients (5,13), and the visual aura is usually followed by the sensory or aphasic aura (10,12). Visual aura occurs in almost every attack, while sensory or aphasic aura occurs in only a fraction of an individuals total number of attacks (5,10). In typical aura with headache, visual aura occurs without other aura symptoms in 39% (5) to 68% (10) of patients, whereas sensory and aphasic auras usually occur in combination with another aura type (usually visual) (5,10,11,14,15). In typical aura without headache, visual aura occurs in isolation in 76% (5) to 84% of patients (10). Therefore, organic diseases (e.g., cerebrovascular ischemia) should always be considered in patients with paresthesias and/or aphasia without visual symptoms and in patients with multiple aura symptoms without headache (see Chapter 11). The following subsections describe the features of the aura symptoms and the associated headache.

Migraine with Aura

193

Visual Aura The most common visual aura phenomenon is the fortication spectrum (or teicopsia, the Greek translation of seeing fortications) almost diagnostic for migraine with aura (Fig. 1) (16,17). The fortication spectrum often starts as a hazy spot near the center or in the periphery of the visual eld, and subsequently a star-shaped gure of scintillating lights develops, which gradually expands into a semicircular zigzag line (fortication) (1820). The fortication line keeps expanding or moving across the visual eld until it reaches the midline (or crosses the midline) or the periphery of the visual eld, and then it dissolves. The fortication line may change its shape during the gradual development. The zigzag line comprises parallel lines of white light, but colored lights are experienced in some patients, usually behind the advancing scintillation (14,15,19). In the wake of the fortication line, that is, in the inner circle of the spectrum, a scotoma (partial loss of sight) often follows, but the spectrum may also appear without a scotoma (1820). The scotoma may develop into a complete hemianopsia (15). Other patients observe a nonscintillating scotoma (Fig. 2). This negative scotoma might completely escape observation, or may only come to the attention of the patient when it reaches a certain size (15). Repetitive fortication spectra or scotoma in the same attack have been observed (15,17,19). Less characteristic visual aura symptoms include shimmering, photopsias (ashes of light), heat waves (20), or rare metamorphopsia such as micropsia, macropsia, telescopic ` vision, mosaic vision, deja vu, or jamais vu (21). The prevalence of the visual aura characteristics has been described in detail by Eriksen et al. (5) and Russell and Olesen (Table 5) (10). The visual aura is unilateral, that is, it affects only one side of the visual eld in two-thirds of patients (5,10). The side of the visual aura may differ between attacks (20). The fortication line or scotoma is most often unilateral, while less characteristic visual disturbances, e.g., ickering light, may be observed in the entire visual eld (5,14). The visual aura develops gradually over more than ve minutes in 81% (5) to 97% of patients (10) (Table 5). The duration of the visual aura is less than one hour in 90% of patients (5,10,12).

Figure 1 Fortication spectrum in visual aura experienced by the author (M.K. Eriksen). The visual aura develops gradually over 20 minutes: (1) Shimmering in the right lateral part of the visual eld. (2) A zigzag-shaped line of scintillating lights develops leaving a scotoma in its wake. (3,4) The fortication spectrum migrates across the visual eld and expands reaching a maximum diameter of 20 cm. (5) The fortication spectrum reaches the midline of the visual eld and dissolves in shimmering. No headache, but tiredness follows the aura.

194

Eriksen and Olesen

Figure 2 Negative scotoma in visual aura experienced by the author (M.K. Eriksen). (A) The word European in the heading of a poster as observed before the onset of aura. (B) The same word as perceived during an attack of visual aura. Initially hazy spots in the entire visual eld develop. Then, a difculty reading text located to the left of the center of xation is noted. Blind spots cover part of the word and the letters still visible seem fractioned. The aura duration is 45 minutes and a migraine headache begins during the aura.

If the visual aura is followed by a headache, the duration of the visual aura is longer (median of 30 minutes and interquartile range 1545) than if the visual aura occurs in isolation (median of 18 minutes and interquartile range 1322) (5). Because the symptomatology of the visual aura can be complex, Eriksen and Olesen developed and validated a simple diagnostic scale for migraine aura known as the visual aura rating scale (VARS) (22). The scale quanties the importance of the cardinal characteristics of the visual aura. The choice of the visual aura for quantication is based on the fact that most patients having migraine with aura experience visual symptoms. The VARS score is the weighted sum of the presence of ve visual symptom characteristics: duration 5 to 60 minutes (three points), develops gradually (two points), scotoma (two points), zigzag lines (two points), and unilateral (one point). A VARS score of 5 or more predicted the diagnosis of migraine with aura with a sensitivity of 96% and a specicity of 98% (22). The VARS serves as a supplement to the ICHD-2 criteria, and is a useful tool in the differential diagnosis of migraine with visual aura. Sensory Aura Sensory aura is characterized by paresthesias (pinprick, needle sensation, and tingling) or numbness most often experienced in the upper extremity (8996% of patients) or periorally (68% of patients) (5,10). Less often, the aura involves the lower extremity or torso (Table 5). The initial sensation of sensory aura observed by the patient is usually paresthesia followed by numbness (14). The aura often starts in the ngertips and spreads slowly up the extremity, then subsequently affects the face, lips, or tongue (cheirooral/handmouth distribution) (10,12,14,20). The involvement of the tongue is very typical for migraine aura and is rarely seen in cerebrovascular ischemia (13). Involvement of the tongue may result in dysarthria. If the hand and arm is affected, the patient may have problems holding on to things due to numbness or loss of position sense in the affected extremity. This may not be misinterpreted as motor weakness. The sensory aura is unilateral in 85% of patients (5,10),

Migraine with Aura

195

Table 5 Characteristics of Migraine with Typical Aura According to the Second Edition of the International Classication of Headache Disorders Visual aura (%) Eriksen 2004 (5) (n 358)

Sensory aura (%) Eriksen 2004 (5) (n 196)

Aphasic aura (%) Eriksen 2004 (5) (n 116) Russell 1996 (10) (n 29)

Symptoms Acute onset of aura Gradually developing auraa 530 min 3160 min >60 min Patient cannot say Durationa <5 min 530 min 3160 min >60 min Location Unilateral Visual aura starting in: The center of visual eld The periphery of visual eld Patient cannot say Scotoma Preserved central vision Zigzag lines (fortication) Flickering light Sensation of sensory aura: Face Tongue Hand Arm Foot Leg Body Impaired production language Impaired comprehension of language (not due to headache)

Russell 1996 (10) (n 161)

Russell 1996 (10) (n 51)

19

25

68 4 0 9

82 11 4 69 20 8 69

58 4 12 64 22 14 86

82 2 14 2 67 12 20 84

44 23 22 96 26

59 24 17 72b 38

<1 72 18 10 64

28 49

62 28

23 70 12

10 50 22

57 91

81 87

68 41 89 52 14 14 9

67 62 96 78 24 24 18

p < 0.05. The data were recorded as numerical data. b In the study by Russell et al. this gure does not include patients with impaired language due to paraphasia. A total of 76% of patients had paraphasia.

196

Eriksen and Olesen

but the affected side may change from attack to attack (14). The sensory aura spreads gradually over more than ve minutes in 75% (5) to 98% of patients (10) (Table 5). The duration of the sensory aura is less than one hour in more than 80% of patients (5,10,12), with a median duration of 30 minutes (5). Dysphasic Aura Dysphasic aura is characterized by aphasia, but additionally dysarthria may occur (5,10,12,14). Aphasic aura is dened as impaired production of language (not due to dysarthria) or impaired comprehension of language. Most patients with impaired production of language have problems nding the right words (paraphasia) (Table 5). Approximately half of patients with aphasia also experience problems articulating words (dysarthria) (5,10). Many patients experience speech disturbances when their paresthesias reach the face or tongue. Dysarthria is reported in 15% of patients with sensory aura without aphasia (5). The duration of the aphasic aura is less than one hour in more than 75% of patients (Table 5) with a median duration of 30 minutes (interquartile range 853) according to Eriksen et al. (5), and a mean duration of 43 43 (SD) minutes according to Russell and Olesen (10). Atypical Aura Symptoms Visual, sensory, or aphasic aura symptoms are essential to diagnose migraine with typical aura, but less frequent aura symptoms may cooccur. A syndrome of various atypical aura symptoms has been dened as a subtype of migraine with aura, basilartype migraine (see below). Other symptoms have not been documented by systematic observations, including olfactory hallucinations, anxiety, neglect, depersonalization, automatic behavior, and transient global amnesia (23). Headache and Associated Symptoms in Migraine with Aura The relationship between the aura and the headache is still not fully claried (see Chapter 6). In a study with regional cerebral blood ow, the evolution of aura and headache was observed during the attack (24). In 58 out of 59 cases, the aura came before the headache. In two large retrospective studies of migraine with aura, the headache occurred after the onset of aura in 82% (5) to 93% (10), simultaneously with the aura in 5% (10) to 11% (5), and before the aura in 3% (10) to 8% (5) of patients. When the headache occurs before the aura, it is more likely to be a tension-type headache (9), or even a headache related to febrile illness or some other systemic condition. Attacks of migraine without aura and migraine with aura may cooccur in the same individual (5,8,25). Furthermore, if the aura occurs during sleep, if the visual aura is exclusively negative (e.g., a scotoma), or if the aura phenomenon occurs in areas of noneloquent cortex (see Chapter 6), the patient may report the subsequent headache as an attack of migraine without aura. The headache following the aura differs from migraine without aura (see Chapter 13) in many patients. In a population-based study of 38 patients with migraine with aura and 58 patients with migraine without aura randomly selected among 1000 Danes, the headache that followed aura was less intense and shorter lasting than that following migraine without aura (25). The tendency for nausea, vomiting, and photo- and phonophobia was identical. In a clinic population, Manzoni et al. also observed a less intense and shorter-lasting headache than in migraine without

Migraine with Aura

197

aura (12). The headache following the aura fulls the ICHD-2 criteria for migraine without aura in 57% of patients, more often in females than males (5). Approximately 90% of the attacks reach moderate or severe headache intensity; 55% to 70% of the patients have throbbing headache, 85% have aggravation of headache by routine physical activity or simple head movements, and 60% have a unilateral headache (5,10). In two studies where symptoms were recorded during attacks (24) or prospectively (20), the headache almost always occurred over the hemisphere affected by the aura (therefore contralateral to the clinical manifestation of aura). The headache is associated with nausea in 75%, vomiting in 50%, photophobia in 85%, and phonophobia in 60% of patients (5,10). Other associated or premonitory phenomena as seen in migraine without aura may also occur (see Chapter 13).

FAMILIAL AND SPORADIC HEMIPLEGIC MIGRAINE The prevalence of hemiplegic migraine in a population study conducted was 0.01% (26). Accordingly, motor aura is observed in an extremely small fraction of migraine patients. In clinic-based studies, motor weakness has been reported in 21% (14), 18% (11), 6% (27), and 0% (12) of patients with migraine with aura. The vastly differing results may be caused by difculties distinguishing true weakness and dysfunction due to sensory loss. Other organic diseases should always be considered in patients with hemiparesis (see Chapter 11). Half of the cases of hemiplegic migraine show an autosomal dominant mode of inheritance with variable penetration (FHM), while the remaining are nonfamilial cases (sporadic hemiplegic migraine) (Table 3) (see Chapter 9). Attacks of hemiplegic migraine may be precipitated by minor head injuries (3,28,29). Most clinical features of familial and sporadic hemiplegic migraine are similar (3,4,30). The motor aura affects the face or tongue in approximately 50% of the cases, hand or arm in 95%, foot or leg in 60%, and torso in 15% to 30% (3,4,10). The motor aura is always unilateral (3,4,10), and it has a hemiparetic distribution in half of the patients (4,26). In a study by Thomsen et al., of 147 patients with FHM, the motor aura was characterized by reduced strength (99%) or accid paralysis (49%) (26). If the arm was affected, the patients had problems holding on to things (91%), problems carrying the same load as usual (96%), problems controlling the movement of the affected extremity (80%), or problems holding their arm above their head (68%). If the leg was affected, some patients had problems walking (45%) or they experienced dragging of their leg when they walked (36%) (26). The motor aura develops focally and then gradually spreads to involve more and more muscles (4,10,14,26). The duration of the motor aura exceeds one hour in 59% of sporadic cases and 48% of familial cases (4,26). Although the aura is prolonged, the duration of the motor aura lasts less than 24 hours in more than 90% of patients (4,26). Besides the motor aura, at least one typical aura symptom (visual, sensory, or aphasic) is present during attacks (4,26,28). In 252 patients with familial or sporadic hemiplegic migraine (ICHD-1 criteria) studied by Thomsen et al., 28% had three aura symptoms and 68% had four aura symptoms (3,4). The features of the visual, sensory, and aphasic aura are identical to the features described in migraine with typical aura, except that in hemiplegic migraine the aura has a signicantly longer duration, and the sensory aura is more widespread and always has a unilateral localization (4,10,26,30). The duration of the visual, sensory, or aphasic aura exceeds one

198

Eriksen and Olesen

hour in more than one-third of patients with hemiplegic migraine (4,26), but the duration is 24 hours or less in 90% of patients (4,26). Basilar-type symptoms such as dysarthria, vertigo, tinnitus, hypacusia, diplopia, bilateral visual symptoms or paresthesias, and decreased level of consciousness are frequently reported in hemiplegic migraine during the end of the aura (3,4,29,31). In the study by Thomsen et al. of 252 patients with familial or sporadic hemiplegic migraine, basilar-type aura, which fullled the ICHD-1 criteria, was present in 70% of patients (3,4). Cerebellar ataxia during attacks or chronically progressive ataxia is seen in FHM1, where FHM is caused by mutations in the CACNA1A gene on chromosome 19 (28,29,32). These patients may present ataxic speech, wide-based ataxic gait, nystagmus, tremor, and disturbed ngernose and kneeheel test (3,28,29). The chronic ataxia may progress independently of the frequency or severity of hemiplegic attacks. Changes in consciousness from confusion to coma have been reported as well (3,28,29). A headache follows every aura in more than 90% of patients with hemiplegic migraine, and the headache fulls the diagnostic criteria for migraine without aura (see Chapter 13) in 75% of these patients (4,26).

BASILAR-TYPE MIGRAINE Basilar-type migraine is characterized by aura symptoms clearly originating from the brainstem or both hemispheres simultaneously, without motor weakness. Originally, the terms basilar artery migraine or basilar migraine were used (33), but because involvement of the basilar artery territory is uncertain (i.e., the disturbance may be bihemispheric), the term basilar-type migraine is preferred (see Chapter 6). The basilar-type aura symptoms comprise dysarthria, vertigo, tinnitus, hypacusia, diplopia, bilateral visual symptoms or paresthesias, decreased level of consciousness, and ataxia (Table 4). In addition, most patients have typical visual, sensory, or aphasic aura during attacks, and the basilar-type aura is always followed by a headache (9,34). Diagnostic caution is recommended if these symptoms are absent. There is considerable diagnostic uncertainty regarding this syndrome, and the diagnosis should be made only after the exclusion of other possible causes. Basilar-type symptoms are seen in 70% of patients with hemiplegic migraine (4,26,31), but a basilar-type migraine diagnosis requires that motor symptoms be absent (ICHD-2). Attacks of basilar-type migraine co-occur in 8% of patients with migraine with typical aura (9), but attacks of basilar-type migraine are rarer than attacks of typical aura (34). The occurrence exclusively of attacks of basilar-type migraine is rare. In a study by Eriksen et al. of 322 patients with migraine with nonhemiplegic aura, only 0.6% (two patients) had exclusively basilar-type migraine (9). Struznegger et al. found only 49 patients with basilar-type migraine in one department over a 10-year period, of whom 20 had exclusively basilar-type attacks (34). The severity of basilar-type migraine varies between patients, from mild, shortlasting attacks, most frequently including dysarthria, diplopia, tinnitus, hypacusia, or bilateral visual symptoms or paresthesias, to severe attacks including vertigo or impaired consciousness. In general, dizziness (severe imbalance, nausea, and motion sensitivity) or vertigo (illusion of movement) are often reported minutes to hours before a migraine attack, more often in migraine with aura than in migraine without aura (25). During the headache phase, pain, vomiting, and malaise may incorrectly be reported as dizziness. If vertigo lasts minutes and occurs just before the onset of a migraine attack in the context of other aura symptoms, it may be diagnostic for

Migraine with Aura

199

basilar-type migraine (35). In a study of 91 patients, Cutrer and Baloh found that the duration of migraine dizziness/vertigo had a bimodal distribution, with attacks lasting minutes to 2 hours or 6 to 24 hours (35). In migraineurs, dizziness/vertigo frequently occurs during headache-free periods (3537). The interrelation between migraine and dizziness/vertigo is not well understood. Impaired consciousness during migraine attacks is difcult to diagnose by history. Nevertheless, confusion, stupor, somnolence, agitation, syncope, and coma have been reported during migraine, especially in adolescents (33,34,38). The most frequently reported symptoms are confusion lasting from 15 minutes to 24 hours and syncope from one to ve minutes (34). However, in many cases, these symptoms may have a secondary nature, e.g., a sleepy patient with dysphasia may seem confused to relatives, and syncope may be caused by vasovagal attacks or changes in cardiac rhythm due to vomiting. Coma has been reported mainly in patients with FHM with cerebral edema after trivial head trauma or with cerebrospinal uid sterile pleocytosis and fever during attacks (28,39,40). More clinical studies are needed to fully elucidate if basilar-type migraine is a rational entity different from other migraine subtypes.

DIFFERENTIAL DIAGNOSES In clinical practice, it is important to know the clinical features of aura-like symptoms, which prompt further investigation. If more than one aura symptom is present in a subject with migraine with aura, patients almost always have a visual aura besides other aura symptoms. In hemiplegic migraine, patients have at least one additional aura symptom besides their motor aura. In migraine with nonhemiplegic aura, attacks of aura without headache may occur, but in hemiplegic migraine, the aura is almost always followed by a migraine headache. In all subtypes of migraine with aura, the aura symptoms develop gradually or occur in succession. Diagnostic caution is required if sensory, aphasic, or motor symptoms occur without visual symptoms, when aura-like symptoms are not followed by a headache, and in acute onset of aura-like symptoms. Further, the age at onset of hemiplegic migraine is usually below the age of 35, and patients with hemiplegic migraine seldom have attacks after the age of 50 (3,4). Thus, hemiplegic migraine is seen mostly in the younger segment of patients. The main differential diagnoses of migraine with aura are transient ischemic attacks, stroke, epilepsy (postictal weakness following seizures or Todd phenomenon), psychogenic attacks, and visual disturbances in migraine without aura. In cases with diagnostic uncertainty, appropriate investigations should rule out intracranial pathology.

REFERENCES
1. The International Classication of Headache Disorders. 2nd ed. Cephalalgia 2004; 24(1):1160. 2. Eriksen MK, Thomsen LL, Olesen J. Sensitivity and specicity of new diagnostic criteria for migraine with aura. J Neurol Neurosurg Psychiatry 2005; 76:212217. 3. Thomsen LL, Eriksen MK, Rmer SF, Andersen I, Olesen J, Russell MB. A population based study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain 2002; 125:13791391.

200

Eriksen and Olesen

4. Thomsen LL, Ostergaard E, Olesen J, Russell MB. Evidence for a separate type of migraine with aurasporadic hemiplegic migraine. Neurology 2003; 60:595601. 5. Eriksen MK, Thomsen LL, Olesen J. Clinical characteristics of 362 patients with familial migraine with aura. Cephalalgia 2004; 24:564575. 6. Eriksen MK, Thomsen LL, Olesen J. Prognosis of migraine with aura. Cephalalgia 2004; 24:1822. 7. Cologno D, Torelli P, Manzoni CG. Migraine with aura: a review of 81 patients at 1020 years follow-up. Cephalalgia 1998; 18:690696. 8. Russell MB, Rasmussen BK, Fenger K, Olesen J. Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population. Cephalalgia 1996; 16:239245. 9. Eriksen MK, Thomsen LL, Olesen J. New international classication of migraine with aura (ICHD-2) applied to 362 migraine patients. Eur J Neurol 2004; 11:583591. 10. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain 1996; 119:335361. 11. Jensen K, Tfelt-Hansen P, Lauritzen M, Olesen J. Classic migraine. A prospective recording of symptoms. Acta Neurol Scand 1986; 73:359362. 12. Manzoni GC, Farina S, Lanfranchi M, Solari A. Classic migraine: clinical ndings in 164 patients. Eur Neurol 1985; 24:163169. 13. Fisher CM. Late-life migraine accompaniments: further experience. Stroke 1986; 17:10331042. 14. Bucking H, Baumgartner G. Klinik und Pathophysiologie der initialen neurologischen Symptome bei fokalen Migraenen (Migraine ophthalmique, migraine accompagnd). Arch Psychiatr Nervenkr 1974; 219:3752. 15. Alvarez WC. The migrainous scotoma as studied in 618 persons. Cephalalgia 2005; 25:801810. 16. Schiller F. The migraine tradition. Bull Hist Med 1975; 49:119. 17. Airy H. On a distinct form of transient hemiopsia. Philos Trans R Soc Lond B Biol Sci 1870; 160:247264. 18. Jolly F. Uber Flimmerskotom und Migraene. Berlin Klin Wschr 1902; 42:973976. 19. Lashley KS. Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psychiatr 1941; 46:259264. 20. Russell MB, Iversen HK, Olesen J. Improved description of the migraine aura by a diagnostic aura diary. Cephalalgia 1994; 14:107117. 21. Sacks O. Migraine. Faber & FaberLondon1991. 22. Eriksen MK, Thomsen LL, Olesen J. The Visual Aura Rating Scale (VARS) for migraine aura diagnosis. Cephalalgia 2005; 25:801810. 23. Olesen J, Cutrer MF. Migraine with aura and its subforms. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. Philadelphia: Lippincott Williams & Wilkins, 2000:345358. 24. Olesen J, Friberg L, Olsen TS, et al. Timing and topography of cerebral blood ow, aura and headache during migraine attacks. Ann Neurol 1990; 28:791798. 25. Rasmussen BK, Olesen J. Migraine with aura and migraine without aura. An epidemiological study. Cephalalgia 1992; 12:221228. 26. Lykke Thomsen L, Kirchmann Eriksen M, Faerch Romer S, et al. An epidemiological survey of hemiplegic migraine. Cephalalgia 2002; 22:361375. 27. Bana DS, Graham JR. Observations on prodromes of classic migraine in a headache population. Headache 1986; 26:216219. 28. Duscros A, Denier C, Joutel A, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in neuronal calcium channel. N Engl J Med 2001; 345:1724. 29. Terwindt GM, Ophoff RA, Haan J, et al. Variable clinical expression of mutations in P/Q-type calcium channel gene in familial hemiplegic migraine. Neurology 1998; 50:11051110.

Migraine with Aura

201

30. Eriksen MK, Thomsen LL, Olesen J. Migraine with aura and its borderlands. In: Olesen J, ed. Frontiers in Headache Research. Vol. 13. Oxford: Oxford University Press 2005: 6270. 31. Haan J, Terwindt GM, Ophoff RA, Bos PLJM, Frants RR, Ferrari MD. Is familial hemiplegic migraine a hereditary form of basilar migraine? Cephalalgia 1995; 15:477481. 32. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 channel gene CACNL1A4. Cell 1996; 87:543522. 33. Bickerstaff ER, Birm MD. Basilar artery migraine. Lancet 1961; 1:1517. 34. Struznegger MH, Meienberg O. Basilar artery migraine: a follow-up study of 82 cases. Headache 1985; 25:408415. 35. Cutrer FM, Baloh RW. Migraine-associated dizziness. Headache 1992; 32:300304. 36. Kayan A, Hood JD. Neuro-otological manifestations of migraine. Brain 1984; 107:11231142. 37. Neuhauser H, Leopold M, von Brevern M, Arnold G, Lempert T. The interrelations of migraine, vertigo and migrainous vertigo. Neurology 2001; 56:436441. 38. Ehyai A, Fenichel GM. The natural history of acute confusional migraine. Arch Neurol 1978; 35:368369. 39. Kors EE, Terwindt GM, Vermeulen FL, et al. Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol 2001; 49:753760. 40. Vahedi K, Denier C, Ducros A, et al. CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 2000; 55:10401042.

15
Childhood Periodic Syndromes
Vincenzo Guidetti, Federica Galli, Azzurra Alesini, and Federico Dazzi
Department of Child and Adolescent Neurology and Psychiatry, University of Rome La Sapienza, Rome, Italy

INTRODUCTION Medically unexplained physical symptoms are common disorders in pediatric practice. The periodic syndromes (PS) are one of the most recurrent complaints in so-called pain-prone children (1). According to Arav-Boger and Spirer (2), the PS are a group of disorders characterized by limited periods of illness that recur regularly for years in otherwise healthy individuals. Periods of similar duration, a benign course, onset in infancy with persistence for years are the most common characteristics. These disorders may be divided into two major categories: periodic fever syndromes (familial Mediterranean fever, hyperimmunoglobulinemia, periodic fever, hereditary angioedema, cyclic neutropenia, Behcets syndrome, and familial periodic paralysis) and PS without fever [cyclical vomiting (CV), recurrent abdominal pain (RAP), recurrent headaches, benign paroxysmal vertigo (BPV), and recurrent limb pain]. There is no detectable organic cause for these disorders, and most are expressions of reaction to stress, depression, poor psychosocial adjustment, or negative life events. Moreover, patients may pass from one syndrome to another, during a long follow-up period. In 1933, Wyllie and Schlesinger (3) coined the expression periodic disorders of childhood to describe the occurrence of episodic pyrexia, headache, vomiting, and abdominal pain in childhood and suggested that these disorders might persist into adult life. The PS were further described by Cullen and MacDonald (4), who noted the prevalence of migraine in adult relatives of children with PS. Barlow (5) noted that the PS were frequently associated with migraine. Migraine is frequently associated with a range of other symptoms such as periodic abdominal pain, CV, and other PS. In many cases, the associated symptoms are more signicant than head pain per se and often occur in the absence of headache. As for PS, the outstanding feature of migraine is the paroxysmal or periodic occurrence (6). The denition of PS is descriptive and covers a large number of pediatric disorders characterized by repeated attacks with complete remission between episodes (7).

203

204

Guidetti et al.

There is no accordance about which disorders may be collected as PS, but there is consensual agreement that CV, abdominal pain, and vertigo should be among them (610). Many reports consider PS as equivalents or precursors of migraine (7), and emphasize the fact that children with PS often also suffer from migraine or develop it later in life (11,12). The positive familial history of migraine in subjects with PS [65% in abdominal migraine or CV, according to Al-Twaijri and Shevell (9)], as well as their response to antimigraine treatment, strengthen the hypothesis of a common pathogenesis (7,8). However, the relationship between PS and migraine remains unclear. Al-Twaijri and Shevell (9) consider PS [BPV, abdominal migraine or CV, benign paroxysmal torticollis (BPT), acephalgic migraine, and acute confusional migraine] as migraine equivalents. Lanzi et al. (7) assessed the prevalence of PS (recurrent vomiting, abdominal pain, vertigo, paroxysmal torticollis, and also migrating limb pain, recurrent hyperthermia with no visible cause, car sickness, sleep disturbances, and eating disorders) in a group of migrainous children and adolescents. Their results support the view of PS as predictive of the subsequent development of migraine or of a psychosomatic pathology. Another study (8), however, evidenced that only a percentage of PS subjects develop migraine, and that some of these PS have a common outcome, i.e., develop into typical migraine. In the rst International Classication of Headache Disorders (ICHD) (13), childhood PS that were considered as equivalents of migraine were BPV, BPT, and alternating hemiplegia of childhood (14). The second edition of the ICHD (10) considers the following as precursors of migraine: CV, abdominal migraine, and BPV. BPT and alternating hemiplegia of childhood are considered in the appendix of the second edition (2004), because the evidence is not sufcient to insert them in the main body of the classication.

CYCLICAL VOMITING CV is a rare and easily misdiagnosed syndrome, whose etiology, pathogenesis, and treatment are yet unclear (15). The syndrome was rst described by Heberden in France (16) and by Gee in England (17), but according to Li (18), Whitney, in 1898, recognized a potential connection between CV and migraine. It was based on the similarities in clinical features, the co-occurrence of both disorders in the same child, and the positive family history of migraine (18). The disorder, not included in the rst edition of the ICHD [International Headache Society (IHS), 1988] (13), is dened in the second edition (ICHD-2, 2004) (10) as recurrent episodic attacks, usually stereotypical, of vomiting and intense nausea. Attacks are associated with autonomic symptoms such as pallor and lethargy (87% and 91%, respectively) (Box 1) (18). CV is a self-limiting episodic condition of childhood, with periods of complete recovery between attacks. The episodes have a rapid onset, more often during the night or early morning. There is a peak frequency of attacks (usually every 1015 minutes), with a steady decrease over time. The frequency of attacks ranges from 1 to 70 per year, with a mean of 12 attacks per year (6). CV is a recurrent disorder in children, with an estimated prevalence of 1.9% (19). The initial presentation of CV is controversial: it usually occurs between 3 and 5.1 to 5.3 years of age (6,11,19), and disappears before puberty or during adolescence in two-thirds of the cases (8).

Childhood Periodic Syndromes

205

Box 1 Diagnostic criteria of CV according to the ICHD-2 A. At least 5 attacks fullling criteria B and C B. Episodic attacks, stereotypical in the individual patient, intense nausea, and vomiting lasting from 1 hr to 5 days C. Vomiting during attacks occurs at least 4 times/hr for at least 1 hr D. Symptom free between attacks E. Not attributed to another disorder

Li (18) made a distinction between a severe but intermittent pattern of CV, and a chronic, but not severe, daily pattern. Migraine symptoms refer more frequently to the rst category. By a clinical point of view, a relationship between CV and migraine has been suggested frequently: up to 40% of patients with CV have headache during attacks, and in 27% of cases, CV progresses to migraine in adulthood (20). Also, Dignan et al. (19) supported the association between CV and migraine, hypothesizing that CV transforms into typical migraine. Moreover, according to these authors, the onset of CV precedes migraine (about 8.3 years). However, migraine patients may continue to have episodic vomiting. Support for the relationship between CV and migraine comes from several sources, including electrophysiological studies. Quantitative electroencephalographic (EEG) changes are similar in CV and migraine. Visual-evoked responses identied similarities between CV and migraine with or without aura (19). However, even if most cases of CV seem to be related to migraine (6), there are patients with similar symptoms, but different etiologies. The diagnosis should be reviewed if the patient is not symptom-free between attacks. Moreover, Oki et al. (21) reported that recurrent vomiting without gastrointestinal disease can be a manifestation of epilepsy, abdominal migraine, or the syndrome of periodic adrenocorticotropin and vasopressin discharge. CV associated with behavioral disturbances, including withdrawal, irritability, and aggression, has been called acute confusional migraine. Wilson (22) outlined that the distinction between epilepsy and migraine is not always plain in childrenvomiting and alteration of awareness may suggest both a diagnosis of complex partial seizures and the so-called abdominal migraine. To distinguish the migraine equivalent from abdominal epilepsy, an ictal EEG recording is needed. The treatment of CV remains controversial and unsatisfactory (6). According to Li (18), in the absence of a recognized pathophysiology, the relationship is only empirical. The ve strategies to manage a child with CV are outlined in Box 2. According to Li (18), abortive drugs may be ondansetron (0.30.4 mg/kg IV or

Box 2 Principles of treatment for CV Supportive care during the episode (quiet and dark room, avoid overstimulation, and occasionally analgesics to reduce abdominal pain) Abortive pharmacologic agents [the drug used most commonly to relieve nausea and vomiting is intravenous ondansetron (6)] Prophylactic pharmacologic therapy Avoidance of triggers, when identied Family support

206

Guidetti et al.

orally 48 every 46 hours), granisetron (10 mg/kg every 46 hours), ketorolac (0.51.9 mg/kg every 68 hours), sumatriptan [2559 mg orally or 20 mg nasal (more than 40 kg)], and midrin (26 years old: max 75 mg/die in three doses; 712 years old: max 100 mg/die in three doses). Prophylactic drugs (18) are propanolol (1020 mg, 2 or 3 times per day), cyproheptadine (0.3 mg/kg/day divided 3 times a day), amitriptyline (2025 mg/ day every hour), phenobarbital (23 mg/kg/day every hour), carbamazepine (510 mg/kg/day, divided twice a day), and erythromycin (20 mg/kg/day, divided 23 times per day).

RAP AND ABDOMINAL MIGRAINE Abdominal symptoms are common in children and adults with migraine. Abdominal pain probably relates to migraine (23), and its occurrence without headache in adults was rst described by Buchanan in 1921 (6). The origin of the term is controversial: according to Symon the term abdominal migraine was introduced by Brams in 1923 (24) (probably referring only to adults). Li (18) reported that this term was coined in 1956 to identify a group of children with recurrent episodes of abdominal pain. According to Symon (6), RAP is a common problem in childhood and an organic cause (e.g., urinary tract disorder) or a surgical correction involves just a small percentage of children. Authors agree about the high prevalence of RAP (1,25): 10% to 25% of schoolchildren and 10% to 14% of adolescents. Al-Twaijri and Shevell (9) considered RAP as a migraine equivalent, beginning between 4 and 10 years of age and resolving within two years. According to Cavazzuti and Ferrari (8), half of the cases of RAP disappear before puberty or during adolescence. The ICHD-2 (10) describes RAP as an idiopathic recurrent disorder, seen mainly in children, characterized by episodic midline abdominal pain, manifesting in attacks lasting 1 to 72 hours with normality between episodes (Box 3). The pain is usually severe enough to interfere with normal daily activities. Children may nd it difcult to distinguish anorexia from nausea. The pallor is often accompanied by dark shadows under the eyes. Sometimes, ushing is the main vasomotor phenomenon. Most children with abdominal migraine will develop migraine later. The diagnosis of abdominal migraine is not yet universally accepted by neurologists, although it appears to be gaining greater acceptance. It is important to recognize that RAP is a relatively uncommon cause of recurrent abdominal pain in children and that most children will have other conditions that may or may not be found on investigation.

Box 3 Diagnostic criteria of RAP according to the ICHD-2 A. At least 5 attacks fullling criteria BD B. Attacks of abdominal pain lasting 172 hr (untreated or unsuccessfully treated) C. Abdominal pain has all the following characteristics: midline location (periumbilical or poorly localized), dull or just sore quality, and moderate or severe intensity D. During abdominal pain, at least 2 of the following are seen: anorexia, nausea, vomiting, and pallor E. Not attributed to another disorder

Childhood Periodic Syndromes

207

Apart from the location of the pain, abdominal migraine resembles migraine. The attack may be preceded by a prodromal period of listlessness or drowsiness; the pain is of moderate-to-severe intensity and associated with vasomotor symptoms, anorexia, nausea, and vomiting. There is little evidence-based treatment for RAP. In most children, the attack will subside if they lie down in a quiet and darkened room. Vomiting frequently gives relief. Trigger factors are similar to those for migraine headache (stress, travel, exposure to bright or ickering lights, and some foods) and should be avoided when possible. Analgesic drugs may be given, but they are not always successful in relieving pain (e.g., paracetamol and ibuprophen). This may be due to gastric stasis, which prevents drug absorption. If symptoms are frequent and severe despite treatment, prophylaxis may be suggested (e.g., unarizine). Even if there is no denitive evidence from controlled studies to support the hypothesis of a psychological cause of RAP (6), children and adolescents with RAP have been described as anxious, fearful and timid, and suffering from other somatic symptoms, too. A prevalence as high as 85% to 100% of anxiety or mood disorders has been found in children with RAP. Robinson et al. (26) found that RAP children suffered from a greater number of stressful experiences in the few months before the onset of pain. In their study, children with RAP or headache exhibited primarily anxiety or mood disorders (25).

BPV OF CHILDHOOD Vertigo is a common symptom in childhood, with 20% of schoolchildren presenting one episode over a 1-year period (27). These episodes may occur in association with trauma or infections or be nonassociated. Recurrent transient episodes may present as unreal sensation of rotation of the patient or patients surroundings with no loss of consciousness, no associated neurological or auditory abnormalities, and with complete recovery between attacks (6). Vertigo has long been recognized by clinicians as a frequent accompanying symptom of the adult migraine. This association has not been so easily identied in the pediatric population, and, as a consequence, children may undergo unnecessary evaluations (28). BPV was recognized in the rst ICHD (13), even if as equivalent of migraine. According to the ICHD-2 (10), this probably heterogeneous disorder is characterized by recurrent brief episodic attacks of vertigo occurring without warning and resolving spontaneously in otherwise healthy children (Box 4). BPV is often associated with nystagmus or vomiting; unilateral throbbing headache may occur in some attacks. The episodes of BPV are characterized by unsteadiness, pallor, and sometimes fear. Usually, these episodes resolve within

Box 4 Diagnostic criteria of BPV according to the ICHD-2 A. At least 5 attacks fullling criteria B B. Multiple episodes of severe vertigo, occurring without warning and resolving spontaneously after minutes to hours C. Normal neurological examination and audiometric and vestibular functions between attacks D. Normal EEG

208

Guidetti et al.

two years after their onset (9). Cavazzuti and Ferrari (8) referred that most cases of early-onset vertigo disappear before puberty or during adolescence. According to Weisleder and Fife (28), Basser (29) was the rst author to note the association between balance disorders and headache. Basser described attacks of headache associated with clockwise rotational vertigo. A few years later, Fenichel (30) suggested that BPV in younger children was an early manifestation of migraine. He coined the term Benign Paroxysmal Vertigo of Childhood. More recently, Parker (31) highlighted that migraine in children can be associated with neurologic disturbances such as vertigo, seizures, and movement disorders the so-called migraine variants. The most common trigger factor for BPV is fatigue; relief factors are lying, sitting down, or sleeping. Moreover, BPV children may have other features of the PS, including CV and RAP (6). No treatment is usually given, and attempts by antimigraine drugs have been done (e.g., diphenylhydramin), but there are no controlled trials on therapy (6). Abu-Arafeh and Russell (27) studied the prevalence, causes, and clinical features of BPVthe overlap in the clinical features of BPV and migraine (mode of presentation, vasomotor symptoms during attack, triggering and relieving factors, and associated gastrointestinal symptoms) supported the strong relationship between the two disorders. The link is so strong that many authors consider BPV as a precursor or early manifestation of migraine (28).

BENIGN PAROXYSMAL TORTICOLLIS BPT of infancy is an under-recognized, self-limiting, benign disorder (32). It is a rare paroxysmal dyskinesia characterized by attacks of only head tilt or accompanied by vomiting and ataxia, which may last from hours to days. Attacks rst happen during infancy, between two and eight months of age (14), and resolve by ve years, with episodes occurring from every two weeks to every two months (33). The ICHD-2 considers BPT in its appendix, because further scientic evidence must be presented before it can be moved into the main body of classication. It is dened as recurrent episodes of head tilt to one side, with slight rotation and spontaneous remission. The condition occurs in infants, with onset in the rst year of age (Box 5). The childs head can be turned to the normal position during the attacks: some resistance may be encountered but can be overcome. BPT may evolve into BPV or migraine, or stops without further symptoms. This observation needs further validation by patients diaries, structured interviews, and longitudinal data collection. The differential diagnosis needs to consider gastro-esophageal reux, idiopathic torsional

Box 5 Diagnostic criteria of BPT according to the ICHD-2 A. Episodic attacks, in a young child, with all of the following characteristics and fullling criteria B: tilt of the head to one side (not always the same side), with or without slight rotation, lasting minutes to days, remitting spontaneously, and tending to recur monthly B. During attacks, symptoms and/or signs of one or more of the following occur: pallor, irritability, malaise, vomiting, and ataxia C. Normal neurological examination between attacks D. Not attributed to another disorder

Childhood Periodic Syndromes

209

Box 6 Diagnostic criteria of alternating hemiplegia of childhood according to the ICHD-2 A. Recurrent attacks of hemiplegia alternating between the two sides of the body B. Onset before the age of 18 mo C. At least one other paroxysmal phenomenon is associated with the bouts of hemiplegia or it occurs independently, such as tonic spells, dystonic posturing, choreoathetoid movements, nystagmus, or other ocular motor abnormalities and autonomic disturbances D. Evidence of mental and/or neurological decit(s) E. Not attributed to another disorder

dystonia, and complex partial seizure, but particular attention must be paid to the posterior fossa and craniocervical junction, because congenital or acquired lesions may produce torticollis. Moreover, a family history for BPT is common (34,35), as is family history for migraine (36). In conclusion, torticollis may not be so evident if other manifestations (vomiting, pallor, ataxia, etc.) of the attack are more impressive. However, the recognition of the symptom at the beginning of the attack may increase the likelihood of identifying the childhood migraine equivalent to plan the right antimigraine therapy (33).

ALTERNATING HEMIPLEGIA OF CHILDHOOD The ICHD-2 (10) considers this disorder in its appendix. It is dened as infantile attacks of hemiplegia involving each side alternately, associated with a progressive encephalopathy, other paroxysmal phenomena and mental impairment (Box 6). This is a heterogeneous condition that includes neurodegenerative disorders. A relationship with migraine is suggested on clinical grounds. The possibility that it is an unusual form of epilepsy cannot be ruled out. Finally, there are other PS that are sometimes recognized as being somehow related to migraine. We briey describe them as follows:  Episodic spontaneous hypothermia: Episodic hypothermia lower than 35 C, marked facial pallor, and absence of shivering. The episodes could last for a few hours or days, and recur once a week or every two to three months (37).  Car (motion) sickness: General discomfort, characterized by nausea, vomiting, pallor, and perspiration (7).  Migrating limb pain: Pain presenting gradually and with low intensity, localized in the lower limbs, and not aggravated by an erected position or walking. Duration varies between a few minutes and several hours (7). CONCLUSION Some authors (11,18) stressed the chronological pattern and long-term aspects of PS symptoms. They concluded that the rst symptom to appear is CV, followed by abdominal pain and paroxysmal vertigo. Headache is the nal symptom in this group. The sequentiality of such disturbances in each subject leads to the assumption that the PS is the expression of a single disorder, which manifests itself

210

Guidetti et al.

polymorphously, rather than a precisely timed process (11). In particular, Li (18) supported the hypothesis that PS is an age-related presentation of migraine. Gifn et al. (33) gave further evidence that it may be considered as a childhood migraine equivalent and may be associated with a calcium channelopathy. In light of these observations, we believe that the identication of PS in childhood is extremely importanta series of useless investigations can be avoided, helping the diagnosis of migraine. In conclusion, the relationship between PS and migraine is still not clear, but the probable predictive value of PS may be useful to classify and manage migraine.

REFERENCES
1. Campo JV, Fritsch SL. Somatization in children and adolescents. J Am Acad Child Adolesc Psychiatr 1994; 33(9):12231235. 2. Arav-Boger R, Spirer Z. Periodic syndromes of childhood. Adv Pediatr 1997; 44: 389417. 3. Wyllie WG, Schlesinger B. The periodic group of disorders in childhood. Br J Child Dis 1933; 30:121. 4. Cullen KJ, MacDonald WB. The periodic syndrome: its nature and prevalence. Med J Aust 1963; 2:167173. 5. Barlow CF. Headaches and Migraine in Childhood. Oxford: Spast Intern Med Pub, 1984. 6. Symon DNK. Equivalents, variants and precursors of migraine. In: Guidetti V, Russell G, Sillanpaa M, Winner P, eds. Headache and Migraine in Childhood and Adolescence. London: Martin Dunitz, 2002:215227. 7. Lanzi G, Zambrino CA, Balottin U, Tagliasacchi M, Vercelli P, Termine C. Periodic syndrome and migraine in children and adolescents. Ital J Neurol Sci 1997; 18(5): 283288. 8. Cavazzuti GB, Ferrari P. Childhood periodic syndromes and their long-term development. Semin Pediatr Neurol 1995; 2(2):127143. 9. Al-Twaijri WA, Shevell MI. Pediatric migraine equivalents: occurrence and clinical features in practice. Pediatr Neurol 2002; 26:365368. 10. Headache Classication Subcommittee of International Headache Society. The International Classication of Headache Disorders. 2nd ed. Cephalalgia 2004; 24(suppl 1): 1151. 11. Lanzi G, Balottin U, Fazzi E, Rosano FB. The periodic syndrome in pediatric migraine sufferers. Cephalalgia 1983; 3(suppl 1):9193. 12. Hammamond JE. The periodic syndrome and migraine. Practitioner 1976; 217:384389. 13. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):196. 14. Winner P, Lewis D. Clinical features of migraine. In: Guidetti V, Russell G, Sillanpaa M, Winner P, eds. Headache and Migraine in Childhood and Adolescence. London: Martin Dunitz, 2002:169177. 15. Cupini LM, Santorelli F, Iani C, Fardello G, Calabresi P. Cyclic vomiting syndrome, migraine, and epilepsy: a common underlying disorder? Headache 2003; 43:407409. 16. Heberden W. Chapter 29. In: Payne T, ed. Commentaries on History and Care of Disease. London: Mews-Gate, 1802:99. [Reprinted in Birmingham, AL: Classics of Medicine Library; 1982:99]. 17. Gee S. On tful or recurrent vomiting. St Bartolomews Hosp Rep 1882; 18:16. 18. Li BUK. Cyclic vomiting syndrome: age-old syndrome and new insights. Semin Pediatr Neurol 2001; 8(1):1321.

Childhood Periodic Syndromes

211

19. Dignan F, Symon DNK, Abu Arfeh I, Russel G. The prognosis of cyclical vomiting syndrome. Arch Dis Childh 2001; 84:5557. 20. Haan J, Kors EE, Ferrari MD. Familial cyclic vomiting syndrome. Cephalalgia 2002; 22:552554. 21. Oki J, Miyamoto A, Takahashi S, Itoh J, Sakata Y, Okuno A. Cyclic vomiting and elevation of creatine kinase associated with bitemporal hypoperfusion and EEG abnormalities: a migraine equivalent? Br Dev 1998; 20:186189. 22. Wilson J. Migraine and epilepsy. Dev Med Child Neurol 1992; 34:645647. 23. Anttila P, Metsahonkala L, Mikkelsson M, Helenius H, Sillanpaa M. Comorbidity of other pains in schoolchildren with migraine or nonmigrainous headache. J Pediatr 2001; 138(2):176180. 24. Brams WA. Abdominal migraine. JAMA 1922; 78:2627. 25. Liakopoulou-Kairis M, Alieraki T, Protagora D. Recurrent abdominal pain and headache: psychopathology, life events and family functioning. Eur Child Adolesc Psychiatr 2002; 11:115122. 26. Robinson JO, Alverez JH, Dodge JA. Life events and family history in children with recurrent abdominal pain. J Psychos Res 1990; 34:171178. 27. Abu-Arafeh I, Russell G. Paroxysmal vertigo as a migraine equivalent in children: a population-based study. Neurol Res 2002; 24(7):663665. 28. Weisleder P, Fife TD. Dizziness and headache: a common association in children and adolescent. J Child Neurol 2001; 16:727730. 29. Basser L. Benign paroxysmal vertigo of childhood. Pediatr Ann 1964; 87:141152. 30. Fenichel GM. Migraine as a cause of benign paroxysmal vertigo of childhood. J Pediatr 1967; 71:114115. 31. Parker C. Complicated migraine syndromes and migraine variants. Pediatr Ann 1997; 26:417421. 32. Snyder CH. Paroxysmal torticollis in infancy. A possible form of labyrinthitis. Am J Dis Childh 1969; 117:458460. 33. Gifn NJ, Benton S, Goadsby PJ. Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation. Dev Med Child Neurol 2002; 44:490493. 34. Sanner G, Bergstrom B. Benign paroxysmal torticollis in infancy. Acta Paediatr Scand 1979; 68:219223. 35. Roulet E, Deonna T. Benign paroxysmal torticollis in infancy. Dev Med Child Neurol 1988; 30:409410 (Letter). 36. Deonna T, Martin D. Benign paroxysmal torticollis in infancy. Arch Dis Childh 1981; 56:956958. 37. Ruiz C, Gener B, Garaizar C, Prats JM. Episodic spontaneous hypothermia: a periodic childhood syndrome. Pediatr Neurol 2003; 28:304306.

16
Retinal, or Monocular, Migraine
Brian M. Grosberg and Seymour Solomon
Department of Neurology, The Monteore Headache Center, Albert Einstein College of Medicine, New York, New York, U.S.A.

INTRODUCTION Retinal, or monocular, migraine is a rare and poorly understood disorder characterized by attacks of monocular visual impairment associated with migraine headache. Galezowski rst described this entity as ophthalmic megrim in 1882 in a series of four patients with permanent retinal defects attributed to migraine (1). In two of these patients, prior attacks of migraine headache were associated with bouts of transient monocular visual loss (TMVL). Since then, a number of patients with monocular visual defects beginning before, during, or after attacks of otherwise typical migraine have been reported with various designations (246). The term retinal migraine was introduced by Carroll in 1970 to describe patients with episodes of TMVL and permanent monocular visual loss (PMVL), specically in the absence of migraine headache (47). Most subsequent observers have used the term retinal migraine for those cases of monocular visual impairment temporally associated with attacks of migraine. Some have noted that unilateral visual loss was not restricted exclusively to the retina and advocated the term anterior visual pathway migraine or ocular migraine (6,48). The authors prefer the term monocular migraine, because it distinguishes between the loss of vision in one hemield and that of one eye and includes sites other than the retina, such as the choroid or the optic nerve.

DIAGNOSTIC CRITERIA Over the last two decades, there have been several proposed denitions for retinal migraine. In 1986, Troost dened retinal migraine as a transient or permanent monocular visual disturbance accompanying a migraine attack or occurring in an individual with a strong history of migrainous episodes (49). Two years later, the rst edition of the International Classication of Headache Disorders (ICHD-1) developed by the International Headache Society (IHS) established more rigid criteria, requiring at least two attacks of fully reversible monocular scotoma or blindness lasting less than 60 minutes, associated with headache (type unspecied) (50).
213

214

Grosberg and Solomon

Table 1 2004 IHS Criteria for the Diagnosis of Retinal Migraine A. At least two attacks fullling criteria B and C B. Fully reversible monocular positive and/or negative visual phenomena (e.g., scintillations, scotomata, or blindness) conrmed by examination during an attack or (after proper instruction) by the patients drawing of a monocular eld defect during an attack C. Headache fullling criteria BD for 1.1 Migraine without aura begins during the visual symptoms or follows them within 60 min D. Normal ophthalmologic examinations between attacks E. Not attributed to another disorder
Abbreviation: IHS, International Headache Society.

Criteria for the diagnosis of retinal migraine were revised in the 2004 edition of the ICHD-2 to include positive and/or negative monocular visual phenomena. Visual features still had to be transient in nature, but were no longer limited to 60 minutes. In addition, the headache had to fulll criteria for migraine without aura (Table 1) (51). Based on our patients and a review of the literature [Grosberg BM, Solomon S, Friedman DI, Lipton RB. Retinal migraine reappraised (submitted for publication).] (5254), we believe that either migraine without aura or migraine with aura occurs with retinal migraine, that the visual defects may occur before, during, or after the headache, and that PMVL may be part of the syndrome, comparable with the syndrome of migrainous infarction. Our suggestions for revision of the criteria of retinal/monocular migraine are noted in Table 2. In a review of the English language medical literature (53,54), we identied 73 cases and added four new cases from the Monteore Headache Unit that fullled our criteria of retinal migraine with TMVL or PMVL. Because most cases were
Table 2 Proposed Modication of Criteria for Retinal (or Preferably Monocular) Migraine Monocular migraine with TMVL or defect A. At least two attacks fullling criteria B and C B. Fully reversible monocular positive and/or negative visual phenomena (e.g., scintillations, scotomata, or blindness) conrmed by examination during an attack or (after proper instruction) by the patients drawing of a monocular eld defect during an attack C. Headache fullling criteria BD for 1.1 Migraine without aura or 1.2 Migraine with aura begins during the visual symptoms or precedes or follows them within 60 min D. Normal ophthalmologic examination between attacks E. Not attributed to another disorder Monocular migraine with PMVL or defect A. At least one attack fullling criteria B and C B. Irreversible monocular positive and/or negative visual phenomena (e.g., scintillations, scotomata, or blindness) conrmed by examination during or following the attack C. Headache fullling criteria BD for 1.1 Migraine without aura or 1.2 Migraine with aura begins during the visual symptoms or precedes or follows them within 60 min D. Abnormal ophthalmologic examination E. Not attributed to another disorder
Note: The vast majority of patients experienced only one attack of PMVL. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss.

Retinal, or Monocular, Migraine

215

described before the publication of IHS criteria, some of the details of the headache and visual loss were sometimes incomplete.

CLINICAL FEATURES In most cases of TMVL and PMVL, the migraine headache was ipsilateral to visual loss. In contrast to the current IHS criteria for retinal migraine, nearly 75% of patients with monocular visual loss had a history of migraine with aura (Fig. 1). With the exception of two patients who had somatic sensory phenomena (12,33), all others had typical cerebral visual auras. The temporal relationship between the visual loss and the headache was quite variable. In the vast majority of patients, the onset of visual loss preceded or accompanied the headache; less often, the visual loss followed an attack of migraine. The visual symptoms occurred within one hour of the attack. Recurrent visual disturbances were strictly unilateral and without side shift in the majority of patients, although some experienced side-alternating attacks. Patients with the transient form of retinal migraine were more than twice as likely to have visual loss in which strict laterality was not preserved during repeated attacks. The duration of TMVL varied widely between patients and within individual patients. The duration of the transient visual symptoms was as short as a few seconds but usually was many minutes to one hour (Fig. 2). One-third of cases experienced repeated attacks of TMVL, lasting both less than 30 minutes and more than one hour. Prolonged but fully reversible monocular visual loss rarely occurred, sometimes lasting hours, days, or even, weeks (12,14,19,26,28,45). As one may expect, ophthalmologic examination during an attack was infrequent. When such examinations were

Figure 1 Relative frequency by migraine type of TMVL, TMVL leading to PMVL, and PMVL. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss; MA, migraine with aura; MO, migraine without aura.

216

Grosberg and Solomon

Figure 2 Frequency distribution of duration of monocular visual loss in patients with the transient form of retinal migraine.

performed, they usually were normal. Severe narrowing or occlusion of retinal arteries or veins was rarely observed (14,8,11,12,17,18,23,28,31,32,39,43). The diagnoses of anterior or posterior ischemic optic neuropathy was reported in a dozen or so cases (6,7,10,22,25,29,30,35,37,38,46). Other ndings included retinal pigmentary change (4), central retinal venous occlusion (5,13,20), central serous retinopathy (49), optic nerve atrophy (13), optic disk edema (22), and hemorrhages of the optic nerve, retina, or vitreous (1,9,15). Positive and negative visual phenomena were reported in retinal migraine associated with TMVL and PMVL. Typical descriptions of positive visual phenomena included ashing rays of light, zigzag lightning, and other teichopsia, whereas perceptions of bright-colored streaks, halos, or diagonal lines were less commonly experienced. The negative visual losses included blurring, grey-outs and blackouts, causing partial or complete blindness. Elementary forms of scotoma were perceived as blank areas, black dots, or spots in the eld of vision. Visual eld defects may be altitudinal, quadrantic, central, or arcuate. Complex patterns of monocular visual impairment, such as the appearance of black paint dripping down from the upper corner of my left eye, the coalescence of peripherally located spots and tunnel vision, were noted rarely. Only approximately 50% of the cases met the current IHS criteria for TMVL and, of those, approximately 50% subsequently developed PMVL. The authors believe that irreversible visual loss is part of the spectrum of retinal migraine, probably representing an ocular form of migrainous infarction. Irreversible monocular visual loss resulted from retinal infarction or optic nerve ischemia or was otherwise not specied (Fig. 3). Retinal migraine is primarily a disorder of young women. The gender and age ranges are noted in Table 3 (54). The gender difference was striking in patients with PMVL. The condition occurred 16 times more commonly in women than in men. Those with PMVL also tended to be approximately 10 years older than those with TMVL (37 vs. 26 years, respectively). A family history of migraine was noted in approximately 25% of the patients with TMVL and in almost one-third of patients with PMVL. Because many reports did not include information on family history, these numbers may be underestimated. Only two patients had familial retinal migraine (36).

Retinal, or Monocular, Migraine

217

16%

36% 48%

Vasopasm/Occlusion

Ischemic optic neuropathy

Not classified

Figure 3 Etiologies of PMVL in patients with the permanent form of retinal migraine. Abbreviation: PMVL, permanent monocular visual loss.

EPIDEMIOLOGY AND PROGNOSIS Retinal migraine is thought to be a rare disorder, but its true prevalence is unknown. Recent studies with automated perimetry have demonstrated subclinical visual eld defects in patients with migraine (55). There was a direct correlation between these ndings and duration of disease and advancing age. Although retinal migraine usually has been viewed as a benign condition, it appears that subclinical precortical visual dysfunction and permanent attacks of partial or complete monocular visual loss occur in patients with migraine more often than commonly appreciated (56). In one study, the records of 413 patients with nonarteritic anterior ischemic optic neuropathy (AION) were reviewed. Of these, 2.2% had migraine-related AION (57).

Table 3 Demographic and Clinical Features of the Patients with Retinal Migraine Analyzed in Our Review (n 77) Characteristics Men Women Age at onset (years) (Range of ages) Subtypes of HA MwA M w/o A PM
a b

TMVL (n 21) 11 10 27.0 (1253) 16 (8F,8M) 2 (2M) 1 (1F)

Transformed PMVLa (n 20) 5 15 25.0 (854) 13 (9F,4M) 2 (2F) 5 (4F,1M)

PMVLb (n 36) 2 32 37.1 (1564) 22 (20F,2M) 9 (9F) 2 (2F)

Transformed PMVL refers to patients who experienced TMVL and subsequently developed PMVL. In PMVL, the gender and subtype of migraine were not reported in two and three patients, respectively. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss; n, number; MwA, migraine with aura; Mw/oA, migraine without aura; PM, probable migraine; F, female; M, male.

218

Grosberg and Solomon

In our survey, approximately half of the patients who experienced TMVL, subsequently experienced PMVL (52). Some patients with TMVL may present with considerable variation in phenotype (either continue to have TMVL or experience new attacks of PMVL), while others may only experience PMVL without a preexisting history of TMVL. No specic factor has been identied to account for this variation in phenotype or for the heterogeneity of this condition. Minor risk factors for vascular disease were identied in only a few patients with TMVL and PMVL. They included hypertension, hyperthyroidism, pregnancy, diabetes, oral contraceptive use, smoking, and increased levels of factor VIII. These conditions were not thought to be the main cause of the visual loss.

PATHOPHYSIOLOGY The underlying pathophysiology of retinal migraine remains largely unknown. In some cases, vasospasm of the retinal or ciliary circulation may have caused retinal or optic nerve ischemia; this may explain the amaurosis and rare funduscopic ndings during acute attacks of retinal migraine (58). An alternative theory is spreading depression of retinal neurons, a phenomenon that has been demonstrated in the chick retina (59). Similarly, we believe that those rare cases with prolonged monocular defects associated with migraine headache could have a mechanism similar to that seen in the cerebral cortex of migraineurs who have persistent aura without infarction.

DIFFERENTIAL DIAGNOSIS When evaluating a headache patient with the complaint of visual impairment, it is important to establish whether one or both eyes are affected. Retrochiasmatic lesions usually cause homonymous hemianopias with varying degrees of congruence, whereas prechiasmatic lesions (i.e., optic nerve, retina, or media) produce monocular visual loss. Patients often have difculty distinguishing between the loss of vision in one hemield and the loss of vision in one eye. To accurately make this distinction, the patient must alternately cover each eye and compare their views. Once unilateral visual loss is conrmed in this manner, the clinician needs to identify or exclude secondary causes of transient monocular blindness (TMB), because retinal migraine is a diagnosis of exclusion. Differentiating retinal migraine from other causes of TMB can be challenging. Visual loss associated with retinal migraine is usually of longer duration and the evolution is usually slower in onset than with microembolization. Moreover, the typical shade dropping over one visual eld described by many patients who have microembolization has not been described by patients with retinal migraine. If atypical features are present in a patients history or general physical, ophthalmologic, or neurologic examinations, imaging studies or other diagnostic testing are warranted. Features that should prompt concern for an underlying secondary cause of headache with TMB include absence of history typical for migraine, onset after age 50, incomplete resolution of monocular visual loss, concomitant medical problems that can precipitate attacks of TMB, and the presence of atypical neurologic signs or symptoms (Fig. 4). All cases with persistent monocular visual loss should be fully investigated. To exclude the possibility of a cardioembolic

Retinal, or Monocular, Migraine

219

Figure 4 Clinical factors favoring retinal migraine versus other causes of monocular visual loss. Abbreviations: TMVL, transient monocular visual loss; PMVL, permanent monocular visual loss.

source, investigations such as electrocardiography, echocardiography, and holter monitoring need to be performed. Diagnostic testing in patients with suspected ischemic disease of the eye or brain should include duplex scanning, computed tomography (CT), magnetic resonance imaging (MRI) and angiography (MRA), uorescein angiography, and in uncertain cases, conventional angiography. Neuroimaging can exclude an orbital or intracranial mass. Other diagnostic possibilities such as vasculitis, hypercoagulable states, illicit drug use, and rheumatologic disorders require a complete laboratory evaluation consisting of a complete blood count with differential and platelet count, prothrombin time, partial thromboplastin time, toxic drug screen, lupus anticoagulant and anticardiolipin antibody levels, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody titer, antiphospholipid antibodies, protein C and S, antithrombin III levels, and serum protein electrophoresis. MANAGEMENT There are no clear guidelines on the management of patients with retinal migraine. One approach to treatment has focused on the avoidance of potential migraine triggers (i.e., stress, use of oral contraceptives, or smoking) in patients with infrequent attacks.

220

Grosberg and Solomon

It has been suggested that prophylactic therapy be deferred in patients with infrequent attacks, i.e., less than one attack per month (60). However, this course of action may not be prudent, because episodes of PMVL can occur in migraineurs with and without prior attacks of TMVL. There is currently insufcient clinical information to support specic recommendations for acute and preventive medical therapy in the treatment of retinal migraine. Early medical management with daily aspirin and a migraine-preventative agent may be advisable in an attempt to prevent irreversible ocular damage. Prophylactic medications that have been tried with anecdotal benet include calcium-channel blockers (i.e., verapamil, nifedipine, or nimodipine), tricyclic antidepressants (i.e., nortriptyline), beta-blockers (i.e., propanolol), and neuromodulators (i.e., divalproex sodium or topiramate). During the acute attacks, beta-agonists (i.e., isoproterenol), vasodilators (i.e., amyl nitrate or nitroglycerin), acetazolamide, and oral and intravenous preparations of corticosteroids have been advocated. Given the potential risk of worsening any underlying vasospasm, medications with vasoconstrictive properties, i.e., ergotamines, triptans, etc., should not be used.

REFERENCES
1. Galezowski X. Ophthalmic megrim: an affection of the vasomotor nerves of the retina and retinal centre which may end in a thrombosis. Lancet 1882; 1:176179. 2. Beversdorf D, Stommel E, Allen C, Stevens R, Lessell S. Recurrent branch retinal infarcts in association with migraine. Headache 1997; 37:396399. 3. Brown GC, Magargal LE, Shields JA, Goldberg RE, Walsh PN. Retinal arterial obstruction in children and young adults. Ophthalmology 1981; 88:1825. 4. Connor RCR. Complicated migraine: a study of permanent neurological and visual defects caused by migraine. Lancet 1962; 2:10721075. 5. Coppeto JR, Lessell S, Sciarra R, Bear L. Vascular retinopathy in migraine. Neurology 1986; 36:267270. 6. Corbett JJ. Neuro-ophthalmic complications of migraine and cluster headaches. Neurol Clin 1983; 1:973995. 7. Cowan CL Jr, Knox DL. Migraine optic neuropathy. Ann Ophthalmol 1982; 14:164166. 8. de Silva HJ, de Silva U, Illangasekera UL. Central retinal artery occlusion associated with migraine. Ceylon Med J 1992; 37:5556. 9. Dunning HS. Intracranial and extracranial vascular accidents in migraine. Arch Neurol Psych 1942; 48:396406. 10. Eagling EM, Sanders MD, Miller SJH. Ischaemic papillopathy: clinical and uorescein angiographic review of forty cases. Br J Ophthalmol 1974; 58:9901008. 11. Fisher CM. Transient monocular blindness associated with hemiplegia. Arch Ophthalmol 1952; 47:167203. 12. Fisher CM. Cerebral ischemialess familiar types. Clin Neurosurg 1970; 18:267335. 13. Friedman MW. Occlusion of central retinal vein in migraine. Arch Ophthalmol 1951; 45:678682. 14. Fujino T, Akiya S, Takagi S, Shiga H. Amaurosis fugax for a long duration. J Clin Neuroophthalmol 1983; 3:912. 15. Gaynes PM, Towle PA. Hemorrhage in hyaline bodies (drusen) of the optic disc during an attack of migraine. Am J Ophthalmol 1967; 63(6):16931696. 16. Gee JR. Resolution of symptoms with divalproex sodium in retinal migraine [abstr]. Headache 2004; 44:508509. 17. Glenn AM, Shaw PJ, Howe JW, Bates D. Complicated migraine resulting in blindness due to bilateral retinal infarction. Br J Ophthalmol 1992; 76:189190.

Retinal, or Monocular, Migraine

221

18. Gray JA, Carroll JD. Retinal artery occlusion in migraine. Postgrad Med J 1985; 61: 517518. 19. Grosberg BM, Solomon S. Retinal migraine: two cases of prolonged but reversible monocular visual defects. Cephalalgia. DOI: 10.1111/j.1468-2982.2006.01056x. 20. Gutteridge IF, Cole BL. Perspectives on migraine: prevalence and visual symptoms. Clin Exp Optom 2001; 84(2):5670. 21. Hachinski VC, Porchawka J, Steele JC. Visual symptoms in the migraine syndrome. Neurology 1973; 23:570579. 22. Hunt JR. A contribution to the paralytic and other persistent sequelae of migraine. Am J Med Sci 1915; 150:313331. 23. Hykin PG, Gartry D, Brazier DJ, Graham E. Bilateral cilio-retinal artery occlusion in classic migraine. Postgrad Med J 1991; 67:282284. 24. Inan LE, Uysal H, Ergun U, Yurdakul M, Karagoz H. Complicated retinal migraine. Headache 1994; 34:5052. 25. Iniguez C, Morales-Asin F, Ascaso J, Larrode P, Mauri JA. Ischemic optic neuropathy and migraine. Cephalalgia 2000; 20:431. 26. James CB, Buckley SA, Cock S, Elston JS. Retinal migraine. Lancet 1993; 342:690. 27. Joffe SN. Retinal blood vessel diameter during migraine. The Eye Ear Nose Throat Mon 1972; 52:338342. 28. Katz B. Migrainous central retinal artery occlusion. J Clin Neuroophthalmol 1986; 6(2): 6971. 29. Katz B, Bamford CR. Migrainous ischemic optic neuropathy. Neurology 1985; 35: 112114. 30. Katz B. Bilateral sequential migrainous ischemic optic neuropathy. Am J Ophthalmol 1985; 99:489. 31. Killer HE, Forrer A, Flammer J. Retinal vasospasm during an attack of migraine. Retina 2003; 23(2):253254. 32. Krapin D. Occlusion of the central retinal artery in migraine. New Engl J Med 1964; 270:359360. 33. Kupersmith MJ, Warren FA, Hass WK. The non-benign aspects of migraine. Neuroophthalmology 1987; 7(1):110. 34. Kupersmith MJ, Hass WK, Chase NE. Isoproterenol treatment of visual symptoms in migraine. Stroke 1979; 10(3):299305. 35. Lee AG, Brazis PW, Miller NR. Posterior ischemic optic neuropathy associated with migraine. Headache 1996; 36:506509. 36. Lewinshtein D, Shevell MI, Rothner AD. Familial retinal migraines. Pediatr Neurol 2004; 30:356357. 37. McDonald WI, Sanders MD. Migraine complicated by ischaemic papillopathy. Lancet 1971; 2:521523. 38. OHara M, OConnor PS. Migrainous optic neuropathy. J Clin Neuroophthalmol 1984; 4:8590. 39. Pearce J. The ophthalmological complications of migraine. J Neurol Sci 1968; 6:7381. 40. Poole CJM, Russell RWR, Harrison P, Savidge GF. Amaurosis fugax under the age of 40 years. J Neurol Neurosurg Psychiatr 1987; 50:8184. 41. Ring C. Permanent visual changes following migraine. Transatl Ophthalmol Soc NZ 1971; 23:5963. 42. Rothrock J, Walicke P, Swenson MR, Lyden PD, Logan WR. Migrainous stroke. Arch Neurol 1988; 45:6367. 43. Silberberg DH, Laties AM. Occlusive migraine. Trans Pa Acad Ophthalmol Otolaryngol 1974; 27(1):3438. 44. Spierings EL. Flurries of migraine (with) aura and migraine aura status. Headache 2002; 42(4):326327. 45. Sullivan-Mee M, Bowman B. Migraine-related visual eld loss with prolonged recovery. J Am Optom Assoc 1997; 68:377388.

222

Grosberg and Solomon

46. Weinstein JM, Feman SS. Ischemic optic neuropathy in migraine. Arch Ophthalmol 1982; 100:10971100. 47. Carroll D. Retinal migraine. Headache 1970; 10:913. 48. Walsh FB, Hoyt WF. Clinical Neuro-ophthalmology. 3rd ed. Baltimore: Williams and Wilkins, 1969. 49. Troost BT. Migraine. In: Duane TB, ed. Clinical Ophthalmology. Vol. 2. Hagerstown: Harper and Row, 1986:1112. 50. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):35. 51. Headache Classication Subcommittee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain, 2nd ed. Cephalalgia 2004; 24(suppl 1):1160. 52. Grosberg BM, Solomon S, Bigal ME, Lipton RB. Retinal migraine: two new cases and a review of the literature. Neurology 2005; 61(suppl 1):221. 53. Grosberg BM, Solomon S, Bigal ME, Lipton RB. Is irreversible visual loss part of the retinal migraine spectrum. Neurology 2005; 61(suppl 1):221. 54. Grosberg BM, Solomon S, Lipton RB. Retinal migraine. Curr Pain Headache Rep 2005; 9:268271. 55. Lewis RA, Vijayan N, Watson C, Keltner J, Johnson CA. Visual eld loss in migraine. Ophthalmology 1989; 96:321326. 56. McKendrick AM, Vingrys AJ, Badcock DR, Heywood JT. Visual eld losses in subjects with migraine headaches. Invest Ophthalmol Vis Sci 2000; 41:12391247. 57. Lana-Peixoto MA, Mattos RM Jr, Horizonte B. Migraine-related anterior ischemic optic neuropathy [abstr]. Neurology 1998; 50(suppl 4):A4. 58. Troost BT, Zagami AS. Ophthalmoplegic migraine and retinal migraine. In: Olesen J, Tfelt-Hansen P, Welch KM, eds. The Headaches. Philadelphia: Lippincott Williams & Wilkins, 2000:511517. 59. Van Harrevald A. Two mechanisms for spreading depression in the chick retina. J Neurobiol 1978; 9:419431. 60. Hupp SL, Kline LB, Corbett JJ. Visual disturbances of migraine. Surv Ophthalmol 1989; 33:221236.

17
Status Migrainosus, Persistent Aura, Migraine-Associated Seizures (Migralepsy), and Migrainous Infarction
Jessica Crowder, Curtis Delplanche, and John F. Rothrock
Department of Neurology, University of South Alabama College of Medicine, Mobile, Alabama, U.S.A.

INTRODUCTION Although migraine is often considered a benign condition, many migraine sufferers experience hours or days of disability. Some experience prolonged auras and complications of their attacks, including stroke and seizures. Although serious acute complications generally are thought to be rare and chronic sequelae yet more uncommon for many sufferers, migraine is surely not benign. In a substantial minority, migraine can affect health and quality of life adversely for an extended period and even permanently. Beyond the huge economic and social burden migraine imposes is a particular misery endured by that 2% of the general population suffering from chronic migraine; there exist both well documented and theoretical complications of the disorder, which exert a disproportionately large adverse impact upon public health. Of those complications, status migrainosus, persistent migrainous aura, migraine-associated seizures, and migrainous infarction will be addressed specically in this chapter.

STATUS MIGRAINOSUS The current International Headache Society (IHS) classication system denes status migrainosus as an attack of migraine with severe, debilitating headache persisting more than 72 hours (1). Episodes typically begin with headaches and associated symptomatology, which is characteristic of the individuals usual migraine attacks, but the headache may build to become atypically severe, and regardless, the symptom complex fails to resolve spontaneously or in response to attempted treatment. The prevalence and incidence of status migrainosus are unknown. In one clinicbased investigation of 100 consecutive patients with IHS migraine, 22% reported at
223

224

Crowder et al.

least occasional attacks persisting for more than 72 hours. (Rothrock J. Unpublished data). Conditions that clearly appear to predispose to status migrainosus are menses and pregnancy. From 40% to 70% percent of females with migraine experience worsening of the headache disorder just prior to or during menses (menstrually related migraine: MRM), and 7% to 12% suffer attacks exclusively in association with menses (pure menstrual migraine) (24). While results from investigations on the subject have varied, it does appear that some of the attacks that happen in association with menses may be different than those suffered at other times of the month. Specically, MRM is often more severe, prolonged, and refractory to treatment, and aura is less likely to be present, contrasted with nonmenstrual attacks (14). In another unpublished survey of clinic-based migraine patients, almost half of 50 consecutive females with MRM reported at least occasional menstrual attacks persisting more than 72 hours (Rothrock J. Unpublished data). Status migrainosus is by no means conned to menstruating females. The following case provides a particularly vivid example. Case 1 A 12-year-old female with a three-year history of episodic migraine was referred for evaluation and management of unremitting headache with associated nausea, vomiting, photophobia, and sonophobia. Although her headache attacks had been previously limited to no more than two days in duration, the attack precipitating the referral had begun six weeks prior, and previous treatment had resulted in only brief and partial alleviation of her symptoms. At its most severe, head pain was nonlateralized, pulsatile, and aside from its persistence in all other ways, identical to her previous migraine attacks. She had been unable to attend school for three weeks preceding her evaluation, and her mother understandably was frantic. Prior self-administered treatment of this attack with various oral triptans, intranasal and injectable sumatriptan, a course of high-dose oral prednisone, a compound containing butalbital, acetaminophen, and caffeine, and initiation of prophylactic therapy with propranolol, amitriptyline, and divalproex sodium had proved unsuccessful. She had been hospitalized twice, and treatment with intravenous dihydroergotamine (DHE)/prochlorperazine, intravenous steroids, intravenous divalproex sodium, and intravenous magnesium failed to terminate the attack. Her past medical history was otherwise unremarkable. Her academic record at school was excellent, and she had experienced no obvious social dysfunction. As regards family history, her mother and maternal grandmother had migraine. Her general and neurologic examinations were unremarkable. Brain magnetic resonance imaging (MRI) was normal. She was admitted and treated with intravenous hydration and a single dose of droperidol 2.5 mg administered intravenously. Within 30 minutes of receiving droperidol, her headache and associated symptoms ceased and did not recur. She was discharged the following day. What causes status migrainosus? Why do some headache attacks fail to resolve with sleep, active treatment intervention, or the simple passage of time? Why do some migraineurs appear to be especially prone to prolonged attacks? No easy answers are forthcoming. As evidenced by the comments made previously, in some female patients, hormonal factors must play a major role in generating status migrainosus, but even then the complication occurs in males as well and also in females when no obvious hormonal inuence is evident.

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

225

Attacks involving severe headache that persist despite treatment are more likely to develop into status migrainosus. This is a common occurrence in patients who awaken with a fully developed migraine that then fails to respond to his/her typically reliable treatment intervention. In such cases, it appears that the peripheral and central pathways that signal head pain may have become acutely sensitized to the point that the migraine will resist most conventional pharmacologic treatment and require days rather than hours to resolve spontaneously; recent research has suggested that in such cases the patients response to a given therapeutic agent may vary according to the specic stage of central sensitization that he or she has reached (5). Theoretically, frequent attacks of prolonged migraine could alter receptor sensitivity to the point that status migrainosus would become ones characteristic attack pattern rather than an exception, and recent observations that high-attack frequency represents a risk factor for transformation of episodic migraine into chronic daily headache would seem to support this notion (6). The treatment of status migrainosus is based largely on tradition, anecdote, and case series rather than class I or II evidence. For years, the mainstay of selfadministered therapy has been a short course of high-dose oral steroids, but precious little scientic data to support such treatment currently exist (7). In 2003, clinicians and investigators advocated repetitive self-administration of intranasal, subcutaneous, or intramuscular DHE, or a short course of an oral triptan. In one small study, naratriptan 2.5 mg administered twice daily for one week appeared to be effective in treating intractable migraine (8). Clinician-administered therapies for status migrainosus typically have included vigorous intravenous hydration and parenterally administered DHE, ketorolac, magnesium, dopamine antagonists, or divalproex sodium. Of the dopamine antagonists, prochlorperazine alone or in combination with DHE is effective in treating acute, severe migraine, and can be mixed with DHE within the same syringe (9). Parenterally administered metoclopramide or chlorpromazine also can be effective for acute, severe migraine (10,11), and Wang et al. reported a success rate of 88% when they administered intravenous droperidol to a small group of patients with status migrainosus (12). With all of these dopamine antagonists, acute dystonic reactions, sedation, and akathisia represent potential side effects, and the last occurs so commonly with droperidol that coadministration of diphenhydramine or a benzodiazepine is recommended. In addition, prolongation of the corrected QT (QTC) interval may occur following parenteral administration of a dopamine antagonist, and with droperidol use, pre- and posttreatment electrocardiograms currently are suggested. Intravenous administration of valproate appears safe and may be effective for treating patients with status migrainosus that has failed to respond to other medications (13,14). Doses of 500 to 1500 mg do not require performance of an electrocardiogram or telemetry monitoring. Propofol, a drug commonly used for induction of anesthesia, has been reported to be effective in treating cases of persistent, treatment-refractory migraine (15,16). The utility of such treatment may be limited by the requirement for continuous patient monitoring and immediate access to airway management equipment in the event of acute respiratory failure. While treatment usually is performed in an intensive care unit or an recovery room setting, we currently lack data to indicate the necessity for such precautions or, for that matter, results from scientically sound studies that have established this drugs safety and utility for the treatment of acute migraine or status migrainosus.

226

Crowder et al.

An algorithm for a suggested treatment that blends common sense with what clinical data are available is presented in Table 1. All doses recommended in Table 1 are based on the assumption that the patient is an adult with normal weight. Some of these options should be used routinely and some rarely, if at all. Virtually all patients with status migrainosus who have failed self-administered therapy will require vigorous intravenous hydration, and this is particularly so if they have had associated anorexia, nausea, and vomiting. In typically normotensive patients, even relatively modest elevations of blood pressure should be treated with alacrity so as to prevent superimposed hypertensive encephalopathy. If pain relief is insufcient to this task, then intravenous labetalol 10 to 20 mg often will be effective; if several doses of labetalol fail to bring down a markedly elevated blood pressure to an acceptable level, then it is time to call for help and more aggressive measures. Some other pharmacologic interventions listed in Table 1 may be used together or in sequence, and in other cases coadministration is contraindicated. For example, while it is acceptable to treat a patient simultaneously with vigorous IV hydration, IV steroids, IV valproate, and a dopamine antagonist, coadministration of two dopamine antagonists makes little sense and may precipitate side effects. Along the same line, one should not administer injectable sumatriptan within 24 hours of the patient receiving DHE, and at least six hours should elapse before DHE is administered subsequent to treatment with injectable sumatriptan. A nal word: success in treating migrainosus status with intravenous magnesium appears to be restricted largely to patients with low levels of serum-ionized magnesium; unfortunately, results from the test performed to analyze that level will not be available until the dust has settled and the crisis is long past.
Table 1 Options and Recommendations for Treating Status Migrainosus Patient administered encourage vigorous oral hydration with appropriate uids (free water or, if nausea and vomiting have occurred, salt/sugar-containing beverages) prednisone 60 mg q.d. for 23 daysa a fast-acting triptanb t.i.d. or slow-acting triptanc b.i.d. for 37 daysa Physician administered vigorous IV hydration with isotonic saline containing glucose meticulous management of acute hypertension sumatriptan 6 mg SCa; if ineffective, ketorolac 30 mg IV DHE 1 mg IVa plus an antiemeticd droperidol 2.75 mg IM plus diphenhydramine 50 IM (with pre- and post-Rx ECG) chlorpromazine 12.5100 mg IV metoclopramide 20 mg IV prochlorperazine 510 mg IV sodium valproate 5001500 mg in 125500 mL NS at 20 mg/min dexamethasone 410 mg IV magnesium IV propofol IV
If no clinical contraindications. Sumatriptan 25100 mg, zolmitriptan 2.55 mg, rizatriptan 10 mg, almotriptan 12.5 mg, eletriptan 40 mg. c Naratriptan 2.5 mg b.i.d. or frovatriptan 2.5 mg b.i.d. d Metoclopramide 1020 mg, prochlorperazine 510 mg, promethazine 2550 mg. Abbreviation: ECG, electrocardiogram.
b a

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

227

PROLONGED AURA Migraine attacks involving aura with little or no associated headache and aura symptoms atypically prolonged once were lumped together by many as complicated migraine, a nonspecic term that possesses little or no clinical utility. Complicated migraine thankfully was consigned to the scrap heap when the First Edition of the International Classication of Headache Disorders (ICHD-1) was published in 1988. The ICHD-2 (2004) again provides a clear distinction between these various clinical presentations: typical aura without headache (1.2.3), persistent aura without infarction (1.5.3), and migrainous infarction (1.5.4) (1). Migraine aura without temporally associated headache (sometimes referred to as acephalgic migraine), migraine with prominent aura, and migraine with prolonged aura frequently are considered to lie on a continuum with migraineassociated stroke (MAS), and many clinicians persist in regarding these variants with particular suspicion, specically avoiding the use of vasoactive medications (e.g., the triptans and ergotamines) when confronted with them. The scientic evidence for harm is lacking but so is the evidence for safety. At infrequent intervals clinicians who regularly treat migraine will encounter a patient who reports episodes of aura that persist for hours, days, or even months, with or without associated head pain. While the origin(s) of this phenomenon are obscure, persistent aura may be triggered by sudden termination of prophylactic therapy (17). Not surprisingly, patients with prolonged or otherwise atypical migrainous aura often are misdiagnosed as having transient ischemic attacks, partial seizure activity, or some other nonmigrainous entity. In the past, prolonged aura was reported to be notoriously difcult to terminate with abortive therapy or to suppress with prophylactic agents (18). As the following case demonstrates, however, certain of the newer antiepileptic drugs (AEDs) may be effective in treating these patients, and published case series involving treatment with furosemide or acetazolamide similarly have indicated positive treatment results (1921). Case 2 A 53-year-old woman reported a history of episodic migraine beginning at age 33. Four years prior to her initial evaluation, she began to experience visual aura (bright ashing dots of light, zigzags, blind spots, and sparkles) in association with her migraine headaches, along with facial symptoms characteristic of migrainous sensory aura. Her aura symptoms became increasingly pervasive, and for at least two years preceding initial evaluation, she noted persistent pulsating, bright ashes of light in all visual elds. During that period she also experienced constant, lowintensity headache, along with headache intensications characteristic of migraine on an average of once or twice per month. Her headaches and aura symptoms had failed to respond to prophylactic treatment with propranolol, naproxen sodium, amitriptyline, verapamil, or metoprolol, and injectable sumatriptan had made no acute impact on her symptoms. There were no abnormal ndings on physical examination. Brain MRI and electroencephalogram (EEG) were normal. Divalproex sodium 250 mg b.i.d. was prescribed for migraine prophylaxis. At her follow-up visit three weeks later she reported that she had been entirely headache free for nine days and was experiencing no aura symptoms. She remained on divalproex sodium for another two months and had only one attack of migraine (without aura) during that time.

228

Crowder et al.

Although the biogenesis of prolonged auraand aura generally, for that matterremains uncertain, the nature of the symptoms typically described and their responsiveness to AEDs that suppress cortical hypersensitivity and cortical spreading depression (CSD) speak less in favor of vasoconstriction as the generator of aura and more toward a primary neuronal origin (22,23). Taken further, it should be noted that patients with prolonged aura have been reported to experience no adverse consequences from triptan therapy (24). One also occasionally encounters the phenomenon of migraine aura status, wherein aura episodes of more typical duration atypically follow one another in rapid succession. Both sensory and visual aura status have been described, and in one small case series, the episodes of aura ceased following initiation of treatment with acetazolamide, recurred when treatment was stopped, and then ceased again when treatment was resumed (24). In another case series, divalproex sodium has been reported to help (25). In ve patients who transformed into daily migraine with aura, phenytoin appeared to provide some benet (26).

MIGRALEPSY The cases that follow highlight four different issues that commonly arise when one confronts the association between migraine and seizure activity: (i) not infrequently, an individual may experience both; (ii) some migraineurs appear to have seizures only when subjected to the stress of a severe migraine attack; (iii) the distinction between migrainous aura and epilepsy can be surprisingly difcult to make; and (iv) despite the association between the two conditions, not every episode of altered consciousness that occurs during a migraine attack reects true epilepsy. Case 3 suggests that an association may exist between migraine and idiopathic epilepsy. As in this case, individuals may have both conditions, and attacks of one may occur temporally independent of the other.

Case 3 A 28-year-old female who presents with a long-standing history of episodic migraine with and without aura also reported a 14-year history of generalized tonic/ clonic (GTC) seizures. Her seizures had occurred both during attacks of severe migraine headache (with or without aura) and independent of migraine attacks. She had had a total of six GTC seizures and no overt evidence of partial seizure activity. She was taking topiramate 50 mg b.i.d. for prophylaxis of both migraine and seizures. Her migraine was well controlled, and her last seizure occurred over two years ago. Her mother had migraine with and without aura. Her maternal grandmother had migraine, and a maternal aunt had both migraine and primary generalized epilepsy. Her examination was normal, as were brain MRI and EEG. This patient denitely had a GTC seizure, but it occurred as an isolated event and in the setting of an acute migraine attack with associated head pain, which was severe. Does she have epilepsy per se? Does she require chronic treatment with an AED to prevent seizure recurrence? Her case typies what most would term migralepsy, and we will devote the majority of this section to addressing the intricacies of this challenging clinical presentation.

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

229

Case 4 A 34-year-old female, with attacks of migraine with and without aura since the age of 12, reported a two-year history of daily headaches that uctuated widely in severity and at times intensied to resemble her previous migraine; those intensications often were heralded by visual and sensory aura, involved functionally disabling headache and lasted for days. In the midst of one recent attack, she recently suffered a GTC seizure (her rst ever) with associated tongue biting and postictal confusion/ agitation but no incontinence. Her mother, father, a brother, and multiple second- and third-degree relatives had apparent migraine, but there was no known family history of epilepsy. Her examination, brain imaging, and EEG were normal. Case 4 illustrates a number of interesting issues: (a) in manyif not most individuals who report migraine with visual aura, the auras symptomatology likely reects a genetically hypersensitive occipital cortex, (b) the distinction between migrainous visual aura and partial seizure activity arising from occipital neurons can be difcult to make, and (c) whatever its originmigrainous or epileptic hyperexcitability of occipital neurons may be provoked by a triggering stimulus to a threshold beyond which aura, seizure activity, or both may result. Case 5 A 36-year-old female reported a lifelong history of migraine, which for years had been most prominent during menses. At age 28, she experienced her rst visual aura, a kaleidoscope that developed over about 15 to 20 minutes and then resolved entirely and without any temporally associated headache. A neurologic examination performed at that time was normal, as was brain MRI. Since that event, she continued to have occasional episodes of similar visual aura with or without temporally associated headache, and she noted that such episodes tended to occur particularly during menses and especially if at those times she jogged just to the east of a long line of trees behind which the setting sun emitted intermittent ashes of bright light. On one such occasion while jogging she lost consciousness for about ve minutes following the onset of aura, and observers report that while unconscious she exhibited stiffening and shaking of all four extremities. After regaining consciousness she noted a severe headache and found that she had bitten the lateral aspect of her tongue. Her father had migraine. There was no known family history of epilepsy. Her neurologic examination and brain MRI were normal. Her baseline EEG was normal, but in response to photic stimulation, she developed a highly disorganized pattern of waveforms posteriorly and occasional spike discharges over the posterior leads. Case 5 represents a situation faced all too often by specialists and nonspecialists alike; this patients diagnosis and management need to be cleaned up, and a previous misdiagnosis needs to be corrected. It is far more plausible that the patient is experiencing migraine-associated syncope rather than seizures, and that the one isolated episode of possible seizure activity that her husband did observe most likely represented a syncopal t, i.e., a brief, generalized seizure that was provoked by syncope and was, in itself, of no prognostic signicance. Migraine-associated syncope is common. Although many published reports have suggested that migraine may convey some degree of autonomic dysfunction, diagnostic evaluation (e.g., tilt-table testing) of patients such as the one presented here often fails to yield results that assist

230

Crowder et al.

in clinical management. This is a situation wherein common sense should prevail; unless the patient or a reliable observer reports unequivocal, unprovoked seizure activity or EEG (routine or extended/video) is highly suggestive, assigning a diagnosis of epilepsy and committing the patient to AED therapy indenitely would seem to be in no ones best interest. Derived from combining migraine and epilepsy, migralepsy is an older term that recently has been reintroduced to indicate a composite of symptoms encountered in both disorders. Migraine and epilepsy typically are distinct from one another, but they can share common symptomatology; e.g., seizures frequently are followed by a headache indistinguishable from that of migraine. Moreover, the EEG of migraineurs may exhibit epileptiform features even in individuals without any history of seizure symptoms (27,28). In describing cases of migralepsy that involved patients who suffered temporally associated acute migraine and seizure activity, it was proposed that migraine might represent a fragmentary variant of epilepsy; intercalated seizure is a more recent term, implying the occurrence of an epileptic seizure during the aura phase of a migraine attack (29). The ICHD-2 denes migraine-triggered seizure (1.5.5) as a seizure triggered by a migraine aura (1). The diagnostic criteria include (a) a history of migraine fullling criteria for migraine with aura (1.2) and (b) a seizure occurring during or within one hour following the migraine aura. The classication document also notes that migraine and epilepsy are prototypical examples of paroxysmal brain disorders. While migraine-like headaches are quite frequently seen in the postictal period, sometimes a seizure occurs during or following a migraine attack. This phenomenon, sometimes referred to as migralepsy, has been described in patients with migraine with aura (1). Both migraine and epilepsyespecially when epilepsy involves seizures arising from the occipital cortexmay produce prominent visual symptomatology. While the symptoms themselves may be identical in the two conditions, a migraine aura is typically longer lasting than an occipital seizure; the aura of migraine usually lasts 15 to 20 minutes, while the visual symptoms of an occipital seizure most often persist for only 1 to 2 minutes. In both conditions, the symptoms have a dynamic temporal pattern, wherein they initially appear, then build, and nally diminish. Several researchers have reported that patients with migralepsy may have visual seizures consisting of brief visual hallucinations involving colored dots or discs, highly stylized contours of geometric gures, or single or multicolored spots that often rotate; the seizures thus described lasted for 1 to 2 minutes and were followed by a scotoma that slowly evolved into unilateral or bilateral hemianopia (3032). Electroencephalography, performed when these positive symptoms were present, conrmed they were epileptic in origin. The Association of Migraine and Epilepsy It requires no great leap of faith to accept that epileptic seizures could result from the same cortical changes that induce migraine attacks. Both conditions are believed to reect genetically derived neuronal hypersensitivity, and they appear to be comorbid. The reported prevalence of epilepsy in individuals with migraine has ranged from 1% to 17%, with a median of 5.9%, and the reported migraine prevalence in individuals with epilepsy has ranged from 8% to 15% (33). In one study examining the association between migraine and epilepsy, Lipton et al. found migraine to be 2.4 times more common in individuals with epilepsy than in individuals without epilepsy

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

231

(34). Although many of the relevant studies have had methodologic limitations, including selection bias, a lack of appropriate case controls and variable or nonspecic denitions of migraine and epilepsy, there appears to be strong evidence for an association between the two conditions. The biologic basis of the association may be multifactorial. In what would represent a unidirectional and causal relationship, migraine conceivably could produce epilepsy by inicting ischemic brain injury, in which case one would expect migraine to predate the onset of epilepsy. On the other hand, epilepsy theoretically could produce migraine by activating the trigeminovascular system, leading one to anticipate an increased prevalence of migraine after the onset of epilepsy but not before (35). The data actually show an excess of migraine both before and after the onset of epilepsy, leading one to reject both of these unidirectional causal models. Shared environmental risk factors could contribute to comorbidity. For example, the risk of migraine is higher in subjects with epilepsy caused by head trauma, and as head trauma may produce acquired migraine, the comorbidity of the conditions theoretically could result from the effect of head injury in generating both. Because their association persists even in individuals with idiopathic or cryptogenic epilepsy, however, this specic environmental factor cannot account for all the comorbidity present. Although one might presume the two conditions share a similar genetic basis that could account for their comorbidity, a large study by Ottman and Lipton failed to conrm that hypothesis (36). In short, while both disorders may possess a genetic basis, the genetic permutations involved appear to differ. With the rejection of a unidirectional model, an environmental cause and the shared gene hypothesis, Silberstein and Lipton have proposed that it is simply the similar state of increased excitability within the brain that accounts for the comorbidity of migraine and epilepsy (37). Enhanced neuronal excitability and an inherently reduced threshold to triggering stimuli are integrated in this model, and at the cellular level, a reduction in neuronal magnesium or disturbances of neurotransmitter systems may provide the pathophysiologic basis for producing the hyperexcitability. In theory, genetic predisposition, environmental factors, or both could contribute to these alterations. The EEG in Migralepsy Differentiating between migraine and epilepsy can be difcult. While the EEG is a useful tool in evaluating epilepsy, it is far less valuable in the diagnosis of migraine, and the Quality Standards Subcommittee of the American Academy of Neurology in fact has determined that EEG is of no utility in headache diagnosis (38). Electroencephalography has not been shown to distinguish reliably among headache subtypes, nor is it an effective screening test for excluding structural causes of headache. Epileptiform discharges and focal slowing may occur in the EEG tracings of nonepileptic patients with or without migraine, and in contrast to EEGs recorded during a clinical seizure, those recorded during an attack of migraine with aura are usually normal. Focal slowing sometimes occurs during migraine aura but is not a consistent nding. Even the photic harmonic response appearing at greater than 20 Hz, originally thought to be characteristic of migraine, can be seen in children without a history of migraine and is thus not specic to that condition (39). Even so, some studies have noted correlative EEG characteristics in migraine and epilepsy. Schachter et al. reported that among nonepileptic subjects, the

232

Crowder et al.

overnight EEGs of 12.5% of those with migraine and 13.3% of those with a family history of epilepsy showed spikes, an incidence signicantly higher than that observed in the general population (40). Marks and Ehrenberg studied 395 adult seizure patients, 20% of whom also had migraine, and subjects with catamenial epilepsy or migraine with aura were at increased risk for an association between the two disorders. Sixteen percent of their migraine subjects experienced seizures during or immediately following an aura, and in two subjects, EEGs recorded during the transition from aura to partial seizure demonstrated distinctive changes on the EEG during the aura, which preceded development of an electrographic complex partial seizure; and periodic lateralized epileptiform discharges (PLED) were recorded in ve other subjects in close temporal association to their migraine episodes. None of these patients had any of the usual diseases associated with PLEDs (established stroke, brain abscess, glioblastoma, or viral encephalitis), and their PLEDs usually resolved within 24 hours. Some of the patients had clinical seizures when PLEDs were present on their EEGs (28). Extended electroencephalography combined with closed-circuit video recording can help differentiate between migrainous and epileptic symptoms and help facilitate the diagnosis of migralepsy. In one study involving two patients with migralepsy, continuous video-EEG telemetry demonstrated changes during migraine aura, which were atypical for electrographic epilepsy, along with the bursts of spike activity more characteristic of EEG ndings during an epileptic seizure (41). In most reported cases involving migralepsy, however, the EEG does not show the progressive increases and declines in the frequency and amplitude of rhythmic, repetitive epileptiform activity typically observed during pure epileptic seizures. Finally, despite the persistence of clinical symptoms, the EEG during migraine aura may show a waxing and waning pattern, with abnormal sequences separated by completely normal EEG activity. MRI and Migralepsy Evanescent brain MRI abnormalities following an attack of migraine complicated by seizure activity have been reported. Mateo et al. have described a patient with repeated episodes of migraine with aura-associated seizures, whose MRI demonstrated recurrent and reversible abnormalities (42). The origin of the abnormalities observed remains unclear. Summary What we know: migraine and epilepsy are bidirectionally comorbid. What we suspect: this comorbidity is derived from the cortical hypersensitivity (presumably genetic in origin) inherent in both conditions. What we observe: there are patients with migraine and isolated or recurrent seizure activity, whose seizures occur only in the setting of an acute migraine attack (migralepsy). What we dont know: how to identify clearly those patients with migralepsy who will require long-term treatment with AEDs. MIGRAINE AND STROKE While migraine and stroke are associated, the following two cases characterize the complexity of that association and the broad clinical spectrum encompassed by MAS.

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

233

Case 7 A 37-year-old woman with a long-standing history of migraine without aura presented with acute and persistent right arm and leg weakness, without associated headache, visual impairment, or speech disturbance. Her neurologic examination was notable for pronator drift of the right arm and mild weakness to direct testing of the right hand intrinsics and hip exors. Serial brain computed tomography (CT) demonstrated the evolution of a small area of infarction within the left corona radiate.

Case 8 A 31-year-old female reported an 11-year history of episodic headaches characteristic of migraine. On four occasions, she had experienced left hemiparesis during a typical headache, and on one other occasion her headache was accompanied by expressive aphasia, right hemiparesis, and acute/persistent left eye visual loss. Her initial neurologic examination was notable for a partial left afferent papillary defect, 20/400 acuity in the left eye, mild left hemiparesis, extensor plantar responses bilaterally, and left hand dysgraphesthesia and tactile extinction. Noncontrasted brain CT demonstrated old infarcts in both cerebral hemispheres at the vertex. Elective arteriography was notable only for nonvisualization of the left ophthalmic artery. Four days following elective arteriography, she developed a severe, pulsatile, nonlateralized headache with associated dysarthria, acute worsening of her chronic left hemiparesis, and new visual loss affecting the right eye. Emergent catheter-directed arteriography demonstrated tapering stenosis and occlusion of the right internal carotid artery several centimeters distal to the extracranial bifurcation (Fig. 1). The ndings were quite suggestive of internal carotid dissection, but follow-up angiography performed two days later was normal. Her new dysarthria, increased left hemiparesis, and new right eye visual loss slowly improved, and within a month she was back to her neurologic baseline. Follow-up brain CT demonstrated only the old areas of infarction noted on the baseline study. A recent meta-analysis of 14 relevant epidemiologic studies indicated that stroke risk is increased about twofold in young-to-middle-aged migraineurs relative to case controls or age- and gender-matched general population samples, and Stang et al. recently reported stroke risk to be similarly increased two to threefold in a large cohort of individuals !55 years of age who reported a history of migraine with aura (43,44). Interestingly, as Case 7 exemplies, most strokes suffered by migraineurs occur temporally remote from an acute migraine attack; of the approximately 3000 cases of stroke estimated to occur annually in young-to-middle-aged migraineurs in the United States, only about 1000 take place during a migraine episode and meet the ICHD-2 criteria for migrainous infarction (1.5.4) (1). Two obvious questions follow: how is stroke generated during an acute migraine attack; and what is it about migraine that leads an individual to be at increased risk for stroke even when he or she is acutely migraine free? No easy answers are forthcoming, and several possible explanations exist. Migraine may act as a cofactor in producing stroke or interacting with another risk factor, or migraine may be an innocent bystander, serving merely as a marker for another coexisting condition that by itself is independently responsible for

234

Crowder et al.

Figure 1 Selective right common carotid arteriogram demonstrates tapering stenosis and occlusion of the extracranial internal carotid, felt to be a consequence of migraineassociated vasospasm.

causing stroke. Alternatively, something about the migraine process itself might generate stroke. A number of additive risk factors for stroke in migraineurs have been reported by various investigators, and with at least a few of these it is simple to conjecture how they might interact with migraine to produce stroke. If, as some have suggested, migraine may produce a prothrombotic stateacutely (i.e., during attacks), chronically, or boththen the additional prothrombotic potential provided by an oral contraceptive (OCP) conceivably could be sufcient to produce symptomatic cerebral thrombosis (4547). Smoking could interact with migraine in a similar fashion, each reinforcing the others propensity for promoting arterial thrombosis (48). Is migraine merely an innocent bystander in the stroke process? Mitral valve prolapse (MVP) is found more commonly in migraineurs than in the general population, and in the 1980s, some investigators touted MVP as a potentially common cause of the ubiquitous stroke of unknown cause. Does the increased stroke risk in migraineurs simply reect the higher prevalence of MVP in that population? Apparently not. In two studies describing relatively large groups of patients with acute stroke complicating a migraine attack, the prevalence of MVP was low (49,50). In a similar vein, others have identied migraine-associated patent foramen

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

235

ovale (PFO) as the potential generator of at least a proportion of cases of migrainous infarction, but questions regarding PFO and causation persist (51). Does migraine act directly and independently to cause stroke? Is there something intrinsic to the migraine process itself that, taken to excess, will result in stroke? CSD is believed to represent the biologic underpinning of migrainous aura, and, as mentioned previously, some studies have reported an increased risk of stroke in populations of migraine patients with aura, which may be disproportionately high in those patients whose visual auras consist primarily of amaurosis, without positive features (22,4347). If migrainous aura results from CSD that includes an oligemic component, then particularly severe or prolonged CSD-related cerebral oligemia might produce irreversible neuronal damage. A variety of other mechanisms for the direct production of migrainous infarction have been proposed (e.g., migraine-associated arterial dissection, migrainous arteriopathy, and genetically associated calcium channelopathies), and amongst this group migraine-associated vasospasm deserves particular mention. An obvious limitation to the investigation of mechanisms potentially generating migrainous infarction is the fact that very few centers encounter such patients in numbers sufcient to generate compelling case series, let alone scientically sound casecontrol studies. In one exception to this, a study involving a relatively large series of patients with migrainous infarction, Bougaslavssky and colleagues found no arteriographic evidence of vasospasm in their patients who suffered ischemic stroke during an acute migraine attack (49). In another study, however, 4 of 6 (67%) patients with migrainous infarction, who underwent arteriography within 72 hours of stroke onset, did exhibit clear evidence of cerebral vasospasm; in some cases, the arterial spasm was widespread, extending beyond the symptomatic territory, and both in those cases and in the others where the spasm selectively involved the symptomatic artery, abnormalities were found in the anterior circulation as frequently as the posterior (52). Given the uncertainties as to the mechanism(s) that may generate migrainous infarction or MAS, dogmatic advocation of any particular treatment strategy for preventing or treating such strokes is difcult to justify. Whether a history of migraine further increases the stroke risk associated with OCP use, remains controversial, and in terms of primary stroke prevention in the migraine population, routinely to deny OCPs to female migraineurs seems to make little sense and invite unwanted conception; it is estimated that implementation of such wrongheaded management on a widespread basis would result in 700,000 unplanned pregnancies annually in the United States (4547,53,54). Certainly migraine, aura, active cigarette smoking, and use of an OCP with a relatively high estrogen content by women aged 35 or greater represent a combination of factors that may elevate the risk of stroke or other thrombotic complications to an unacceptable level, and such patients should be counseled to cease smoking and to consider an alternate means of contraception (or at least an OCP containing less or no estrogen). Females whose migraine pattern changes drastically for the worse following initiation of OCP use represent another subpopulation in whom alternatives for contraception should be considered, and this is particularly relevant when a patient with no previous aura history develops aura after beginning an OCP, or, even more alarming, when the patient with known migraine with aura begins to experience aura that is atypically prolonged or otherwise unusual (e.g., signicant aphasia, weakness, or both). Estrogen-containing OCPs or hormone replacement therapy probably are best avoided in all female migraineurs who have suffered a previous thrombotic event, especially if that event was thrombotic or thromboembolic stroke.

236

Crowder et al.

Interestingly (and of concern), in one casecontrol study involving a relatively large number of patients with migrainous infarction who were followed prospectively, the stroke recurrence rate was quite high (10% per patient year of followup); this occurred even in patients treated with anticoagulant therapy, antiplatelet agents, or both (50). What constitutes optimal therapy for secondary stroke prevention in patients with prior migrainous infarction remains unknown, but it would seem self-evident that minimizing attack frequencyand particularly the frequency of prolonged, severe migraine attackswould lessen stroke risk. Such management often will require prescription of an effective prophylactic agent and a combination of agents for acute migraine treatment that are effective but do not promote vasoconstriction. A scattering of case reports have suggested that betablockers may be a poor choice in patients at risk for migrainous infarction, and an even thinner scientic basis exists to support the use of calcium antagonists (e.g., verapamil) instead (5558). Long-term treatment with an antiplatelet agent also is recommended, but, again, the evidence to support such treatment is at best sparse. Finally, based on tradition more than any scientic basis, cerebral arteriography is probably best avoided in patients with acute migraine unless the clinical situation clearly demands such diagnostic intervention. Yet more obscure is what comprises optimal management of the patient with apparent acute migrainous infarction. Certainly rapid control of the patients pain, vigorous intravenous rehydration, and judicious blood pressure management are interventions that would be difcult for any to dispute, but the utility of intravenous tissue plasminogen activator (tPA), intra-arterial angioplasty/thrombolysis/ vasodilators, or other heroic measures lacks a basis to justify either vigorous support or vehement opposition. In short, given the absence of evidence-based guidelines, the treatment of migrainous infarction and MASwhether intended for primary prevention, secondary prevention, or acute interventioncalls for an especially strong dose of common sense.

REFERENCES
1. Headache Classication Committee of the International Headache Society. The international classication of headache disorders (2nd ed). Cephalalgia 2004; 24(suppl 1): 1160. 2. MacGregor EA, Chia H, Vohrah RC, Wilkinson M. Migraine and menstruation: a pilot study. Cephalalgia 1990; 10:305310. 3. Grannella F, Sances G, Zanferrari C, Costa A, Martignoni E, Manzoni GC. Migraine without aura and reproductive life events: a clinical epidemiological study in 1300 women. Headache 1993; 33:385389. 4. Grannella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centers. Cephalalgia 2004; 24:707716. 5. Burstein R, Jakubowski M, Collins B. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol 2004; 55(1):1926. 6. Scher AI, Stewart WE, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003; 106:8189. 7. Raskin N. Treatment of status migrainosus: the American experience. Headache 1990; 30(suppl 2):550553. 8. Gallagher D, Mueller O. Managing intractable migraine with naratriptan. Headache 2003; 43:991993.

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

237

9. Kabbouche M, Vockell A, LeCates S, Powers S, Hershey A. Tolerability and effectiveness of prochlorperazine for intractable migraine in children. Pediatrics 2001:107. 10. Cameron J, Lane P, Speechley M. Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache. Acad Emerg Med 1995; 2:597602. 11. Friedman B, Corbo J, Lipton R, et al. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraine. Neurology 2005; 64:463468. 12. Wang S, Silberstein S, Young W. Droperidol treatment of status migrainosus and refractory migraine. Headache 1997; 37:377. 13. Norton J. Use of intravenous valproate sodium in status migraine. Headache 2000; 40:755757. 14. Popeney C. IV Depacon and po Depakote ER for treatment of status migrainosus and prevention of episodic migraine. Cephalalgia 2003; 23:739. 15. Krusz J, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable migraine. Headache 2000; 40:224230. 16. Drummond-Lewis J, Scher C. Propofol: a new treatment strategy for refractory migraine headache. Pain Med 2002; 3:366369. 17. Bento M, Esperanca P. Migraine with prolonged aura. Headache 2000; 40:5253. 18. Liu GT, Schatz NJ, Galetta SL, Volpe NJ, Skobieranda F, Kosmorsky GS. Persistent positive visual phenomena in migraine. Neurology 1995; 45:664668. 19. Lampl C, Buzath A, Klinger D, Neumann K. Lamotrigine in the prophylactic treatment of migraine auraa pilot study. Cephalalgia 1999; 19:5863. 20. Rozen T. Treatment of a prolonged aura with intravenous furosemide. Neurology 2000; 55:732733. 21. Haan J, Sluis P, Sluis LH, et al. Acetazolamide treatment for migraine aura status. Neurology 2000; 55:15881589. 22. Amemori T, Gorelova NA, Burnes J. Spreading depression in the olfactory bulb of rata: reliable initiation and boundaries of propagation. Neuroscience 1987; 22:2936. 23. Lauritzen M. Pathophysiology of the migraine aura: the spreading depression theory. Brain 1994; 117:199210. 24. Klapper J, Mathew N, Nett R. Triptans in the treatment of basilar migraine and migraine with prolonged aura. Headache 2001; 41:981984. 25. Rothrock J. Successful treatment of persistent migraine aura with divalproex sodium. Neurology 1997; 48:261262. 26. Merima D, Kuritzky A. Daily migraine with aura: a new migraine variant. Headache 2000; 40:389392. 27. Lennox WG, Lennox MA. Epilepsy and Related Disorders. Boston: Little, Brown, 1960. 28. Marks DA, Ehrenberg BL. Migraine related seizures in adults with epilepsy, with EEG correlation. Neurology 1993; 43:24762483. 29. Manzoni GC, Terzano MG, Mancia D. Possible interference between migrainous and epileptic mechanisms in intercalated attacks. Case report. Eur Neurol 1979; 18: 124129. 30. DeRomanis F, Buzzi MG, Cerbo R, et al. Migraine and epilepsy with infantile onset and electroencephalographic ndings of occipital spike-wave complexes. Headache 1991; 31:378383. 31. DeRomanis F, Feliciani M, Cerbo R. Migraine and other clinical syndromes in children affected by EEG occipital spike-wave complexes. Funct Neurol 1988; 3: 187203. 32. Panayiotopoulos CP. Differentiating occipital epilepsies from migraine with aura, acephalgic migraine, and basilar migraine. In: Panayiotopoulos CP, ed. Benign Childhood Partial Seizures and Related Epileptic Syndromes. London: John Libbey & Company Ltd, 1999:281302. 33. Andermann E, Andermann FA. Migraine-epilepsy relationships: epidemiological and genetic aspects. In: Andermann FA, Lugaresi E, eds. Migraine and Epilepsy. Boston: Butterworths, 1987:281291.

238

Crowder et al.

34. Lipton RB, Ottman R, Ehrenberg BL, Hauser WA. Comorbidity of migraine: the connection between migraine and epilepsy. Neurology 1994; 44:2832. 35. Moskowitz MA. The trigeminovascular system. In: Olesen J, Tfelt-Hansen P, Welch KM, eds. The Headaches. New York: Raven Press, 1993:97104. 36. Ottman R, Lipton RB. Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility? Neurology 1996; 47:918924. 37. Silberstein SD, Lipton RB. Headache and epilepsy. In: Ettinger AB, Devinsky O, eds. Managing Epilepsy and Co-existing Disorders. Boston: Butterworth-Heinemann, 2002:239254. 38. Practice parameter: the electroencephalogram in the evaluation of headache (summary statement). Report of the Quality Standards Subcommittee. Neurology 1995; 45:1411 1413. 39. Gronseth GS, Greenberg MK. The utility of the electroencephalogram in the evaluation of patients presenting with headache: a review of the literature. Neurology 1995; 45: 12631267. 40. Schachter SC, Ito M, Wannamaker BB, et al. Incidence of spikes and paroxysmal rhythmic events in overnight ambulatory computer-assisted EEGs of normal subjects: a multicenter study. J Clin Neurophysiol 1998; 15:251255. 41. Ehrenberg BL. Unusual clinical manifestations of migraine, and the borderland of epilepsy re-explored. Semin Neurol 1991; 11:118127. 42. Migraine-associated seizures with recurrent and reversible magnetic resonance imaging abnormalities. Mateo I, Foncea N, Vincente I, Beldarrain M, Garcia-Monco J. Headache 2004; 44:265270. 43. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005; 330:63. 44. Stang PE, Carson AP, Rose KM, et al. Headache, cerebrovascular symptoms and stroke: the Atherosclerosis Risk in Communities Study. Neurology 2005; 64:15731577. 45. Tzourio C, Tehindrazanarivelo A, Iglesias S, et al. Case-control study of migraine and risk of ischemic stroke in young women. BMJ 1995; 310:830833. 46. Carolei A, Marini C, DeMatteis G. History of migraine and risk of cerebral ischemia in young adults. The Italian National Research Council Study Group on Stroke in the Young. Lancet 1996; 347:15031506. 47. Merikangas KR, Fenton BT, Cheng SH, Stolar MJ, Risch N. Association between migraine and stroke in a large-scale epidemiological study of the United States. Arch Neurol 1997; 54:362368. 48. Iglesias S, Visy J, Hubert J, Tehindrazanarivelo A, Tzourio C, Bousser M. Migraine as a risk factor for ischemic stroke: a case-control study [abstract]. Stroke 1993; 24:171. 49. Bogousslavsky J, Regli F, Van Melle G, Payot M, Uske A. Migraine stroke. Neurology 1988; 38:223227. 50. Rothrock J, North J, Madden K et al. Migraine and migrainous stroke: risk factors and prognosis. Neurology 1993; 43:24732476. 51. Milhaud D, Bogousslavsky J, van Melle G, Liot P. Ischemic stroke and active migraine. Neurology 2001; 57:18051811. 52. Rothrock J, Walicke P, Swenson M, Lyden P, Logan W. Migrainous stroke. Arch Neurol 1988; 45:6367. 53. Chang C, Donaghy M, Poulter N. Migraine and stroke in young women: case control study. The World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999; 318:1318. 54. Gillum L, Mamidipudi S, Johnston S. Ischemic stroke risk with oral contraceptives. A meta-analysis. JAMA 2000; 284:7278. 55. Prendes J. Considerations on the use of propranolol in complicated migraine. Headache 1980; 20:9395.

Status Migrainosus, Persistent Aura, Migralepsy, and Migrainous Infarction

239

56. Gilbert G. An occurrence of complicated migraine during propranolol therapy. Headache 1982; 22:8183. 57. Bardwell A, Trott J. Stroke in migraine as a consequence of propranolol. Headache 1987; 27:381383. 58. Mendizabal J, Greiner F, Hamilton W, Rothrock J. Migrainous stroke causing thalamic infarction and amnesia during treatment with propranolol. Headache 1997; 37:594596. 59. Friedenberg S, Dodick D. Case report: migraine-associated seizure: a case of reversible MRI abnormalities and persistent nondominant hemisphere syndrome. Headache 2000; 40:487.

18
Principles of Headache Management
Marc S. Husid
Department of Neurology, Walton Headache Center, Medical College of Georgia, Augusta, Georgia, U.S.A.

Alan M. Rapoport
The New England Center for Headache, Stamford, Connecticut, and Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, U.S.A.

INTRODUCTION William Oslers principle that it is more helpful to approach the person who has the disease than the disease the person has is well taken in regard to headache (1). As noted by Dr. Fred Sheftell, One can take a logical approach to the diagnosis and treatment of headache and still miss the boat . . . All diagnosis and treatment takes place in the atmosphere of a relationship between the physician and patient. It is the quality of that atmosphere which often constitutes the difference between treatment success and failure. A nonbiased and nonjudgmental approach should be the template upon which diagnosis and treatment is built (1). No two physicians approach the evaluation and management of headache patients in exactly the same way, nor need they. As John R. Graham once wrote, Any style will be effective providing it clearly demonstrates to the patient that the physician is interested in him and his life as a person, as well as in the details of the medical complaint (2). Managing patients with headache disorders can be challenging yet very rewarding to the caregivers, patients, and their families. Appropriate treatment begins with the initial interview, careful physical and neurological examination, and in particular, the assurance that the physician and patient derive from all the information available that everything possible has been done to exclude the presence of organic causes of headache (3). Some headache specialists use established headache guidelines in addition to their own knowledge to develop individualized treatment programs for each patient. Recently, the U.S. Headache Consortium developed evidence-based guidelines for the management of migraine, covering diagnosis as well as acute, preventive, and nonpharmacologic treatment (4). The Canadian Headache Society (5) and the U.K. Migraine in Primary Care Advisors Migraine Guidelines Development Group
241

242

Husid and Rapoport

Box 1 General principles for headache management 1. 2. 3. 4. 5. 6. 7. Establish a diagnosis Assess disability and other factors Educate patients about their condition and its treatment Establish realistic expectations Encourage patients to become active in their own care Develop an appropriate, individualized treatment plan Schedule regular follow-up visits to reassess and modify treatment

(6) have published similar guidelines. All of these guidelines recommend similar strategies for management of migraine (Box 1). To enhance the treatment program and maximize physician efciency, a team approach may be employed, using medical assistants, nurses, nurse practitioners, physician assistants, pharmacists, and other health care professionals. The use of headache diagnostic questionnaires, diaries, and impact assessments further increases efciency and diagnostic accuracy, and improves care (7). (See Appendix 1.)

ESTABLISHING THE DIAGNOSIS History Taking Accurate history taking is the most important aspect of any medical consultation. This is particularly true for the headache patient. In more than 90% of cases, the history will establish the diagnosis or lead to a differential diagnosis, which may be further claried by examination and diagnostic testing when necessary (8). Good history taking enhances mutual respect and trust between the patient and physician, which can make the difference between success and failure of treatment (1). Headache patients not only want headache relief, but also seek physicians who are genuinely concerned about their well being, project a positive attitude, and are willing to listen, answer their questions, and work with them. Indeed, the secret of good history taking is to be a good listener (9). This truism dates back to 1904, when Osler said, Listen to the patient, he is telling you the diagnosis. (10). Yet, the ability to sit back and listen does not come easily to physicians. Many doctors feel that their patients are not adept at telling a succinct story and that interruption is necessary to get through the appointment in the allotted time. In a study of the effect of physician behavior on the collection of data, Beckman and Frankel found the average time that a patient was allowed to talk before being interrupted by the physician was 18 seconds. However, when patients were allowed to tell their stories without interruption, they usually spoke for no longer than 150 seconds. Therefore, physicians who interrupted saved a maximum of 132 seconds, on average. Furthermore, physician interruptions had a negative affect on the patients perception of the physicians competence, his or her compliance with the treatment plan, and overall satisfaction (10). The use of intake forms, which the patient can ll out prior to their initial evaluation leverages the busy physicians time, and allows him/her to focus on the diagnosis and treatment. Figure 1 consists of clinical forms we use in gathering patient histories (8). We have found it helpful to have patients complete the forms prior to their rst visit. A nurse or other medical personnel can review, amplify, and summarize all critical factors providing the physician a concise, comprehensive overview (Fig. 3).

Principles of Headache Management

243

Figure 1 Patient information and medical history form.

Patients in our headache clinics are asked to differentiate the severity of their headaches on a 1 to 3 scale as follows:  Severe or level 3 headaches are those that render the patient totally or almost totally incapacitated (the patient would strongly prefer to be at bed rest).  Moderate or level 2 headaches interfere with the patients ability to function normally, but are only partially incapacitating (patients would prefer to be medicated).

244

Husid and Rapoport

Figure 1 (Continued)

 Mild or level 1 attacks are mild or dull, do not interfere with functioning, and may not be noticed when the patients attention is distracted. Many patients do not need, but still take medication for these milder headaches. For each headache type present, the following parameters are explored: 1. Age of onset and description of early/rst headache 2. Frequency, pattern, and timing of attacks a. Previously (at onset) b. Currently

Principles of Headache Management

245

Figure 1 (Continued)

3. 4. 5. 6.

c. Mode of increase, gradual or sudden, for those patients who experienced an increase in the frequency over time Location and laterality of typical headache attacks (if unilateral, we ask if it is side-locked or alternating) Quality of pain during a typical headache attack (throbbing, stabbing, pressure, etc.) Duration of pain (with and without treatment) Presence and description of any premonitory features

246

Husid and Rapoport

Figure 1 (Continued)

7. 8. 9. 10.

Presence and description of aura Associated symptoms Provocative and relieving factors Postural relationships (postural relationships characteristic of high or low pressure headache syndromes may be lost with the passage of timeSaper J, personal communication) (9) 11. Behavior during headache (The new International Classication of Headache Disorders-2 lists aggravation by or causing avoidance of routine physical activity as a diagnostic criteria for migraine, and a sense of restlessness or agitation for cluster headache) 12. Trigger factors

Principles of Headache Management

247

Figure 1 (Continued)

13. Presence of and time to recurrence, and how often it occurs 14. Past medications (including nonprescriptional medications). Our forms help collect information on: a. Name and type (brand or generic) b. Dose c. Frequency of administration d. Duration of administration and dates e. Routes of administration f. Effectiveness g. Side effects h. Allergies

248

Husid and Rapoport

Figure 1 (Continued)

15. Current medications (for headache and other conditions). Information is collected similar to that described for past medications 16. Past medical history 17. Past surgical history 18. Family history of headache

Principles of Headache Management

249

Figure 2 Physician summary sheet.

19. Habit history (including sleep, diet, exercise, smoking, and alcohol/ drugs) 20. Menstrual association and hormonal factors that may inuence the headache 21. Psychosocial history As previously discussed, these forms are mailed to a new patient before his/her rst visit. At the time of the rst visit, a nurse reviews the information with the patient

250

Husid and Rapoport

Figure 3 Summary face sheet for the patient information and medical history forms.

for completeness and accuracy. For those patients who do not bring the forms, the nurse completes the forms based on the history provided (Fig. 1). Finally, after reviewing the forms, taking the patients history by himself/herself, and examining the patient, the doctor arrives at an initial diagnosis/differential diagnosis, determines the need for further testing, and develops the initial treatment plan, which we record on a summary face sheet (Fig. 3). Openness on the part of the physician during the history taking and examination is essential. One approach is to ask the patient to describe a typical day from the time he/she gets up in the morning to the time he/she goes to sleep (Sheftell FD, personal communication). One can get a very good idea about how someone manages his/her time, to what extent he/she is overwhelmed, and how much time he/she leaves for personal me time. It is not unusual to see a patient whose life

Principles of Headache Management

251

is lled with demands and taking care of everyone else, who has no insight as to the extent of these demands and the negative effects that these demands have (1). Alternatively one can say This must have really changed your life; how have you dealt with it? as a means of gaining an insight into how headaches have affected the patients life and how well he/she has coped (9). A useful nal question to ask is if anything has been left out that the patient feels is important or that would help to better understand his/her headaches. By the end of the initial consultation, the physician should not only have an idea in regard to diagnosis and initial treatment plan, but also a good sense of who this person i.e., the patient is (1). Of course, the nature of history taking will vary depending upon the setting (i.e. primary care vs. a headache specialist), the physicians personal preferences and training, and the amount of time available. To assist in the rapid identication of patients with migraine in the primary care setting, a number of screening questionnaires have been developed. These questionnaires can be completed by the patient before his/her appointment, or in the examination room while waiting to be seen by his/her physician (see Chapter 12). As a follow-up to any of the headache questionnaires, the physician may make additional queries of the patient to conrm the diagnosis, as necessary, keeping in mind that while it is essential to exclude secondary disorders when determining diagnosis (see Chapter 11), a stable pattern of severe, recurrent, disabling primary headache is usually migraine. The Examination The general physical examination performed during the initial consultation for headache, should include at a minimum the following:  Vital signs  Cardiac status  Extracranial structures (sinuses, scalp, arteries, cervical paraspinal muscles, temporomandibular joints)  Thyroid  Range of motion and presence of pain in the cervical spine A screening neurologic examination capable of detecting most of the abnormal signs likely to occur in patients with headaches secondary to intracranial or systemic disease should include the following (7):          Signs of meningeal irritation (e.g., neck exion) The presence of bruits over the cranium, orbits, or neck Optic fundi, visual elds, and pupillary reactions Sensory function of the trigeminal nerve, including corneal reexes Motor power of the face and limbs Deep tendon reexes Plantar responses Gait Mental status

A complete examination includes appropriate evaluation of the patients mental status. A blunted, restricted, sad, or labile affect may indicate depression and anxiety. Evaluation for the presence of such disorders, including panic attacks, is

252

Husid and Rapoport

important because they are comorbid in many patients with chronic daily headache. Cognitive disturbance is suggested by intrusive obsessional thoughts, and the inability to concentrate or provide a good history. Patients with posttraumatic headache may show signicant decits in concentration and memory, and may also have difculty in performing complex tasks (1). Some simple tests can be useful in assessing cognitive tness, such as asking the patient to subtract serial 7s, spell ve-letter words forward and backward, or recall phone numbers. Screening for psychiatric comorbidity, particularly anxiety and depression, is important. Many centers use the Minnesota Multiphasic Personality Inventory (MMPI), the Hamilton Depression Scale, the Zung Anxiety and Depression scales, the Beck Inventory, or the Prime-MD (8). We routinely use the MMPI-2 for all new patients at our headache clinics, although other centers prefer briefer screenings. ASSESSING DISABILITY Pain is a subjective experience that is often difcult to express. Therefore, the greatest impact on diagnosis and treatment may come not from the patients description of pain intensity, location and characteristics, but from specic statements about function such as Doctor, these headaches are causing me to miss three or four days of work each month or My headaches dont allow me to care for my family several days a month (10). Assessment of the disability is therefore a crucial part of headache management. The treatment proposal of several guidelines is based on the disability status. The most widely used headache disability tools include the Migraine Disability Assessment questionnaire and the Headache Impact Test (HIT-6). Tools for assessing headache severity and comorbidity are discussed in detail in Chapter 13. EDUCATING PATIENTS
Migraine is helped a good deal by some old remedies like hope, encouragement, recognition, attention, ventilation, education, and reassurance. These remedies need to be dispensed at each visit, along with others. John Graham (11)

Taking the time to educate the headache patient is particularly important because migraine has so many potential aggravating factors that, with the proper knowledge, the patient can control. Patients should be encouraged to lead their lives at a reasonable rate with a comfortable, predictable rhythm. The benecial role of exercise and relaxation in mitigating headache should be stressed, and patients must be made aware of the correlation between certain activities such as skipping meals and not getting enough sleep and the physiologic responses that lead to triggering a migraine attack. Having patients keep a headache calendar enables them to track and eliminate these trigger behaviors. Table 1 lists the common headache triggers. Headache calendars will be reviewed in more detail later in this chapter. In addition, patients must be informed about the dangers of excessive use of pain medications. The most signicant causative factor in the production of

Principles of Headache Management Table 1 Potential Migraine Triggers Dietary Skipped/delayed meals Foods and Beverages Dairy Drugs Caffeine-containing beverages and medications Ilicit drugs Medications (cimetidine, danazol, diclofenac, digitalis, dipyridamole, disulram, H2 receptor blockers, hydralazine, indomethacin, nifedipine, nimodipine, nitrofurantoin, nitroglycerine, estrogen, reserpine, sildenal, tadalal, vardenal, etc.) Endogenous Stress

253

Other exogenous Environmental factors Bright or ickering light Loud noise

Changes in behavior Inconsistent sleep times

Cured meats Caffeine (and caffeine withdrawal) Alcoholic beverages, especially red wine

Sleeping more/less than usual Menstruation Fluctuation in hormonal levels (pregnancy, menopause)

Weather changes Strong odors Certain chemicals

Aspartame MSG Nitrites

Abbreviation: MSG, monosodium glutamate. Source: From Refs. 8, 1519.

Benzene Insecticides Nicotine

intractable headaches is the overuse of off-the-shelf medications, bultabital-containing medications, opiates, benzodiazepines, ergotamine tartrate, and occasionally even triptans. This condition was previously referred to as analgesic rebound headaches and, more recently, as medication overuse headache. Patients rarely respond adequately to preventive or acute-care medications or behavioral therapies until these agents have been withdrawn completely for a minimum of two months. As part of the educational process, the physician should also discuss the rationale for a particular treatment, how to use it, what adverse events are likely, what the expected benets are, and when the patient can expect to see them. All medications may cause adverse effects, and patients must be informed of those that occur most frequently. Patients are usually willing to tolerate some side effects as long as they know in advance what to expect, how long they will last, and when to call for help. Providing medication handout sheets, with details on benecial effects, adverse

254

Husid and Rapoport

effects, and warning signs that should trigger a call for medical attention, helps to reinforce verbal instructions. Starting patients on low doses of acute and preventive medications and increasing the dosage gradually helps to minimize adverse effects and enhances patient compliance. General Care During Pregnancy and Lactation Special instructions are warranted for women with migraine of childbearing potential. They should be warned not to become pregnant while taking headache medication. If they plan to become pregnant, they should be encouraged to schedule an appointment to discuss management of their migraines during pregnancy. They should also be instructed to take 1 mg of folate daily to reduce the incidence of neural tube defects, as should any woman of childbearing potential. If a woman plans to breastfeed her infant, a discussion is held prior to delivery on which drugs are and are not compatible, and how to take triptans when breastfeeding (12). ESTABLISHING REALISTIC EXPECTATIONS Addressing the patients expectations is fundamental to reaching a good outcome. Establishing realistic expectations by setting appropriate goals and discussing the expected benets of therapy and how long it will take to achieve them goes a long way in ensuring patient compliance. Ensure that the patient understands there are no magic remedies that will cure headaches forever (11). Although approximately 90% of patients with migraine can be helped substantially, our present incomplete understanding of the pathogenesis of migraine means there is no complete and permanent x (3). Therefore, a practical goal of migraine treatment is alleviation and control of pain and substantial reduction of disability, rather than complete elimination of pain (11). One should avoid making assumptions about what brought the patient to the clinic. Each patient is an individual with his or her own concerns, fears, questions, and expectations. Packard notes that while a number of factors may contribute to a poor outcome, frequently it occurs because the patients expectations were never properly claried or discussed, or they were not consistent with the physicians. In a 1979 survey of 100 headache patients presenting to a general neurology clinic, he found that while two-third of physicians thought patients primarily sought pain relief, the patients themselves reported they were more interested in having the causes of the pain explained to them (13). Dr. Rapoport suggests asking Why have you come for help at this time, and how would you like me to help you? You might be surprised when the patient says, I need a letter for my boss or my mother insisted I visit the doctor or I am worried my own physician missed a brain tumor. ENCOURAGING PATIENTS TO BECOME ACTIVE IN THEIR OWN CARE Closely related to educating patients and establishing expectations is the idea of encouraging patients to become active in their own care. The physician must encourage the patient to assume control of his or her own migraine management. If the patient is not willing to do most of the work, and insists on looking for the magic pill (despite the setting of realistic expectations), headache relief may be hard to achieve. Dr. Saper likes to tell such patients, Pills can take us a long way, but

Principles of Headache Management

255

cant ght your behaviors. And, Pills cant address that which you wont do for yourself. (11). If patients repeatedly fail to comply with suggested lifestyle changes, the physician should challenge the patients to determine their motivation for behaviors that treat their body with such disregard (10). Therefore, patients should fully understand that without their active participation, therapeutic failure is likely. Just as diabetics must take responsibility for monitoring blood sugar and maintaining an appropriate diet, so must headache patients take appropriate benecial measures. They must also take responsibility for not running out of medication, for calling at appropriate times, and for following a mutually agreed-upon treatment plan. When compliance issues are evident, it is important for patients and physicians to jointly review obstacles to compliance and discuss the means for getting around them (8).

HEADACHE CALENDARS Many physicians, including us, nd headache calendars essential for effective headache management. Calendars require self-monitoring of symptoms and medication intake, which automatically involves patients as active participants. In addition, the information provided is enlightening to both patient and physician. Figure 4 shows the blank calendar that we use for clinical purposes.

Figure 4 Patient headache calendar from The New England Center for Headache. Patients are asked to track the severity of each headache, medication intake, menstrual cycles, triggering events, and degree of relief from acute care medication on a calendar. The completed calendars are discussed with the patient at each revisit and form the basis for treatment decision.

256

Husid and Rapoport

On the calendar, patients write their names, the month, and the year in the appropriate places. They categorize their headache as mild1; moderate2; or severe3. Zero represents no headache on this 4-point scale familiar to headache experts throughout the world. Days of the month appear at the top of the form and are divided into morning, afternoon, evening, and sleep time. (Headaches reported during sleep mean that patients have been awakened from sleep by headache, and not the number of hours spent sleeping.) Medications are listed in spaces at the left side of the form. The bottom of the calendar is for recording degree of headache relief, triggers, and menstrual days. Potential trigger factors are listed on the back of the calendar. When properly completed, the calendar presents an at-a-glance picture of headache intensity, frequency, duration, response to acute treatment, and relationship between headaches and menses.

DEVELOPING AN APPROPRIATE, INDIVIDUALIZED TREATMENT PLAN Each patient is unique and their treatment plan should be individualized to take into account all facets of their disease process, other medical problems and treatments, their likes and dislikes, and their personality. We use gure 2 to record this information.

Schedule Regular Follow-Up Visits As with other chronic illnesses that are manageable, but not yet curable, regular follow-up visits are essential for successful long-term care (Fig. 5). Migraine usually occurs over many decades of the patients life. During this long period of time, it is not uncommon for the pattern of headaches (frequency, intensity, duration, symptomatology, and impact) to uctuate or change permanently, necessitating a change in the treatment plan. For example, preventive medications may be needed during periods of high attack frequency, but then can often be withdrawn after 6 to 12 months of good control.

WHY HEADACHE TREATMENT FAILS Acknowledging that management of patients with headache disorders is often difcult, Lipton and colleagues have summarized common reasons for treatment failure leading to referral to subspecialty headache centers, and grouped them into ve broad categories: (i) the diagnosis is incomplete or incorrect; (ii) important exacerbating factors have been missed; (iii) pharmacotherapy has been inadequate; (iv) nonpharmacologic treatment has been inadequate; and (v) other factors, including unrealistic expectations and comorbidity, exist. They freely share their combined decades of personal experience successfully managing these refractory patients by providing an orderly approach for us to follow. The authors acknowledge that while some patients will remain refractory, this is a relatively small minority, and conclude, Persistence in treating these patients can be very rewarding. (14) (see Chapter 32).

Principles of Headache Management

257

Figure 5 Revisit sheet.

CONCLUSION One of the most poignant, and all too frequent, experiences for anyone who sees patients with headache disorders is to have a patient describe how their life has been ruined by headachesthrough divorce, loss of jobs, and interference with family and

258

Husid and Rapoport

social responsibilitiesonly to learn that they have never been correctly diagnosed or appropriately managed. Many such patients in our practices come in for their rst revisit two to three weeks into therapy and tell us they are better than they have been in many years. Their elation over how much better they feel diminished by the realization of how different their lives could have been if they had only found someone who knew and cared earlier. Experiences like these, which demonstrate the ability to dramatically improve the lives of people with migraine, are what led many headache specialists to this eld.

REFERENCES
1. Sheftell FD. Approach to the patient with headache. In: Samuels MA, Feske S, Mesulam MM, Pessin MS, Preston DC, Rolak LA, Spierings ELH, Sudarsky LR, Wen P, eds. Ofce Practice of Neurology, 2nd ed. New York: Churchill Livingston, 2003. 2. Graham JR. The headache patient and the doctor. In: Adler CS, Adler SM, Packard RC, eds. Psychiatric Aspects of Headache. Baltimore: Williams and Wilkins, 1987:3440. 3. Raskin NH. Headache. 2nd ed. New York: Churchill Livingstone, 1988. 4. Silberstein SD for the US Headache Consortium. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review). Neurology 2000. 5. Pryse-Phillips WEM, Dodick DW, Edmeads JG, et al. Guidelines for the diagnosis and management of migraine in clinical practice. Can Med Assoc J 1997; 156:12731287. 6. Dowson AJ, Lipscombe S, Sender J, Rees T, Watson D on behalf of the MIPCA Migraine Guidelines Development Group. New Guidelines for the management of migraine in primary care. Curr Med Res Opin 2002; 18:414439. 7. Dowson AJ, Sender J, Lipscombe S, et al. Establishing principles for migraine management in primary care. Int J Clin Pract 2003; 57:493507. 8. Rapoport AM, Sheftell FD. Headache Disorders: A Management Guide for Practitioners. Philadelphia: W.B. Saunders, 1996. 9. Patten J. History-taking and physical examination. In: Patten J, ed. Neurological Differential Diagnosis. 2nd ed. London: Springer-Verlag, 1996:15. 10. South V, Sheftell F. Communicating with the patient. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache: And Other Head Pain. New York: Oxford University Press, 2001:599606. 11. Graham JR. Migraine: questions, theories, and answers. Neurol Clin 1983; 1:551566. 12. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. London: Martin Dunitz, 2002:257267. 13. Packard RC. Differing expectations of headache patients and their physicians. In: Adler CS, Adler SM, Packard RC, eds. Psychiatric Aspects of Headache. Baltimore: Williams & Wilkins, 1987:2933. 14. Lipton RB, Silberstein SD, Saper JR, Bigal ME, Goadsby PJ. Why headache treatment fails. Neurology 2003; 60:10641070.

FURTHER READING (PATIENT EDUCATION RESOURCES)

1. Rapoport AM, Sheftell FD, Tepper SJ. Conquering Headache: An Illustrated Guide to Understanding the Treatment and Control of Headache. 5th ed. Hamilton, London: Decker DTC, 2004. 2. Tepper SJ. Understanding Migraine and Other Headaches. Jackson: University Press of Mississippi, 2004.

Principles of Headache Management

259

3. Young WB, Silberstein SD. Migraine and Other Headaches. 1st ed. New York: AAN Press, 2004. 4. Livingstone I, Novak D. Breaking the Headache Cycle: A Proven Program for Treating and Preventing Recurring Headaches. 1st ed. New York: Henry Holt, 2003. 5. Saper JR, Magee KR. Freedom from Headaches. 2nd ed. New York: Fireside, 1981.

260

Husid and Rapoport

APPENDIX 1 In 2003, an international advisory board of headache specialists reviewed published guidelines for the management of migraine in primary care and agreed on the following 12 evidence-based principles (11): 1. Understand that almost all headaches are benign/primary and can be managed by all practicing clinicians. 2. Use questions/a questionnaire to assess the impact of headache on daily living and everyday activities, for diagnostic screening and to aid management decisions. 3. Share migraine management between the clinician and the patient. 4. Provide individualized care for migraine and encourage patients to manage their own migraine. 5. Follow-up patients, preferably with migraine calendars or diaries. 6. Reevaluate the success of therapy regularly using specic outcome measures and monitor the use of acute and preventive medications. 7. Adapt migraine management to changes that occur in the illness and its presentation over the years. 8. Provide migraine specic acute medication to all migraine patients and recommend they be taken at the appropriate time during the attack (early, when pain is mild). 9. Provide rescue medication/symptomatic treatment for when the initial therapy fails. 10. Offer to prescribe preventive medications, as well as suggesting lifestyle changes, to patients who have four or more migraine attacks per month, who are resistant to acute medications or cannot take them due to contraindications, or who have very disabling migraines, even if the pain is controlled by acute care medication. 11. Consider the patients comorbid illnesses in the choice of appropriate preventive medications. 12. Work with patients to achieve comfort with mutually agreed upon treatment and ensure that it is practical for their lifestyle and headache presentation.

19
Behavioral and Educational Approaches to the Management of Migraine: Clinical and Public Health Applications
Kenneth A. Holroyd
Psychology Department, Ohio University, Athens, Ohio, U.S.A.

INTRODUCTION This chapter provides an overview of behavioral and educational interventions for the management of migraine. Behavioral treatments and the clinic and home-study formats for administering these treatments are described rst. Next, a brief overview of the evidence base that supports the effectiveness of behavior therapy for adult and pediatric migraine is provided. Educational interventions to improve the response of the health-care system to migraine are then described. Finally, programs for teaching behavioral migraine management skills in community institutions such as schools and the workplace, and via mass media such as the Internet and television are described. It is argued that community interventions can play a signicant role in a public health approach to the secondary prevention of chronic headache disorders.

BEHAVIORAL INTERVENTIONS Behavioral interventions focus on the prevention of headaches, although behavioral headache management skills also may be used to abort headaches and to cope with headaches that do occur. The goals of behavioral treatment are to increase personal control over headaches, reduce the frequency and severity of headaches, and reduce headacherelated disability and affective distress, as well as to limit reliance on poorly tolerated or unwanted pharmacotherapy. Relaxation Training Relaxation skills (1) enable headache sufferers to exert control over specic headache-related physiological responses and to lower physiological and mental

261

262

Holroyd

arousal. Patients are instructed to practice a graduated hierarchy of relaxation techniques (diaphragmatic breathing, progressive muscle relaxation, relaxation imagery, and meditation) initially for 20 to 30 min/day; then, as they are able to master increasingly brief relaxation techniques (cue-controlled relaxation and self-control relaxation), to relax briey (e.g., for 30 seconds) throughout the day, and whenever they notice mental or bodily signs of tension or signs signaling headache onset. Biofeedback Training Thermal (hand warming) feedback, feedback of skin temperature from a nger, and electromyographic (EMG) feedback, feedback of electrical activity from muscles of the scalp, neck, and sometimes the upper body, are the most commonly used biofeedback modalities, although electroencephalographic (neurofeedback) biofeedback with the goal of teaching self-regulation of cortical excitability has received recent attention (2). Patients are instructed to use a home biofeedback-training device or to practice the self-regulation skills they are learning during clinic-based biofeedback training sessions for about 20 to 30 min/day, and, as they master the physiological self-regulation skills, they are encouraged to integrate their use of self-regulation skills into their daily routine in the same manner as described above for relaxation skills. Cognitive-Behavior (Stress Management) Therapy Cognitive-behavior therapy addresses cognitive and affective variables that may increase vulnerability to headaches and precipitate headaches, and are components or consequences of headache (35). Cognitive behavioral interventions direct patients attention to the role their thoughts and behavior play in generating stress (and stress-related headaches), and in increasing headache-related disability. Patients monitor the circumstances in which their headaches occur, including their bodily sensations, thoughts, and feelings prior to the onset of headaches. Once headache-related stressful situations are identied, the patient and counselor collaboratively identify and challenge dysfunctional cognitions. Cognitive targets may be stress-generating thoughts or an underlying belief or assumption that distills the common meaning or theme from many stress-generating thoughts. The goal is to teach patients to catch stress-generating thoughts, thereby controlling stress and other negative effects, and to render the patient less vulnerable to stress-related negative effect. Integration of Treatment Techniques Typically, the above three treatments are not used in isolation, but as components of an intervention for teaching the self-management of headaches (4). Additional treatment components include (i) education about headaches and the principles of behavioral migraine management, (ii) exercises to assist the patient in identifying migraine triggers and early migraine warning signs, (iii) instruction on how to evaluate the effectiveness of, and to most effectively use, migraine medications, (iv) pain-coping strategies for living with migraine that continues to occur, and (v) the

Behavioral and Educational Approaches to the Management of Migraine

263

development of a migraine management plan, including a plan for coping with any reoccurrence of headaches following treatment. See Lipchik et al. (4) for a more detailed treatment description.

TREATMENT DELIVERY Treatment can be administered either individually or in a group, and can be administered in a clinic-based (clinician-administered) treatment format, or in a home-based treatment format that involves more limited face-to-face clinician contact, or, in some instances, only phone contact with a clinician.

Clinic-Based Treatment Clinic-based treatment typically involves 6 to 12 weekly sessions, 45 to 60 minutes in length, if treatment is administered individually, and 60 to 120 minutes in length, if treatment is administered in a group. This treatment format provides more health careprovider time and attention, and allows the provider greater opportunity to directly observe the patient than a home-based treatment format, but requires more frequent clinic visits. Descriptions of clinic-based treatment are available in Blanchard and Andrasik (5) for individual treatment, and Scharff and Marcus (6) for group treatment.

Home-Based Treatment Home-based treatment typically involves only three to four (monthly) treatment sessions. Clinic visits introduce each new headache management skill and address problems encountered in acquiring or implementing these skills. The learning of migraine management skills occurs primarily at home and is guided by patient manuals and audiotapes. Monthly phone calls allow the clinician to address problems that arise in home-based learning and in the application of headache management skills. Home-based and clinic-based treatment formats have yielded similar outcomes when compared directly (79) or when compared via a metaanalysis of 13 studies (10). Lipchik et al. (4) and Blanchard and Andrasik (5) provide detailed descriptions of limited-contact treatment. In a logical extension of the above home-based treatment format, three successful trials (1113) have entirely eliminated clinic visits, substituting weekly phone calls for the mix of monthly clinic visits and phone calls described above. In two trials with adolescents, home-study programs used workbooks and audiotapes (11,12) in the third trial, with younger children (712 years old), an interactive computer programguided home study was followed (13). Telephone supervision of a home-study program has the potential to greatly increase the availability of behavioral treatment because neither clinic visits nor a local behaviorally trained clinician is required. However, home study requires a motivated patient, and, for children and adolescents, a supportive home environment (11). Information is needed about appropriate candidates for home study, and about the optimal design of home-study programs.

264

Holroyd

EFFICACY Adults Evidence reviews prepared by Duke Universitys Center for Clinical Health Policy Research examined the efcacy of behavioral, physical, and pharmacological treatments for migraine in adults, reviewing 70 trials and including 39 trials in a meta-analysis (14). Figure 1 presents both the estimated effect size and the percentage reduction in migraine for four widely used psychological treatments. It can be seen that each behavioral intervention produces moderate reductions in migraine activity. The U.S. Headache Consortium clinical guidelines for the management of migraine (15,16) drew primarily on this evidence report in concluding Relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and cognitive-behavioral therapy may be considered as treatment options for the prevention of migraine.

Figure 1 Effect size with 95% condence interval (top axis) and percent reduction in migraine (bottom axis). Abbreviations: CBT, cognitive-behavior therapy; EMG-BF, electromyographic biofeedback training; TBF RLX, thermal biofeedback training plus relaxation training; RLX, relaxation training; control, headache-monitoring control. Source: From Ref. 14.

Behavioral and Educational Approaches to the Management of Migraine

265

Figure 2 Within group effect sizes (outliers removed) with 95% condence interval. Abbreviations: TBF, thermal biofeedback training; RLX, relaxation training; CBT, cognitive-behavior therapy. Source: From Ref. 18.

Pediatric Migraine in children and adolescents appears to be more responsive to behavioral treatment than migraine in adults. A comparison of thermal biofeedback training results from four pediatric (N 49) and six adult (N 103) trials indicated that children achieved greater control of hand temperature (5.5% vs. 3.9% increase) and larger reductions in migraine activity (62% vs. 34% decrease, p < 0.02) than adults (17). Figure 2 presents results from a meta-analysis of 17 trials of behavioral treatments in pediatric migraine (18). Although the mean effect sizes in Figure 2 do not translate directly into equivalent headache improvement values, an effect size of 1 or greater can be considered clinically signicant. To illustrate, for one study (12), an effect size of about two corresponds to 66% of adolescents showing clinically signicant (50% or more) reductions in migraine, and an effect size of about one corresponds to 44% of adolescents showing clinically signicant reductions in migraine.

INTEGRATING DRUG AND BEHAVIORAL TREATMENTS Adults In the absence of trials that directly compare the effectiveness of drug and behavioral therapies, meta-analysis provides the best method of comparing the effectiveness of these two treatment modalities. Holroyd et al. (19) compared results reported in 25 preventive drug (propranolol) therapy trials and in 35 thermal biofeedback/relaxation trials that included over 2400 patients. Nearly identical outcomes were reported with propranolol and thermal biofeedback training: each treatment yielded, on an average, a 44% reduction in migraine activity when daily diaries were used as the outcome measure, whereas (pill) placebo yielded only a 14% reduction in migraine activity. Because propranolol provides a good proxy for the effectiveness of

266

Holroyd

preventive medication in general (1923), these results suggest that relaxation/ thermal biofeedback and preventive medication are about equally effective in the management of episodic migraine. Two trials that examined the benets of adding propranolol (60 mg to either 120 or 180 mg/day) to relaxation/biofeedback therapy found that propranolol signicantly enhanced the effectiveness of relaxation/biofeedback training (24,25). However, in one of these trials (25), propranolol was more effective than relaxation/biofeedback training, and about as effective as the combined treatment, though the high dropout rate from biofeedback training alone (38% of patients) raises the possibility that outcomes in this trial were compromised because of poor patient compliance (26). Pediatric Current clinical guidelines for drug therapy in pediatric migraine (27) conclude that there is inadequate data to judge the effectiveness of available preventive medications for pediatric migraine, with the exception of unarizine (not available in the United States). In contrast, a similar evidence-based review of behavioral therapies concluded that there is adequate data to indicate relaxation training is effective and thermal biofeedback training is probably effective for pediatric migraine (28). Only two trials have directly compared behavioral and preventive drug therapies for pediatric migraine and both trials found behavior therapy, but not preventive drug therapy, effective in controlling migraines. One trial with children (mean 11 years) (29) found a 12-session relaxation/stress-management treatment more effective than metoprolol (50100 mg/day); 80% of children who received relaxation/stress management, but only 42% of children who received metoprolol, recorded clinically signicant reductions (50% or more) in migraine. A second trial with children (612 years old) (30) found relaxation training with self-hypnosis more effective in reducing migraines than propranolol (3 mg/kg/day) or placebo; propranolol and placebo did not differ in effectiveness. Little information about the effectiveness of preventive drug therapies for pediatric migraine is available, and even less information is available about the relative effectiveness or combined effects of drug and behavior therapies. However, available evidence suggests that behavior therapy may be at least as effective as drug therapy for pediatric migraine. Given the lack of side effects associated with behavior therapy, and current concerns about long-term preventive drug therapy in children and adolescents, behavior therapy, including relaxation/thermal biofeedback training, should be a rst-line treatment for pediatric migraine.

EDUCATION FOR SELF-MANAGEMENT Educational interventions designed to help individuals manage chronic diseases such as arthritis, asthma, and diabetes, and chronic conditions such as low back pain, have been effective in reducing symptoms, disability, and, in some cases, medical costs (3135). However, education for self-management has largely been ignored in the headache literature, possibly because migraine is not commonly recognized as a chronic disease. Fortunately, three recent cohort studies (N 54497) have evaluated the implementation of group headache education programs in staff model health maintenance

Behavioral and Educational Approaches to the Management of Migraine

267

organization (HMO) settings (3638). In each case, a one-session group headache education program (e.g., types of headaches, pathophysiology, headache recording, medical management, triggers, and aggravating factors) that also provided opportunity for participant-initiated discussion was integrated with an individual treatmentplanning visit. The three education programs varied in the attention devoted to behavioral change (e.g., stress management), and in the degree the education program was integrated with other HMO services. In each study, implementation of the headache education program was associated with improvements in headache-related disability (severe headaches or standard measures of disability) and reductions in the number of headache-related emergency department visits (3479%; M 54%). Reduced headache-related visits (36,38), net cost savings (36), and improved satisfaction with headache care (38) also were reported. Consistent ndings across three different HMO settings suggests even a brief, well-designed headache education program can improve the response of the HMO environment to migraine; further, controlled effectiveness studies of headache education are needed. In the single randomized trial to date (39), 100 consecutive patients at a university-based headache clinic were randomized to medical treatment by a headache specialist, or medical treatment plus group headache education. Three 90-minute headache education classes (didactic instruction about migraines and migraine treatment, plus opportunity for discussion) were coled by individuals with migraine who had received leadership training. Participants experienced primarily chronic (15 day/mo or more) migraine, transformed migraine, and/or medication overuse headache. At a six-month evaluation, group education produced signicantly greater improvements in headaches and headache-related disability than medical treatment alone. Group education also was associated with less acute medication use, better medication compliance, fewer unscheduled headache clinic visits, and fewer physician phone calls than medical treatment alone. These results provide a strong argument for the further development and evaluation of educational interventions to facilitate self-management of chronic headaches. Fundamental to the notion of education for self-management is the observation that it is the individual who must solve problems that arise in managing and in adapting to their chronic disease in specic daily life situations (40). Guided by social learning theory (41,42), current self-management interventions seek to foster condence in the application of both specic disease management skills and general problem-solving skills (31,43,44). In designing future educational interventions, it is recommended that investigators draw on theoretical guidance from social learning theory and on the body of experience that has been obtained implementing selfmanagement programs for other chronic diseases.

COMMUNITY APPLICATIONS Programs for teaching behavioral migraine management skills in the community have the potential to play an important role in a public health approach to migraine. Community interventions have the potential to reach the 50% of individuals with migraine who do not seek conventional medical treatment (45,46). Moreover, by enabling individuals to acquire behavioral migraine management skills early in the course of their migraines, community interventions may also play a role in the secondary prevention of chronic headache disorders, including transformed migraine and medication overuse headache.

268

Holroyd

School Larsson et al. have taught relaxation skills for the management of headaches in secondary schools in Uppsala, Sweden for 20 years. A summary of the seven relaxation-training trials (N 228; age 1018 years) (47) revealed that clinically signicant (50% or more) improvements in migraine were obtained in about half (52%) of the students who participated in a 6- to 10-session, therapist-administered, group relaxationtraining program; follow-up data further indicated improvements were maintained for at least 6 to 10 months (47). Unfortunately, neither a relaxationtraining program conducted by a school nurse, nor a self-help relaxationtraining program that included a relaxation manual and audiotapes of relaxation instructions proved similarly effective (only 13% and 17% of students clinically improved, respectively); in fact, neither school nurseadministered nor self-help relaxation training programs were more effective than psychological placebo, or simply having students record their headaches. This nding is echoed by the second research group, who found that relaxation training conducted by school gym instructors was similarly ineffective (48). School-based group relaxation trainingat least when administered by a behaviorally trained clinicianappears effective in managing migraines for many adolescents. Methods of teaching school personnel the clinical skills necessary to effectively administer relaxation training will be needed if behavioral headache management programs are to be offered to the large number of adolescents with recurrent headaches in the school setting. Worksite Worksite interventions have received little empirical attention. This is surprising, given that lost productivity costs due to headache are estimated at $20 billion in the United States (49), and health promotion programs capable of offering programs for headache management are available in many corporations. The Managing Headache in the Workplace Program consists of an informational slide show, neurologist-led small group discussion session, and written handouts. At a one-month follow-up evaluation completed by 75% (of 492) program participants in both ofce and factory settings, an increased use of behavioral headache management skills, such as keeping a headache diary (11% of participants at baseline vs. 40% at follow-up), breathing/relaxation exercises (19% vs. 34% of participants), and regular exercise (20% vs. 39% of participants) were reported. This was accompanied by signicant reductions in headache-related disability on standard disability measures. Schneider et al. (50) used multimedia touch screen computer kiosks to deliver a headache management program at J.P. Morgan ofces in both New York and Delaware. The program provided individualized summaries of headache information (e.g., likely triggers, aggravating factors, and modied diagnosis based on a computer algorithm), and, at the New York sites, also provided generic information on headache management (e.g., biofeedback, coping with headaches, and communicating with physicians) and access to an onsite neurologist. Data from users (N 177) at a three-month follow-up indicated small but statistically signicant reductions in headache days (5.54 headache days per month), but more impressive reductions in the number of visits to the urgent-care/emergency department for headache (1.740.42 visits in six months). Unfortunately, high attrition (51%) between the baseline and follow-up assessments compromised this evaluation.

Behavioral and Educational Approaches to the Management of Migraine

269

These pilot studies raise the possibility that relatively simple on-site or Web-based behavioral migraine management education programs, possibly offered as a part of an ongoing worksite health promotion program, could produce signicant benets for both the employee and the employer. Controlled trials of worksite headache management interventions are clearly needed.

Internet Initial efforts to teach behavioral headache management skills via the Internet have been modestly effective, but plagued by high (up to 50%) drop out rates, even when telephone contact has been added to reduce drop outs (5154). The best study to date (53) randomized 156 participants from more than 10 countries (who reported a physician diagnosis of either migraine or tension-type headache) to either Internet-based treatment or a delayed treatment control group. The online program (downloadable treatment manual and audio les and e-mail communication with a behavioral clinician) was adapted from muscle relaxation and hand-warming materials successfully used in earlier ofine home-based migraine treatment studies (55). Almost 40% of users who completed the migraine management program, but only 6% of controls, recorded clinically signicant (50% or more) reductions in migraine activity. However, over 40% of participants failed to complete the program. Dropouts reported less severe headaches, smaller improvements, and fewer (2.3 vs. 3.8) years of computer experience, than those who completed treatment. Initial Internet-based behavioral migraine management programs have yielded modest results, particularly when program dropouts are taken into account. However, these programs have demonstrated that Internet-based treatment does enable some users to effectively manage their migraines. The primary beneciary of rst-generation Internet programs has probably been the highly motivated, computer-literate user, with uncomplicated headache problems. However, initial programs have not made use of the full capabilities of the Internet, for example, the capability to provide support (e.g., chat rooms) (56) or to tailor treatment to the users learning style and progress in the program. Second-generation programs undoubtedly will make more sophisticated use of these capabilities. It is important to identify who learns behavioral migraine management skills via the Internet and to assure that Internet treatment failure does not discourage participants from seeking future treatment.

Television A series of television programs in the Netherlands on managing headaches best illustrates population-based behavioral headache management (57). Approximately 15,000 participants purchased home-study materials (workbook and three audio cassettes) that presented a variety of relaxation and cognitive behavioral skills for managing headaches. One TV program was devoted to teaching each headache management skill; in addition, 10 accompanying radio programs provided an opportunity for participants to hear solutions to representative problems encountered by other program participants. Unfortunately, the outcome was assessed in only a small sample (N 271) of participants; nonetheless, the 164 participants who completed the program evaluation recorded, on an average, a 50% average reduction in the frequency of headaches, and a reduction of about 4.5 days of lost work-time over four months. The strong public interest in this program, and the preliminary

270

Holroyd

positive-outcome data raise the possibility that behavioral headache management skills can be effectively taught to a large audience via the mass media. CONCLUSION Migraine is a lifetime disorder for many, and in some individuals, progressive in form. Recent ndings indicating that more severe and chronic forms of the disorder may be associated not only with neuroplastic changes in pain transmission/modulation circuits but also with worrisome neurodegenerative change have drawn attention to a long ignored topicprevention. It has been argued here that behavioral and educational interventions have a signicant role to play in a comprehensive approach to the clinical management of migraine, and will play a central role in any public health approach to the secondary prevention of the chronic and severe forms of migraine that are of growing concern. ACKNOWLEDGMENTS Support for this review was provided, in part, by a grant from The National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS # NS32374). Figure 2 was prepared by Kathleen Romanek. Jana Drew provided comments on an earlier draft of this manuscript. REFERENCES
1. Bernstein DA, Borkovec TD, Hazlett-Stevens H. New Directions in Progressive Relaxation Training: A Guidebook for Helping Professions. Westport, CT: Praeger, 2000. 2. Schwartz MS, Andrasik F. Biofeedback: A Practitioners Guide. New York: Guilford Press, 2003. 3. Holroyd KA, Lipchik GL, Penzien DB. Behavioral management of recurrent headache disorders. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache and Other Headache Pain. New York, NY: Oxford University Press, 2001:562598. 4. Lipchik GL, Holroyd KA, Nash JM. Cognitive-behavioral management of recurrent headache disorders: a minimal-therapist contact approach. In: Turk DC, Gatchel RS, eds. Psychological Approaches to Pain Management. New York: Guilford Pubs, 2002:356389. 5. Blanchard EB, Andrasik F. Management of Chronic Headaches: A Psychological Approach. Elmsford, NY: Pergamon Press, 1985. 6. Scharff L, Marcus DA. Interdisciplinary outpatient group treatment of intractable headache. Headache 1994; 34:7378. 7. Richardson GM, McGrath PJ. Cognitive-behavioral therapy for migraine headaches: a minimal-therapist-contact approach versus a clinic-based approach. Headache 1989; 29:352357. 8. Teders SJ, Blanchard EB, Andrasik F, Jurish SE, Neff DF, Arena JG. Relaxation training for tension headache: comparative efcacy and cost-effectiveness of a minimal therapist contact versus a therapist delivered procedure. Behav Ther 1984; 15:5970. 9. Jurish SE, Blanchard EB, Andrasik F, Teders SJ, Neff DF, Arena JG. Home- versus clinic-based treatment of vascular headache. J Consult Clin Psychol 1983; 51:743751. 10. Haddock CK, Rowan AB, Andrasik F, Wilson PG, Talcott GW, Stein RJ. Home-based behavioral treatments for chronic benign headache: a meta-analysis of controlled trials. Cephalalgia 1997; 17:113118.

Behavioral and Educational Approaches to the Management of Migraine

271

11. Cottrell C, Drew J, Gibson J, Holroyd K, ODonnell F. Telephone administered behavioral treatment of adolescent migraine: a feasibility study. Headache. In press. 12. McGrath PJ, Humphreys P, Keene D, et al. The efcacy and efciency of a selfadministered treatment for adolescent migraine. Pain 1992; 49:321324. 13. Connelly M, Rapoff M, Thompson N, Connely W. Headstrong: a pilot study of a CDROM Intervention for recurrent pediatric headache. J Pediat Psychol 2005. 14. Goslin R, Gray R, McCrory D. Behavioral and Physical Treatments for Migraine Headache. Technical Review 2.2. Vol. 2003. Duke Center for Health Policy Research (prepared for Agency for Health Care Policy and Research), 1999. 15. Silberstein S, Rosenberg J. Multispecialty consensus on diagnosis and treatment of headache. Neurology 2000; 54:15531554. 16. Campbell JK, Penzien DB, Wall EM. Evidence-Based Guidelines for Migraine Headache: Behavioral and Physical Treatments. : US Headache Consortium, 2000:Vol. 2001. 17. Sarano E, Goehring P. Age comparisons in acquiring biofeedback control and success in reducing headache pain. Ann Behav Med 2000; 22:1016. 18. Hermann C, Kim M, Blanchard EB. Behavioral and pharmacological intervention studies of pediatric migraine: an exploratory meta-analysis. Pain 1995; 60:239256. 19. Holroyd KA, Penzien DD, Cordingley G. Propranolol in the management of recurrent migraine: a meta-analytic review. Headache 1991; 31:333340. 20. Diener H-C, Tfelt-Hansen P, Dahlof C, et al. Topiramate in migraine prophylaxis: results from a placebo-controlled trial with pronalolol as an active control. J Neurol 2004; 251:943950. 21. Ziegler D, Hurwizt A, Preskorn S, Hassanein R, Seim J. Propanolol and amitriptyline in prophylaxis of migraine. Arch Neurol 1993; 50:825830. 22. Solomon G. Verapamil and propanolol in migraine prophylaxis: a double-blind, crossover study. Headache 1986; 20:325. 23. Kaniecki R. A comparison of divalproex with pronanolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 1997; 54:11411145. 24. Holroyd KA, France JL, Cordingley GE, et al. Enhancing the effectiveness of relaxation/thermal biofeedback training with propranolol HCI. J Consult Clin Psychol 1995; 63:327330. 25. Mathew NT. Prophylaxis of migraine and mixed headache: a randomized controlled study. Headache 1981; 21:105109. 26. Holroyd KA. Assessment and psychological treatment of recurrent headache disorders. J Consult Clin Psychol 2002; 70:656677. 27. Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. Practice parameter: pharmacological treatment of migraine headache in children and adolescents. Neurology 2004; 63:221524. 28. Holden EW, Deichmann MM, Levy JD. Empirically supported treatments in pediatric psychology: recurrent pediatric headache. J Pediat Psychol 1999; 24:91109. 29. Sartory GM, Muller B, Metsch J, Pothmann R. A comparison of psychological and pharmacological treatment of pediatric migraine. Beh Res Ther 1998; 36:11551170. 30. Olness K, MacDonald JT, Uden DL. Comparison of self-hypnosis and propranolol in the treatment of juvenile migraine. Pediatrics 1987; 79:593597. 31. Lorig K, Holman H. Self-management education: history, denition, outcomes, and mechanisms. Ann Behav Med 2003; 26:17. 32. Bodenheimer T, Lorig K, Holman H, Grumbach K. Patient self management of chronic disease in primary care. JAMA 2002; 288:24692475. 33. Von Korff M, Gruman J, Schaefer J, Curry SJ, Wagner EH. Collaborative management of chronic illness. Ann Intern Med 1997; 127:10971102. 34. Lorig K, Sobel D, Ritter P, Laurent D, Hobbs M. Effect of a self-management program on patients with chronic disease. Eff Clin Pract 2001; 4:256262. 35. Newman S, Steed L, Mulligan K. Self-management interventions for chronic illness. Lancet 2004; 364:15231537.

272

Holroyd

36. Maizels M, Saenz V, Wirjo J. Impact of a group-based model of disease management for headache. Headache 2003; 43:621627. 37. Harpole L, Samsa G, Jurgelski A, Shipley J, Bernstein A, Matchar D. Headache management program improves outcome for chronic headache. Headache 2003; 43:715724. 38. Blumenfeld A, Tischio M. Center of excellence for headache care: group model at Kaiser Permanente. Headache 2003; 403:431440. 39. Rothrock J, Parada V, Sims C, Key K, Walters N, Zweier R. The impact of Intensive patient education on clinical outcome in a clinic-based migraine population. Headache (in press). 40. Holroyd KA, Creer T. Self-management of Chronic Disease: Handbook of Clinical Interventions and Research. New York: Academic Press, 1986. 41. Bandura A. Self-efcacy: The Exercise of Control. New York: W.H. Freeman, 1997. 42. Tobin D, Reynolds R, Holroyd K, Creer T. Self-management and social learning theory. In: Holroyd K, Creer T, eds. Self-Management of Chronic Disease: Handbook of Clinical Interventions and Research. New York: Academic Press, 1986. 43. Lorig K. The integration of theory with practice: a 12-year case study. Health Educ Q 1992; 19:355368. 44. Marks R, Allegrante J, Lorig K. A review and synthesis of research evidence for self-efcacy-enhancing interventions for reducing chronic disability: implications for health education practice. Health Promote Pract 2005; 6:3743. 45. Lipton R, Diamond S, Reed M, Diamond M, Stewart W. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001; 41:638645. 46. Brandes J. Global trends in migraine care: results from the MAZE survey. CNS Drugs 2002; 16:1318. 47. Larsson BM, Carlsson J, Fichtel A, Melin L. Relaxation treatment of adolescent headache sufferers: results from a school based replication series. Headache 2005; 45:692701. 48. Passchier J, Van den Bree MBM, Emmen HH, Osterhaus SOL, Orlebeke JF, Verhage F. Relaxation training in school classes does not reduce headache complaints. Headache 1990; 30:660664. 49. Stewart W, Ricci JA, Chee E, Morganstein M, Lipton R. Lost Productive time and cost due to common pain conditions in the U.S. workforce. JAMA 2003; 290:24432454. 50. Schneider WJ, Furth PA, Blalock TH, Sherrill TA. A pilot study of a headache program in the workplace. J Occup Environ Med 1999; 41:868871. 51. Strom L, Peterson R, Andersson G. A controlled trial of self-help treatment of recurrent headache conducted via the Internet. J Consult Clin Psychol 2000; 68:722727. 52. Andersson G, Lundstom P, Strom L. A controlled trial of self-help treatment of recurrent headache conducted via the Internet. Headache 2003; 43:353361. 53. Devineni T, Blanchard E. A randomized controlled trial of an internet-based treatment for chronic headache. Beh Res Ther 2005; 43:277292. 54. Hicks C, von Baeyer C, McGrath P. Online psychological treatment for pediatric recurrent pain: a randomized evaluation. J Pediat Psychol (in press). 55. Blanchard EB, Andrasik F, Appelbaum KA, et al. The efcacy and cost-effectiveness of minimal-therapist-contact, non-drug treatments of chronic migraine and tension headache. Headache 1985; 25:214220. 56. Lorig K, Laurent D, Deyo R, Marnell M, Minor M, Ritter P. Can a back pain e-mail discussion group improve health status and lower health care costs? A randomized study. Ann Intern Med 2002; 162:792796. 57. de Bruin-Kofman AT, van de Wiel H, Groenman NH, Sorbi MJ, Klip E. Effects of a mass media behavioral treatment for chronic headache: a pilot study. Headache 1997; 37:415420.

20
Nonspecic Migraine Acute Treatment
Abouch Krymchantowski
Outpatient Headache Unit, Instituto de Neurologia, and Deolindo Couto, Headache Center of Rio, Rio de Janeiro, Brazil

Stewart J. Tepper
The New England Center for Headache, Stamford, and Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

INTRODUCTION The objective of acute migraine therapy is to restore the patient to normal function by rapidly and consistently alleviating the head pain and the associated symptoms of nausea, vomiting, and sensory phobias, ideally without side effects and recurrence of the attack within 24 hours (1). Several drug options and different formulations are available to treat migraine acutely. Acute migraine treatments are often divided into specic and nonspecic categories. Migraine-specic medications, such as the triptans and ergots, relieve migraine but are generally ineffective on noncephalic pain. Nonspecic agents are effective across a broad range of pain disorders not linked to migraine. The choice of a medication for migraine depends on individual characteristics such as headache intensity, speed of onset, presence of associated symptoms, the degree of incapacitation (disability or impact), and the patients response (2,3). The nonspecic treatments for migraine attacks are the subject of this chapter. Examples are aspirin, acetaminophen (APAP) (and other simple analgesics), nonsteroidal anti-inammatory drugs (NSAIDs), neuroleptics, opioids, and combination analgesics. These combinations often include caffeine, short-acting barbiturates, and other pharmacological agents. In addition, the use of drugs that target other symptoms besides pain (such as nausea) has been suggested for treating migraine attacks as well. It may be argued whether it is still valid to suggest beginning acute treatment of migraine with nonspecic migraine medications in the era of the triptans. However, triptan monotherapy, especially when administered orally, does not always result in rapid, consistent, and complete relief of all migraine attacks as desired by patients (4). In addition, the efcacy of some nonspecic migraine agents, such as various NSAIDs, has been demonstrated in many trials (5). Therefore, to study these compounds is necessary to analyze their efcacy in relation to specic medications, the
273

274

Krymchantowski and Tepper

possibility of increasing the treatment efcacy by combining more than one drug, and the appropriate strategy for selecting acute migraine medication to maximize the likelihood of getting to the right treatment the rst time.

SIMPLE ANALGESICS The efcacy of acetylsalicylic acid (ASA) and APAP (called paracetamol in some countries) is well established in the acute treatment of migraine. Dipyrone (not available in the United States but widely used worldwide) was also proven effective for migraine attacks (6). Aspirin Although ASA has anti-inammatory activity and antinociceptive properties, it is generally grouped with the analgesics. ASA has been studied in tablet form (doses ranging from 500 to 1000 mg) and also intravenously. It is worth remembering that standardized migraine trial designs were rst established in the early 1990s, after most of the studies on ASA were conducted. Nonetheless, a few studies with ASA are worthy of evaluation in migraine. In 1980, Tfelt-Hansen and Olesen demonstrated that 1000 mg of ASA was as effective as 1000 mg of APAP in treatment of migraine (7). In several controlled trials, ASA was compared to other oral nonspecic antimigraine preparations, such as APAP plus codeine, or ergot alkaloids. Overall, the efcacies were comparable, but due to the differences with regard to dosages and formulations, the various study results remain comparatively inconclusive (8). Several recent studies showed that oral aspirin is more effective than placebo in the treatment of migraine and associated symptoms (9,10). Two randomized controlled studies compared 100 mg sumatriptan with 900 mg ASA plus 10 mg metoclopramide (MCP). In the rst study, patients were instructed to wait until they had moderate to severe pain, and then treat three attacks, and the primary end point was pain relief (also called headache response or headache relief) (moderate to severe pain was reduced to mild or no pain within two hours of treatment) at two hours. In the rst attack, headache relief occurred in 45% of the patients taking ASA/MCP compared to 56% of those taking sumatriptan, a data not statistically signicant. In the second and third attacks, sumatriptan 100 mg was superior to ASA/MCP. Recurrence over 48 hours was higher with sumatriptan than ASA/MCP (42% vs. 33%). No information on four-hour relief or pain-free results was published, but six-hour complete relief (migraine free) was higher for sumatriptan in all three attacks (11). The second study was a comparison of lysine ASA 900 mg (LASA, not available in the United States) plus 10 mg MCP versus sumatriptan 100 mg over two attacks. The primary end point was headache relief at two hours after treating moderate to severe pain in the rst attack. There was no signicant difference between the LASA/MCP and the sumatriptan, this time for either attack. Migraine free at two hours and recurrence over 24 hours were statistically the same for LASA/ MCP and sumatriptan. As with the previous study, four-hour headache relief and pain-free data were not published (12). In the mid-1970s, an injectable form of lysine ASA became available in some countries for various pain conditions (not available in the United States). It was studied

Nonspecic Migraine Acute Treatment

275

for migraine attacks and proved to be superior to placebo, as effective as nonoral ergotamine, and less effective but better tolerated than subcutaneous sumatriptan (13). The U.S. Headache Consortium guidelines have suggested that aspirin/APAP/ caffeine (AAC) is effective for moderate-level migraine (14). Most studies taken into consideration enrolled patients with less severe, less disabling migraine attacks, a population of migraineurs for whom over-the-counter (OTC) medications were appropriate (15). In three large-scale placebo-controlled studies, 1220 patients either with migraine without aura or migraine with aura were preselected as efcacyevaluable subjects. Among them, 172 patients suffering from migraine, but not vomiting during more than 20% of their attacks and not presenting severe attackrelated disability (requiring bed rest for more than 50% of their attacks) were included in this analysis. Thus, they were preselected using strict and nonstandard inclusion criteria. Of these patients, 89 were randomized to the AAC and 83 to placebo. The end points of pain intensity, functional disability, nausea, vomiting, photophobia, and phonophobia were rated at baseline and at several time points after medication. From one hour and continuing through six hours postdose, the proportion of responders was signicantly greater (p 0.01) for AAC than placebo. With regard to pain severity, AAC was superior to placebo from 0.5 to 6 hours (p 0.05), as well as for the parameters of functional disability, photophobia, and phonophobia in which the AAC group responded signicantly greater than placebo from two to six hours postdose. Once the pain reached moderate or severe intensity, these patients took two tablets of AAC, each containing 250 mg APAP, 250 mg aspirin, and 65 mg caffeine. The combination of AAC was also evaluated for menstrually related migraine (MRM) in a post hoc analysis of 1220 subjects (16). The study included 185 women with treated MRM, and 781 women with treated migraine not associated with menses. At all time points from one to six hours (p 0.01), the migraine characteristics of functional disability, photophobia, and phonophobia were signicantly improved in both groups of female migraineurs. Both groups also demonstrated signicant relief of pain intensity over placebo, as soon as 0.5 hour postdose through six hours (p 0.05). Nausea was relieved sooner in women with migraine not related to menses (two hours postdose, p 0.01) than in the group with menstrually related attacks, who had greater nausea relief than the placebo group at six hours postdose (p 0.05). However, as noted above, the studies on AAC for acute migraine treatment are not as strong methodologically as those suggesting effectiveness for triptans. In the OTC medication studies, patients were selected to mimic the population that uses OTC medications more often (reduced frequency of vomiting, low disability, and less severe attacks), while in the triptan studies, subjects with low frequency of attacks or mild severity of pain are often excluded. As a result, the evidence for effectiveness in the acute treatment of migraine is not equivalent for AAC and the triptans. Acetaminophen APAP was evaluated in combination with MCP and in combination with codeine (17,18). In both trials, it was superior to placebo. However, when APAP was used alone, it was no better than placebo (19). In comparative trials, APAP 500 mg was not signicantly different from mefenamic acid, an NSAID, when both were used with 10 mg MCP (20). In another study, the combined use of APAP 1 g with 20 and 30 mg of domperidone (an antinauseant not available in the United States) proved to shorten the duration of a headache attack from 17 hours (when used with placebo) to 12 hours, when used with both dosages of domperidone (21).

276

Krymchantowski and Tepper

Dipyrone The pirazolonic derivative dipyrone (metamizol), an inexpensive simple analgesic frequently used in some countries (not available in the United States), has been studied for both migraine with and without aura in its intravenous (IV) formulation in a randomized, double-blind, placebo-controlled design. It was found to be highly and quickly effective in its analgesic action as well as in working against the associated symptoms of nausea, photophobia, and phonophobia. In addition, IV dipyrone was also effective in reducing the duration of the aura in the patients receiving it. The adverse events were similar among the patients using placebo and metamizol (6). Nonsteroidal Anti-inammatory Drugs There are numerous types of NSAIDs currently used in clinical practice, which may belong to different chemical groups. In general they are effective in various inammatory conditions, such as rheumatoid arthritis. For the acute treatment of migraine attacks, most of the anthranilic class (e.g., tolfenamic acid) and propionic acid class (e.g., naproxen) have been proven effective in randomized controlled studies (5). The rst among the so-called new NSAIDs studied was tolfenamic acid. It was tested in the treatment of migraine during the late 1970s, and was superior to both placebo and APAP, with similar efcacy to ASA and ergotamine (22,23). In addition, the rapid release form of 200 mg tolfenamic acid was as effective as 100 mg sumatriptan for headache relief at two hours in two attacks treated. The pain-free rates at two hours also revealed nonsignicant differences between the active treatment groups, which were superior to placebo. With regard to recurrence, there were no statistically signicant differences between rapid-release tolfenamic acid, sumatriptan, and placebo with percentages ranging from 13% to 27% in all groups treating the rst and second attacks (24). The propionic acid derivative naproxen and its more quickly absorbed formulation naproxen sodium were both superior to placebo in treating migraine attacks. The dosages of naproxen ranged from 750 to 1250 mg and that of naproxen sodium ranged from 825 to 1375 mg. The headache severity as well as the consumption of escape medications was lower in the active-drug group compared to placebo (25,26). Ibuprofen, another member of this group, was more effective than placebo in dosages ranging from 800 to 1200 or 400 mg as an arginine salt (not available in the United States) (2729). When compared to APAP for the treatment of migraine attacks in children, both were effective and superior to placebo (30). Other nonsteroidal propionic acids such as urbiprofen, ketoprofen, and pirprofen (not available in the United States) were also evaluated in acute migraine treatment and proven superior to placebo and APAP (31,32). In a trial comparing the efcacy of rectal ketoprofen (not available in the United States) and ergotamine in maintaining the working capacity, the NSAID demonstrated superiority (33). Diclofenac, an NSAID derivative of acetic acid, was tested in migraine attacks and was shown to be superior to placebo and APAP (34,35). As it is one of the few NSAIDs also available for intramuscular (IM) injection in most of the world, but not the United States, diclofenac sodium was also evaluated for migraine in this parenteral formulation and showed efcacy when compared to placebo. This was conrmed by self-assessment cards and reports of patients preferences. The tolerability of injectable diclofenac is similar to placebo (36). Other NSAIDs that may be used parenterally are ketorolac (available in the United States) and lysine clonixinate (not available in the United States). Both were also

Nonspecic Migraine Acute Treatment

277

effective in treating migraine attacks when given orally (37,38), and 60 mg IM ketorolac was found as effective as 75 mg meperidine plus 25 mg promethazine (39), 100 mg meperidine plus 50 mg hydroxyzine (40), and 25 mg chlorpromazine intravenously (41). In another study, ketorolac 30 mg administered intravenously was superior to 20 mg sumatriptan nasal spray (42). The prole of adverse events for ketorolac is similar to other nonsteroidal anti-inammatory agents, except for a higher propensity for severe gastrointestinal consequences such as ulcers and bleeds (38,43,44). Lysine clonixinate, derived from nicotinic acid and resembling ufenamic acid, also proved effective for migraine attacks (not available in the United States). In its oral form, lysine clonixinate 250 mg was not superior to placebo in those patients with severe migraine headache, despite its effectiveness in reducing head pain and consumption of escape medications when it was used for moderate headache (37). However, the use of lysine clonixinate IV 200 mg (not available in the United States) was signicantly superior to placebo in providing pain-free status and reducing escape-medication use after 60, 90, and 120 minutes in severe migraine attacks (45). The tolerability of this compound is acceptable, but signicantly more patients had mild adverse events with active drug than those who used placebo. Despite its widespread clinical use and known efcacy, indomethacin is not commonly encountered in reviews of migraine treatment. It has prominent antiinammatory activity and its analgesicantipyretic properties are more potent than that of aspirin, through inhibition of prostaglandin-forming cyclooxygenase (COX), inhibition of the motility of polymorphonuclear leukocytes, uncoupling properties of oxidative phosphorylation at supratherapeutic concentrations, and depression of the biosynthesis of mucopolysaccharides (46). Although indomethacin has been recommended for mild to moderate migraine attacks (47), it has proved to be superior to sumatriptan only when used in combination with prochlorperazine and caffeine in a small dose of 25 mg in suppository formulation. The patients also had signicantly better performances with regard to nausea and sustained pain free with the combination, in comparison to 25 mg sumatriptan suppository for moderate or severe migraine attacks (48). However, indomethacin is not commonly used for therapy as an analgesic or antipyretic because of the high incidence of side effects, although it is considered safe and has an acceptable prole of tolerability (49). The efcacy of NSAIDs in the treatment of migraine is unquestionable. Different trials with various dosages and formulations have also demonstrated efcacy orally, especially when combined with MCP. In addition, injectable formulations of NSAIDs have been shown highly effective even for severe attacks. The further development of new formulations, which may enable even faster absorption for the oral NSAIDs, as well as higher serum levels within the rst 30 minutes after administration, is warranted. Rofecoxib, a COX-2 inhibitor is effective in the treatment of migraine, as demonstrated by one published and one unpublished double-blind, placebocontrolled, outpatient trials (50). As of this writing, it has been withdrawn from the market worldwide due to cardiovascular concerns.

MEDICATIONS FOR THE TREATMENT OF NAUSEA During migraine attacks, gastric stasis with consequent delayed absorption of orally administered drugs may impair the treatment response of some patients. In addition, nausea and vomiting may cause additional suffering and discomfort during headache

278

Krymchantowski and Tepper

attacks (51). Dopamine and reduced cholinergic transmission may be involved in these processes of gastrointestinal hypomotility and delayed gastric emptying; therefore emesis, which occurs in migraine, is promoted by conditions that prime visceral afferents by decreasing intestinal motility and slowing gastric emptying (51). Prokinetic agents (mostly acting peripherally and as agonists of 5-HT4 receptors or antagonists of 5-HT3 receptors such as ondansetron, granisetron, and alosetron) and dopamine receptor antagonists may therefore be of value in the management of these migraine symptoms. In addition, they may also promote the absorption of antimigraine therapies that otherwise would pass slowly through only the gastrointestinal tract during a migraine attack (51). In fact, MCP, domperidone, and, recently, trimebutine (the latter two medications not available in the United States) have been used as migraine acute therapies, either as starting medications or in conjunction with triptans and/or NSAIDs (10,21,5256), although the mechanisms by which they may work in monotherapy remains unclear despite the hypersensitivity of dopamine receptors in migraine patients (57,58) (see section on Neuroleptics). Neuroleptics such as prochlorperazine, chlorpromazine, and thiethylperazine (the latter medication not available in the United States), as well as the muscarinic receptor antagonists diphenhydramine, cyclizine, and promethazine (also used as histamine H1-receptor antagonists) have been also used as medications to combat nausea and vomiting in acute migraine treatment, although they may have auxiliary antipain effects in migraine as well (5962). The severe nausea and vomiting accompanying migraine attacks may represent one of the reasons for the utilization of these neuroleptics, which can be used in doses ranging from 25 mg orally or 25 mg intramuscularly for chlorpromazine to 10 mg orally, 25 mg rectally, or 10 mg intramuscularly for prochlorperazine. As noted above, the mechanism of action of the neuroleptics in migraine may be more than their antidopamine activity and extend to serotonergic, histaminic, and adrenergic actions as well (63). A recent randomized controlled trial compared high doses of IV MCP (ranging from 1080 mg, mean around 40 mg) with subcutaneous sumatriptan 6 mg. Both drugs were better than placebo, and MCP was at least as effective as sumatriptan (64).

COMBINATIONS OF NSAIDs AND TRIPTANS Although triptans provide a tremendous positive impact on patient care and clinical practice, they are still far from providing optimum efcacy and sustained pain-free measures, and therefore fall below the expectations of patients and physicians (64,65). Up to 31% of patients taking sumatriptan discontinue its use due to lack of efcacy, headache recurrence, cost, and/or side effects (6669). The combination of a triptan plus an NSAID reduces recurrence in clinical practice and may be more efcacious than the single use of both agents. In one study (70), 240 moderate or severe attacks were treated with 100 mg sumatriptan and 200 mg of tolfenamic acid resulting in a decreased recurrence rate from 62.5% to 23.8% (70). In a second study, the combination of 100 mg sumatriptan and 550 mg naproxen sodium signicantly reduced recurrence from 59% to 25.5% compared to the use of sumatriptan plus placebo (p < 0.0003) (71). Rizatriptan, another 5-HT1B/1D agonist, was also studied in combination with the then available COX-2 selective inhibitor rofecoxib, both in an open (72)

Nonspecic Migraine Acute Treatment

279

and in a controlled design (73). In the controlled study, the combination of 10 mg rizatriptan plus 50 mg rofecoxib was more efcient than rizatriptan alone, or as the combination of rizatriptan plus 200 mg tolfenamic acid. Recurrence was also signicantly reduced with both combinations in comparison to rizatriptan alone. These studies suggest the advantage of combining a triptan with an NSAID with regard to efcacy, reduction of recurrence, and improvement of sustained pain-free measures over the treatment with a single option.

NEUROLEPTICS IN THE TREATMENT OF PAIN The phenothiazine derivatives exert different actions in migraine. In addition to an analgesic effect, some of these compounds are powerful alpha-adrenergic and dopaminergic antagonists. This may render additional efcacy in migraine headache and nausea, but also has implications in tolerability, making these drugs less attractive for routine use, even in emergency departments (74,75). Studies conducted in migraine patients found efcacy of IV chlorpromazine in doses of 0.1 mg/kg and 12.5 mg in comparison with placebo, meperidine (0.4 mg/kg), lidocaine (50 mg), and ergotamine (1 mg) (7678). Chlorpromazine may cause severe postural hypertension, sedation, and drowsiness. Therefore, it is recommended that the patients have an IV catheter, receive the administration of 400 to 500 mL of saline before the infusion of the drug, and remain in bed for at least two hours after it has been given. The dosage ranges from 0.1 to 0.7 mg/kg and can be repeated after 30 to 60 minutes if necessary (7678). Prochlorperazine is another neuroleptic with proven efcacy in migraine, and may be better tolerated than chlorpromazine (60). Its use as an IV injection of 10 mg was superior to placebo as well as to MCP (10 mg) (79,80). Prochlorperazine may be administered in 25 mg suppositories as well (81). Finally, IV haloperidol has been recently suggested for severe refractory migraine attacks in the emergency department, based on a small open study (82).

OPIOIDS The opium derivatives used in migraine belong to the alkaloid group known as phenanthrenes. Morphine, codeine, thebaine (not available in the United States), and its derivatives represent the members of this group used in clinical practice. For headache patients, different codeine-containing oral combinations have been studied. In migraine, 400 mg APAP 25 mg codeine and 650 mg APAP 16 mg codeine were both superior to placebo (17,83,84). Other oral combinations of APAP codeine buclizine dioctyl sodium sulfosuccinate were compared to placebo as well. One study, which showed superiority over placebo, did not use a double-blind design (85), while another study analyzing this combination with proper methodology did not demonstrate effectiveness against placebo (86). Other comparisons between codeine-containing combinations and ASA 1000 mg or ergotamine 2 mg cyclizine 50 mg caffeine 100 mg did not show statistically signicant differences (83,87). The combination of tramadol HCl (37.5 mg), a mu-opioid agonist plus APAP (325 mg) was compared to placebo in a randomized, double-blind, placebo-controlled multicenter study evaluating 154 patients who took the active drug and 151 patients who took placebo. The dosage was 75 mg tramadol 650 mg APAP, and after two hours,

280

Krymchantowski and Tepper

signicantly more patients on the combination achieved pain relief (56% vs. 34%, p < 0.001). In addition, pain relief was superior among tramadol/APAP patients from 30 minutes postdose (p 0.022) through six hours (p < 0.001) (88). Transnasal opioids have also been suggested for the acute migraine treatment. The nasal spray of butorphanol (1 mg) was tested against placebo and methadone (10 mg IM) in 96 patients. Butorphanol was superior to both placebo and methadone (89). In another study, butorphanol (1 mg) yielded headache relief in two hours in 60% of the patients compared to 18% of the placebo group (90). Parenteral opioids are frequently used for migraine in emergency departments. Butorphanol 2 mg IM was compared to meperidine 75 mg hydroxyzine 50 mg IM. The drugs were not signicantly different, although both were effective in reducing headache intensity (91). Meperidine 0.4 mg/kg dimenhydrinate IV was compared with chlorpromazine 0.1 mg/kg IV in 15-minute interval dosages to a maximum of three doses. The pain intensity was assessed after 45 minutes and chlorpromazine was signicantly better than meperidine dimenhydrinate (p < 0.001) (78). Opioids were also compared with NSAIDs. IM meperidine 75 mg was evaluated against IM ketorolac 60 mg and showed signicantly better efcacy over ketorolac after one hour (92). Meperidine (100 mg) hydroxyzine (50 mg) IM were compared with ketorolac (60 mg) IM, and both reduced the headache intensity at 60 minutes. However, there was no signicant difference between the two treatment options (40). Meperidine (75 mg) promethazine (25 mg) IM were tested against ketorolac (60 mg) IM. Headache relief was dened as a reduction of four or more units on a scale of 0 to 10 in specic time points. At one hour, no signicant difference between these two treatment options was observed (39). After considering the above data, the following recommendations were made by the U.S. Headache Consortium: Nasal butorphanol is a treatment option when other medications cant be used or as a rescue medication when severe sedation is not a critical issue for the patient. Oral opioid combinations may be considered when sedation will not put the patient at risk and/or the risk for abuse has been addressed. Parenteral opioids may be considered a choice only in a supervised setting and again sedation will not put the patient at risk and/or the risk for abuse has been addressed (14,85,93).

NONSPECIFIC VS. SPECIFIC TREATMENTS The decision on whether to use a nonspecic treatment or a triptan, despite clinical practice experience supporting the better effectiveness of the triptans, remains controversial. The clinical trials generally do not reect the favorable experience with triptans in clinical practice, and comparisons made between the triptans and other nonspecic treatments do not always support the superiority of triptans (94). In a very elegant review, Lipton et al. analyzed all prospective, randomized, double-blind studies, which compared an oral triptan with a drug belonging to another pharmacological class and used the criteria of the International Headache Society (IHS) to dene migraine (95). Nine studies were eligible and most used primary end points of pain relief and pain free at two hours using a four-point categorical pain scale (none, mild, moderate, or severe). Interestingly, seven studies did not demonstrate differences favoring the triptans in regard to the primary end points (12,24,96100). Only two studies, comparing the efcacy of sumatriptan or eletriptan with ergotamine tartrate caffeine showed the triptan to be unequivocally superior to a comparator drug (101,102).

Nonspecic Migraine Acute Treatment

281

These results are inconsistent with clinical practice among experienced headache physicians, which suggests that, for many patients, although triptans provide vastly superior efcacy in comparison to nonspecic agents (103), they are not associated with rapid and complete relief of migraine pain in all patients (64). However, the clinician is still often faced with the decision whether to begin treating a migraine patient with a triptan or a combination of nonspecic treatments rst, and the question is how to select the right treatment the rst time for acute treatment. Lipton et al., after surveying various approaches to acute migraine treatment, described three strategies for treating diagnosed acute migraine, which he called Step care across attacks, Step care within attacks (also called Staged Care), and Stratied Care (104). In Step care across attacks, the least expensive nonspecic medication is selected by the physician for the patient to use rst. It may be recommended that the patient use this medicine on several attacks. If this medication fails to abort the headache satisfactorily, and the patient returns to see the same physician after these treatment failures, the physician will then step up to the next drug, usually another nonspecic drug, and so forth. This may go on until a medication works, or the patient lapses from care, or the doctor nally steps up to a specic medication, generally a triptan. An example of this would be starting with naproxen sodium, then a mixture of ASA plus MCP or ASA plus APAP and caffeine, then step up to an opioid, and nally to a triptan. Step care within attacks involves starting with a nonspecic medication at the beginning of a migraine attack, and then if it fails, having the patient take a triptan at that point, after the migraine has progressed. The triptan is used as a rescue. The third strategy is stratied care, dened as matching treatment to a patients characteristics or the characteristics of the disease. One approach is to measure disability, time loss, or impact as a surrogate marker of disease severity and give triptans to the more disabled patients and nonspecic medications to the less disabled. The most critical decision for the clinician is deciding which approach will result in the best outcome for patients. Prior to 2000, this decision was based on common sense but not randomized prospective evidence. However, a study published by Lipton et al. in JAMA in 2000, gives strong evidence that a stratied approach yields optimal clinical outcome (104). The Disability in Strategies of Care (DISC) study is the only randomized prospective comparison of Step care between attacks, Step care across attacks, and Stratied care. All primary end points were superior with stratied care as the strategy for treatment, as opposed to the step care strategies. Stratied care was superior to step care across attacks and step care within attacks for headache response at one and two hours. Stratied care was signicantly superior for headache relief over Step care across attacks at four hours as well. Thus, the DISC study has yielded prospective evidence for matching disability to treatment, and patients without medical contraindications and with more than 10 days of at least 50% disability in the last three months should be given triptan therapy at the outset as their rst medication for acute treatment, not ASA/ MCP and presumably comparable nonspecic treatments, and stepped up across attacks or in the same attack. The strategy for deciding nonspecic versus triptan therapy should be stratied care based on disability, with the more disabled patients receiving triptans rst, and the less disabled patients, nonspecic treatment rst (Fig. 1).

282

Krymchantowski and Tepper

Figure 1 Treatment strategy for migraine attacks based on disability assessment.

CONCLUSIONS Although the existence of accumulating evidence corroborates the efcacy of some nonspecic therapies for the acute treatment of a migraine attack, such as NSAIDs, clinical practice suggests that specic treatment options are better, despite the fact that superiority was not always demonstrated in the few controlled trials comparing triptans with some of the nonspecic pharmacological agents. Rather, the combination of these serotonergic agonists with an NSAID (and perhaps with a gastrokinetic drug as well) seems to provide better outcome on efcacy measures. In addition, the way drug options are used probably may represent the difference between success and ineffectiveness in treating these patients across multiple attacks. The strategy of considering the disability for that specic patient, along with the frequency in which it is provoked, drives the choice for specic agents that may or may not be used in combination with another pharmacological class. The variation of routes in which drugs are employed may also represent a better path to obtain more consistent pain relief. In a patient presenting with attacks rapidly progressing with frequent nausea and vomiting, the rectal administration of indomethacin plus the subcutaneous use of sumatriptan can provide pain-free rates much faster than conventional orally taken drug options. Individual preference as well as population differences must be taken into account clinically, along with the synergy of combinations, to maximize benet for our patients.

Nonspecic Migraine Acute Treatment

283

REFERENCES
1. Dodick DW. Acute and prophylactic management of migraine. Clin Cornerstone 2001; 4:3652. 2. Tfelt-Hansen P, Lipton RB. Prioritizing treatment. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven Press, 1993:359362. 3. Goadsby PJ, Lipton RB, Ferrari MD. Migrainecurrent understanding and treatment. N Engl J Med 2002; 346:257270. 4. Lipton RB, Hamelsky SW, Dayno JM. What do patients with migraine want from acute migraine treatment? Headache 2002; 42(suppl 1):39. 5. Limmroth V, Przywara S. Analgesics. In: Diener HC, ed. Drug Treatment of Migraine and Other Headaches. Monogr Clin Neurosci 2000; 17:3043. 6. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous dipyrone in the acute treatment of migraine without aura and migraine with aura: a randomized, double blind, placebo controlled study. Headache 2002; 42(9):862871. 7. Tfelt-Hansen P, Olesen J. Paracetamol (acetaminophen) versus acetylsalicylic acid in migraine. Eur Neurol 1980; 19:163165. 8. Limmroth V, Katsarava Z, Diener H-C. Acetylsalicylic acid in the treatment of headache. Cephalalgia 1999; 19:545551. 9. Lipton RB, Goldstein J, Baggish JS, Yataco AR, Sorrentino JV, Quiring JN. Aspirin is efcacious for the treatment of acute migraine. Headache 2005; 45(4):283292. 10. Diener HC, Bussone G, de Liano H, et al. EMSASI Study Group. Placebo-controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia 2004; 24(11):947954. 11. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. A Study to Compare Oral Sumatriptan with Oral Aspirin plus Metoclopramide in the Acute Treatment of Migraine. Eur Neurol 1992; 32:177184. 12. Tfelt-Hansen P, Henry P, Mulder LJ, Scheldewaert RG, Schoenen J, Chazot G. The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet 1995; 346:923926. 13. Diener HC for the ASASUMAMIG Study Group. The efcacy and safety of Acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the cute treatment of migraine. A double-blind, double-dummy, randomized multicenter parallel group study. Cephalalgia 1999; 19(6):581588. 14. Silberstein SD, for the US Headache Consortium. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 55:754763. 15. Goldstein J, Hoffman HD, Armellino JJ, et al. Treatment of severe, disabling migraine attacks in an over-the-counter population of migraine sufferers: results from three randomized, placebo-controlled studies of the combination of acetaminophen, aspirin, and caffeine. Cephalalgia 1999; 19:684691. 16. Silberstein SD, Armellino JJ, Hoffman HD, et al. Treatment of menstruation-associated migraine with the nonprescription combination of acetaminophen, aspirin, and caffeine: results from three randomized, placebo-controlled studies. Clin Ther 1999; 21(3):475491. 17. Boureau F, Joubert JM, Lasserre V, Prum B, Delecoeullerie G. Double-blind comparison of an acetaminophen 400 mg-codeine 25 mg combination versus aspirin 1000 mg and placebo in acute migraine attack. Cephalalgia 1994; 14:156161. 18. Dexter SR, Graham AN, Johnson ES, Ratcliffe EM, Wilkinson MIP, Rose AJ. Doubleblind controlled study of Paramax in the acute treatment of common and classical migraine. Br J Clin Pract 1985; 39:388392. 19. Diamond S. Treatment of migraine with isometheptene, acetaminophen and dichlorphenazone combination: a double-blind, cross-over trial. Headache 1976; 16: 282287.

284

Krymchantowski and Tepper

20. Peateld RC, Petty RG, Rose FC. Double blind comparison of mefenamic acid and acetaminophen (paracetamol) in migraine. Cephalalgia 1983; 3:129134. 21. MacGregor EA, Wilkinson M, Bancroft K. Domperidone plus paracetamol in the treatment of migraine. Cephalalgia 1993; 13:124127. 22. Hakkaranainen H, Gustafsson B, Stockman O. A comparative trial of ergotamine tartrate, acetylsalicylic acid and a dextropropoxyphene compound in acute migraine attacks. Headache 1978; 18:3539; Hakkaranainen H, Parantainen J, Gothoni G, Vapaatalo H. Tolfenamic acid and caffeine: a useful combination in migraine. Cephalalgia 1982; 2:173177. 23. Hakkaranainen H, Vapaatalo H, Gothoni G, Parantainen J. Tolfenamic acid is as effective as ergotamine during migraine attacks. Lancet 1979; 2:326328. 24. Myllyla VV, Havanka H, Herrala L, et al. Tolfenamic acid rapid release versus sumatriptan in the acute treatment of migraine: comparable effect in a double-blind, randomized, controlled, parallel-group study. Headache 1998; 38:201207. 25. Johnson ES, Ratcliffe DM, Wilkinson M. Naproxen sodium in the treatment of migraine. Cephalalgia 1985; 5:510. 26. Nestvold K, Kloster R, Partinen M, Sulkava R. Treatment of acute migraine attack: naproxen and placebo compared. Cephalalgia 1985; 5:115119. 27. Havanka-Kanniainen H. Treatment of acute migraine attack: ibuprofen and placebo compared. Headache 1989; 29:507509. 28. Kloster R, Nestvold K, Vilming ST. A double-blind study of ibuprofen versus placebo in the treatment of acute migraine attacks. Cephalalgia 1992; 12:169171. 29. Sandrini G, Franchini S, Lanfranchi S, Granella F, Manzoni GC, Nappi G. Effectiveness of ibuprofen-arginine in the treatment of acute migraine attacks. Int J Clin Pharmacol Res 1998; 18:145150. 30. Hamalainen ML, Hoppu K, Valkeila E, Santavuore P. Ibuprofeno or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebocontrolled, cross-over study. Neurology 1997; 48:103107. 31. Awidi AS. Efcacy of urbiprofen in the treatment of acute migraine attacks: a doubleblind cross-over study. Curr Ther Res 1982; 32:492497. 32. Guidotti M, Zanasi S, Garagiola U. Pirprofen in the treatment of migraine and episodic headache attacks: a placebo-controlled cross-over clinical trial. J Int Med Res 1989; 17:4854. 33. Kangasneimi P, Kaaja R. Ketoprofen and ergotamine in acute migraine. J Intern Med 1992; 231:551554. 34. Massiou H, Serrurier D, Lassere O, Bousser MG. Effectiveness of oral diclofenac in the acute treatment of common migraine attacks; a double-blind study versus placebo. Cephalalgia 1991; 11,5963. 35. Dahlof C, Bjorkman R. Diclofenac-K (50 and 100 mg) and placebo in the acute treatment of migraine. Cephalalgia 1993; 13:117123. 36. Del Bene E, Poggioni M, Garagiola U, Maresca V. Intramuscular treatment of migraine attacks using diclofenac sodium: a cross-over clinical trial. J Int Med Res 1987; 15:4448. 37. Krymchantowski AV, Barbosa JS, Cheim C, Alves LA. Oral lysine clonixinate in the acute treatment of migraine: a double-blind, placebo-controlled study. Arq Neuropsiquiatr 2001; 59:4649. 38. Gillis JC, Brogden RN. Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs 1997; 53(1):13988. 39. Davis CP, Torre PR, Williams C, et al. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: evaluations by patients. Am J Emerg Med 1995; 13: 145150. 40. Duarte C, Dunaway F, Turner L, Aldag J, Frederick R. Ketorolac versus meperidine and hydroxyzine in the treatment of acute migraine headache: a randomized, prospective, double-blind trial. Ann Emerg Med 1992; 21:11161121.

Nonspecic Migraine Acute Treatment

285

41. Shrestha M, Singh R, Moreden J, Hayes JE. Ketorolac versus chlorpromazine in the treatment of acute migraine without aura. A prospective randomized double-blind trial. Arch Intern Med 1996; 156:17251728. 42. Meredith JT, Wait S, Brewer KL. A prospective double-blind study of nasal sumatriptan versus IV ketorolac in migraine. Am J Emerg Med 2003; 21(3):173175. 43. Maliekal J, Elboim CM. Gastrointestinal complications associated with intramuscular ketorolac tromethamine therapy in the elderly. Ann Pharmacother 1995; 29:698701. 44. Traversa G, Walker AM, Ippolito FM, et al. Gastrointestinal toxicity of different nonsteroidal anti-inammatory drugs. Epidemiology 1995; 6:4954. 45. Krymchantowski AV, Silva MT. Intravenous lysine clonixinate for the acute treatment of severe migraine attacks: a double-blind, randomized, placebo-controlled study. Curr Therap Res Clin Exp 2003; 64(8):505513. 46. Insel PA. Analgesic-antipyretic and anti-inammatory agents and drugs employed in the treatment of gout. In: Hardman JG, Limbird LE, eds. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill 1996; 27: 617657. 47. Peroutka SJ. Drugs effective in the treatment of migraine. In: Hardman JG, Limbird LE, eds. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill 1996; 21:487502. 48. Di Monda V, Nicolodi M, Aloisio A, et al. Efcacy of a xed combination of indomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter, randomized, crossover trial. Headache 2003; 43:835844. 49. Pareja JA, Caminero AB, Franco E, et al. Dose, efcacy and tolerability of long-term indomethacin treatment of chronic paroxysmal hemicrania and hemicrania continua. Cephalalgia 2001; 21(9):906910. 50. Silberstein S, Tepper S, Brandes J, et al. Randomized, placebo-controlled trial of rofecoxib in the acute treatment of migraine. Neurology 2004; 62:15521557. 51. Dahlof CG, Hargreaves RJ. Pathophysiology and pharmacology of migraine. Is there a place for antiemetics in future treatment strategies? Cephalalgia 1998; 18:593604. 52. Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A prospective, doubleblind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Ann Emerg Med 1990; 19:10831087. 53. Amery WK, Waelkens J. Prevention of the last chance: an alternative pharmacological treatment of migraine. Headache 1983; 23:3738. 54. Waelkens J. Dopamine blockade with domperidone. Bridge between prophylactic and abortive treatment of migraine? A dose-nding study. Cephalalgia 1984; 4:8590. 55. Chabriat H, Joire JE, Danchot J, Grippon P, Bousser MG. Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicenter, double-blind, placebo-controlled study. Cephalalgia 1994; 14:297300. 56. Krymchantowski AV, Bigal ME, Lipton RB, Moreira PF. Rizatriptan vs. rizatriptan plus trimebutine for the acute treatment of migraine: a double-blind, randomized, cross-over, placebo-controlled study [abstr]. Headache 2004; 44:463. 57. Peroutka SJ. Dopamine and migraine. Neurology 1997; 49(3):650656. 58. Peroutka SJ, Wilhoit T, Jones K. Clinical susceptibility to migraine with aura is modied by dopamine D2 receptor (DRD2) NcoI alleles. Neurology 1997; 49(1):201206. 59. Tfelt-Hansen P. Antiemetic, prokinetic, neuroleptic, and miscellaneous drugs in the acute treatment of migraine. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:445452. 60. Jones J, Sklar D, Dougherty J, White W. Randomized double-blind trial of intravenous prochlorperazine for the treatment of acute headache. JAMA 1989; 261:11741176. 61. McEwen J, OConnor H, Dinsdale H. Treatment of migraine with intramuscular chlorpromazine. Ann Emerg Med 1987; 16:758763.

286

Krymchantowski and Tepper

62. Bruntton LL. Agents affecting gastrointestinal water ux and motility; emesis and antiemetics; bile acids and pancreatic enzymes. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon LW, Gilman AG, eds. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw Hill, 1996:917936. 63. Fozard J. Basic mechanisms of antimigraine drugs. Adv Neurol 1982; 33:295307. 64. Friedman BW, Corbo J, Lipton RB, Bijur PE, Esses D, Solorzano C, Gallagher EJ. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Neurology 2005; 64(3):463468. 65. Peroutka SJ. Beyond Monotherapy: Rational polytherapy in migraine. Headache 1998; 38:1822. 66. Bates D, Ashford E, Dawson R, et al. Subcutaneous sumatriptan during the migraine aura. Neurology 1994; 44:15871592. 67. Visser WH, de Vriend RH, Jaspers NHWM, Ferrari MD. Sumatriptannonresponders: a survey in 366 migraine patients. Headache 1996; 36:471475. 68. Dahlof CG. How does sumatriptan perform in clinical practice? Cephalalgia 1995; 15(suppl 15):2128. 69. Visser WH, de Vriend RH, Jaspers NHWM, Ferrari MD. Sumatriptan in clinical practice: a 2-year review of 453 migraine patients. Neurology 1996; 47:4651. 70. Krymchantowski AV, Adriano M, Fernandes D. Tolfenamic acid decreases migraine recurrence when used with sumatriptan. Cephalalgia 1999; 19(3):186187. 71. Krymchantowski AV. Naproxen sodium decreases migraine recurrence when administered with sumatriptan. Arq Neuropsiquiatr 2000; 58(2-B):428430. 72. Krymchantowski AV, Barbosa JS. Rizatriptan combined with rofecoxib vs. rizatriptan for the acute treatment of migraine: an open label pilot study. Cephalalgia 2002; 22(4): 309312. 73. Krymchantowski AV, Bigal ME. Rizatriptan versus rizatriptan plus rofecoxib versus rizatriptan plus tolfenamic acid in the acute treatment of migraine. BMC Neurol 2004; 28; 4(1):10. 74. Baldessarini RJ. Drugs and the treatment of psychiatric disorders: psychosis and anxiety. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon LW, Gilman AG, eds. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw Hill, 1996:399430. 75. Lasagna L, Dekornfeld J. Methotrimeprazine: a new phenothiazine derivative with analgesic properties. JAMA 1961; 178:887890. 76. Bigal ME, Bordini CA, Speciali JG. Intravenous chlorpromazine in the emergency department treatment of migraines: a randomized controlled trial. J Emerg Med 2002; 23(2):141148. 77. Bell R, Montoya D, Shuaib A, Lee M. Comparative trial of three agents in the treatment of acute migraine. Ann Emerg Med 1990; 19:10791082. 78. Lane P, McLellan B, Baggoley C. Comparative efcacy of chlorpromazine and meperidine with dimenhydrinate in migraine headache. Ann Emerg Med 1989; 18:360365. 79. Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995; 26:541546. 80. Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as a single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996; 14:262265. 81. Jones EB, Gonzalez ER, Boggs JG, Grillo JA, Elswick RK Jr. Safety and efcacy of rectal prochlorperazine for the treatment of migraine in the emergency department. Ann Emerg Med 1994; 24:237241. 82. Monzillo HP, Nemoto PH, Costa AR, Sanvito WS. Acute treatment of migraine in emergency room: open comparative study between dexametasone and haloperidol. Preliminary results. Arq Neuropsiquiatr 2004; 62(2-B):513518.

Nonspecic Migraine Acute Treatment

287

83. Gawel MJ, Szalai JF, Stiglick A, Aimola N, Weiner M. Evaluation of analgesic agents in recurring headache compared with other clinical pain models. Clin Pharmacol Ther 1990; 47:504508. 84. Silberstein SD, McCrory DC. Opioids. In Diener HC, ed. Drug Treatment of Migraine and Other Headaches. Monogr Clin Neurosci 2000; 17:222236. 85. Carasso RL, Yehuda S. The prevention and treatment of migraine with an analgesic combination. Br J Clin Pract 1984; 38:2527. 86. Uzogara E, Sheehan DV, Manschreck TC, Jones KJ. A combination drug treatment for acute common migraine. Headache 1986; 26:231236. 87. General Practitioner Research Group. Migraine treated with an antihistamine-analgesic combination. Practitioner 1973; 211:357361. 88. Silberstein SD, Freitag FG, Rozen TD, et al. Tramadol HCl/acetaminophen versus placebo in the treatment of acute migraine pain [abstr]. Headache 2004; 44:464. 89. Diamond S, Freitag FG, Diamond ML, Urban G. Transnasal butorphanol in the treatment of migraine headache pain. Headache Quart 1992; 3:164171. 90. Hoffert MJ, Couch JR, Diamond S, et al. Transnasal butorphanol in the treatment of acute migraine. Headache 1995; 35:6569. 91. Belgrade MJ, Ling LJ, Schleevogt MB, Ettinger MG, Ruiz E. Comparison of singledose meperidine, butorphanol, and dihydroergotamine in the treatment of vascular headache. Neurology 1989; 39:590592. 92. Larkin GL, Prescott JE. A randomized, double-blind, comparative study of the efcacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. Ann Emerg Med 1992; 21:919924. 93. Snow V, Weiss K, Wall EM, Mottur-Pilson C. American Academy of Family Physicians, American College of Physicians-American Society of Internal Medicine. Pharmacologic management of acute migraine and prevention of migraine headache. Ann Intern Med 2002; 137(10):840849. 94. Lipton RB, Bigal ME, Goadsby PJ. Double-blind clinical trials of oral triptans vs other classes of acute migraine medicationa review. Cephalalgia 2004; 24:321332. 95. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):196. 96. DSMSG (Diclofenac-K/Sumatriptan Migraine Study Group). Acute treatment of migraine attacks: efcacy and safety of a non-steroidal anti-inammatory drug, diclofenac-potassium in comparison to oral sumatriptan and placebo. Cephalalgia 1999; 19:232240. 97. Dib M, Massiou H, Weber M, Henry P, Garcia-Acosta S, Bousser MG. Bi-Profenid Migraine Study Group. Efcacy of oral ketoprofen in acute migraine. A double-blind randomized clinical trial. Neurology 2002; 58:16601665. 98. OSAM (Oral Sumatriptan and Aspirin Plus Metoclopramide Comparative Study Group). A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. Eur Neurol 1992; 32:177184. 99. Freitag FG, Cady R, DiSerio F, et al. Comparative study of isometheptene mucate, dichlorphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine. Headache 2001; 41:391398. 100. Geraud G, Compagnon A, Rossi A. COZAM Study Group. Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double-blind, randomized, three-attack study. Eur Neurol 2002; 47(2):8898. 101. The Multinational Oral Sumatriptan and Cafergot Comparative Study Group. A randomized, double-blind comparison of sumatriptan and Cafergot in the acute treatment of migraine. Eur Neurol 1991; 31(5):314322. 102. Diener HC, Jansen JP, Reches A, et al. Efcacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicenter,

288

Krymchantowski and Tepper

randomized, double-blind, placebo-controlled comparison. Eur Neurol 2002; 47(2): 99107. 103. Lipton RB, Bigal ME, Rush S, Yekonsky J, Liberman JN, Bartleson JD. Migraine practice among neurologists. Neurology 2004; 62(11):19261931. 104. Lipton RB, Stewart WF, Stone AM, et al. Stratied care vs. step care strategies for migraine. The Disability in Strategies of Care (DISC) Study. JAMA 2000; 284: 25992605.

21
Specic Acute Migraine Treatment: Ergotamine and Triptans
Hans-Christoph Diener
Department of Neurology, University of Duisburg-Essen, Essen, Germany

Volker Limmroth
Department of Neurology, Cologne City Hospitals, University of Cologne, Cologne, Germany

INTRODUCTION This chapter summarizes the results of treatment trials with ergots and 5-HT1B/Dagonists (triptans) for the treatment of acute migraine attacks. A comparison between antimigraine drugs is only possible in randomized controlled trials (RCTs) with head-to-head comparisons. When direct comparisons are not available, indirect, although less reliable, information can be gained by comparing net therapeutic gain. Therapeutic gain is the difference in efcacy between active drug and placebo (1). Another way to indirectly compare the different triptans is a meta-analysis (2,3). The primary end point in most headache trials is the improvement from severe or moderate head pain to mild or no pain after 120 minutes. The most recent recommendations of the International Headache Society, however, propose two-hour pain-free and 24-hours sustained pain-free (pain-free after two hours, no rescue medication, and no recurrence) as the appropriate end points for clinical trials in migraine treatment (4). Moderate or severe migraine attacks should be treated with specic migraine drugs. These include ergot alkaloids (also called ergots) and triptans. Specic means that these drugs theoretically only work on migraine (and on cluster headache), but not on tension-type headache or other conditions such as tooth pain or general pain (although several case reports show that these drugs can also be effective to some extent in a gamut of other secondary headache syndromes). ERGOTAMINE Ergotamine and dihydroergotamine (DHE) have been available for a long time. The standard dose of oral ergotamine is 1 to 2 mg. Ergotamine is also available in some countries in suppository form at a dose of 2 mg. DHE is available as
289

290

Diener and Limmroth

tablet and in some countries as nasal spray. This chapter will concentrate on the oral form of ergotamine. The number of good clinical trials incorporating ergotamine is rather small. Tfelt-Hansen et al. provided a summary of 18 controlled double-blind trials of oral ergotamine, or oral ergotamine plus caffeine (5). In 10 of these trials, ergotamine was compared with placebo, whereas ergotamine served as the standard comparative drug in eight other trials without placebo control. The dose of ergotamine varied from 1 to 5 mg with a median of 2 mg, and in several trials, repeated intake of ergotamine was used. The reported parameters for efcacy were not all validated and varied considerably from benet based on a clinical interview to use of changes on a verbal headache scale. Other methodological aws in these trials include the lack of clearly stated inclusion criteria, no reporting of baseline criteria and the randomization procedure, unusual design of some of the crossover trials with a variable number of attacks per patient, and superiority claims without appropriate statistics (5). Despite the limited number of studies with contemporary methodology that involve ergotamine, there is evidence for the efcacy of ergotamine, and this is summarized briey below.  Ergotamine (15 mg) was superior to placebo for some parameters in seven trials and no better than placebo in three studies using a dose of 2 to 3 mg (6).  In two comparative trials, there was no signicant difference in measures of pain relief at two hours between oral ergotamine 2 mg plus 200 mg caffeine and oral diclofenac-potassium 50 or 100 mg (7). However, diclofenacpotassium reduced pain more effectively than ergotamine plus caffeine at one hour after treatment and, in contrast to the comparator, was also signicantly different compared with placebo.  Drugs such as ergocristine, tolfenamic acid, dextropropoxyphene, naproxen sodium, and pirprofen were generally found comparable to ergotamine.  The combination of lysine-acetylsalicylate (equivalent to 900 mg aspirin) plus metoclopramide (10 mg) was superior to the combination of ergotamine and caffeine (2 mg ergotamine and 200 mg caffeine) for most of the outcome parameters assessed (8). ERGOTAMINE VS. ORAL TRIPTANS The effect of oral ergotamine in the acute treatment of migraine has been compared to that of oral triptans in randomized controlled clinical trials. The rst study performed without placebo investigated the efcacy and tolerability of oral sumatriptan 100 mg and oral ergotamine 2 mg plus caffeine 200 mg in a multicenter, randomized, double-blind, double-dummy, parallel-group trial (9). In the trial, 580 patients were treated. Sumatriptan was signicantly more effective than the ergotaminecaffeine combination at reducing the intensity of headache from severe or moderate to mild or none; 66% (145/220) of those treated with sumatriptan improved in this way by two hours, compared with 48% (118/246) of those treated with ergotamine plus caffeine ( p < 0.001) (Fig. 1). The onset of headache resolution was more rapid with sumatriptan, whereas recurrence of migraine headache within 48 hours was lower with ergotamine plus caffeine. Sumatriptan was also signicantly more effective at reducing the incidence of photophobia/phonophobia ( p < 0.001), nausea ( p < 0.001), and vomiting ( p < 0.01) two hours after treatment, and fewer patients on

Specic Acute Migraine Treatment: Ergotamine and Triptans

291

Figure 1 Selected end points from a trial comparing sumatriptan 100 mg versus ergotamine (2 mg) plus caffeine. Source: From Ref. 9.

sumatriptan (24%) than on ergotamine plus caffeine (44%, p < 0.001) required other medication after two hours (9). The overall incidence of patients reporting adverse events was 45% after sumatriptan and 39% after ergotamine plus caffeine; the difference was not signicant. Oral sumatriptan was well tolerated and was more effective than ergotamine plus caffeine in the acute treatment of migraine. In a more recent study, the efcacy and tolerability of oral ergotamine was compared with that of eletriptan in the acute treatment of migraine (10). In a double-blind, parallel-group, randomized placebo-controlled trial, patients (n 773) took up to two doses of study medication to treat an acute migraine attack. The patients were randomized to receive 40 mg eletriptan, 80 mg eletriptan, ergotamine 2 mg plus caffeine 200 mg, or placebo (in the ratio 2:2:2:1) as the rst dose (Fig. 2). The onset of headache relief was more rapid in eletriptan groups, with response rates at one hour of 29% and 39% for 40 and 80 mg eletriptan, respectively, compared to 13% for ergotamine plus caffeine and placebo (p < 0.002). Both doses of eletriptan were signicantly more effective than ergotamine plus caffeine in terms of headache response (54% and 68% vs. 33%; p < 0.0001) and pain-free response (28% and 38% vs. 10%; p < 0.0001) at two hours after treatment. It is noteworthy that ergotamine plus caffeine was not superior to placebo for the primary outcome parameter. Eletriptan was also signicantly superior (p < 0.005) to ergotamine plus caffeine in terms of functional response and the incidence of accompanying symptoms at two hours. The incidence of treatment-related adverse events for patients based on the rst dose of study medication was 32%, 43%, 34%, and 34% in the eletriptan 40 mg, 80 mg, ergotamine plus caffeine and placebo groups, respectively. Finally, in a crossover preference study, rizatriptan 10 mg was preferred to ergotamine and caffeine (11).

292

Diener and Limmroth

Figure 2 Selected end points from a trial comparing ergotamine (2 mg) plus caffeine, eletriptan 40 mg, and eletriptan 80 mg. Source: From Ref. 10.

Ergotamine has vasoconstrictive properties and is therefore contraindicated in uncontrolled hypertension, coronary heart disease, peripheral vascular disease, cerebrovascular disease [stroke and transient ischemic attack (TIA)], hepatic or renal disease, and during pregnancy. The too-frequent intake of ergotamine can lead to an increase of migraine frequency and diffuse headaches, called medication-overuse headache (1215). In summary, ergotamine either as monosubstance or in combination with caffeine is only slightly more effective than placebo and is clearly inferior to sumatriptan, rizatriptan, or eletriptan. Patients who show a good response when treating migraine attacks with ergotamine can remain on this drug. Patients who do not respond should be switched to a triptan. The only patients who might benet from the longer duration of action of ergotamine are those with short action of triptans or multiple recurrences when taking triptans.

TRIPTANS The available triptan medications are listed in Table 1. Sumatriptan The most comprehensive review about the efcacy and adverse events of 6 mg subcutaneous, 100 mg oral, and 20 mg intranasal sumatriptan was written by Tfelt-Hansen (16). He calculated the numbers needed to treat (NNT), which is the number of patients needed to be treated in the active drug group in order to obtain signicant relief (which would not have been obtained with placebo), and numbers needed to harm (NNH), which is the number of patients needed to be exposed to

Specic Acute Migraine Treatment: Ergotamine and Triptans Table 1 Available Triptan Medications Generic Sumatriptan Formulations Tablets Nasal spray Subcutaneous injection Suppositories Tablets Orally disintegrating tablet Nasal spray Tablets Orally disintegrating tablet Tablets Tablets Tablets Tablets Doses

293

Zolmitriptan

Rizatriptan Naratriptan Almotriptan Frovatriptan Eletriptan

25, 50, and 100 mg 10 and 20 mg 6 mg 25 mg 2.5 and 5 mg 2.5 and 5 mg 2.5 and 5 mg 5 and 10 mg 5 and 10 mg 1 and 2.5 mg 12.5 mg 2.5 mg 20 and 40 mg 80 mg in some countries but not in the United States

a drug in order to have more side effects than placebo, to evaluate side effects. Twelve RCTs were performed with 100 mg oral sumatriptan. The success rate was 58% (1067/1854) for sumatriptan compared to 25% (256/1036) for placebo resulting in a NNT of 3.0 (95% CI 2.83.4) and a NNH of 8.3 (95% CI 6.312.2) (Table 2). For subcutaneous sumatriptan, 12 RCTs were available. The success rate of sumatriptan after one hour was 69% (1337/1927) and of placebo 19% (226/1200) resulting in a NNT of 2.0 (1.92.1) and a NNH of 3.0 (2.73.4). Finally, six trials were performed with intranasal sumatriptan, and a success rate after two hours of 61% (563/917), compared to 30% (149/503) for placebo, and an NNT of 3.1 (2.73.8) were achieved. These data clearly indicate that subcutaneous sumatriptan is the most effective treatment but causes more side effects than oral sumatriptan. In a large dose-nding trial, 50 and 100 mg oral sumatriptan were equally effective and superior to 25 mg sumatriptan. The 50 mg dose had fewer side effects than the higher dose and therefore is the preferred initial dose (17). Following more than 80 international trials of oral and subcutaneous application, sumatriptan was developed in intranasal and suppository formulations for patients unable to take tablets and unwilling to inject themselves. In the intranasal formulation, sumatriptan has a tmax of one hour (subcutaneously 0.2 hour and orally
Table 2 Numbers Needed to Treat and Numbers Needed to Harm in a Meta-Analysis of Sumatriptan Trials Formulation Sumatriptan tablet 100 mg Sumatriptan nasal spray Sumatriptan injection Number of trials analyzed 12 6 12 NNT (95% condence interval) 3.0 (2.83.4) at 2 hr 3.1 (2.73.8) at 2 hr 2.0 (1.92.1) at 1 hr NNH (95% condence interval) 8.3 (6.312.2) at 2 hr Not reported 3.0 (2.73.4) at 1 hr

Abbreviations: NNT, numbers needed to treat; NNH, numbers needed to harm.

294

Diener and Limmroth

1.5 hour) and a half-life of two hours (18). In a dose-nding study (n 544), dosages of 2.5, 5, 10, and 20 mg were compared (19). Dosages of 5, 10, and 20 mg reduced the headache within two hours signicantly in 49%, 46%, and 64% of the patients, respectively. Two additional trials comparing 10 and 20 mg with placebo (n 409 and 436) showed a signicant relief of headache within two hours in 43% to 54% of the patients receiving the 10 mg dose and in 62% to 63% receiving 20 mg compared to 29% to 35% with placebo (20). A retrospective analysis of four pooled trials performed between 1993 and 1994 including 2395 patients showed no inuence of sex, age, migraine type (with or without aura), weight, pretreatment headache duration, and migraine prophylaxis on the success rates (21). The approved doses for the nasal spray are 10 and 20 mg. The major side effect is taste disturbance. It should be noted that only a small proportion of sumatriptan is absorbed through the nasal mucosa. Sumatriptan as a suppository was tested in a double-blind, placebo-controlled trial including 431 patients with dosages of 6, 12.5, 25, 50, and 100 mg. Dosages of 12.5 mg and upwards showed a signicant improvement of headache within two hours. However, there were no statistical differences between these dosages. Two hours following the drug administration, 65%, 72%, 66%, and 70% of the patients receiving 12.5, 25, 50, and 100 mg, respectively, reported signicant improvement of headache (22). A randomized double-blind, parallel-group, placebo-controlled trial in 184 patients compared 12.5 mg and 25 mg sumatriptan suppositories with placebo. Relief rates two hours postdose were 68% in the high-dose group, 47% with 12.5 mg, and 25% with placebo (23). The approved dose of the sumatriptan suppository is 25 mg. Predictors for the Response to Sumatriptan The determinants for optimal response to sumatriptan were unknown. The Sumatriptan Naratriptan Aggregate Patient database was introduced and contained data from 128 clinical trials including 28,407 migraine sufferers treating over 130,000 attacks (24). These data were analyzed to identify factors predicting response (headache relief and pain-free response) to sumatriptan. A total of 24 possible univariate predictors of headache response in 3706 patients (18 years and older) receiving sumatriptan tablets 100 mg or placebo in a double-blind study were tested using recursive partitioning and logistic regression techniques. Seven predictors of headache relief two hours postdose were identied (25). Predictors included the following:  Moderate pain at baseline (was the strongest predictor, with an adjusted p 3.32 1035)  Absence of a disability requiring bed rest (second strongest predictor, adjusted p 3.11 1018)  Absence at baseline of vomiting, pulsating pain, nausea, or photophobia/ phonophobia  Onset of headache during daytime hours Logistic regression conrmed that treatment with sumatriptan was the strongest predictor of headache relief, with signicant baseline covariates being pain severity, level of disability, and presence or absence of vomiting. A similar pattern of results was reported for predictors of pain-free response two hours after taking sumatriptan. This analysis showed that pretreatment pain severity is the most important predicting factor for response to sumatriptan in migraine attacks: the lower the baseline severity, the better.

Specic Acute Migraine Treatment: Ergotamine and Triptans

295

Recently, a fast soluble tablet of sumatriptan, which reaches peak plasma levels earlier, was developed (26). Direct comparisons with the normal tablet in terms of onset of action are not yet available. In patients who do not respond to oral sumatriptan, it might be worthwhile to combine sumatriptan with an antiemetic drug such as metoclopramide, which might speed up the gastric passage (27). Pharmacokinetic and clinical studies revealed no interaction of sumatriptan with DHE, butorphanol, naratriptan, or drugs used for migraine prophylaxis such as propranolol, unarizine, pizotifen, paroxetine, and uoxetine (28,29). Systemic sumatriptan exposure is increased in patients who are treated with monoamine oxidase inhibitors (MAOIs). One study, however, treated 28 patients who were on MAOIs with 6 mg sumatriptan and found no increase in adverse events but observed a lower recurrence rate (30). Other Triptans Following sumatriptan, several new 5-HT1B/D-agonists have been developed and introduced. The further development of new 5-HT1B/D-agonists was motivated by the intention to improve the pharmacological and pharmacokinetic properties of sumatriptan. Sumatriptan has a poor oral bioavailability (14%) and a low penetration of the bloodbrain barrier. The low penetration, however, seems not to affect the efcacy of sumatriptan. If a central mechanism is indeed crucial for the clinical efcacy of triptans, this could indicate that the bloodbrain barrier becomes leaky during a migraine attack. Most of the new drugs have already been studied extensively in clinical trials. Almotriptan, frovatriptan, eletriptan, naratriptan, rizatriptan, and zolmitriptan are approved in most countries. Naratriptan Naratriptan has, in some aspects, a better pharmacokinetic prole than sumatriptan: the bioavailability of the oral formulation is almost 60% (sumatriptan 14%), which reduces the effective dosage to 2.5 mg. Moreover, the half-life is about ve hours, two to three times longer than the half-life of oral sumatriptan, which may account for a reduced percentage of patients with headache recurrence in some studies (31,32). On the other hand, the tmax is reached only after three hours (sumatriptan 1.5 hours). Dose-nding trials with doses of naratriptan between 0.1 and 10 mg showed the best relationship between efcacy and side effects to be at doses of 2.5 mg (32,33). Publications initially reported only four-hour efcacy data, which indicated a slow onset of action. Goadsby (34) had access to two-hour data and calculated NNT for naratriptan 2.5 mg of 4.8 compared with 3.0 for 50 and 100 mg oral sumatriptan. The low dose of oral naratriptan was chosen based on tolerability. At an oral dose of 2.5 mg, naratriptan has a favorable side-effect prole and is undistinguishable from placebo (35). The 1 mg dose of naratriptan is available in the United States. Naratriptan has a low recurrence rate after initial efcacy (36). It should be noted that recurrence can only occur in patients who initially have a positive response to a headache drug. Naratriptan should be used in patients with moderate migraine attacks, who are unable to tolerate the side effects of oral sumatriptan or another triptan. Zolmitriptan Zolmitriptan was the second triptan to enter the market. The pharmacokinetic prole offers interesting improvements compared to oral sumatriptan. With an oral

296

Diener and Limmroth

bioavailability of almost 50% (sumatriptan 14%), the necessary clinically effective dosage could be signicantly reduced. In addition to its vascular effects, zolmitriptan has a central mode of action (37,38). Zolmitriptan has been evaluated over a wide range of doses (125 mg) and has shown a consistently high headache response rate across placebo-controlled trials (3942). The decision was made to market the oral 2.5 mg dose. Later, the 5 mg dose was introduced. Headache response rate for the 2.5 mg dose at two hours was 62% (N 219) compared to 36% for placebo (N 108) (43). The rate of pain-free response after two hours across all dose-nding studies was 25% (N 438) (44). The rate of headache recurrence (2733%) was comparable to that of sumatriptan. One placebo-controlled study compared zolmitriptan 5 mg with sumatriptan 100 mg (42). This study employed an unusual skewed randomization ratio (1:8:8) for placebo, zolmitriptan, and sumatriptan. Due to the small number of patients in the placebo group resulting in large condence intervals, no difference was seen between the three treatment groups in terms of the primary endpoint, e.g., complete headache response. In a long-term safety and efcacy trial including more than 2200 patients with over 20,000 migraine attacks using 5 mg of oral zolmitriptan, neither safety nor efcacy was affected when the drug was used in up to 30 consecutive attacks (45). Zolmitriptan nasal spray (5 mg) has a higher efcacy than oral application and an earlier onset of action (46). The two-hour response rate of the 5 mg spray was 70% compared to 30% with placebo (47). In contrast to sumatriptan, nasal zolmitriptan is absorbed via the nasal mucosa (Fig. 3) (48). Side effects and central nervous system adverse events of oral zolmitriptan are similar to those of oral sumatriptan, although zolmitriptan can cross the bloodbrain barrier (49). Zolmitriptan has no interactions with DHE, ergotamine, pizotifen, uoxetine, paracetamol, or selegeline (50). Coadministration of propranolol resulted in a 56% increase in the area under the plasma concentrationtime curve of zolmitriptan (51). With a dose of 2.5 mg zolmitriptan, no additional side effects were seen when combining it with propranolol. MAO-A inhibitors (moclobemide) result in increased plasma levels of zolmitriptan and its metabolites. Therefore, it would be prudent to limit the total daily dose should

Figure 3 Uptake of labeled Zolmitriptan from the nasal mucosa and the subsequent increase of zolmitriptan serum levels.

Specic Acute Migraine Treatment: Ergotamine and Triptans

297

several doses be required (50). In clinical practice, 2.5 mg zolmitriptan is at least equivalent to 50 mg sumatriptan. In some patients who do not respond to sumatriptan, zolmitriptan is effective, and vice versa (52,53). A dosage of 5 mg of zolmitriptan is equivalent to 100 mg sumatriptan. Some patients who do not respond to 2.5 mg zolmitriptan will show a response to the 5 mg dose. Rizatriptan Rizatriptan also has an improved pharmacokinetic prole compared to sumatriptan. The oral bioavailability of rizatriptan is about 40% versus 14% for oral sumatriptan. Rizatriptans tmax is one hour, suggesting the potential for a faster onset of action in favor of rizatriptan. The half-life, however, is about three hours. Two clinical dosending studies have been carried out including 865 patients. Dosages were tested between 2.5 and 40 mg. Dosages of 5 mg and above were effective, with 10 mg being the most effective dosage with reasonable side effects. Two hours following the administration of the drug, 21%, 47%, 52%, 56%, and 64% of the patients receiving 2.5, 5, 10, 20, and 40 mg rizatriptan, respectively, (placebo 18%, and sumatriptan 100 mg 46%) reported relief from headache (Fig. 4) (54). In a large placebocontrolled trial (N 1473), rizatriptan 10 mg had a success rate of 71%, rizatriptan 5 mg 62%, and placebo 35% (55). Two placebo-controlled studies compared rizatriptan to oral sumatriptan and found that rizatriptan 10 mg had earlier onset of headache relief than sumatriptan 100 and 50 mg (56,57). Rizatriptan 10 mg was also superior to sumatriptan 100 mg on pain-free response and reduction in functional disability. Rizatriptan 10 mg demonstrated consistent response across four migraine attacks (58). Of the 252 patients who treated three attacks with rizatriptan, 96%, 86%, and 60% reported relief from headache at two hours in one out of three, two out of three, and three out of three attacks, respectively. In another comparative trial, the efcacies of zolmitriptan and rizatriptan were identical for the two-hour headache response (59). Concerning the end points, time to pain-free and pain-free after two hours, rizatriptan was superior to zolmitriptan. Rizatriptan was clearly

Figure 4 Dose-nding trial of rizatriptan. Percentage of patients with headache relief two hours following drug administration. Source: From Ref. 54.

298

Diener and Limmroth

superior to naratriptan (60,61). Forty-ve percent of patients were pain-free two hours after intake of 10 mg rizatriptan (n 201) compared to 21% with 2.5 mg naratriptan (n 213) and 8% with placebo (n 107). In addition to oral tablets, rizatriptan is available in a wafer that dissolves instantly on the tongue without liquid. Trial results with this application form indicate that the efcacy is comparable to that of the tablet but that patients prefer the wafer (6264). Side effects increased dose dependently and were typical for drugs of this class. Rizatriptan has an interaction with propranolol (not with metoprolol). Patients who are on propranolol prophylaxis for their migraine should only take rizatriptan 5 mg. Rizatriptan has comparable recurrence to oral sumatriptan (57). In summary, rizatriptan 10 mg has a slightly faster onset of action and is somewhat more effective than oral sumatriptan. The fast dissolving wafer is preferred by patients. Eletriptan Eletriptan has been approved recently in oral doses of 20 and 40 mg. In some countries, the 80 mg dose is also approved. Like the other new 5-HT1B/D-agonists, eletriptan has an improved oral bioavailability (almost 50%), is rapidly absorbed, and has a half-life of four to ve hours (65). In a dose-nding trial with 857 migraine patients, 20, 40, and 80 mg of eletriptan were evaluated against 100 mg of sumatriptan and placebo (Fig. 5). Headache response two hours following the administration of the drug could be observed in 55%, 65%, 77%, and 56% of the patients receiving 20, 40, 80 mg of eletriptan, and sumatriptan 100 mg, respectively (placebo 24%) (66). One should note, however, that sumatriptan was encapsulated in the comparative trials, which might have affected absorption (67,68). The rate of adverse events in

Figure 5 Dose-nding trial of eletriptan in comparison with sumatriptan and placebo: percentage of patients with headache relief two hours following drug administration. Sumatriptan was encapsulated. Source: From Ref. 65.

Specic Acute Migraine Treatment: Ergotamine and Triptans

299

the group receiving 80 mg eletriptan was higher compared with the rate in the group receiving 100 mg sumatriptan. In all other treatment groups, the rate of adverse events was signicantly lower. A second trial compared 40 mg eletriptan (n 452) with 80 mg (n 461) and placebo (n 238) (69). Headache relief after two hours was reported by 62% and 65% of the patients in the active treatment groups and 19% of patients on placebo. Of those patients with a headache response at two hours after 80 mg eletriptan, 21% had a headache recurrence after a mean time of 19 hours. In another comparative trial, 40 and 80 mg eletriptan were signicantly better effective than cafergot (2 mg ergotamine plus 200 mg caffeine) (10). In comparative trials, eletriptan was superior to naratriptan (70) and zolmitriptan (71). Eletriptan was effective in migraine patients who had a poor response to rizatriptan (72) or a combination analgesic drug (73). Almotriptan In dose-nding studies, 2, 6.25, 12.5, and 25 mg almotriptan were compared to placebo. Almotriptan was superior to placebo from a dose of 6.25 mg onward. Headache response after two hours was 58.5% with 12.5 mg almotriptan compared to 32.5% with placebo. The pain-free rates after two hours were 38% with 12.5 mg almotriptan and 11% with placebo (74,75). In another placebo-controlled trial with 722 patients, 6.25 and 12.5 mg almotriptan were used to treat three consecutive migraine attacks (76). Efcacy after two hours was 38% for placebo, 60% for 6.25 mg almotriptan, and 70% for 12.5 mg almotriptan. Efcacy in two out of three migraine attacks was 64% for the lower and 75% for the higher dose. Headache recurrence was identical in the three treated attacks and ranged between 28.7% and 30.1% for the two almotriptan doses. Another comparative trial compared 12.5 and 25 mg almotriptan, and 100 mg sumatriptan. The efcacies of sumatriptan and almotriptan were identical (77). Almotriptan had fewer side effects. Pascual performed a meta-analysis of 2294 patients treated with almotriptan (75). The efcacy of 12.5 mg almotriptan after two hours was 64% compared to 35% of placebo. The results for pain-free after two hours were 36% versus 14% (Fig. 6). In another comparative trial including 1173 patients with 50 mg sumatriptan, almotriptan showed identical efcacy with the exception of the two-hour pain-free rate, which was higher for sumatriptan (78). Long-term trials showed sustained efcacy, few adverse events, and a low number of dropouts due to adverse events (79,80). Frovatriptan Frovatriptan has an interesting receptor prole. The compound has a higher afnity to 5-HT1B/1D-receptors than sumatriptan, but is an agonist of 5-HT7-receptors as well (81). This is interesting because activation of 5-HT7-receptors (in higher dosages) might cause vasodilatation, e.g., on coronary vessels (possibly indicating no cardiovascular side effects due to vasoconstriction). In oral dose-nding studies (140 mg), dosages of 2.5 mg and above were effective (82,83). The pharmacokinetic properties, however, are similar to those of naratriptan; the drug is relatively slowly absorbed and reaches its tmax after two hours. Results for pain-free after two hours are 15% for 2.5 mg frovatriptan compared to 5% with placebo resulting in a therapeutic gain of 10% only. The second best outcome parameter is improvement of headache from severe or moderate to mild or no headache, the so-called Glaxo criterion. The efcacy rate for frovatriptan 2.5 mg is between 38% and 42%. Because there are no direct comparative trials with other triptans (except sumatriptan), an

300

Diener and Limmroth

Figure 6 Selected end points from a meta-analysis assessment of trials comparing almotriptan and placebo. Source: From Ref. 75.

indirect way to compare triptans is by calculating therapeutic gain (16). Therapeutic gain for 2.5 mg frovatriptan ranges from 15% to 26% compared to 33% for sumatriptan (100 mg), 22% for naratriptan (2.5 mg), 29% for zolmitriptan (2.5 mg), 36% for rizatriptan (10 mg), and 42% for eletriptan (40 mg) (84). Frovatriptan therefore ranges at the low end of efcacy, at least at two-hourtime points. Four-hour data, however, appear to be less important, because patients want a fast onset of action. The rate of headache recurrence varies between 25% and 40% for the other triptans. Lowest recurrence rates have been reported for naratriptan (25%) and eletriptan 80 mg (24%). One has to keep in mind that recurrence can occur only after initial improvement of headache, therefore, drugs with a low efcacy, such as naratriptan and frovatriptan, also will have a low recurrence rate. The only way to get around this problem is to report sustained pain-free data: pain-free after two hours, no recurrence for the next 24 hours, and no intake of rescue medication. These data are not yet reported for frovatriptan. In summary, frovatriptan offers no advantages over the other triptans. The Triptan Meta-Analysis Ferrari et al. performed a meta-analysis of 53 triptan trials, 12 of which had not yet been published (2). The analysis was based on data from 24,089 patients. End points for the analysis were headache response (improvement of headache from severe or moderate to mild or no headache) two hours after intake of study medication and pain-free response. Other end points were headache recurrence and consistency in two out of three treated migraine attacks. Studies were included if they were randomized, double-blind, and compared one triptan to placebo or another triptan. Oral sumatriptan 100 mg was taken as the reference drug. A total of 59% of patients

Specic Acute Migraine Treatment: Ergotamine and Triptans

301

had a headache response after two hours and 29% were pain-free. Sustained painfree, which means pain-free after two hours, no recurrence, and no intake of rescue medication, were 20% of patients. Consistency was 67%. Sumatriptan 50 mg is as effective as the 100 mg dose, but has fewer side effects. Rizatriptan 10 mg is more effective than 100 mg sumatriptan, but has a higher recurrence rate. Rizatriptan has the best consistency. Naratriptan and frovatriptan are less effective than sumatriptan but show a lower recurrence rate. Zolmitriptan 2.5 and 5 mg are as effective as sumatriptan and have a similar side effect prole. Eletriptan is available in doses of 20 and 40 mg, and in some countries in an 80 mg dose. Doses of 20 mg are inferior to sumatriptan and 40 mg are equivalent. Eletriptan 80 mg is more effective than sumatriptan and has a lower recurrence rate but more side effects. Almotriptan 12.5 mg is as effective as sumatriptan for headache response and seems to be superior for painfree. This, however, is no longer the case, when therapeutic gain is calculated. Almotriptan has a good side-effect prole.

Shortcomings of Triptans Even the new 5-HT1B/D-agonists will not solve the problems of this class of substances. Despite improved pharmacokinetics and pharmacodynamics, up to 40% of all attacks and up to 25% of all patients do not respond to any of these substances. It is unclear whether the nonresponders have a variant of migraine or a different 5HT-receptor prole. Central sensitization may play a role (see below). Some patients may suffer from tension-type headache with migraine features and are likely to not respond to a triptan. If a patient with migraine does not respond to a particular triptan on three attacks, it is worthwhile to try another triptan (52). If a patient does not respond to three oral triptans, SC sumatriptan should be tested. If this also is not effective, the patient is either a triptan-nonresponder or does not suffer from migraine. Most 5-HT1B/D-agonists have a ceiling effect where higher doses do not lead to improved efcacy. Eletriptan is the exception20, 40, and 80 mg have a linear doseefcacy relationship. Longer half-lives of new migraine drugs were supposed to decrease headache recurrence (85). Drugs with longer half-lives than sumatriptan also show headache recurrence, although with a slightly longer time interval (83,86).

Comparison with Nonsteroidal Anti-inammatory Drugs An interesting aspect of the treatment of acute migraine attack is the fact that triptans up to now have not convincingly been shown to be superior to aspirin or nonsteroidal anti-inammatory drugs (NSAIDs). At the end of the 1980s, two trials compared oral sumatriptan 100 mg with lysinated aspirin in combination with metoclopramide (87,88). These studies showed either no or only a minor difference in efcacy measured as improvement of headache. A more recent study compared 2.5 mg zolmitriptan with 900 mg lysinated aspirin in combination with 10 mg metoclopramide (89). Six hundred sixty-six patients were included in the study and treated for two migraine attacks. Improvement of headache from severe or moderate to mild or no headache was achieved in 33.4% of patients in the zolmitriptan group and in 32.9% in the aspirin group. This difference was statistically not signicant. A signicant difference was found for a secondary end point, pain-free after two

302

Diener and Limmroth

hours (10.7% for zolmitriptan and 5.3% for aspirin). In another double-blind, placebocontrolled, crossover study, patients received either 75 or 150 mg ketoprofen (NSAID), 2.5 mg zolmitriptan, or placebo. Two hundred thirty-ve patients who were treated for 838 migraine attacks were available for the intention-to-treat analysis. Improvement of headache two hours after administration of study drug was reported in 62.6% of patients receiving 75 mg ketoprofen, 61.6% after 150 mg ketoprofen, 66.8% following zolmitriptan, and 27.8% after placebo. The difference between the three active treatments was not signicant (90). We performed two placebo-controlled trials comparing 50 mg sumatriptan with 1000 mg aspirin without antiemetics. In both trials, aspirin was equivalent to sumatriptan in terms of efcacy, and both drugs were superior to placebo (91,92). The results of these studies indicate that it is worthwhile to try aspirin or a NSAID in de novo migraine patients. Patients in whom this approach has failed in the past should receive a triptan. Triptans Taken When Headache Is Mild In patients with established diagnosis of migraine, treatment effects are better when a triptan is used while the headache is mild (9396). This approach should only be used in patients with infrequent migraine attacks and in patients who can distinguish migraine from tension-type headache. Otherwise, the triptan may be used too frequently and lead to medication-overuse headache (see below). Nonresponders About 20% to 30% of patients are nonresponders to triptans. Burstein et al. (97) observed that some patients developed allodynia in the head and face region, which they explained as central sensitization. In an elegant series of experiments, Burstein could show that patients who do not develop allodynia during a migraine attack almost always respond to treatment with SC sumatriptan, while 80% of patients who had allodynia at the time of injection did not respond (98). This result indicates that triptans might have a peripheral mode of action and will not be effective once central sensitization has taken place. This observation may have major implications for the treatment of migraine attacks in clinical practice. Nonresponders to a particular triptan should be asked if they are hypersensitive to nonpainful stimuli in the face and on the head. If this is the case, they should be treated as early as possible. Recurrence Triptans and ergots have a limited time of efcacy. Therefore, in about 15% to 40% of all migraine attacks, the symptoms recur after initial improvement (85). In these cases, a second dose of triptan can be taken. Some patients, however, do not want to take a second dose. In these patients, headache recurrence can be prevented by giving a slow-release NSAID either together with the triptan or a few hours before the expected recurrence (99). Use of Triptans During the Aura The aura is unaffected by treatment with a triptan. This has been shown for sumatriptan (100) and eletriptan (101). Therefore, triptans should only be given when the

Specic Acute Migraine Treatment: Ergotamine and Triptans

303

aura symptoms have disappeared. In addition, triptans do not prevent the occurrence of headache when given during the aura. Migraine in the Emergency Room Patients coming to the emergency room with a severe migraine attack usually expect to receive a potent treatment. The treatment options here are aspirin IV (1000 mg) (102), sumatriptan SC (103), DHE IV (12 mg) (104), metamizole (dipyrone) IV (100 mg) (105), and, as recently shown, IV valproic acid (106). Medication-Overuse Headache All new 5-HT1B/D-agonists taken too often will decrease the time interval between migraine attacks, which results in medication-overuse headache such as has been observed in conjunction with ergotamine, DHE, and sumatriptan (107111). A population-based study in Denmark indicated that a small number of patients use sumatriptan on a daily or almost daily basis (109). Whether these patients had chronic cluster headache or were abusing sumatriptan is not known. We observed medication-overuse headache after use of zolmitriptan and naratriptan (112). Of this group, ve patients using zolmitriptan only (who had never taken ergotamine derivatives or other triptans before) developed drug-induced headache after a period of six months, partly with a dosage of 7.5 mg a week (i.e., three tablets weekly). This indicates that second-generation triptans with their improved pharmacological prole cause drug-induced chronic daily headache faster and at lower dosages than expected or that a pronounced central effect of action supports the development of drug-induced chronic daily headache. Safety All 5-HT1B/D-agonists have vasoconstrictive activity. Using human coronary arteries, there was no difference; the vasoconstriction was almost identical between the triptans (113,114). Therefore, all triptans are contraindicated in patients with vascular disease. Postmarketing surveillance studies and case reports indicate that sumatriptan, albeit rarely, is associated with serious cardiovascular events including myocardial infarction (MI), cardiac arrhythmia, TIA, stroke, and ischemic colitis. The frequency of serious adverse events is about 1:1 million treated attacks (115). Almost all serious adverse events occurred in patients with contraindications or other diseases than migraine. A positron emission tomography study in healthy volunteers showed that 6 mg sumatriptan SC had no inuence on myocardial perfusion (116). Another trial observed no changes in myocardial blood ow in migraineurs after the use of naratriptan (117). Large-scale epidemiological studies conrmed that migraine patients have an increased risk of stroke. The risk of stroke and MI is not increased in patients treating their migraine attacks with a triptan compared with analgesics or NSAIDs (118,119). GlaxoSmithKline established a pregnancy register to obtain data from patients and newborns, when sumatriptan was taken during pregnancy (although not recommended). Up to now, the data from almost 300 pregnancies are available and indicate that there is no increased risk of major birth defects (120122). Two other observational studies found no increase in fetal malformations (123,124).

304

Diener and Limmroth

CONCLUSIONS The introduction of the rst triptan in the early 1990s revolutionized the acute treatment of migraine and provided new insights into the pathophysiology and pharmacology of migraine. A decade later, seven triptans in over 20 different preparations are available and allow the physician to customize the treatment of acute attacks according to the patients needs. With over 200 clinical trials and long-term safety results from several thousand patients, triptans can be considered as safe and well tolerated. Comparative trials showed that triptans are superior to ergotamine derivatives in both clinical efcacy and tolerability. Triptans, however, are not the nal answer for the acute treatment of migraine attacks, because a signicant percentage of migraine patients do not respond to this group. But it will take at least a decade for new drug entities to challenge the triptan family as drugs of rst choice in the acute treatment of migraine.

REFERENCES
1. Tfelt-Hansen P. Preliminary analysis of randomized placebo-controlled clinical trials with newer 5-HT1D receptor agonists for the treatment of migraine attacks. In: Olesen J, Tfelt-Hansen P, eds. Headache Treatment: Trial Methodology and New Drugs. New York: Lippincott-Raven 1997:6:253256. 2. Ferrari MD, Roon KI, Lipton RB, Goadsby P. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001; 358:16681675. 3. Belsey JB. Reconciling effectiveness and tolerability in oral triptan therapy: a qualitative approach to decision making in migraine management. J Clin Res 2001; 4:105125. 4. Tfelt-Hansen P, Block G, Dahlof C, et al. for the International Headache Society Clinical Trials Subcommittee. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000; 20:765786. 5. Tfelt-Hansen P, Saxena PR, Dahlof C, et al. Ergotamine in the acute treatment of migraine. A review and European consensus. Brain 2000; 123:918. 6. Dahlof C. Placebo-controlled clinical trials with ergotamine in the acute treatment of migraine. Cephalalgia 1993; 13:166171. 7. McNeely W, Goa KL. Diclofenac-potassium in migraine. Drugs 1999; 57:9911003. 8. Titus F, Lainez J, Leira R, Diez E, Monteiro P, Dexeus I. Double-blind, multicentric, comparative study of lysin acetylsalicylate (1620 mg equivalent to 900 mg aspirin) metoclopramide (10 mg) versus ergotamine (2 mg) caffeine (200 mg) in the treatment of migraine. Cephalalgia 1999; 19:371. 9. The Multinational Oral Sumatriptan Cafergot Comparative Study Group. A randomized, double-blind comparison of sumatriptan and Cafergot in the acute treatment of migraine. Eur Neurol 1991; 31:314322. 10. Diener HC, Reches A, Pascual J, Jansen J-P, Pitei D, Steiner T. on behalf of the Eletriptan Cafergot Comparative Study Group. Efcacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicenter, randomized, double-blind, placebo-controlled comparison. Eur Neurol 2002; 47:99107. 11. Christie S, Gobel H, Mateos V, Allen C, Vrijens F, Shivaprakash M. Rizatriptan Ergotamine/Caffeine Preference Study Group. Crossover comparison of efcacy and preference for rizatriptan 10 mg versus ergotamine/caffeine in migraine. Eur Neurol 2002; 49:2029.

Specic Acute Migraine Treatment: Ergotamine and Triptans

305

12. Horton BT, Peters GA. Clinical manifestations of excessive use of ergotamine preparations and management of withdrawal effect: report of 52 cases. Headache 1963; 3:214226. 13. Diener HC, Limmroth V. Medication-overuse headache: a worldwide problem. Lancet Neurol 2004; 3:475483. 14. Olesen J, Bousser M-G, Diener H, et al. for the International Headache Society. The International Classication of Headache Disorders. 2nd ed. Cephalalgia 2004; 24(suppl 1):1160. 15. Diener HC, Katsarava Z. Medication overuse headache. Curr Med Res Opin 2002; 17:1721. 16. Tfelt-Hansen P. Efcacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat. Cephalalgia 1998; 18:532538. 17. Pfaffenrath V, Cunin G, Sjonell G, Prendergast S. Efcacy and safety of sumatriptan tablets (25 mg, 50 mg, and 100 mg) in the acute treatment of migraine: dening the optimum doses of oral sumatriptan. Headache 1998; 38:184190. 18. Moore KHP, Hussey EK, Shaw S, Fuseau E, Duquesnoy C, Pakes GE. Safety, tolerability, and pharmacokinetics of sumatriptan in healthy subjects following ascending single intranasal doses and multiple intranasal doses. Cephalalgia 1997; 17:541550. 19. Becker WJ. on behalf of the Study Group. A placebo-controlled, dose-dening study of sumatriptan nasal spray in the acute treatment of migraine. Cephalalgia 1995; 15(suppl 14):271276. 20. Ryan R, Elkind A, Baker CC, Mullican W, DeBussy S, Asgharnejad M. Sumatriptan nasal spray for the acute treatment of migraine. Neurology 1997; 49:12251230. 21. Ashford E, Salonen R, Saiers J, Woessner M. Consistency of response to sumatriptan nasal spray across patient subgroups and migraine types. Cephalalgia 1998; 18:273277. 22. Gobel H. on behalf of the Study Group. A placebo-controlled, dose dening study of sumatriptan suppositories in the acute treatment of migraine. Cephalalgia 1995; 15(suppl 14):232. 23. Tepper SJ, Cochran A, Hobbs S, Woessner M. on the behalf of the S2B351 Study Group. Sumatriptan suppositories for the acute treatment of migraine. Int J Clin Pract 1998; 52:3135. 24. Barrows C, Saunders W, Austin R, Putnam G, Mansbach H, for the SNAP Study Group. The sumatriptan/naratriptan aggregated patient (SNAP) database: aggregation, validation and application. Cephalalgia 2004; 24:586595. 25. Diener HC, Ferrari M, Mansbach H. for the SNAP Database Study Group. Predicting the response to sumatriptan: the Sumatriptan Naratriptan Aggregate Patient Database. Neurology 2004; 63:520524. 26. Walls C, Lewis A, Bullman J, et al. Pharmokinetic prole of a new form of sumatriptan tablets in healthy volunteers. Curr Med Res Opin 2004; 20:803809. 27. Schulman E, Dermott K. Sumatriptan plus metoclopramide in triptan-nonresponsive migraineurs. Headache 2003; 43:729733. 28. Perry CM, Markham A. Sumatriptan. An updated review of its use in migraine. Drugs 1998; 55:889922. 29. Joffe RT, Sokolov ST. Co-administration of uoxetine and sumatriptan: the Canadian experience. Acta Psychiatr Scand 1997; 95:551552. 30. Freitag FG, Diamond S, Diamond M, Urban G, Pepper B. Subcutaneous sumatriptan in patients treated with monoamine oxidase inhibitors and other prophylactic agents. Headache Q 1998; 9:165171. 31. Klassen A, Elkind A, Asharnejad M, Webster C, Laurenza A. on behalf of the Naratriptan S2WA3001 Study Group. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, parallel-group study. Headache 1997; 37:630645.

306

Diener and Limmroth

32. Mathew NT, Asgharnejad M, Peykamian M, Laurenza A. on behalf of the Naratriptan S2WA3001 Study Group. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, crossover study. Neurology 1997; 49:14851490. 33. Gunasekara NS, Wiseman LR. Naratriptan. CNS Drugs 1997; 8:402408. 34. Goadsby PJ. Treatment of acute migraine attacks with naratriptan. In: Diener H-C, ed. Drug Treatment of Migraine and other Frequent Headaches. Basel: Karger AG, 2000:134140. 35. Heywood J, Bomhof MAM, Pradalier A, Thaventhiran L, Winter P, Hassani H. Tolerability and efcacy of naratriptan tablets in the acute treatment of migraine attacks for 1 year. Cephalalgia 2000; 20:470474. 36. Sheftell F, OQuinn S, Watson C, Pait D, Winter P. Low migraine headache recurrence with naratriptan: clinical parameters related to recurrence. Headache 2000; 40:103110. 37. Goadsby PJ, Knight YE. Direct evidence for central sites of action of zolmitriptan (311C90): an autoradiographic study in cat. Cephalalgia 1997; 17:153158. 38. Ellrich J, Messlinger K, Chiang CY, Hu JW. Modulation of neuronal activity in the nucleus raphe magnus by the 5-HT1-receptor agonist naratriptan in rat. Pain 2001; 90:227231. 39. Ferrari MD. 311C90: increasing the options for the therapy with effective acute antimigraine 5HT1B/D receptor agonists. Neurology 1997; 48(suppl 3):2124. 40. Rapoport AM, Ramadan NM, Adelmann JU, et al. on behalf of The 017 Clinical Trial Study Group. Optimizing the dose of zolmitriptan (Zomig, 311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, dose-nding study. Neurology 1997; 49:12101218. 41. Dahlof C, Diener HC, Goadsby PJ, et al. Zolmitriptan, a 5-HT1B/D receptor agonist for the acute oral treatment of migraine: a multicenter, dose-range nding study. Eur J Neurol 1998; 5:535543. 42. Geraud G, Olesen J, Pfaffenrath V, et al. on behalf of the Study Group. Comparison of the efcacy of zolmitriptan and sumatriptan: issues in migraine trial design. Cephalalgia 2000; 20:3038. 43. Solomon GD, Cade RK, Klapper JA, Earl NL, Saper JR, Ramadan NM. on behalf of The 042 Clinical Trial Study Group. Clinical efcacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. Neurology 1997; 49:12191225. 44. Schoenen J, Sawyer J. Zolmitriptan (Zomig, 311C90), a novel dual central and peripheral 5HT1B/1D agonist: an overview of efcacy. Cephalalgia 1997; 17(suppl 18):2840. 45. The International 311C90 Long-Term Study Group. The long-term tolerability and efcacy of oral zolmitriptan (Zomig, 311C90) in the acute treatment of migraine. An international study. Headache 1998; 38:173183. 46. Becker WJ, Lee D. Zolmitriptan nasal spray is effective, fast-acting and well tolerated during both, short- and long-term treatment. Cephalalgia 2001; 21:271. 47. Dowson AJ, Boes-Hansen S, Farkkila AM. Zolmitriptan nasal spray is fast-acting and highly effective in the acute treatment of migraine. Eur J Neurol 2000; 7(suppl 3):82. 48. Sorensen J, Bergstrom M, Antoni A, et al. Distribution of 11C-zolmitriptan nasal spray assessed by positron emission tomography (PET). Eur J Neurol 2000; 7(suppl 3):82. 49. Edmeads JG, Millson DS. Tolerability prole of zolmitriptan (Zomig; 311C90), a novel dual central and peripherally acting 5HT1B/1D agonist. Cephalalgia 1997; 17:4152. 50. Rolan P. Potential drug interactions with the novel antimigraine compound zolmitriptan (Zomig (R), 311C90). Cephalalgia 1997; 17(suppl 18):2127. 51. Peck RW, Seaber EJ, Dixon RM, et al. The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women. Clin Pharmacol Ther 1998; 63(3):342353. 52. Stark S, Spierings ELH, McNeal S, Putnam GP, Bolden-Watson CP, OQuinn S. Naratriptan efcacy in migraineurs who respond poorly to oral sumatriptan. Headache 2000; 40:513520.

Specic Acute Migraine Treatment: Ergotamine and Triptans

307

53. Pascual J, Munoz R, Leira R. An open preference study with sumatriptan 50 mg and zolmitriptan 2.5 mg in 100 migraine patients. Cephalalgia 2001; 21:680684. 54. Visser WH, Terwindt GM, Reines SA, Jiang K, Lines CR, Ferrari MD. for the Dutch/U.S. Rizatriptan Study Group. Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Arch Neurol 1997; 53: 11321137. 55. Teall J, Tuchmann M, Cutler N, et al. on behalf of the Rizatriptan 022 Study Group. Rizatriptan (MAXALT) for the acute treatment of migraine and migraine recurrence. A placebo-controlled, outpatient study. Headache 1998; 38:281287. 56. Tfelt-Hansen P, Teall J, Rodriguez F, et al. on behalf of the Rizatriptan 030 Study Group. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Headache 1998; 38:748755. 57. Goldstein J, Ryan R, Jiang K, et al. and the Rizatriptan Protocol 046 Study Group. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 and 50 mg in migraine. Headache 1998; 38:737747. 58. Kramer MS, Matzura-Wolfe D, Polis A, et al. Rizatriptan Multiple Attack Study Group. A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Neurology 1998; 51:773781. 59. Pascual J, Vega P, Diener HC, Allen C, Vrijens F, Patel K. and the RizatriptanZolmitriptan Study Group. Comparison of rizatriptan 10 mg vs. zolmitriptan 2.5 mg in the acute treatment of migraine. Cephalalgia 2000; 20:455461. 60. Bomhof M, Paz J, Legg N, Allen C, Vandormael K, Patel K. Comparison of rizatriptan 10 mg vs. naratriptan 2.5 mg in migraine. Eur Neurol 1999; 42:173179. 61. Goadsby PJ. Rizatriptan in acute treatment of migraine: update on new comparative data. Cephalalgia 2000; 20(suppl 1):1015. 62. Ahrens SP, Farmer MV, Williams D, et al. Rizatriptan Wafer Protocol 049 Study Group. Efcacy and safety of rizatriptan wafer for the acute treatment of migraine. Cephalalgia 1999; 19:525530. 63. Adelman JU, Mannix LK, Seggern von RL. Rizatriptan tablet versus wafer: patient preference. Headache 2000; 40:371372. 64. Klapper JA, OConnor S. Rizatriptan wafer-sublingual vs. placebo at the onset of acute migraine. Cephalalgia 2000; 20:585587. 65. Diener HC, McHarg A. Pharmacology and efcacy of eletriptan for the treatment of migraine attacks. Int J Clin Pract 2000; 54:670674. 66. Goadsby PJ, Ferrari MD, Olesen J, et al. for the Eletriptan Steering Committee. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology 2000; 54:156163. 67. Milton KA, Kleinermans D, Scott N, Cooper JDH. The bioequivalence of standard sumatriptan tablets and two encapsulated forms of sumatriptan. Int J Pharm Med 2001; 15:2126. 68. Salonen R, Kori S, Scott A, Richardson MS. Encapsulated sumatriptan is not bioequivalent to commercial sumatriptan. Headache 2003; 43:923924 [comment]; 924928 [author reply]. 69. Diener HC. Eletriptan therapy. In: Diener HC, ed. Drug Treatment of Migraine and Other Headaches. Basel: Karger, 2000:184189. 70. Garcia-Ramos GME, Hilliard B, Bordini CA, Leston J, Hettiarachchi J. Comparative efcacy of eletriptan vs. naratriptan in the acute treatment of migraine. Cephalalgia 2003; 23:869876. 71. Steiner T, Diener H, MacGregor E, Schoenen J, Muirhead N, Sikes C. Comparative efcacy of eletriptan and zolmitriptan in the acute treatment of migraine. Cephalalgia 2003; 23:942952. 72. Goldstein J, Tiseo P, Denaro J, Sikes C. Efcacy of eletriptan in migraine patients reporting unsatisfactory response to rizatriptan. Poster presentation at the 7th Biennial European Headache Federation Congress, 2004.

308

Diener and Limmroth

73. Diamond M, Hettiarachchi J, Hilliard B, Sands G, Nett R. Effectiveness of eletriptan in acute migraine: primary care for Excedrin nonresponders. Headache 2004; 44:209216. 74. Cabarrocas X, Zayas JM. on behalf of the Almotriptan Oral Study Group. Efcacy data on oral almotriptan, a novel 5-HT1B/D agonist. Headache 1998; 38:377. 75. Pascual J. Therapy with other triptans: almotriptan. In: Diener HC, ed. Drug Treatment of Migraine and Other Headaches. Basel: Karger, 2000:197205. 76. Pascual J, Falk RM, Piessens F, et al. Consistent efcacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: results of a large, randomized, double-blind, placebo-controlled study. Cephalalgia 2000; 20:588596. 77. Cabarrocas X, Zayas JM, Suris M. on behalf of the Almotriptan Oral Study Group. Equivalent efcacy of oral almotriptan, a new 5-HT1B/D agonist, compared with sumatriptan 100 mg. Headache 1998; 38:377378. 78. Spierings E, Gomez-Mancilla B, Grosz D, Rowland C, Whaley F, Jirgens K. Oral almotriptan vs. oral sumatriptan in the abortive treatment of migraine: a double-blind, randomized, parallel-group, optimum-dose comparison. Arch Neurol 2001; 58:944950. 79. Mathew NT. for the Oral Almotriptan Study Group. A long-term open-label study of oral almotriptan 12.5 mg for the treatment of acute migraine. Headache 2002; 42:3240. 80. Cabarrocas X, Esbri R, Peris F, Ferrer P. Long-term efcacy and safety of oral almotriptan: interim analysis of a 1-year open study. Headache 2001; 41:5762. 81. Brown AM, Ho M, Thomas DR, Parson AA. Comparison of functional effects of frovatriptan, sumatriptan and naratriptan on human recombinant 5-HT1 and 5-HT7 receptors. Headache 1998; 38:376. 82. Goldstein J, Elkind A, Keywood C, Klapper J, Ryan R. A low dose range-nding study of frovatriptan: a potent selective 5-HT1B/D agonist for the acute treatment of migraine. Headache 1998; 38:382383. 83. Goldstein J, Keywood C. and the 251/96/14 Study Group. Frovatriptan for the acute treatment of migraine: a dose-nding study. Headache 2002; 42:4148. 84. Ferrari MD. How to assess and compare drugs in the management of migraine: success rates in terms of response and recurrence. Cephalalgia 1999; 19(suppl 23):28. 85. Visser WH, Jaspers N, de Vriend RHM, Ferrari MD. Risk factors for headache recurrence after sumatriptan: a study in 366 migraine patients. Cephalalgia 1996; 16:264269. 86. McDavis HL, Hutchison J. Frovatriptan Phase III Investigators. Frovatriptan- a review of overall clinical efcacy. Cephalalgia 1999; 19:363364. 87. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. Eur Neurol 1992; 32:177184. 88. Tfelt-Hansen P, Henry P, Mulder LJ, Schaeldewaert RG, Schoenen J, Chazot G. The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet 1995; 346:923926. 89. Geraud G, Compagnon A, Rossi A. The COZAM Study Group. Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double-blind, randomized, three-attack study. Eur Neurol 2002; 47:8898. 90. Dib M, Massiou H, Weber M, Henry P, Garcia-Acosta S, Bousser M. Bi-Profenid Migraine Study Group. Efcacy of oral ketoprofen in acute migraine: a double-blind randomized clinical trial. Neurology 2002; 58:16601665. 91. Diener HC, Eikermann A, Gessner U, et al. Efcacy of 1,000 mg effervescent acetylsalicylic acid and sumatriptan in treating associated migraine symptoms. Eur Neurol 2004; 52:5056. 92. Diener HC, Bussone G, de Liano H, et al. The EMSASI Study Group. Placebocontrolled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia 2004; 24:947954. 93. Ryan RE, Diamond S, Giammarco RAM, Aurora SK, Reed RC, Fletcher PE. Efcacy of zolmitriptan at early time points for acute treatment of migraine and treatment of recurrence. CNS Drugs 2000; 13:215226.

Specic Acute Migraine Treatment: Ergotamine and Triptans

309

94. Pascual J, Cabarrocas X. Within-patient early versus delayed treatment of migraine attacks with almotriptan: the sooner the better. Headache 2002; 42:2831. 95. Cady RK, Sheftell F, Lipton RB, et al. Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials. Clin Ther 2000; 22:10351048. 96. Mathew N. Early intervention with almotriptan improves sustained pain-free response in acute migraine. Headache 2003; 43:10751079. 97. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614624. 98. Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against development of cutaneous allodynia. Ann Neurol 2004; 55:1926. 99. Krymchantowski AV, Adriano M, Fernandes D. Tolfenamic acid decreases migraine recurrence when used with sumatriptan. Cephalalgia 1999; 19:186187. 100. Bates D, Ashford E, Dawson R, et al. Subcutaneous sumatriptan during the migraine aura. Neurology 1994; 44:15871592. 101. Olesen J, Diener HC, Schoenen J, Hettiarachchi J. No effect of eletriptan administration during the aura phase of migraine. Eur J Neurol 2004; 11:671677. 102. Diener HC. for the ASASUMAMIG Study Group. Efcacy and safety of intravenous acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine. A double-blind, double-dummy, randomized, multicenter, parallel group study. Cephalalgia 1999; 19:581588. 103. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325:316321. 104. Silberstein S, Douglas C, McCrory D. Ergotamine and dihydroergotamine: history, pharmacology, and efcacy. Headache 2003; 43:144166. 105. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous dipyrone in the acute treatment of migraine without aura and migraine with aura: a randomized, double blind, placebo controlled study. Headache 2002; 42(9):862871. 106. Leniger T, Pageler L, Stude P, Diener H, Limmroth V. Comparison of intravenous valproate with intravenous lysine-acetylsalicylic acid in acute migraine. Headache 2005; 45:4246. 107. Diener HC, Tfelt-Hansen P. Headache associated with chronic use of substances. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven Press, 1993:721727. 108. Kaube H, May A, Diener HC, Pfaffenrath V. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308:1573. 109. Gaist D, Tsiropoulus I, Sindrup SH, Hallas J, Rasmussen BK, Kragstrup J. Inappropriate use of sumatriptan: population based register and interview study. Br J Med 1998; 316:13521353. 110. Gaist D. Use and overuse of sumatriptan. Pharmaco-epidemiological studies based on prescription register and interview data. Cephalalgia 1999; 19:735761. 111. Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener H. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 2002; 59:10111014. 112. Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after frequent use of new 5-HT agonists zolmitriptan and naratriptan. Lancet 1999; 353:378. 113. Maassen van den Brink A, Reekers M, Bax WA, Ferrari MD, Saxena PR. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 1998; 98:2530. 114. Maassen van den Brink A, Broek vdRWM, Vries dR, Bogers AJJC, Avezaat CJJ, Saxena PR. Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels. Neurology 2000; 55:15241530. 115. Welch KMA, Mathew NT, Stone P, Rosamond W, Saiers J, Gutterman D. Tolerability of sumatriptan: clinical trials and post-marketing experience. Cephalalgia 2000; 20:687695.

310

Diener and Limmroth

116. Lewis PJ, Barrington SF, Marsden PK, Maisey MN, Lewis LD. A study of the effects of sumatriptan on myocardial perfusion in healthy male migraineurs using 13NH3 positron emission tomography. Cephalalgia 1997; 48:15421550. 117. Gnecchi-Ruscone T, Bernard X, Pierre P, et al. Effect of naratriptan on myocardial blood ow and coronary vasodilator reserve in migraineurs. Neurology 2000; 55:9599. 118. Hall G, Brown M, Mo J, MacRae K. Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 2004; 62:563568. 119. Velentgas P, Cole JA, Mo J, Sikes CR, Walker AM. Severe vascular events in migraine patients. Headache 2004; 44:642651. 120. Shuhaiber S, Pastuszak A, Schick B, et al. Pregnancy outcome following rst trimester exposure to sumatriptan. Neurology 1998; 51:581583. 121. Kallen B, Lygner PE. Delivery outcome in women who used drugs for migraine during pregnancy with special reference to sumatriptan. Headache 2001; 41:351356. 122. Fox AW, Chambers CD, Anderson PO, Diamond ML, Spierings ELH. Evidence-based assessment of pregnancy outcome after sumatriptan exposure. Headache 2002; 42:815. 123. Olesen C, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. Pregnancy outcome following prescription for sumatriptan. Headache 2000; 40:2024. 124. OQuinn S, Ephross SA, Williams V, Davis RL, Gutterman DL, Fox AW. Pregnancy and perinatal outcomes in migraineurs using sumatriptan: a prospective study. Arch Gynecol Obstet 1999; 263:712.

22
Preventive Treatment for Migraine
Stephen D. Silberstein
Department of Neurology, Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTIONWHY AND WHEN TO USE MIGRAINE-PREVENTIVE MEDICATIONS Migraine is a common episodic headache disorder characterized by attacks that consist of various combinations of headache and neurologic, gastrointestinal, and autonomic symptoms. It has a one-year prevalence of approximately 18% in women, 6% in men, and 4% in children (1,2). The second edition of the International Classication of Headache Disorders (ICHD-2) (3) subclassies migraine into migraine without aura (1.1) and migraine with aura (1.2), the aura being the complex of focal neurologic symptoms that most often precede or accompany an attack (3). Migraine varies widely in its frequency, severity, and impact on the patients quality of life. A treatment plan should consider not only the diagnosis, symptoms, and any coexistent or comorbid conditions the patient may have, but also the patients expectations, needs, and goals (4). The pharmacologic treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Acute treatment attempts to relieve or stop the progression of an attack or the pain and impairment once an attack has begun. It is appropriate for most attacks and should be used for a maximum of two to three days a week. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benets include improving responsiveness to acute attack treatment, improving function, and reducing disability. There is a possibility that preventive treatment may also prevent episodic migraines progression to chronic migraine and result in health-care cost reductions. Silberstein et al. (5) retrospectively analyzed resource utilization information in a large claims database. The addition of migraine preventive drug therapy to therapy that consisted of only an acute medication was effective in reducing resource consumption. During the second six months after the initial preventive medication, as compared with the six months preceding preventive therapy, ofce and other outpatient visits with a migraine diagnosis decreased by 51.1%; emergency department (ED) visits with a migraine diagnosis decreased by 81.8%; computed tomography (CT) scans with a migraine diagnosis decreased by 75.0%; magnetic resonance
311

312

Silberstein

Box 1 U.S. Evidence-Based Guidelines for MigrainePreventive Treatment 1. Recurring migraine that signicantly interferes with the patients daily routine despite acute treatment (e.g., two or more attacks a month that produce disability that lasts three or more days, or headache attacks that are infrequent but produce profound disability) 2. Failure of, contraindication to, or troublesome side effects from acute medications 3. Overuse of acute medications 4. Special circumstances, such as hemiplegic migraine or attacks with a risk of permanent neurologic injury 5. Very frequent headaches (more than two a week), or a pattern of increasing attacks over time, with the risk of developing medication overuse headache 6. Patient preference, that is, the desire to have as few acute attacks as possible

imagings (MRIs) with a migraine diagnosis decreased by 88.2%; and other migraine medication dispensements decreased by 14.1% (5). According to the U.S. Evidence-Based Guidelines for Migraine (6), circumstances that might warrant preventive treatment are shown in Box 1. These rules are stricter during pregnancysevere disabling attacks accompanied by nausea, vomiting, and possibly dehydration are required for preventive treatment to be prescribed (7). It is clear that preventive therapy is not being utilized to nearly the extent it should be. Results from the American Migraine Study I and II and the Philadelphia phone survey II demonstrated that migraine preventive therapy is underutilized. In the American Migraine Study II, 25% of all people with migraine, or more than seven million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest (2). However, only 5% of all migraineurs currently use preventive therapy to control their attacks (8). The major medication groups for preventive migraine treatment (Table 1) include anticonvulsants, antidepressants, b-adrenergic blockers, calcium channel
Table 1 Preventive Prescription Drugs ACE inhibitors/angiotensins Receptor antagonist Anticonvulsants Valproate, gabapentin, topiramate Antidepressants TCAs, SSRIs, MAOIs b-adrenergic blockers Propranolol/nadolol/metoprolol/atenolol Calcium channel antagonists Verapamil/unarizine Neurotoxins Serotonin antagonists Methysergide/methergine Others NSAIDs, riboavin, magnesium, feverfew, butterbur root, neuroleptics
Abbreviations: ACE, angiotensin-converting enzyme; TCA, tricyclic antidepressants; SSRI, selective serotonin reuptake inhibitor; MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal anti-inammatory drug.

Preventive Treatment for Migraine Table 2 Migraine Comorbid Diseases Cardiovascular Hyper-/hypotension Raynauds Mitral valve prolapse Angina/myocardial infarction Stroke Psychiatric Depression Mania Panic disorder Anxiety disorder Neurologic Epilepsy Essential tremor Positional vertigo GI Irritable bowel syndrome Other Asthma Allergies
Abbreviation: GI, gastrointestinal.

313

antagonists, serotonin antagonists, neurotoxins, nonsteroidal anti-inammatory drugs (NSAIDs), and others (including riboavin, minerals, and herbs). If preventive medication is indicated, the agent should be preferentially chosen from one of the rst-line categories, based on the drugs side-effect prole and the patients coexistent and comorbid conditions (Table 2) (9). MECHANISM OF ACTION OF PREVENTIVE MEDICATIONS The migraine aura is probably due to cortical spreading depression (CSD), a decrease in electrical activity that moves across the cerebral cortex at a rate of 2 to 3 mm/min. Headache probably results from activation of meningeal and blood vessel nociceptors combined with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Trigeminal sensory neurons contain substance P, calcitonin generelated peptide (CGRP), and neurokinin A. Stimulation results in the release of substance P and CGRP from sensory C-ber terminals and neurogenic inammation (NI). The neuropeptides interact with the blood vessel wall, producing dilation, plasma protein extravasation, and platelet activation (10). Neurogenic inammation sensitizes nerve bers (peripheral sensitization), which now respond to previously innocuous stimuli, such as blood vessel pulsations, causing, in part, the pain of migraine. Central sensitization (CS) of trigeminal nucleus caudalis neurons can also occur. CS may play a key role in maintaining the headache. Brainstem activation also occurs in migraine without aura, in part due to increased activity of the endogenous antinociceptive system. The migraine aura can trigger headache: CSD activates trigeminovascular afferents. Stress can also activate meningeal plasma cells via a parasympathetic mechanism, leading to nociceptor activation (11).

314

Silberstein

Migraine may be a result of a change in processing of pain and sensory input. The aura is triggered in the hypersensitive cortex (CSD). Headache is generated by central pain facilitation and NI. CS can occur, in part, mediated by supraspinal facilitation. Decreased antinociceptive system activity and increased peripheral input may be present. Most migraine preventive drugs were designed to treat other disorders. Serotonin antagonists were developed based on the concept that migraine is due to excess 5-hydroxytryptamine (5-HT). Antidepressants downregulate 5-HT2 and b-adrenergic receptors. Anticonvulsant medications decrease glutamate and enhance gamma-aminobutyric acid (GABAA). Potential mechanisms of migraine preventive medications include raising the threshold to migraine activation by stabilizing a more reactive nervous system, enhancing antinociception, inhibiting CSD, inhibiting peripheral sensitization and CS, blocking NI, and modulating sympathetic, parasympathetic, or serotonergic tone. Oshinsky has shown that descending control from the upper brainstem, through serotonergic and noradrenergic systems, modulates the trigeminal nucleus caudalis and prevents CS. Moskowitz has recently shown that preventive medications given chronically, but not acutely, block CSD (12). Principles of Preventive Therapy The following principles are useful regardless of the chosen preventive medication:  The chosen drug should be started at a low dose and increased slowly until therapeutic effects develop, the ceiling dose for the chosen drug is reached, or side effects become intolerable.  Each treatment must be given an adequate trial. A full therapeutic trial may take two to six months. In controlled clinical trials, efcacy is often rst noted at four weeks and continues to increase for three months.  Interfering, overused, and contraindicated drugs must be avoided. To obtain maximal benet from preventive medication, the patient should not overuse analgesics, opioids, triptans, or ergot derivatives.  Therapy must be reevaluated: Migraine headaches may improve, independent of treatment. If the headaches are well controlled, the drug dosage must be slowly tapered and, if possible, discontinued. Many patients experience continued relief with a lower dose of the medication, and others may not require it at all.  A woman of childbearing potential must be made aware of potential risks and the medication that will have the least adverse effect on the fetus must be picked (13).  Patients must be made to involve themselves in their care to maximize compliance. Patient preferences must be taken into account when deciding between drugs of relatively equivalent efcacy. The rationale for a particular treatment, when and how to use it, and what are the likely side effects must be discussed. The patients expectations must be addressed. The expected benets of therapy and how long it will take to achieve them must be discussed with the patients.  Comorbidity, which is the presence of two or more disorders whose association is more likely than chance, must be considered. Conditions that are comorbid with migraine include stroke, epilepsy, mitral valve prolapse, Raynauds syndrome, and certain psychological disorders, including depression, mania, anxiety, and panic (Table 2) (1417).

Preventive Treatment for Migraine

315

SPECIFIC MIGRAINE-PREVENTIVE AGENTS b-Adrenergic Blockers b-blockers, the most widely used class of drugs in prophylactic migraine treatment, are approximately 50% effective in producing a greater than 50% reduction in attack frequency. Rabkin et al. (18) serendipitously discovered propranolols effectiveness in headache treatment in patients who were being treated for angina (19). The Agency for Healthcare Policy and Research (AHCPR) Technical Report (20) and the U.S. Headache Consortium (21) analyzed 74 controlled trials of b-blockers for migraine prevention. Evidence consistently showed propranolol to be effective for migraine prevention with a daily dose of 120 to 240 mg. No absolute correlation has been found between propranolols dose and its clinical efcacy (22). One meta-analysis revealed that, on average, propranolol yielded a 44% reduction in migraine activity compared with a 14% reduction with placebo. Overall, one out of six patients discontinued propranolol treatment (23). Linde and Rossnagel (24) in a Cochrane analysis included randomized and quasi-randomized clinical trials of at least four weeks duration, comparing the clinical effects of propranolol with placebo or another drug in adult migraineurs. A total of 58 trials with 5072 participants met the inclusion criteria. Overall, the 26 placebocontrolled trials showed clear short-term effects of propranolol over placebo. The 47 comparisons with calcium antagonists, other beta-blockers, and a variety of other drugs did not yield any clear-cut differences. Propranolol was more effective than placebo in the short-term interval treatment of migraine (25). One trial comparing propranolol and amitriptyline suggested that propranolol is more efcacious in patients with migraine alone, and amitriptyline has a superior effect on patients with the phenotypes of migraine and tension-type headache (26). Four trials comparing metoprolol with placebo had mixed results (2730). Metoprolol was similar to propranolol (28,3133), unarizine (34,35), and pizotifen (36). Timolol (3739), atenolol (4042), and nadolol (1417,43,44) are also likely to be benecial based on comparisons with placebo or with propranolol. b-Blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, and pindolol) are not effective for migraine prevention (4550). The only factor that correlates with the efcacy of b-blockers is the absence of partial agonist activity (31,41,5154). Mechanism of Action The mechanism of action of b-blockers is not certain, but it appears that their antimigraine effect is due to inhibition of b1-mediated mechanisms (55). b-Blockade inhibits norepinephrine (NE) release by blocking prejunctional b-receptors. In addition, it results in a delayed reduction in tyrosine hydroxylase activity, the ratelimiting step in NE synthesis, in the superior cervical ganglia. In the rat brainstem, a delayed reduction of the locus ceruleus neuronring rate has been demonstrated after propranolol administration (55). This could explain the delay in the prophylactic effect of the b-blocker. The action of b-blockers is probably central and could be mediated by (i) inhibiting central b-receptors interfering with the vigilance-enhancing adrenergic pathway, (ii) interaction with 5-HT receptors (but not all b-blockers bind to the 5-HT receptors), and (iii) cross-modulation of the serotonin system (56). Propranolol inhibits nitric oxide (NO) production by blocking inducible NO

316

Silberstein

synthase. Propranolol also inhibits kainate-induced currents and is synergistic with N-methyl D-aspartate blockers, which reduce neuronal activity and has membrane-stabilizing properties (57). Schoenen et al. (58) have shown that contingent negative variation (CNV), an event-related slow negative scalp potential, is signicantly increased and its habituation reduced in patients with untreated migraine without aura. CNV normalizes after treatment with b-blockers, which is consistent with central adrenergic hyperactivity in migraine. Migraineurs who have elevated CNV scores have a much better response to b-blocker therapy (80% effective) than migraineurs who have a low or normal score (22% effective), suggesting that the CNV may predict the response to b-blocker treatment (58). Migraineurs exhibit an enhanced, centrally mediated secretion of epinephrine after exposure to light (59); this returns to normal after treatment with propranolol. All b-blockers can produce behavioral adverse events (AEs), such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression, memory disturbance, and hallucinations, indicating that they all affect the central nervous system (CNS). AEs most commonly reported in clinical trials with b-blockers were fatigue, depression, nausea, dizziness, and insomnia. These symptoms appear to be fairly well tolerated and were seldom the cause of premature withdrawal from trials (20). Common AEs include gastrointestinal complaints and decreased exercise tolerance. Less common are orthostatic hypotension, signicant bradycardia, impotence, and aggravation of intrinsic muscle disease. Propranolol has been reported to have an adverse effect on the fetus (60). Congestive heart failure, asthma, and insulin-dependent diabetes are contraindications to the use of nonselective b-blockers. b-Blockers are not absolutely contraindicated in migraine with aura unless a clear stroke risk is present. Whether this includes prolonged aura is uncertain. The reported adverse reactions to propranolol may be either coincidental or idiosyncratic, but the actual risk is uncertain. Some authors have commented on continued improvement (61) and lack of rebound (62) after discontinuing propranolol. Others have found no carry-over effects (63). However, it seems more reasonable to slowly taper b-blockers, because stopping them abruptly can cause increased headache (29) and the withdrawal symptoms of tachycardia and tremulousness (64). Clinical Use Propranolol [approved by the Food and Drug Administration (FDA) for migraine] is a nonselective b-blocker with a half-life of four to six hours. It is also available in a long-acting formulation (65,66). The therapeutically effective dose ranges from 40 to 400 mg/day, with no correlation between propranolol and 4-hydroxypropranolol plasma levels and headache relief (67). The short-acting form can be given three to four times a day, although we recommend twice a day, and the long-acting form, once or twice a day. Propranolol should be started at a dose of 40 mg/day in divided doses and slowly increased to tolerance. An advantage of the regular propranolol is its greater dosing exibility. The dose in children is 1 to 2 mg/kg/day (Table 3). Nadolol is a nonselective b-blocker with a long half-life. It is less lipid soluble than propranolol and has fewer CNS side effects. The dose ranges from 20 to 160 mg/day, given once daily or in split doses. Some authorities prefer it to propranolol because it has fewer side effects (68).

Preventive Treatment for Migraine Table 3 b-Blockers and Antidepressants in the Preventive Treatment of Migraine Agent b-blockers Atenolol Metoprolol Nadolol Propranolol 50200 100200 20160 40400 Daily dose (mg) Comment

317

Timolol Antidepressants Tertiary amines Amitriptyline Doxepin Secondary amines Nortriptyline

2060

Can be used q.d. Less side effects than propranolol Short-acting form must be used b.i.d. The long-acting form must be used q.d. Can be used q.d. Less side effects than propranolol The short-acting form should be used b.i.d. or t.i.d. The long-acting form can be used q.d. or b.i.d. 12 mg/kg in children The dose should be divided Short half-life

10400 10300 10150

Starting dose of 10 mg at bedtime Starting dose of 10 mg at bedtime Starting dose of 1025 mg at bedtime If insomnia present, must be given early in the morning Starting dose of 1025 mg at bedtime

Protriptyline 560 Selective serotonin reuptake inhibitors Fluoxetine tablets 1080 Evidence in the treatment of migraine is controversial Sertraline tablets 25100 Some may worsen the migraine pattern Paroxetine tablets 1030 May be used as an adjuvant in the treatment of migraine and severe depression Venlafaxine tablets 37.5225 Mirtazapine tablets 1545 Monoamine oxidase inhibitors Phenelzine 3090 Strict diet considerations

Timolol (approved by the FDA for migraine) is a nonselective b-blocker with a short half-life. The dose ranges from 20 to 60 mg/day in divided doses. Atenolol is a selective b1-blocker with fewer side effects than propranolol. The dose ranges from 50 to 200 mg/day once daily. Metoprolol is a selective b1-blocker with a short half-life. The dose ranges from 100 to 200 mg/day in divided doses. The long-acting preparation may be given once a day.

Antidepressants Antidepressants consist of a number of different classes of drugs with different mechanisms of action. Only tricyclic antidepressants (TCAs) have proven efcacy in migraine; we cover the newer components for completeness and reader interest. Mechanism of Action TCAs, selective serotonin-reuptake inhibitors (SSRIs), and serotonin NEreuptake inhibitors increase synaptic NE or serotonin (5-HT) by inhibiting high-afnity

318

Silberstein

reuptake. Some are more potent inhibitors of NE, others of 5-HT reuptake. Bupropion is both a dopamine and NE-reuptake inhibitor. Monoamine oxidase inhibitors (MAOIs) block the degradation of catecholamines. The most consistent neurochemical nding with antidepressant treatment (including the TCAs, SSRIs, MAOIs, and electroconvulsive therapy) is a decrease in b-adrenergic receptor density and NE-stimulated cyclic adenosine monophosphate (cAMP) response. Increased a1-receptor system sensitivity is not seen as consistently with antidepressant treatment. Long-term antidepressant treatment decreases 5-HT2receptor binding and imipramine-binding sites (related to the 5-HT uptake system) but does not change 5-HT1receptor binding. A strong interaction exists between the NE and 5-HT systems. Antidepressant treatment b-receptor downregulation is dependent on an intact 5-HT system, whereas lesions of the NE system block the decrease in 5-HT2receptor binding (69). The decrease in 5-HT2 receptorbinding sites does not correlate with a decrease in function; there may be enhanced physiologic responsiveness. In fact, long-term antidepressant treatment actually enhances the efcacy of 5-HT synaptic transmission. The mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. TCAs and electroconvulsive shocks (ECS) enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers reduce the function of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential (70). TCAs upregulate the GABA-B receptor, downregulate the histamine receptor, and enhance the neuronal sensitivity to substance P. Some TCAs are 5-HT2receptor antagonists. TCAs also interact with endogenous adenosine systems. They inhibit adenosine and augment its electrophysiologic actions contributing to antinociception. Adenosine A1 receptor activation results in antinociception mediated by inhibition of adenylate cyclase, whereas adenosine A2 receptor activation is pronociceptive due to stimulation of adenylate cyclase within the sensory nerve terminal (71). Adenosine A3 receptors facilitate pain due to release of histamine and 5-hydroxytryptamine from mast cells (72,73). Neurotrophic factors may also be candidates for mediating the long-term effects of antidepressants. The neurotrophins [a protein class comprising nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, and NT-6] positively modulate monoaminergic neurotransmission (74) and CNS neuron survival, outgrowth, and neuroprotection (75). BDNF binds to and phosphorylates its high-afnity tyrosine kinase receptor and activates intracellular signaling pathways including microtubule-associated protein kinase and cAMP (76). BDNF promotes serotonin neuron development, augments serotonin synthesis and turnover, and increases serotonergic axon ber density. Serotonergic axon densities are decreased in the prefrontal cortex of suicide patients with major depressive disorder (77). In the neocortex and hippocampus, BDNF mRNA and protein are highly expressed (78), and these regions are widely implicated in the pathophysiology of depressive disorders. Environmental stressors, such as immobilization, that produce learned helplessness in animals and precipitate depression in humans decrease BDNF mRNA (79). Intraventricular, dorsal raphe, or hippocampal infusions of BDNF in rats reduce learned helplessness behavior and reduce immobility in the forced swim and inescapable shock models, indicating an antidepressant-like effect. BDNF mRNA increases in animals treated with antidepressant drugs and

Preventive Treatment for Migraine

319

following seizures (80). Antidepressants increase BDNF mRNA in the brain via 5-HT2A and b-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA. In the hippocampus of depressed patients treated with unspecied antidepressants, BDNF protein immunoreactivity was elevated compared with subjects who were not so treated at the time of death (80). Clinical trials are currently evaluating the antidepressant activity of small molecules that increase BDNF mRNA and protein release from cultured cells (76). BDNF protein levels were measured with a two-site enzyme-linked immunosorbent assay in six brain regions of adult male rats that received daily ECS or daily injections of antidepressant drugs. BDNF increased gradually in the hippocampus and frontal cortex, with a peak response by the fourth day of ECS. Increases peaked at 15 hours after the last ECS and lasted at least three days thereafter. Two weeks of daily injections with the MAO-A and MAO-B inhibitor tranylcypromine (810 mg/kg, IP) increased BDNF by 15% in the frontal cortex, and three weeks of treatment increased it by 18% in the frontal cortex and 29% in the neostriatum. Tranylcypromine, uoxetine, and desmethylimipramine did not elevate BDNF in the hippocampus. Elevations in BDNF protein in the brain are consistent with greater treatment efcacy of ECS and MAOIs in drugresistant major depressive disorder and may be predictive for the antidepressant action of the more highly efcacious interventions (80). The mechanism by which antidepressants work to prevent headache is uncertain but does not result from treating masked depression. Antidepressants are useful in treating many chronic pain states, including headache, independent of the presence of depression, and the response occurs sooner than the expected antidepressant effect (81,82). In animal pain models, antidepressants potentiate the effects of coadministered opioids (83). The antidepressants that are clinically effective in headache prevention either inhibit noradrenaline and 5-HT reuptake or are antagonists at the 5-HT2 receptors (84). Clinical Trials and Use A total of 16 controlled trials have investigated the efcacy of the TCAs amitriptyline and clomipramine and the SSRIs uoxetine and uvoxamine (26,27,8599). Amitriptyline has been more frequently studied than the other agents, and is the only antidepressant with fairly consistent support for efcacy in migraine prevention. Three placebo-controlled trials found amitriptyline signicantly better than placebo at reducing headache index or frequency (8890,97). One trial found no signicant difference between amitriptyline and propranolol (97). Another trial reported that amitriptyline was signicantly more efcacious than propranolol for patients with mixed migraine and tension-type headache, whereas propranolol was signicantly better for patients with migraine alone (26). Similarly, a trial conducted in a group of patients with mixed migraine and tension-type headache found that amitriptyline was signicantly better than timed-released dihydroergotamine (TR-DHE) at reducing headache index (87). However, an analysis of the data on headache duration, stratied by severity, showed that amitriptyline was signicantly better than TR-DHE at reducing the number of hours of moderate and mild tensiontype headache-like pain. In contrast, TR-DHE was signicantly better than amitriptyline at reducing the number of hours of extremely severe and severe migraine-like pain. The evidence was insufcient to support the efcacy of clomipramine (27,94) and uvoxamine (99) for migraine prevention. Fluoxetine was signicantly better than placebo in one (85) but not a second (95) migraine prevention trial.

320

Silberstein

Tricyclic Antidepressants Pharmacology of the TCAs. There is wide individual variation in the absorption, distribution, and excretion of the TCAs, with a 10- to 30-fold variation in individuals drug metabolism. There may exist a therapeutic window above which the TCAs are ineffective, but this has been evaluated only for nortriptyline for treatment of depression. TCAs are lipid soluble, have a high volume of distribution, and avidly bind to plasma proteins. The antihistamine and antimuscarinic activity of the TCAs account for many of their side effects (100). A useful rule of thumb is to start low and aim for a dose of 1 to 1.5 mg/kg body weight. The TCAs most commonly used for headache prophylaxis include amitriptyline, nortriptyline, doxepin, and protriptyline. Imipramine and desipramine have been used at times. With the exception of amitriptyline, the TCAs have not been vigorously evaluated; their use is based on anecdotal or uncontrolled reports. None have been approved for migraine. Principles of TCA Use. The following principles are useful when using a TCA.  The TCA dose range is wide and must be individualized.  With the exception of protriptyline, TCAs are sedating. Treatment should be started with a low dose of the chosen TCA taken at bedtime, except in the case of protriptyline, which should be administered in the morning.  If the TCA is too sedating, the tertiary TCA (amitriptyline and doxepin) should be switched over to a secondary TCA (nortriptyline and protriptyline). If a patient develops insomnia or nightmares, TCA should be given in the morning.  SSRIs can be given as a single dose in the morning, although rigorous evidence for activity in migraine is lacking. They are less sedating than the TCAs and some patients may require a hypnotic for sleep induction.  Bipolar patients can become manic on antidepressants. AEs are common with TCA use. The AEs of TCA are due to its interaction with multiple neurotransmitters and their receptors. The antimuscarinic AEs are most common; they include dry mouth, a metallic taste, epigastric distress, constipation, dizziness, mental confusion, tachycardia, palpitations, blurred vision, and urinary retention. Antihistaminic activity may be responsible for carbohydrate cravings, which contributes to weight gain. Adrenergic activity is responsible for the orthostatic hypotension, reex tachycardia, and palpitations that patients may experience. Amitriptyline and other TCAs rarely cause inappropriate secretion of antidiuretic hormone. Any antidepressant treatment may change depression to hypomania or frank mania (particularly in bipolar patients). Ten percent of patients develop tremors, and confusion or delirium may occur, particularly in older patients who are more vulnerable to the muscarinic side effects. Antidepressant treatments may also reduce the seizure threshold (101), although this is not generally a problem in antimigraine treatment. Clinical Use Tertiary Amines. Amitriptyline is a tertiary amine tricyclic that is sedating and has antimuscarinic activity. Patients with coexistent depression are more tolerant and require higher doses of amitriptyline. Administration of the drug should be started at a dose of 10 to 25 mg at bedtime. The dose ranges from 10 to 400 mg/day (Table 3).

Preventive Treatment for Migraine

321

Doxepin is a sedating tertiary amine TCA. The drug should be started at a dose of 10 mg at bedtime. The dose ranges from 10 to 300 mg/day. Secondary Amines. Nortriptyline is a secondary amine that is less sedating than amitriptyline. Nortriptyline is a major metabolite of amitriptyline. If insomnia develops, the drug must be given earlier in the day or in divided doses. The drug is started at a dose of 10 to 25 mg at bedtime. The dose ranges from 10 to 150 mg/day. Protriptyline is a secondary amine similar to nortriptyline. The dosage should be started at 5 mg/day. The dose ranges from 5 to 60 mg/day. Monoamine-Reuptake Inhibitors Selective Serotonin-Reuptake Inhibitors. Evidence for the use of SSRIs is poor. They are helpful for patients with comorbid depression because their tolerability prole is superior to tricyclics. Fluoxetine, uvoxamine, paroxetine, sertraline, and citalopram are specic SSRIs that have minimal antihistaminic and antimuscarinic activity. These drugs produce less weight gain (and in some cases produce weight loss) and have fewer cardiovascular side effects than the TCAs (102). The most common AEs include anxiety, nervousness, insomnia, drowsiness, fatigue, tremor, sweating, anorexia, nausea, vomiting, and dizziness or lightheadedness. Headache was noted in 20.3% of patients on uoxetine; however, it was also noted in 19.9% of patients on placebo (103). The combination of an SSRI and a TCA can be benecial in treating refractory depression (104) and, in our experience, resistant cases of migraine. The combination may require dose adjustment of the TCA because levels may signicantly increase. The efcacy analysis summarized in the AHCPR Evidence Report did not indicate a clear benet of the racemic mixture of uoxetine over placebo. In contrast, a recent randomized controlled trial of S-uoxetine indicated a possible clinical benet in migraine prevention, as measured by a reduction in migraine frequency, as early as one month after initiation of therapy (105). Anecdotal reports (106) and our experience seem to indicate its benet in migraine prophylaxis where coexistent depression is a prominent issue. Some researchers have reported that uoxetine does not improve or may worsen headache (107). A recent single-center, randomized, double-blind, parallel study of uoxetine showed a signicant reduction (p < 0.05) beginning from the third month of treatment in the uoxetine group and no signicant reduction in the placebo group. Fluoxetine should be administered starting at a dose of 10 mg in the morning. The dose ranges from 10 to 80 mg/day. Monoamine Oxidase Inhibitors MAOIs exist in two subtypes: MAO-A, which preferentially deaminates NE and 5-HT, and MAO-B, which preferentially deaminates dopamine. Phenelzine is a nonspecic inhibitor of MAO-A and MAO-B. L-Deprenyl is a selective MAO-B inhibitor that may be effective in the treatment of Parkinsons disease. The MAOI phenelzine at a dose of 15 mg TID was effective in an open study (108), but no placebo-controlled, double-blind trials exist. The dose of phenelzine ranges from 30 to 90 mg/day in divided doses. All patients on MAOI-A must be on a restricted diet and avoid certain medications to prevent hypertensive crisis. Meperidine, sympathomimetics (including Midrin), alcohol, and foods with a high

322

Silberstein

tyramine content (cheddar cheese, fava beans, banana peel, tap beers, Marmite and Veggie-Mite concentrated, yeast extract, sauerkraut, soy sauce, and other soybean condiments) must be avoided (108112). The most common AEs of MAOIs include insomnia, orthostatic hypotension, constipation, increased perspiration, weight gain, peripheral edema, and, less commonly, inhibition of ejaculation or reduced libido. Insomnia can be reduced by giving most of the medication early in the day. The risk of hypertensive crisis may be reduced by having the patient take the MAOI three to four hours before or after eating or taking the entire dose at bedtime, as gut MAO activity rapidly returns to normal (113). Sublingual nifedipine has been used to treat hypertensive crisis when it occurs in MAOI users (114). Calcium-Channel Antagonists Calcium, in combination with a calcium-binding protein such as calmodulin or troponin, regulates many functions, including muscle contraction, neurotransmitter and hormone release, and enzyme activity. Its extracellular concentration is high; its intracellular free concentration is 10,000-fold smaller. The concentration gradient is established by membrane pumps and the intracellular sequestering of free calcium. When stimulated, the cell can open calcium channels in the plasma membrane or release intracellular stores of calcium (115). Pharmacology of the Calcium-Channel Blockers Two types of calcium channels exist: calcium entry channels, which allow extracellular calcium to enter the cell, and calcium release channels, which allow intracellular calcium (in storage sites in organelles) to enter the cytoplasm. They are modulated by ryanodine and inositol 1,4,5-triphosphate receptors (116). Calcium entry channel subtypes include voltage-gated, opened by depolarization, ligand-gated, opened by chemical messengers (such as glutamate) and capacitative, activated by depletion of intracellular calcium stores. Voltage-gated calcium channels mediate calcium inux in response to membrane depolarization and regulate intracellular processes such as contraction, secretion, neurotransmission, and gene expression. They are members of a gene superfamily of transmembrane ion channel proteins that includes voltage-gated potassium and sodium channels. There are six functional subclasses of voltage-gated calcium (Ca2) channels; these are named T, L, N, P, Q, and R. They fall into two major categories: high-voltageactivated channels and the unique low-voltage activated T-type, which are activated at negative potentials (117). Voltage-gated calcium channels are heteromers composed of four or ve distinct subunits, which are encoded by multiple genes. These subunits have different functions, and subunit isoforms give rise to distinct channel subtypes. The a1 subunit of 190 to 250 kDa is the largest; it incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins. The a1 subunit is associated with auxiliary subunits, including a membrane-spanning a2-d complex that increases the amplitude of calcium currents and binds the anticonvulsant gabapentin, and a cytoplasmic b subunit that modies the channels current amplitude, voltage dependence, and activation and inactivation properties (116). The a1 subunit of voltage-gated calcium channels is organized in four homologous domains (IIV) with six transmembrane segments

Preventive Treatment for Migraine

323

(S1S6) in each. The S4 segment serves as the voltage sensor. The pore loop between transmembrane segments S5 and S6 in each domain determines ion conductance and selectivity, and changes of only three amino acids (aa) in the pore loops in domains I, III, and IV will convert a sodium channel to calcium selectivity. An intracellular b subunit and a transmembrane, disulde-linked a2d-subunit complex are components of most types of calcium channels. A g subunit has also been found in skeletal muscle calcium channels, and related subunits are expressed in heart and brain. Although these auxiliary subunits modulate the properties of the channel complex, the pharmacologic and electrophysiological diversities of calcium channels arise primarily from the existence of multiple a1 subunits (118). Calcium currents have diverse physiological and pharmacologic properties. L-type calcium currents require a strong depolarization for activation and are long lasting (117). They are the main calcium currents recorded in muscle and endocrine cells, where they initiate contraction and secretion. N-type, P/Q-type, and R-type calcium currents also require strong depolarization for activation. They are expressed primarily in neurons, where they initiate neurotransmission at most fast synapses and also mediate calcium entry into cell bodies and dendrites. T-type calcium currents are activated by weak depolarization and are transient. They are expressed in a wide variety of cell types, where they are involved in shaping the action potential and controlling patterns of repetitive ring (118). Mammalian a1 subunits are encoded by at least 10 distinct genes. Calcium channels are named using the chemical symbol of the principal permeating ion (Ca) with the principal physiological regulator (voltage) indicated as a subscript (CaV). The numerical identier corresponds to the CaV channel a1 subunit gene subfamily (13 at present) and the order of discovery of the a1 subunit within that subfamily (1 through m). According to this nomenclature, the CaV1 subfamily (CaV1.1 to CaV1.4) includes channels containing a1S, a1C, a1D, and a1F, which mediate L-type Ca2 currents. The CaV2 subfamily (CaV2.1 to CaV2.3) includes channels containing a1A, a1B, and a1E, which mediate P/Q-, N-, and R-type Ca2 currents, respectively. The CaV3 subfamily (CaV3.1 to CaV3.3) includes channels containing a1G, a1H, and a1I, which mediate T-type Ca2 currents (118). The pharmacology of the three families of calcium channel is distinct. The CaV1 channels are the molecular targets of the organic calcium channel blockers used widely in the therapy of cardiovascular diseases. These drugs are thought to act at three separate, but allosterically coupled, receptor sites. Phenylalkylamines are intracellular pore blockers. Dihydropyridines can be channel activators or inhibitors and, therefore, are thought to act allosterically to shift the channel toward the open or closed state, rather than by occluding the pore. Diltiazem and related benzothiazepines are thought to bind to a third receptor site (118). The CaV2 family of calcium channels is relatively insensitive to dihydropyridine calcium channel blockers, but these calcium channels are specically blocked with high afnity by peptide toxins of spiders and marine snails (119). The CaV2.1 channels are blocked specically by o-agatoxin IVA from funnel web spider venom. The CaV2.2 channels are blocked specically by o-conotoxin GVIA and related cone snail toxins. The CaV2.3 channels are blocked specically by the synthetic peptide toxin SNX-482 derived from tarantula venom. These peptide toxins are potent blockers of synaptic transmission because of their specic effects on the CaV2 family of calcium channels. The CaV3 family of calcium channels is insensitive to both the dihydropyridines that block CaV1 channels and the spider and cone snail toxins that

324

Silberstein

block the CaV2 channels. There are no widely useful pharmacological agents that block T-type calcium currents (118,119).

Mechanism of Action in Migraine The mechanism of action of the calcium channel antagonists in migraine prevention is uncertain. They were introduced into the treatment of migraine on the assumption that they prevent hypoxia of cerebral neurons, contraction of vascular smooth muscles, and inhibition of the Ca2-dependent enzymes involved in prostaglandin formation. Perhaps it is their ability to block 5-HT release, interfere with neurovascular inammation, or interfere with the initiation and propagation of spreading depression that is critical (120). The discovery that an abnormality in an a1A subunit (P/Q channel) can produce familial hemiplegic migraine (121) has led to a search for more fundamental associations. Clinical Trials The AHCPR Technical Report identied 45 controlled trials of calcium antagonists, including unarizine (25 trials), nimodipine (11 trials), nifedipine (5 trials), verapamil (3 trials), cyclandelate (3 trials), and nicardipine (1 trial) (20). Flunarizine was compared with placebo in eight migraine prevention trials and effect sizes could be calculated for seven studies (122128), but not the eighth study (129). A meta-analysis of these seven heterogeneous trials was statistically signicant in favor of unarizine. Five comparisons of unarizine with propranolol (130,131), and two with metoprolol (35,132), showed no signicant differences between unarizine and these b-blocking agents. There were no signicant differences between unarizine and pizotifen (133135), or between unarizine and methysergide (136). One trial comparing unarizine and dihydroergocryptine (DEK) (137) reported mixed results, but suggested that differences in the effects of the two treatments were small. Nimodipine had mixed results in placebocontrolled trials. Three placebo-controlled studies suggested no signicant differences (138,139), whereas two reported relatively large and statistically signicant differences in favor of nimodipine (140). Nimodipine was not different than unarizine (141), pizotifen (133) or propranolol (142). Our interpretation and our clinical experience is that nimodipine is ineffective in migraine prevention. The evidence for nifedipine was difcult to interpret. Two comparisons with placebo yielded similar effect sizes that were statistically insignicant, but the 95% condence intervals associated with these estimates were large and did not exclude either a clinically important benet or harm associated with nifedipine (143). Similarly ambiguous results were reported in one comparison with unarizine (144) and two comparisons with propranolol (32,145). One trial found that metoprolol was signicantly better than nifedipine at reducing headache frequency (32). Our conclusion is that nifedipine is ineffective as a migraine preventive. Verapamil was more effective than placebo in two of three trials, but both positive trials had high dropout rates, rendering the ndings uncertain (54,146). The single negative placebo-controlled trial included a propranolol treatment arm. This trial reported no signicant difference between verapamil, propranolol, and placebo (54,147). Our conclusion is that there is no rigorous, randomized, controlled trial evidence to support the use of verapamil in migraine. Diltiazem (6090 mg QID) was effective in two small open studies (148,149). These studies are insufcient to recommend the use of diltiazem.

Preventive Treatment for Migraine

325

Table 4 Selected Calcium-Channel Blockers and Selected Anticonvulsants in the Preventive Treatment of Migraine Agent Daily dose Comment Starting dose of 80 mg b.i.d. or t.i.d. Sustained release can be given q.d. or b.i.d. q.d. at bedtime Weight gain is the most common side effect t.i.d. Dose can be increased up to 3000 mg Starting dose of 1525 bedtime Can be increased by 1525 mg/wk Reaching a dose of 50100 mg must be attempted Can be increased further if necessary Associated with weight loss, not weight gain Starting dose of 250500 mg/day Levels should be monitored if compliance is an issue Maximum dose is 60 mg/kg day

Selected calcium channel blockers Verapamil 120640 mg Flunarizine 510 mg

Selected anticonvulsants Carbamazepine 6001200 mg Gabapentin 6001200 mg Topiramate 100 mg

Valproate/Divalproex

5001500 mg/day

Adverse Events AEs of the Ca2 antagonists are dependent on the drug. Patients frequently report an initial increase in headache. Headache improvement frequently requires weeks of treatment. Two trials of verapamil and one of nifedipine reported high dropout rates due to AEs (20). Side effects with nifedipine were frequent (54%) and included dizziness, edema, ushing, headache, and mental symptoms (143). Clinical Use Verapamil is available as a 40, 80, or 120 mg tablet or as a 120, 180, or 240 mg sustained-release preparation. The drug can be started at a dose of 40 mg two to three times a day, with a maximum of 640 mg/day in divided doses. The sustained-release preparation of verapamil can be given once or twice a day, but unreliable absorption reduces reliability. The most common AE is constipation; dizziness, nausea, hypotension, headache, and edema are less common. Bioavailability is 20%. The absorbed drug is tightly protein bound. Peak plasma levels occur in ve hours; the half-life ranges from 2.5 to 7.5 hours (Table 4). Flunarizine is not available in the United States. It is given at a dose of 5 to 10 mg/day. The most prominent AEs include weight gain, somnolence, dry mouth, dizziness, hypotension, occasional extrapyramidal reactions, and exacerbation of depression. The elimination half-life of unarizine is 19 days. Anticonvulsants Anticonvulsant medication is increasingly recommended for migraine prevention, because it was proved to be effective by placebo-controlled, double-blind trials. With the exceptions of valproic acid, topiramate, and zonisamide, anticonvulsants

326

Silberstein

may interfere substantially with the efcacy of oral contraceptives (150,151). Nine controlled trials of ve different anticonvulsants were included in the AHCPR Technical Report (53,152156). Carbamazepine The only placebo-controlled trial of carbamazepine suggested a signicant benet, but this trial was inadequately described in several important respects (155). Another trial, comparing carbamazepine with clonidine and pindolol, suggested that carbamazepine had a weaker effect on headache frequency than either comparator treatment, although differences from clonidine were not statistically signicant (157). Carbamazepine (Tegretol), 600 to 1200 mg/day, may be effective in preventive migraine treatment (Table 4). Gabapentin Gabapentin (6001800 mg) was effective in episodic migraine and chronic migraine in a 12-week open-label study (158). Gabapentin was not effective in one placebocontrolled, double-blind study (159). In a more recent randomized, placebo-controlled, double-blind trial (160), gabapentin, at a dosage of 1800 to 2400 mg, was superior to placebo in reducing the frequency of migraine attacks. The responder rate was 36% for gabapentin and 14% for placebo (p 0.02). The two treatment groups were comparable with respect to treatment-limiting AEs. Limited data were reported on AEsthe most common were dizziness or giddiness and drowsiness. Relatively high patientwithdrawal rates due to AEs were reported in some trials (20) (Table 4). Valproic Acid Valproic acid is a simple eight carbon, two chain fatty acid with 80% bioavailability after oral administration. It is highly protein bound, with an elimination half-life between 8 and 17 hours. Valproic acid possesses anticonvulsant activity in a wide variety of experimental epilepsy models. Valproate at high concentrations increases GABA levels in synaptosomes, perhaps by inhibiting its degradation; it enhances the postsynaptic response to GABA, and, at lower concentrations, it increases potassium conductance, producing neuronal hyperpolarization. Valproate turns off the ring of the 5-HT neurons of the dorsal raphe, which are implicated in controlling head pain. Disordered GABA metabolism during migraine has been reported (161). Imbalance in the plasma concentrations of GABA, an inhibitory aa, and glutamic acid, an excitatory aa, has also been observed (153156,162). The mechanism of action of valproate in migraine prevention may be related to facilitation of GABA-ergic neurotransmission (163165). Valproate enhances GABA activity within the brain by inhibiting its degradation, stimulating its synthesis and release, and directly enhancing its postsynaptic effects. The valproate concentration required to inhibit GABA transaminase is greater than that which occurs during therapy. However, active metabolites, one of which (2-en-valproic acid) accumulates in the brain, have an anticonvulsant effect and cause GABA accumulation in vivo (163). Other potential mechanisms of action include direct effects on neuronal membranes (it suppresses induced and spontaneous epileptiform activity), inhibition of kindling, and reduction of excitatory neurotransmission by the aa aspartate by blocking its release (164,165). Valproate also attenuates plasma extravasation in the Moskowitz model of NI by interacting with the GABAA receptor. The relevant

Preventive Treatment for Migraine

327

receptor may be on the parasympathetic nerve bers projecting from the sphenopalatine ganglia; in so doing, it attenuates nociceptive neurotransmission (163). In addition, valproate-induced increased central enhancement of GABAA activity may enhance central antinociception (166). Valproate also interacts with the central 5-HT system and reduces the ring rate of midbrain serotonergic neurons (166). Five studies provided strong and consistent support for the efcacy of divalproex sodium (approved by the FDA) (153,167,168) and sodium valproate (162,169). Two placebo-controlled trials of each of these agents showed them to be signicantly better than placebo at reducing headache frequency (154,162,168,169). A single study compared divalproex sodium with propranolol and found differences favoring divalproex sodium; however, the statistical signicance of these results could not be determined (open-label study with high dropout rates) (153). A more recent study (not included in the AHCPR Technical Report) found divalproex sodium more effective compared with placebo, but not signicantly different compared with propranolol, for prevention of migraine in patients without aura (170). An extended release form of divalproex sodium demonstrated comparable efcacy to the tablet formulation (171). The AE prole in the clinical trial, however, showed almost identical AE rates for the placebo and active treatment arms. Clinical Trials. In 1988, prompted by his clinical observations of valproates benets, Sorensen (172) performed a prospective open trial of valproate. He studied 22 patients with severe migraine that was resistant to previous prophylactic treatment. Follow-up in 3 to 12 months revealed that 11 patients were migraine-free, six had a signicant reduction in frequency, one had no change, and four had dropped out (Table 5). In 1992, Hering and Kuritzky (169) evaluated sodium valproates efcacy in migraine treatment in a double-blind, randomized, crossover study. Thirty-two patients were divided into two groups and given either 400 mg of sodium valproate twice a day or placebo for eight weeks. Sodium valproate was effective in preventing migraine or reducing the frequency, severity, and duration of attacks in 86.2% of 29 patients, whose attacks were reduced from 15.6 to 8.8 a month. Jensen et al., in 1994 (152), studied 43 patients with migraine without aura in a triple-blind, placebo- and dose-controlled, crossover study of slow-release sodium valproate. After a four-week medication-free run-in period, the patients were randomized to sodium valproate (n 22) or placebo (n 21). Thirty-four patients completed the trial. Fifty percent of the patients had a reduction in migraine frequency to 50% or less for the valproate group compared with 18% for placebo. During the last four weeks of valproate treatment, 65% responded. The most common AEs (33% valproate and 16% placebo) were intensied nausea and dyspepsia, tiredness, increased appetite, and weight gain, and were usually mild or moderate. Fifty-eight percent of the patients had no AEs. In 1995, in a multicenter, double-blind, randomized, placebo-controlled investigation, Mathew et al. (154) compared the effectiveness and safety of divalproex sodium and placebo in migraine prophylaxis. A four-week, single-blind, placebo-baseline phase was followed by a 12-week treatment phase (four-week dose adjustment, eight-week maintenance). One hundred seven patients were randomized to divalproex sodium or placebo (2:1 ratio), with 70 receiving divalproex sodium and 37 receiving placebo. Forty-eight percent of the divalproex sodiumtreated patients and 14% of the placebo-treated patients showed a 50% or greater reduction in migraine headache frequency from baseline (p < 0.001). No signicant treatmentgroup differences were observed in average peak severity or duration of individual

328

Table 5 Divalproex/Valproate Clinical Trials

Study 800 mg (400 mg b.i.d.) 31.191.9

Patient Population (diagnostic criteria) Design Dosage (mg/day)/ other medication Duration Plasma levels (mg/mL)

No.

Results

Hering and Kuritzky (1992) 1,00015,000 mg/ sodium valproate Mean 73.4

Migraine

29

Jensen et al. (1994)

Migraine without aura

43

Double-blind/ placebo-controlled crossover Double-blind/ placebo-controlled crossover Double-blind/ placebo controlled Double-blind/ placebo-controlled Double-blind/ placebo-controlled 5001000 mg/ Divalproex 5001600 or 1500 mg/ Divalproex ? 5001500 mg/ Divalproex 70120

8 Weeks each; total of 16 weeks 32 Weeks

86.2% of patients responded better to valproate 50% valproate

Mathew et al. (1995)

Migraine with or without aura

107

16 Weeks

18% placebo 48% divalproex

Klapper (1995)

Migraine with or without aura

176

10 Weeks

14% placebo 43% divalproex

Freitag et al. (2002)

Migraine with or without aura

234

12 Weeks

21% placebo 30% divalproex 24% placebo Silberstein

Preventive Treatment for Migraine

329

migraine headaches. Treatment was stopped in 13% of the divalproex sodiumtreated patients and 5% percent of the placebo-treated patients, because of intolerance (p, not signicant). Klapper et al. (168) evaluated the efcacy and safety of divalproex sodium as prophylactic monotherapy in a multicenter, double-blind, randomized, placebocontrolled study. Patients with two or more migraine attacks during the baseline phase were randomized to a daily divalproex sodium dose of 500, 1000, or 1500 mg, or placebo. The primary efcacy variable was four-week headache frequency during the experimental phase. During the experimental phase, the mean reduction in the combined daily divalproex sodium groups was 1.8 migraines per four weeks compared with a mean reduction of 0.5 attacks per four weeks in the placebo group. Overall, 43% of divalproex sodiumtreated patients achieved 50% or more reduction in their migraine attack rates, compared with 21% of placebo-treated patients. A statistically signicant (p < 0.05) doseresponse effect across the dose range placebo, 500, 1000, and 1500 mg, was observed for both overall reduction in attack frequency and a 50% or more reduction in attack frequency. With the exception of nausea, AEs were similar in all groups (divalproex sodium 24%, placebo 7%, p 0.015) and most AEs were mild or moderate in severity. In an open-label study, Silberstein and Collins (173) evaluated the long-term safety of divalproex sodium in patients who had completed one of two previous doubleblind, placebo-controlled studies. The results, including data from the double-blind study, represented 198 patient-years of divalproex exposure. The average dose was 974 mg/day. Reasons for premature discontinuation (67%) included administrative problems (31%), drug intolerance (21%), and treatment ineffectiveness (15%). The most frequently reported AEs were nausea (42%), infection (39%), alopecia (31%), tremor (28%), asthenia (25%), dyspepsia (25%), and somnolence (25%). Divalproex was found to be safe and initial improvements were maintained for periods more than 1080 days. No unexpected AEs or safety concerns unique to the use of divalproex in the prophylactic treatment of migraine were found. Freitag et al. (171) evaluated the efcacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment. Treatment was initiated by administering a dose of 500 g once daily for one week, and the dose was then increased to 1000 mg once daily, with an option, if intolerance occurred, to permanently decrease the dose to 500 mg during the second week. The mean reductions in the fourweek migraine headache rate were 1.2 (from a baseline mean of 4.4) in the extendedrelease divalproex sodium group and 0.6 (from a baseline mean of 4.2) in the placebo group (p 0.006); reductions with extended-release divalproex sodium were signicantly greater than with placebo in all three four-week segments of the treatment period. The proportion of subjects achieving at least 50% reduction in experimental phase migraine headache rate was higher in the extended-release divalproex sodium group (36/119; 30%) than in the placebo group (28/115; 24%), but the difference was not signicant (p 0.251). Nausea, vomiting, and gastrointestinal distress are the most common AEs of valproate therapy. These are generally self-limited and are slightly less common with divalproex sodium than with sodium valproate. When therapy is continued, the incidence of gastrointestinal symptoms decreases, particularly after six months. In three of four placebo-controlled trials, the overall percentage of patients reporting AEs with divalproex sodium or sodium valproate was not higher than with placebo. The fourth trial found signicantly higher rates of nausea, asthenia, somnolence, vomiting, tremor, and alopecia with divalproex sodium. On rare occasions, valproate

330

Silberstein

administration is associated with severe AEs such as hepatitis and pancreatitis. The frequency of these AEs varies with the number of concomitant medications used, the patients age and general state of health, and the presence of genetic and metabolic disorders. Valproate is potentially teratogenic and should not be used by pregnant women or women considering pregnancy (174). Valproate has little effect on cognitive functions and rarely causes sedation. The frequency of these adverse reactions varies with the number of concomitant medications used, the patients age, the presence of genetic and metabolic disorders, and the patients general state of health. These idiosyncratic reactions are unpredictable (175). The risk of valproate hepatotoxicity is highest in children under the age of two years, especially those treated with multiple antiepileptic drugs, those with metabolic disorders, and those with severe epilepsy accompanied by mental retardation and organic brain disease (176). The relative risk of hepatotoxicity from valproate is low in migraineurs. Hyperandrogenism, resulting from elevated testosterone levels, ovarian cysts, and obesity, is of particular concern in young women with epilepsy who use valproate (177). It is uncertain if valproate can cause these symptoms in young women with migraine or mania. Because of valproates potential idiosyncratic interactions with barbiturates (severe sedation and coma), migraine patients who are on valproate should not be given barbiturate-containing combination analgesics for symptomatic headache relief. If these drugs are used, they should be given with caution and at a low dose. Absolute contraindications to valproate are pregnancy and a history of pancreatitis or a hepatic disorder such as chronic hepatitis or cirrhosis of the liver. Other important contraindications are hematologic disorders, including thrombocytopenia, pancytopenia, and bleeding disorders. Valproic acid is available as 250 mg capsules and as a syrup (250 mg/5 mL). Divalproex sodium is a stable coordination complex comprising sodium valproate and valproic acid in a 1:1 molar ratio. An enteric-coated form of divalproex sodium is available as 125, 250, and 500 mg capsules and a sprinkle formulation. Start with 250 to 500 mg/day in divided doses and slowly increase the dose. Monitor serum levels if there is a question of toxicity or compliance. (The usual therapeutic level is from 50 to 100 mg/mL.) The maximum recommended dose is 60 mg/kg/day. An extended release form of divalproex sodium demonstrated comparable efcacy to the tablet formulation. The AE prole in the clinical trial showed almost identical adverse effect rates for the placebo and active treatment arms (178). Topiramate Topiramate is a structurally unique anticonvulsant that was discovered serendipitously. It was originally synthesized as part of a research project to discover structural analogs of fructose-1,6-diphosphate capable of inhibiting the enzyme fructose-1,6bisphosphatase, thereby blocking gluconeogenesis, but it has no hypoglycemic activity. Topiramate is a derivative of the naturally occurring monosaccharide D-fructose and contains a sulfamate functionality. The structural resemblance of its O-sulfamate moiety to the sulfonamide moiety in acetazolamide prompted an evaluation of possible anticonvulsant effects. Topiramate was originally marketed for the treatment of epilepsy (179); it is now FDA approved for migraine. Topiramate is rapidly and almost completely absorbed (180). It is not extensively metabolized and is eliminated predominantly unchanged in the urine.

Preventive Treatment for Migraine

331

The average elimination half-life is approximately 21 hours (180). Topiramate readily enters the CNS parenchyma; in rats, the concentration in whole brain was approximately one-third of that in blood plasma one hour after oral dosing (181). The bioavailability of topiramate from the tablet formulation is about 80%, and is not affected by food (182). In a pharmacokinetic interaction study with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate at doses of 50 to 200 mg/day was not associated with statistically signicant changes in mean exposure [area under the curve (AUC)] to either component of the oral contraceptive. Topiramate is therefore not associated with signicant reductions in estrogen exposure at doses below 200 mg/day. At doses above 200 mg/day, there may be a dose-related reduction in exposure to the estrogen component of oral contraceptives. The anticonvulsant activity of most antiepileptic drugs is thought to be due to a state-dependent blockade of voltage-dependent Na or Ca2 channels or an ability to enhance the activity of GABA at GABAA receptors (181,183). Topiramate can inuence the activity of some types of voltage-activated Na and Ca2 channels, GABAA receptors, and the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate subtype of glutamate receptors. Topiramate also inhibits some isozymes of carbonic anhydrase (CA) and exhibits selectivity for CA II and CA IV (179,184). Topiramate blocks Na channels in a voltage-sensitive, use-dependent manner (185). Topiramate can reduce the amplitude of tetrodotoxin-sensitive voltage-gated Na currents in rat cerebellar granule cells, as measured by whole-cell current-clamp recordings (186). The effects of topiramate on voltage-activated Na channels, voltage-activated calcium channels, GABAA receptors, and AMPA/kainate receptors are all regulated by protein phosphorylation (187190). One or more subunit of each complex is phosphorylated by protein kinase A, protein kinase C, and possibly CA2/CaMactivated kinases. The consensus peptide sequence at the protein kinase Amediated phosphorylation site exhibits homology, i.e., the GluR6 subunit of the AMPA/ kainate receptor contains an RRQS, the b subunit of the GABAA receptor contains RRAS, and some subtypes of the primary subunit of Na and Ca2 channels contain RRNS and RRPT, respectively (R, arginine; Q, glutamine; S, serine; T, threonine; A, alanine; and N, asparagine). Immediately upon binding to the site, topiramate could exert either a positive or a negative allosteric modulatory effect; secondarily, topiramate would prevent protein kinase A from accessing the serine hydroxyl site, thereby preventing phosphorylation, which, over time, would shift a population of channels toward the dephosphorylated state (182). Thus, topiramate may bind to the membrane channel complexes at phosphorylation sites in the inner loop and thereby allosterically modulate ionic conductance through the channels (182). Storer and Goadsby (191) studied the effect of topiramate on trigeminocervical activation in the anesthetized cat. Activation of neurons within the trigeminocervical complex is likely to be the biological substrate for pain in migraine and cluster headache. The superior sagittal sinus (SSS) was isolated and electrically stimulated. Units linked to SSS stimulation were recorded in the most caudal part of the trigeminal nucleus. Topiramate reduced SSS-evoked ring of neurons in the trigeminocervical complex in a dose-dependent fashion. Its inhibition is a plausible mechanism of the action of migraine or cluster headache preventive medicines.

332

Silberstein

Clinical Prole Pilot Studies. Topiramate has been shown to be effective in a number of open-label and pilot studies (192194). In addition, its chronic use has been associated with weight loss, not weight gain (a common reason to discontinue preventive medication). In a preliminary safety and efcacy study (195), 213 patients were randomized (2:1) to topiramate or placebo and were titrated to either 200 mg/day or maximum tolerated dose over an eight-week period, followed by a 12-week maintenance period. For each protocol, the monthly migraine rate, migraine days, and percent reduction in migraine frequency for the intent-to-treat (ITT) population (n 211) were assessed by an analysis of covariance (ANCOVA) with baseline migraine rate as covariate and last observation carried forward. A disproportionately high number of topiramate patients dropped out during the rst four weeks of the study. ANCOVA was insensitive for detection of drugplacebo differences in the ITT population, but was sensitive to demonstrate superiority of topiramate versus placebo for patients completing the trial (n 155, p 0.03). However, a repeated measured analysis using the ITT population demonstrated statistically signicant reductions in monthly migraine rate (p 0.04) and migraine days (p 0.04), and percent reduction in migraine episodes (p 0.02) for topiramate patients versus placebo patients. A weighted regression analysis also demonstrated a statistically signicant reduction in migraine rate for topiramate patients versus placebo patients (p 0.05). Pivotal Phase III trialsEfcacy. Silberstein et al. (195), in the rst pivotal placebo-controlled clinical trial of 487 patients, assessed the efcacy and safety of topiramate (50, 100, and 200 mg/day) in migraine prevention in a 26-week, multicenter, randomized, double-blind, placebo-controlled study (MIGR-001). The primary efcacy measure was the change in mean monthly migraine frequency between baseline and the double-blind phase. Eligible subjects entered a washout period of up to 14 days, which was followed by a prospective baseline period of 28 days. Patients who completed the baseline period and met the entry criteria were randomized to one of four treatment groups: 50 mg/day topiramate, 100 mg/day topiramate, 200 mg/day topiramate, or placebo. Patients randomized to topiramate started at a dose of 25 mg/day; the daily dose was increased by 25 mg weekly (for a total of eight weeks) until patients reached either their assigned dose or maximum tolerated dose, whichever was lower. Patients then continued on that dose for 18 weeks. In the group treated with topiramate 100 mg/day, there was a mean reduction of 2.1 monthly migraine episodes (5.43.3), compared with 0.8 for placebo. The responder rate (patients with 50% or more reduction in monthly migraine frequency) was 52% with topiramate 200 mg/day (p < 0.001), 54% with topiramate 100 mg (p < 0.001), 36% with topiramate 50 mg/day (p 0.039), compared with 23% with placebo (Table 6). Topiramate treatment was also associated with reduced consumption of acutetreatment medications. The onset of efcacy was observed within the rst month of treatment. The 200 mg dose was not signicantly more effective than the 100 mg dose. The most common AEs were paresthesias, fatigue, nausea, anorexia, and abnormal taste. Body weight was reduced by an average of 3.8% in the 100 and 200 mg groups. Brandes et al. (196) assessed the efcacy and safety of topiramate (50, 100, and 200 mg/day) in the prevention of migraine headaches in the second 26-week, multicenter, randomized, double-blind, placebo-controlled study (MIGR-002). The primary and secondary efcacy measures were identical to MIGR-001. A total of 483 patients were randomized to the four treatment groups (placebo, 120; topiramate

Table 6 Topiramate Clinical Trials Design 50 mg (25 BID) 100 mg (50 BID) 200 mg (50 BID) 50 mg (25 BID) 100 mg (50 BID) 200 mg (50 BID) 4 wk baseline; 8 wks titration 18 wks maintenance 4 wk baseline; 8 wks titration 18 wks maintenance 4 wk baseline; 8 wks titration 18 wks maintenance Dosage (mg/day)/ other medication Duration Results

Study

Patient population (Diagnostic criteria)

No.

Preventive Treatment for Migraine

Silberstein et al. (2004)

Migraine with and without aura

487

Double-blind/ placebo-controlled crossover

Brandes et al. (2004)

Migraine with or without aura

483

Double-blind/ placebo controlled

Diener et al. (2004)

Migraine with or without aura

176

Double-blind/ placebo-& propranolol controlled

placebo 23% topiramate 50 mg: 36% topiramate 100 mg: 54% tiouranate 200 mg: 49% placebo 23% topiramate 50 mg: 39% topiramate 100 mg: 49% topiramate 200 mg: 49% placebo 23% topiramate 100 mg: 37% topiramate 200 mg: 35% propranolol 160 mg: 43%

333

334

Silberstein

50 mg/day, 120; topiramate 100 mg/day, 122; and topiramate 200 mg/day, 121). The ITT population consisted of 468 patients. The mean monthly number of migraine periods decreased signicantly for those patients on 100 mg/day of topiramate (from 5.8 to 3.5, p 0.008) or 200 mg/day of topiramate (from 5.1 to 2.9, p 0.001) versus placebo (from 5.6 to 4.5). Signicant reductions were evident as early as the rst month of treatment. A signicantly greater proportion of patients exhibited at least a 50% reduction in mean monthly migraines in the groups treated with 50 mg/day of topiramate (39%, p 0.009), 100 mg/day of topiramate (49%, p 0.001), and 200 mg/day of topiramate (47%, p 0.001). Patients treated with 200 mg/day of topiramate lost an average of 4.8% of body weight from baseline through the double-blind phase. In this second pivotal study, topiramate was associated with signicant improvement in migraine at doses of 100 or 200 mg/day in each efcacy measure assessed. The onset of efcacy was observed as early as the rst month of treatment. Diener et al. (197) compared two doses of topiramate (100 or 200 mg/day) to placebo or propranolol (160 mg/day) in a randomized, double-blind, parallel-group, multicenter trial of 575 subjects conducted in 68 centers in 13 countries. Topiramate 100 mg/day was superior to placebo as measured by average monthly migraine period rate, average monthly migraine days, rate of rescue medication use, and percentage of patients with a 50% or greater decrease in average monthly migraine period rate (responder rate 37%). The topiramate 100 mg/day and propranolol groups were similar in change from baseline to the core double-blind phase in average monthly migraine period rate and other secondary efcacy variables. Topiramate 200 mg/day failed in the primary end point compared to placebo but had a signicantly higher responder rate (35% vs. placebo 22%). Topiramate 100 mg/day (responder rate 37%) was better tolerated than topiramate 200 mg/day, and was comparable to propranolol (responder rate 43%). These ndings provide clear evidence that topiramate is effective in migraine prophylaxis. The 100 mg dose offers the best relationship between efcacy and tolerability. A major shortcoming of this trial is the high dropout rate of patients in the topiramate 200 mg group due to adverse effects. This high dropout rate resulted in the nonsuperiority of topiramate 200 mg over placebo (Table 7). Safety and Tolerability. Data for safety and tolerability in migraine is based on the experience of 1135 patients in multicenter, double-blind studies, who received total daily doses of 50, 100, or 200 mg of topiramate. The most common AE was paresthesia, which occurred in 35% of subjects in the topiramate 50 mg group, 51% in the topiramate 100 mg group, and 49% in the topiramate 200 mg group compared with 6% in the placebo group. Paresthesias were rated as mild-to-moderate in the majority of patients, and were treatment limiting in only 8% of these subjects; when bothersome, they can be controlled with potassium supplementation (198). The other most common AEs were fatigue, decreased appetite, nausea, diarrhea, weight decrease, taste perversion, hypoesthesia, and abdominal pain. The most common CNS AEs were somnolence, insomnia, difculty with memory, language problems, difculty with concentration, mood problems, and anxiety. The percentages of subjects who discontinued due to AEs were 17%, 25%, and 29% in the TPM 50, 100, and 200 mg groups, respectively, and 10% in the placebo group. Most dropouts were due to side effects that occurred early in the trial. There were no clinically important changes in clinical laboratory tests of liver function, renal function, or hematologic parameters, or abnormalities in vital sign measurements or neurologic examinations. In the study that included both topiramate and propranolol, the overall incidence of treatment-emergent and treatment-limiting AEs for topiramate 100 was comparable to propranolol 160 mg/day.

Preventive Treatment for Migraine Table 7 Miscellaneous Medication in the Preventive Treatment of Migraine Agent Daily dose Comment

335

Serotonin antagonists Methysergide 28 mg

Cyproheptadine

1236 mg

Pizotifen a2-agonists Clonidine Guanfacine Miscellaneous Lisinopril Candesartan Feverfew Petasites Riboavin Coenzyme Q Magnesium

1.53 mg

Higher doses are given b.id. or t.i.d. Dose started at 1 mg and increased by 1 mg every three days Should not be taken continuously for long periods b.i.d. or t.i.d. Useful in children Weight gain in most patients t.i.d. Weight gain and drowsiness are common side effects Limited evidence in migraine Limited evidence in migraine Positive small controlled trial Positive small controlled trial Controversial evidence 75 and 100 mg better than placebo in independent trials Positive small controlled trial Two positive controlled trials Controversial evidence

0.050.3 mg/ day 1 mg 1040 mg 16 mg 5082 mg 50100 mg 400 mg 100150 mg 400600 mg

Neurobehavioral AEs occurred at rates comparable to those seen for studies of other conditions, such as monotherapy in epilepsy, utilizing topiramate as a single antiepileptic treatment. The most common of these AEs were dizziness, slowed thinking, somnolence, ataxia, fatigue, confusion, and impaired concentration (199). Most of these AEs were seen during the rst two months of the initial titration period, and had resolved in 60% to 90% of patients with continued use of topiramate. Two studies have prospectively evaluated neuropsychometric changes with adjunctive topiramate treatment in patients with epilepsy (200,201). These studies support clinical observations that AEs occur most prominently during titration, with most changes not persisting after maintenance treatment (201). In clinical practice, the incidence of CNS AEs can be reduced with a low starting dose and a slower dose-escalation rate. Renal calculi can occur with the use of topiramate. The reported incidence is about 1.5%, representing a two to fourfold increase over the estimated occurrence in the general population (202). Most patients faced with this problem do not need surgery and go on to continue treatment with topiramate once they pass the stone (202). Patients who take topiramate for epilepsy have weight loss that occurs early in the treatment and is maximal by 15 to 18 months (203). The weight loss appears to be greatest in patients who are heavier at the onset and is most commonly seen in female patients (204). The mechanism is unclear. Rats treated with stopiramate showed decreased body fat as well as acutely reduced food intake and an increased metabolic rate. These animals also had decreased levels of total insulin, leptin, and corticosterone (205). Other investigators suggest that topiramate inhibits fat deposition. The activity of lipoprotein lipase is reduced in adipose tissue in topiramate-treated rats (108).

336

Silberstein

In the migraine trials, body weight was reduced by an average of 2.3% in the 50 mg group, 3.2% in the 100 mg group, and 3.8% in the 200 mg group. Patients on propranolol gained 2.3% of their baseline body weight. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported infrequently in patients receiving topiramate. There were no cases of this condition reported in the clinical studies. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic ndings can include myopia, anterior chamber shallowing, ocular hyperemia, and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within one month of initiating topiramate therapy. In contrast to primary narrow-angle glaucoma, which is rare in patients under 40 years of age, secondary angle-closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation, may be helpful (206). Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with an elevation in body temperature. Some of the cases were reported after exposure to elevated environmental temperatures. Most of the reports have been in children. Conclusion. The MIGR-001, MIGR-002, and MIGR-003 trials represent the largest controlled clinical trials of topiramate in migraine prevention to date, and together represent the largest controlled trials of a migraine preventive. Topiramate was associated with improvements in each of the efcacy measures presented. Treatment with topiramate 100 or 200 mg/day was associated with signicant reductions in migraine frequency, migraine days, and number of migraine attacks per month. Treatment with topiramate was also associated with reduced use of acute medications (207). Topiramate is effective for migraine prophylaxis. The 100 mg dose seems to have the best efcacy/tolerability ratio. Cognitive side effects are of less concern with doses of 100 mg or less. Topiramate administration should be started with a dose of 15 to 25 mg at bedtime and the dose should be increased by 15 to 25 mg/week. The dose should not be increased if bothersome AEs develop, one must wait until they resolve (they usually do). If they do not resolve, the dosage of the drug should be decreased to the last tolerable dose, then increased by a lower dose more slowly. The aim should be to reach a dose of 50 to 100 mg/day given twice a day. It is our experience that patients who tolerate the lower doses with only partial improvement often have increased benet with higher doses. The dose can be increased to 600 mg/day or higher. Lamotrigine Lamotrigine blocks voltage-sensitive sodium channels, leading to inhibition of neuronal glutamate release of glutamate. Glutamate is essential in the propagation of CSD, which many believe is the basis of the migraine aura. Lamotrigine has been studied as combination therapy for headache prevention in one relatively large, prospective, open-label trial of 65 patients, most of whom had chronic migraine (208). Only 35 patients were compliant with treatment to warrant inclusion in the analysis, with 12 dropping out because of AEs. The primary end point was reduction in frequency of severe headaches. There were 17 (48.6%) responders, at a mean dose

Preventive Treatment for Migraine

337

of 55 mg/day. Those who had migraine with aura had a better response rate (12/18 or 67%), including four of eight whose headaches were chronic. Another open-label study assessed the impact of lamotrigine on aura itself, and found that the drug signicantly reduced both the frequency and duration of aura (208). Chen et al. (209) reported two patients with migraine with persistent aura-like visual phenomena for months to years. After two weeks of lamotrigine treatment, both had resolution of the visual symptoms. Steiner et al. (210) compared the safety and efcacy of lamotrigine and placebo in migraine prophylaxis in a double-blind, randomized, parallel-groups trial. A total of 110 patients entered; after a one-month placebo run-in period, placebo responders and noncompliers were excluded, leaving 77 to be treated with lamotrigine (n 37) or placebo (n 40) for up to three months. Initially, lamotrigine therapy was begun at the full dose of 200 mg/day, but, following a high incidence of skin rashes, a slow dose-escalation was introduced: 25 mg/day for two weeks, 50 mg/day for two weeks, and then 200 mg/day. Attack rates were reduced from baseline means of 3.6 per month on lamotrigine and 4.4 on placebo, to 3.2 and 3.0, respectively, during the last month of treatment. Improvements were greater on placebo, and these changes, not statistically signicant, indicate that lamotrigine was ineffective for migraine prophylaxis. There were more AEs on lamotrigine than on placebo, most commonly rash. With slow dose-escalation, their frequency was reduced and the rate of withdrawal for AEs was similar in both treatment groups. Zonisamide Two retrospective, open-label studies of zonisamide in the preventive treatment of episodic migraine have been reported (211,212). In the study conducted by Drake et al. (211), 34 patients with refractory migraine with or without aura were treated adjunctively with zonisamide at doses as high as 400 mg/day (211). Headache data were obtained from patient headache diaries and telephone reports. A 40% reduction in headache severity, a 50% reduction in headache duration, and a 25% decrease in headache frequency were found at three months compared to baseline values. Four patients (12%) discontinued the drug because of AEs and nine stopped the medicine because they believed it was not working. Krusz reported improvement in 14/33 (42%) of patients, with four dropouts due to AEs (212). Zonisamide was also examined as monotherapy in a small, prospective, open-label study of nine patients with episodic migraine with or without aura (213). The drug was titrated to a mean dose of 244 mg/day, and investigator efcacy ratings were made for all patients who remained on a stable dose of the drug for six weeks. It was effective or very effective in 6 of 9 (67%) patients. Serotonin Antagonists The antiserotonin, migraine-preventive drugs are potent 5-HT2B and 5-HT2Creceptor antagonists, whereas metachlorophenyl piperazine (mCPP), a 5-HT2B and 5-HT2C receptor agonist, induces migraine in susceptible individuals (214216). Methysergide, cyproheptadine, and pizotifen, effective migraine prophylactic drugs, are 5-HT2B and 5-HT2Creceptor antagonists, whereas ketanserin, a selective 5-HT2A and a poor 5-HT2B and 5-HT2Creceptor antagonist, is not (217,218). mCPP, a major metabolite of the antidepressants trazodone and nefazodone, induces migraine hours after the immediate pharmacologic response to the drug

338

Silberstein

(monitored by elevation of plasma cortisol and prolactin) is over. Gordon et al. (215) found that mCPP induced headache in both migraineurs (ve of eight) and nonmigraine controls (four of 10). No signicant differences were found between the migraineurs and normal subjects in terms of their neuroendocrine or headache responses to mCPP, but there were highly signicant associations between the cortisol responses and headache severity and duration. Pizotifen and methylergometrine are potent rabbit jugular vein endothelial cell 5-HT2receptor antagonists. Activation of 5-HT2B or 5-HT2C receptor by mCPP or endogenously released 5-HT could dilate cerebral vessels. Vasodilation, however, is neither necessary nor sufcient to cause headache (219,220), but endotheliumderived NO can activate sensory trigeminovascular bers resulting in CGRP release, which mediates pial artery vasodilation (114) and neurogenic inammation (218,220,221). mCPP itself can produce extravasation in the dural membrane, which can be blocked by selective 5-HT2B antagonists (222). Methysergide is also a 5-HT1receptor agonist (223), but has lower afnity for the 5-HT1 than for the 5-HT2binding site (224). Methysergide-induced contraction of the isolated saphenous vein of dog is also mediated by 5-HT1B receptors (225 227). Chronic, but not acute, treatment with methysergide attenuates dural plasma extravasation following electric stimulation of the rat trigeminal ganglion in the Moskowitz model (228). The difference between acute and chronic drug administration could be due to the accumulation of the active metabolite, methylergometrine. Methysergide (or methylergometrine) presynaptically could inhibit the release of CGRP from perivascular sensory nerves. Methysergide Methysergide is a semisynthetic ergot alkaloid that is structurally related to methylergonovine. It is a 5-HT2receptor antagonist and 5-HT1B/D agonist. It was probably the rst drug developed for migraine prevention (229), but its usefulness is limited by reports of retroperitoneal and retropleural brosis associated with long-term, mostly uninterrupted, administration (230). The AHCPR Technical Report identied 17 controlled trials of methysergide for migraine prevention (136,231241). Four placebo-controlled trials suggested that methysergide was signicantly better than placebo at reducing headache frequency (28,240). Four comparison trials showed no statistically signicant differences between methysergide and pizotifen (234,238). Two trials that directly compared methysergide and propranolol failed to demonstrate any statistically signicant differences between these treatments (31,242). The only trial that compared methysergide with metoprolol reported an unusually low response to metoprolol (6%) and thus a misleading relative increase in methysergide efcacy (242). Methysergide was associated with a higher incidence of AEs than was placebo. AEs noted in trials and clinical practice include transient muscle ache, claudication, gastrointestinal complaints (nausea, vomiting, abdominal pain, and diarrhea), leg cramps, hair loss, weight gain, dizziness, giddiness, drowsiness, lassitude, paresthesia, and hallucinations. Frightening hallucinatory experiences after the rst dose are not uncommon (243). AEs were no more common with methysergide than with pizotifen. The major complication of methysergide is the rare (1/5000) development of retroperitoneal, pulmonary, or endocardial brosis (244,245). The duration of the trials reviewed here was too short to detect them.

Preventive Treatment for Migraine

339

Methysergide is indicated for the treatment of migraine and cluster headache. The dose ranges from 2 to 8 mg/day, with the higher doses being given two or three times a day. Some clinicians nd that they can use higher doses, up to 14 mg/day, without AEs and with higher efcacy (113). To minimize early AEs, patients can start with a dose of 1 mg/day and increase the dose gradually by 1 mg every two to three days. (This can be accomplished by breaking the 2 mg tablets if 1 mg tablets are not available.) Methysergide, in general, should not be taken continuously for long periods, because doing so may produce retroperitoneal brosis (230,244,246). Instead, the drug should be given for six months, stopped for one month, and then restarted. To avoid an increase in headache when methysergide is stopped, the patient should be weaned off the drug over a one-week period. Some authorities use methysergide on a continuous basis with careful monitoring (113), which includes auscultation of the heart and yearly echocardiography, chest X-ray, and abdominal MRI. The drug should be discontinued immediately on suspicion of pulmonary or cardiac retroperitoneal brosis (113). Contraindications to methysergide use include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, brotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Patients who receive methysergide should remain under the supervision of the treating physician and be examined regularly for development of pulmonary/cardiac or peritoneal brosis or vascular complications. Methysergide is an effective migraine preventive medication that is an appropriate consideration in resistant headaches with a high attack frequency. All of the open and controlled studies attest to its efcacy. In addition to being effective in reducing attack frequency, it often acts synergistically with ergotamine for breakthrough attacks. Due to its AEs prole, it should be reserved for severe cases in which other migraine-preventive drugs are not effective. Cyproheptadine Cyproheptadine, an antagonist at the 5-HT2, histamine H1, and muscarinic cholinergic receptors, is widely used in the prophylactic treatment of migraine in children (113,247,248). Curran and Lance (249) found cyproheptadine more effective than placebo but less effective than methysergide. Cyproheptadine is available as 4 mg tablets. The total dose ranges from 12 to 36 mg/day (given two to three times a day or at bedtime). Common AEs are sedation and weight gain; dry mouth, nausea, lightheadedness, ankle edema, aching legs, and diarrhea are less common. Cyproheptadine may inhibit growth in children (250) and reverse the effects of SSRIs. Pizotifen Pizotifen, a 5-HT2receptor antagonist structurally similar to cyproheptadine, is not available in the United States. The U.S. Headache Consortium Guidelines (21) found that evidence was inconsistent for its efcacy from 11 placebocontrolled trials (239,251260) and 19 comparisons with other agents (36,133 135,167,232,234,238,239,251,258,261268). Analysis of the placebo-controlled trials suggested a large clinical effect that was statistically signicant. In direct comparisons with other agents known to be efcacious for migraine prevention, no signicant differences were demonstrated between pizotifen and unarizine (133135), methysergide (232,234,238,239), naproxen sodium (251), or metoprolol

340

Silberstein

(36). However, in the 26 trials reviewed, pizotifen was generally poorly tolerated (20). Substantial weight gain, tiredness, and/or drowsiness were frequently reported. Pizotifen was associated with a high rate of withdrawals due to AEs. Controlled and uncontrolled studies in Europe (269) have shown this drug to be of benet in 40% to 79% of patients. The dose recommendation is 0.5 to 1 mg, one to three times daily by titration. Side effects include drowsiness and weight gain (270). Other Drugs Alpha Antagonists The U.S. Headache Consortium Guidelines and the AHCPR Technical Review included 17 controlled trials of a2 agonists for the prevention of migraine: 16 of clonidine (157,167,271284) and one of guanfacine (282). The evidence from these trials suggests that a2 agonists are minimally, and not conclusively, efcacious. Of the 11 placebo-controlled trials of clonidine, 3 found a signicant difference in favor of the active agent, but the magnitude of the effect was small (275,279,280). Two comparative trials comparing clonidine with the b-blockers metoprolol (283) and propranolol yielded mixed results (284). Two comparative trials showed no signicant differences among clonidine, practolol (275), and pindolol (157). One trial each found no significant differences between clonidine and pizotifen (167), or between clonidine and carbamazepine (157). Clonidines most commonly reported AEs were drowsiness and tiredness. In studies comparing clonidine with b-blockers, AEs occurred at similar rates for both interventions. Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists Schrader et al. (285) conducted a double-blind, placebo-controlled, crossover study of lisinopril, an angiotensin-converting enzyme inhibitor, in migraine prophylaxis. The treatment period was 12 weeks, with one 10 mg lisinopril tablet once daily for one week, then two 10 mg lisinopril tablets once daily for 11 weeks, followed by a two-week washout period. The second treatment period consisted of one placebo tablet, once daily for one week, and then two placebo tablets for 11 weeks. Hours with headache, days with headache, days with migraine, and headache severity index were signicantly reduced by 20% (95% condence interval 536%), 17% (95% condence interval 530%), 21% (95% condence interval 934%), and 20% (95% condence interval 337%), respectively, with lisinopril compared with placebo. Days with migraine were reduced by at least 50% in 14 participants for active treatment versus placebo and in 17 patients for active treatment versus run-in period. Days with migraine were fewer by at least 50% in 14 participants for active treatment versus placebo. Intention to treat analysis of data from 55 patients supported the differences in favor of lisinopril for the primary end points. Tronvik et al. (286) performed a randomized, double-blind, placebo-controlled crossover study of candesartan, an angiotensin II receptor blocker, in migraine prevention. Sixty patients aged 18 to 65 years with two to six migraine attacks per month were recruited. A placebo run-in period of four weeks was followed by two 12-week treatment periods separated by four weeks of placebo washout. Thirty patients were randomly assigned to receive one 16 mg candesartan cilexetil tablet daily in the rst treatment period, followed by one placebo tablet daily in the

Preventive Treatment for Migraine

341

second period. The remaining 30 patients received placebo followed by candesartan. In a period of 12 weeks, the mean number of days with headache was 18.5 with placebo versus 13.6 with candesartan (p 0.001) in the intention-to-treat analysis (n 57). The number of candesartan responders (reduction of 50% or greater compared with placebo) was 18 of 57 (31.6%) for days with headache and 23 of 57 (40.4%) for days with migraine. AEs were similar in the two periods. In this study, the angiotensin II receptor blocker candesartan was effective, with a tolerability prole comparable with that of placebo. Aspirin ONeill and Mann (35) and Masel et al. (287) found that aspirin (ASA) (650 mg/day) decreased headache frequency. Two major multicenter trials, however, proved the efcacy of ASA in the prophylaxis of migraine. In 1988, The British Physician Trial showed that a daily dose of 500 mg ASA reduced the frequency of migraine by an average of 30% (288). In a double-blind trial of low-dose ASA (325 mg every other day) in 22,071 U.S. male physicians (Physician Health Study), Buring et al. (289) found a 20% reduction in headache frequency. Although this is statistically signicant, it may not be clinically signicant. In a small open trial, Baldratti et al. (290) compared the efcacy of ASA (13.5 mg/kg) with propranolol (1.8 mg/kg). In this trial, both drugs were equally effective and reduced the frequency, duration, and intensity of attacks to the same extent. In a double-blind crossover trial, ASA (500 mg daily) was statistically less effective than 200 mg propranolol daily (34). High-dose ASA use may lead to overuse and the development of rebound headaches, although, in practice, ASA is usually implicated with other compounds in combination analgesics. ASA in low doses is indicated for the prophylaxis of myocardial infarction and transient ischemic attacks. We would use ASA only in patients who had prolonged or nonvisual aura. Nonsteroidal Anti-inammatory Drugs Some NSAIDs may be effective in migraine prophylaxis. These include sodium naproxen, fenoprofen, ketoprofen, and tolfenamic acid (291). Some headache disorders (paroxysmal hemicrania and hemicrania continua) are dened by their responsiveness to indomethacin (292294). Although NSAIDs are effective, they must be used with caution because of their gastrointestinal and renal function AEs (295). Botulinum Toxin Type A (Botox1) Silberstein et al. (296) evaluated the safety and efcacy of pericranial botulinum toxin type A injections as prophylactic treatment of chronic moderate-to-severe migraine. One hundred twenty-three patients who had chronic International Headache Society (IHS)dened migraine and a history of two to eight moderateto-severe migraine attacks during a one-month baseline were randomized to treatment with either 0, 25, or 75 U of botulinum toxin type A injected symmetrically into glabellar, frontalis, and temporalis muscles. Diaries were kept for three months postinjection. At 12 centers, 41, 42, and 40 patients were randomized to 0, 25, and 75 U botulinum toxin type A treatment groups and had baseline frequencies of migraine of 4.41, 4.45, and 3.95 attacks per month, respectively. The 25 U botulinum toxin type A treatment group fared signicantly better than the placebo group by the

342

Silberstein

following measures: reduction in mean frequency of moderate-to-severe migraines during days 31 to 60, incidence of 50% reduction in mild-to-severe migraines at days 61 to 90, and improvement by patient global assessment for days 31 to 60 postinjection. The 75 U botulinum toxin type A treatment group was signicantly better than the placebo group on patient global assessment for days 31 to 60, but not other parameters. Botulinum toxin type A treatment was well tolerated, but high-dose botulinum toxin type A showed signicantly more treatment-related AEs than placebo. No serious treatment-related AEs were reported. Pericranial injection of botulinum toxin type A (25 U) showed signicant differences compared with vehicle-induced type in reducing migraine frequency and associated symptoms during the 90 days following injection. Further studies are currently underway. Substance P Antagonist (Lanepitant) Goldstein et al. (297) studied lanepitant, a potent nonpeptide neurokinin-1 receptor antagonist that inhibits neurogenic dural inammation in migraine prevention. Patients with IHS migraine, with and without aura, were enrolled in a 12-week, double-blind, parallel-design study comparing the effect of 200 mg q.d. lanepitant (n 42) and placebo (n 42) on migraine frequency. The primary outcome measure was response rate, i.e., the proportion of patients with a 50% reduction in days of headache. The end point response rate for lanepitant-treated patients (41.0%) was not statistically signicantly (p 0.065) greater than that for placebo-treated patients (22.0%). Leukotriene Receptor Antagonist (Montelukast) A previous, small, open-label study of migraine patients suggested prophylactic efcacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used to treat asthma. Brandes et al. (298) evaluated the efcacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Over the three months of treatment, there was no signicant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (p 0.304). Montelukast 20 mg was not an effective prophylactic for prevention of migraine. Medicinal Herbs, Vitamins, and Minerals (See Chapter 23) According to a national survey (299), between 1990 and 1997, the use of herbal medicinal products by the general U.S. population increased by a staggering 480%. Feverfew (Tanacetum parthenium), a medicinal herb, has traditionally been used for fever, womens ailments, inammatory conditions, psoriasis, toothache, insect bites, rheumatism, asthma, and stomachache. During the last decades, it has also been used for migraine prophylaxis. Five trials were conducted; two that were reported in the AHCPR and three that were conducted after the report was published. One trial was conducted in a self-selected group of feverfew users and showed that withdrawing feverfew led to a statistically signicant increase in headache frequency (300). A pilot study of 17 migraineurs who ate fresh feverfew leaves daily was undertaken at the City of London Migraine Clinic. Patients were given capsules of freeze-dried feverfew or placebo. Those receiving placebo had a tripling in the frequency of migraine attacks. Patients on placebo reported increased nervousness,

Preventive Treatment for Migraine

343

tension headaches, insomnia, or joint stiffness constituting a post-feverfew syndrome (perhaps another example of rebound). The other, more conventional, trial was conducted in a larger group of migraineurs, most of whom (71%) had never used feverfew (301). This trial reported a smaller difference between feverfew and the control treatment than did the other trial, but still found the difference to be statistically signicant in favor of feverfew (p < 0.005). Three trials were not included in the AHCPR report. One was a doubleblind, randomized crossover trial that tested the efcacy of feverfew compared with placebo, and reported that treatment with feverfew was associated with a signicant reduction in pain intensity and nonheadache symptoms (nausea, vomiting, photophobia, and phonophobia) (302). The other trial reported no signicant differences between feverfew, given as an alcoholic extract, and placebo in reducing the migraine frequency (303). Pfaffenrath et al. (304) found no difference between several doses of a new feverfew extract and placebo except in a small subset of patients with more than four migraine attacks a month. Thus, only three of ve studies were positive. The better quality studies were negative. Feverfew may be effective in the prevention of migraine. Pittler and Ernst (305) conducted a new systematic review of the evidence from rigorous clinical trials of feverfews efcacy in migraine prevention, updating their older systematic review (306). The same ve trials, quoted above, met the inclusion criteria. In total, 343 patients participated in the included studies. Three trials (301303) were crossover trials, whereas two (300,304) used a parallel-group design. Two studies were withdrawal studies (302,303), and three were treatment studies (301,303,304). Three trials administered dried, powdered feverfew extract (300302), one used an alcoholic feverfew extract (303), and another used a CO2 extract (304). While the two studies with the highest methodological quality (303,304) showed no benecial events, three others (300302) were in favor of feverfew. Among the four trials with an acceptable sample size, two studies (301,302) reported feverfew to be superior to placebo, while two (303,304) did not. The frequency of migraine was reduced by feverfew in two trials (300,301), while two (303,304) reported no such effect. Results from these trials were mixed and did not convincingly establish that feverfew is efcacious in preventing migraine. Only mild and transient AEs were reported in the included trials. Feverfews AEs include mouth ulceration and a more widespread oral inammation associated with loss of taste (20). Feverfews mechanism of action is uncertain. It is rich in sesquiterpene lactones, especially parthenolide, which may be a nonspecic NE, 5-HT, bradykinin, prostaglandin, and acetylcholine antagonist. The biologic variation in the sesquiterpene lactone content and the long-term safety and effectiveness of feverfew are of concern (300). The sesquiterpene lactone parthenolide has been suggested as the main active component of feverfew. This hypothesis was supported by in vitro experiments that emphasized its biological activity. These studies have demonstrated that the plant has inhibitory effects on platelet aggregation and release of serotonin from blood platelets and leukocytes (307,308). One trial that used feverfew extract with a standardized and constant concentration of parthenolides to treat migraine did not show any benecial effect (303). Thus, the clinical effectiveness of feverfew for migraine prevention has not been established beyond reasonable doubt. More clinical trials are needed, both on a larger scale and with various feverfew extracts, including parthenolide-free sesquiterpene lactone chemotypes (309). At present, the identity

344

Silberstein

of the principle active constituent(s) of feverfew remains unclear. It has recently been suggested that feverfew is a nuclear factor kappa B antagonist (310). Petasites. Petasites hybridus root (butterbur) is a perennial shrub whose extracts have been used for therapeutic purposes in traditional medicine for centuries. Lipton et al. (311) conducted a randomized, double-blind, placebo-controlled trial of Petasites efcacy in migraine prophylaxis. Two hundred forty-ve eligible IHS migraine patients were randomized to one of three arms: petasites extract 50 mg b.i.d., petasites extract 75 mg b.i.d., or placebo b.i.d. Over the four months of treatment, migraine attack frequency was reduced by 26% for placebo, 48% for petasites extract 75 mg b.i.d. (p 0.0012 vs. placebo), and 36% for petasites extract 50 mg b.i.d. (p 0.127 vs. placebo). The most frequently reported AE was mild gastrointestinal events, predominantly burping. This study demonstrates that a standardized petasites extract, 75 mg b.i.d., is more effective than placebo and is well tolerated as a preventive therapy for migraine. Diener et al. (312) performed an independent reanalysis of a randomized, placebo-controlled, parallel-group study on the efcacy and tolerability of a special butterbur root extract (Petadolex1) for the prophylaxis of migraine. To follow regulatory requirements, an independent reanalysis of the original data was performed. Following a four-week baseline phase, 33 patients were randomized to treatment with two 25 mg capsules of butterbur twice a day and 27 to placebo. The mean monthly attack frequency decreased from 3.4 at baseline to 1.8 after three months (p 0.0024) in the active group and from 2.9 to 2.6 in the placebo group (n.s.). The responder rate (improvement of migraine frequency by more than 50%) was 45% in the active group and 15% in the placebo group. Butterbur was well tolerated and may be effective in the prophylaxis of migraine. Riboavin. A mitochondrial dysfunction resulting in impaired oxygen metabolism may play a role in migraine pathogenesis (313316). Riboavin (vitamin B2) is the precursor of avin mononucleotide and avin adenine dinucleotide, which are required for the activity of avoenzymes involved in the electron transport chain. Given to patients with MELAS or mitochondrial myopathies on the assumption that large doses might augment activity of mitochondrial complexes I and II, riboavin improved clinical as well as biochemical parameters (109,317319). Based on the results of an open trial in migraine, a placebo-controlled, doubleblind trial of high dose of vitamin B2 (400 mg) was performed and showed signicant benet (320). Schoenen et al. (320) compared riboavin (400 mg) with placebo in migraineurs in a randomized trial of three months duration. Riboavin was signicantly superior to placebo in reducing attack frequency (p 0.005), headache days (p 0.012), and migraine index (p 0.012). The proportion of patients who improved by at least 50% in headache days, i.e., responders, was 15% for placebo and 59% for riboavin (p 0.002), and the number-needed-to-treat for effectiveness was 2.3. Only three AEs occurred: two in the riboavin group (diarrhea and polyuria) and one in the placebo group (abdominal cramps). None was serious. Coenzyme Q. Rozen et al. (321) assessed the efcacy of coenzyme Q10 as a preventive treatment for migraine headaches in an open-label trial. Thirty-two patients with a history of episodic migraine, with or without aura, were treated with coenzyme Q10 at a dose of 150 mg/day. Thirty-one of 32 patients completed the study; 61.3% of patients had a greater than 50% reduction in number of days with migraine headache. There were no side effects noted with coenzyme Q10. From this open-label investigation, coenzyme Q10 appears to be a good migraine preventive.

Preventive Treatment for Migraine

345

Sandor et al. (322) performed a double-blind, placebo-controlled trial of coenzyme Q10 (100 mg TID) in 42 patients for three months. The 50%-responder rate was 47.6% for coenzyme Q10 and 14.3% for placebo. Magnesium supplementation was effective in one of two trials. One study enrolled 81 patients who had IHS migraine. Patients received 600 mg (24 mmol) of oral magnesium (trimagnesium dicitrate) or placebo daily for 12 weeks. In the weeks 9 to 12, the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared with the baseline (p < 0.05). The number of days with migraine and symptomatic drug consumption also decreased signicantly in the magnesium group. AEs were diarrhea (18.6%) and gastric irritation (4.7%) (323). In another multicenter, prospective, randomized, double-blind, placebocontrolled study, 20 mmol magnesium-L-aspartate-hydrochloride trihydrate given in divided doses was evaluated. An interim analysis was performed with 69 patients (64 women, 5 men). Of these, 35 had received magnesium and 34, placebo. There were 10 responders in each group (28.6% magnesium and 29.4% placebo). There was no benet from magnesium compared with placebo in the number of migraine days or migraine attacks (324). The studies differed in the amount of magnesium (24 mmol vs. 20 mmol) and in the salt (dicitrate vs. aspartate). Those differences may produce differences in bioavailability and efcacy and account for the reported difference.

SETTING TREATMENT PRIORITIES The goals of preventive treatment are to reduce the frequency, duration, or severity of attacks, improve responsiveness to acute attack treatment, improve function, and reduce disability. It may also prevent episodic migraines progression to chronic migraine and result in health-care cost reductions. The medications used to treat migraine can be divided into four major categories: (i) drugs that have documented high efcacy and mild-to-moderate AEs, which include some b-blockers, amitriptyline, topiramate, and divalproex; (ii) drugs that have lower documented efcacy and mild-to-moderate AEs, which include SSRIs, other b-blockers, calcium channel antagonists, gabapentin, riboavin, and NSAIDs; (iii) drugs used based on (A) opinion, (B) mild-to-moderate AEs, or (C) major AEs or complex management; (iv) drugs that either have documented high efcacy but signicant AEs or are difcult to use, which include methysergide and MAOIs; and (v) drugs that have proven limited or no efcacy, which include cyproheptadine, lithium, nifedipine, nimodipine, and phenytoin. Choice should be made based on a drugs proven efcacy, the patients preferences and headache prole, the drugs side effects, and the presence or absence of coexisting or comorbid disease (Table 2). The drug used should be the one that has the best risk-to-benet ratio for the individual patient and takes advantage of the drugs side-effect prole (325,326). An underweight patient would be a candidate for one of the medications that commonly produce weight gain, such as a TCA; in contrast, one would try to avoid these drugs in the overweight patient and consider the use of topiramate. Tertiary TCAs that have a sedating effect would be useful at bedtime for patients with insomnia. Older patients with cardiac disease or patients with signicant hypotension may not be able to use TCAs or calcium channel or b-blockers, but could use divalproex or topiramate. In the athletic patient, b-blockers should be used with caution.

346 Table 8 Preventive Drugs

Silberstein

High efcacy: low-to-moderate AEs Propranolol, timolol, amitriptyline, valproate, topiramate Low efcacy: low-to-moderate AEs NSAIDsAspirin, urbiprofen, ketoprofen, naproxen sodium b-blockersAtenolol, metoprolol, nadolol Calcium-channel blockersVerapamil AnticonvulsantsGabapentin OtherFenoprofen, feverfew, vitamin B2 Pizotifen Unproven efcacy: low-to-moderate AEs AntidepressantsDoxepin, nortriptyline, imipramine, protriptyline, venlafaxine, uvoxamine, mirtazepine, paroxetine, protriptyline, sertraline, trazodone Major AEs or complex management Methergine, MAOIs Proven not effective or low efcacy Acebutolol, carbamazepine, clomipramine, clonazepam, indomethacin, lamotrigine, nabumetone, nicardipine, nifedipine, pindolol
Abbreviations: AEs, adverse events; NSAIDs, nonsteroidal anti-inammatory drugs; MAOIs, monoamine oxidase inhibitors.

Medication that can impair cognitive functioning should be avoided when patients are dependent on their wits (325,326) (Table 8). Comorbid and coexistent diseases have important implications for treatment. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. In some instances, two or more conditions may be treated with a single drug. When migraine and hypertension and/or angina occur together, b-blockers or calcium channel blockers may be effective for all conditions (295). For the patient with migraine and depression, TCAs or SSRIs may be especially useful (327). For the patient with migraine and epilepsy (328) or migraine and bipolar illness (174,329), divalproex and topiramate are the drugs of choice. The pregnant migraineur who has a comorbid condition that needs treatment should be given a medication that is effective for both conditions and has the lowest potential for AEs on the fetus. When individuals have more than one disease, certain categories of treatment may be relatively contraindicated. For example, b-blockers should be used with caution in the depressed migraineur, whereas TCAs, neuroleptics, or sumatriptan may lower the seizure threshold and should be used with caution in the epileptic migraineur. Although monotherapy is preferred, it is sometimes necessary to combine preventive medications. Antidepressants are often used with beta-blockers or calcium channel blockers and topiramate or divalproex sodium may be used in combination with any of these medications. Pascual et al. (330) found that combining a beta-blocker and sodium valproate could lead to an increased benet for patients with migraine previously resistant to either alone. Fifty-two patients (43 women) with a history of episodic migraine, with or without aura, and previously unresponsive to beta-blockers or sodium valproate monotherapy, were treated with a combination of propranolol (or nadolol) and sodium valproate in an open-label fashion. Fifty-six percent had a greater than 50% reduction in migraine days. This open trial supports the practice of combination therapy. Controlled trials are needed to determine the true advantage of this combination treatment in episodic and chronic migraine.

Preventive Treatment for Migraine

347

REFERENCES
1. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. London: Martin Dunitz Ltd., 2002. 2. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41:646657. 3. Headache Classication Committee. The International Classication of Headache Disorders. 2nd ed. Cephalalgia 2004; 24:1160. 4. Lipton RB, Silberstein SD. Why study the comorbidity of migraine? Neurology 1994; 44:45. 5. Silberstein SD, Winner PK, Chmiel JJ. Migraine preventive medication reduces resource utilization. Headache: J Head Face Pain 2003; 43:171178. 6. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM. Evidencebased guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. Neurology 2000; Available at: http// www.neurology.org. 7. Silberstein SD. Headaches in pregnancy. Neurol Clin 2004; 22:727756. 8. Lipton RB, Scher AI, Kolodner K, Liberman J, Steiner TJ, Stewart WF. Migraine in the United States: epidemiology and patterns of health care use. Neurology 2002; 58:885894. 9. Tfelt-Hansen P. Prioritizing acute pharmacotherapy of migraine. In: Olesen J, TfeltHansen P, Welch KMA, eds. The Headaches. 2nd ed. New York: Lippincott Williams & Wilkins, 2000:453456. 10. Dimitriadou V, Buzzi MG, Theoharides TC, Moskowitz MA. Ultrastructural evidence for neurogenically mediated changes in blood vessels of the rat aura mater and tongue following antidromic trigeminal stimulation. Neuroscience 1992; 48:187203. 11. Kandere-Grzybowska K, Gheorghe D, Priller J, et al. Stress-induced dura vascular permeability does not develop in mast cell-decient and neurokinin-1 receptor knockout mice. Brain Res 2003; 980:213220. 12. Silberstein SD. Migraine pathophysiology and its clinical implications. Cephalalgia 2004; 24(suppl 2):27. 13. Silberstein SD. Migraine and pregnancy. Neurologic Clinics 1997; 15:209231. 14. Olerud B, Gustavsson CL, Furberg B. Nadolol and propranolol in migraine management. Headache 1986; 26:490493. 15. Ryan RE, Sudilovsky A. Nadolol: its use in the prophylactic treatment of migraine. Headache 1983; 23:2631. 16. Ryan RE. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J 1984; 108:11561159. 17. Sudilovsky A, Stern MA, Meyer JH. Nadolol: the benets of an adequate trial duration in the prophylaxis of migraine. Headache 1986; 26:325. 18. Rabkin R, Stables DP, Levin NW, Suzman M. The prophylactic value of propranolol in angina pectoris. Am J Cardiol 1996:370383. 19. Weber RB, Reinmuth OM. The treatment of migraine with propranolol. Neurology 1972; 22:366369. 20. Gray RN, Goslin RE, McCrory DC, Eberlein K, Tulsky J, Hasselblad V. Drug treatments for the prevention of migraine headache. Prepared for the Agency for Health Care Policy and Research, Contract No. 290-94-2025. Available from the National Technical Information Service, Accession No. 127953, 1999. 21. Silberstein SD. Practice ParameterEvidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology for the United States Headache Consortium. Neurology 2000; 55:754762.

348

Silberstein

22. Andersson K, Vinge E. Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine. Drugs 1990; 39:355373. 23. Holroyd KA, Penzien DB, Coordingley GE. Propranolol in the management of recurrent migraine: a meta-analytic review. Headache 1991; 31:333340. 24. Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Systematic Rev 2004; 3. 25. Silberstein SD. Migraine. Lancet 2004; 363:381391. 26. Mathew NT. Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 1981; 21:105109. 27. Langohr HD, Gerber WD, Koletzki E, Mayer K, Schroth G. Clomipramine and metoprolol in migraine prophylaxis: a double-blind crossover study. Headache 1985; 25:107113. 28. Andersson PG, Dahl S, Hansen JH, et al. Prophylactic treatment of classical and nonclassical migraine with metoprolol: a comparison with placebo. Cephalalgia 1983; 3:207212. 29. Kangasniemi P, Andersen AR, Andersson PG, et al. Classic migraine: effective prophylaxis with metoprolol. Cephalalgia 1987; 7:231238. 30. Steiner TJ, Joseph R, Hedman C, Rose FC. Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging followup. Headache 1988; 28:1523. 31. Steardo L, Bonuso S, DiStasio E, Marano E. Selective and nonselective beta-blockers: are both effective in prophylaxis of migraine? A clinical trial versus methysergide. Acta Neurol 1982; 4:196204. 32. Gerber WG, Diener H, Scholz E, Niederberger U. Responders and nonresponders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 1991; 11:3745. 33. Olsson JE, Behring HC, Forssman B, et al. Metoprolol and propranolol in migraine prophylaxis: a double-blind multicenter study. Acta Neurol Scand 1984; 70: 160180. 34. Grotemeyer KH, Scharanski HW, Schlake HP, Husstedt IW. Acetylsalicylic acid vs metoprolol in migraine prophylaxis: a double-blind crossover study. Headache 1990; 30:639641. 35. ONeill BP, Mann JD. Aspirin prophylaxis in migraine. Lancet 1978; 8101:11791181. 36. Vilming S, Standnes B, Hedman C. Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine: a double-blind investigation. Cephalalgia 1985; 5:1723. 37. Stensrud P, Sjaastad O. Short-term trial of propranolol in racemic form (Inderal), d-propranolol and placebo in migraine. Acta Neurol Scand 1976; 53:229232. 38. Briggs RS, Millac PA. Timolol in migraine prophylaxis. Headache 1979; 19:379381. 39. Stellar S, Ahrens SP, Meibohm AR, Reines SA. Migraine prevention with timolol: a double-blind crossover study. JAMA 1984; 252:25762580. 40. Forssman B, Lindblad CJ, Zbornikova V. Atenolol for migraine prophylaxis. Headache 1983; 23:188190. 41. Johannsson V, Nilsson LR, Widelius T, et al. Atenolol in migraine prophylaxis: a double-blind crossover multicenter study. Headache 1987; 27:372374. 42. Stensrud P, Sjaastad O. Clinical trial of a new antibradykinin, anti-inammatory drug, ketoprofen (19.583 r.p.) in migraine prophylaxis. Headache 1974; 14:96100. 43. Tobita M, Hino M, Ichikawa N, Takase S, Ogawa A. A case of hemiplegic migraine treated with unarizine. Headache 1987; 27:487488. 44. Freitag FG, Diamond S. Nadolol and placebo comparison study in the prophylactic treatment of migraine. J Am Osteopath Assoc 1984; 84:343347. 45. Ekbom K, Lundberg PO. Clinical trial of LB-56 (d, 14-(2-hydroxy-3-isopropylaminopropoxy) indol): an adrenergic beta-receptor blocking agent in migraine prophylaxis. Headache 1972; 12:1517.

Preventive Treatment for Migraine

349

46. Ekbom K, Zetterman M. Oxprenolol in the treatment of migraine. Acta Neurol Scand 1977; 56:181184. 47. Nanda RN, Johnson RH, Gray J, Keugh HJ, Melville ID. A double-blind trial of acebutolol for migraine prophylaxis. Headache 1978; 18:379381. 48. Ekbom K. Alprenolol for migraine prophylaxis. Headache 1994; 34:476478. 49. Sjaastad O, Stensrud P. Clinical trial of a beta-receptor blocking agent (LB46) in migraine prophylaxis. Acta Neurol Scand 1972; 48:124128. 50. Fanchamps A. Why do not all beta-blockers prevent migraine? Headache 1985; 25:6162. 51. Shanks RG. A review of the relationship between beta-adrenoreceptor antagonists and their action in migraine. In: Rose FC, ed. Advances in headache research. London: John Libbey, 1987:161166. 52. Wideroe TE, Vigander T. Propranolol in the treatment of migraine. Br Med J 1974; 2:699701. 53. Kuritzky A, Hering R. Prophylactic treatment of migraine with long acting propranolol: a comparison with placebo. Cephalalgia 1987; 7:457458. 54. Solomon GD. Verapamil and propranolol in migraine prophylaxis: a double-blind crossover study. Headache 1986; 26:325. 55. Ablad B, Dahlof C. Migraine and b-blockade: modulation of sympathetic neurotransmission. Cephalalgia 1986; 6:713. 56. Koella WP. CNS-related (side-)effects of b-blockers with special reference to mechanisms of action. Eur J Clin Pharmacol 1985; 28:5563. 57. Ramadan NM. Prophylactic migraine therapy: mechanisms and evidence. Curr Pain Headache Rep 2004; 8:9195. 58. Schoenen J, Maertens de Noordout A, Timsit-Bertheir M, Timisit M. Contingent negative variation and efcacy of b-blocking agents in migraine. Cephalalgia 1986; 6: 231233. 59. Stoica E, Enulescu O. Propranolol corrects the abnormal catecholamine response to light during migraine. Eur Neurol 1990; 30:1922. 60. Featherstone HJ. Low dose propranolol therapy for aborting acute migraine. West J Med 1983; 138:416417. 61. Rosen JA. Observations on the efcacy of propranolol for the prophylaxis of migraine. Ann Neurol 1983; 13:9293. 62. Diamond S, Kudrow L, Stevens J, Shapiro DB. Long-term study of propranolol in the treatment of migraine. Headache 1982; 22:268271. 63. Dahlof C. No clear-cut long-term prophylactic effect of one month of treatment with propranolol in migraineurs. Cephalalgia 1987; 7:459460. 64. Frishman WH. Beta adrenergic blocker withdrawal. Am J Cardiol 1987; 59:32F. 65. Pradalier A, Serratrice G, Colard M, et al. Long-acting propranolol on migraine prophylaxis: results of a double-blind, placebo-controlled study. Cephalalgia 1989; 9:247253. 66. Diamond S, Solomon GD, Freitag FG, Mehta ND. Long-acting propranolol in the prophylaxis of migraine. Headache 1987; 27:7072. 67. Cortelli P, Sacquegna T, Albani F, et al. Propranolol plasma levels and relief of migraine. Arch Neurol 1985; 42:4648. 68. Sudilovsky A, Elkind AH, Ryan RE, Saper JR, Stern MA, Meyer JH. Comparative efcacy of nadolol and propranolol in the management of migraine. Headache 1987; 27:421426. 69. Heninger GR, Charney DS. Mechanism of action of antidepressant treatments: implications for the etiology and treatment of depressive disorders. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987:535544. 70. Chaput Y, deMontigny C, Blier P. Presynaptic and postsynaptic modications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991; 5:219229.

350

Silberstein

71. Taiwo YO, Levine JD. Further conrmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. Neuroscience 1991; 44:131135. 72. Sawynok J, Reid A, Poon A. Peripheral antinociceptive effect of an adenosine kinase inhibitor, with augmentation by an adenosine deaminase inhibitor, in the rat formalin test. Pain 1998; 74:7581. 73. Sawynok J, Reid AR, Esser MJ. Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. Pain 1999; 80:4555. 74. Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM. BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res 1996; 710:1120. 75. Lindsay RM, Wiegand SJ, Altar CA, diStefano PS. Neurotrophic factors: from molecule to man. Trends Neurosci 1994; 17:182190. 76. Skolnick P, Legutko B, Li X, Bymaster FP. Current perspectives on the development of non-biogenic amine-based antidepressants. Pharmacol Res 2001; 43:411423. 77. Austin MC, Whitehead RE, Edgar CL, Janosky JE, Lewis DA. Localized decrease in serotonin transporter-immunoreactive axons in the prefrontal cortex of depressed subjects committing suicide. Neuroscience 2002; 114:807815. 78. Altar CA. Neurotrophins and depression. TiPS 1999; 20:5961. 79. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995; 15:17681777. 80. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiat 2003; 54:703709. 81. Panerai AE, Monza G, Movilia P, Bianchi M, Francussi BM, Tiengo M. A randomized, within-patient, cross-over, placebo-controlled trial on the efcacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain. Acta Neurol Scand 1990; 82:3438. 82. Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves post-herpetic neuralgia. Clin Pharmacol Ther 1990; 47:305312. 83. Feinmann C. Pain relief by antidepressants: possible modes of action. Pain 1985; 23: 18. 84. Richelson E. Antidepressants and brain neurochemistry. Mayo Clin Proc 1990; 65: 12271236. 85. Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxis of migraine. Headache 1992; 32:101104. 86. Andersson PG, Petersen EN. Propranolol and femoxetine, a 5HT-uptake inhibitor, in migraine prophylaxis: a double-blind crossover study. Acta Neurol Scand 1981; 64: 280288. 87. Bonuso S, DiStasio E, Barone P, Steardo L. Timed-release dihydroergotamine in the prophylaxis of mixed headache: a study versus amitriptyline. Cephalalgia 1983; 3: 175178. 88. Couch JR, Hassanein RS. Migraine and depression: effect of amitriptyline prophylaxis. Trans Am Neurol Assoc 1976; 101:234237. 89. Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol 1979; 36:695699. 90. Gomersall JD, Stuart A. Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial. J Neurol Neurosurg Psychiat 1973; 36: 684690. 91. Jacobs H. A trial of opipramol in the treatment of migraine. J Neurol Neurosurg Psychiat 1972; 35:500504.

Preventive Treatment for Migraine

351

92. Kangasniemi PJ, Nyrke T, Lang AH, Petersen E. Femoxetinea new 5HT uptake inhibitorand propranolol in the prophylactic treatment of migraine. Acta Neurol Scand 1983; 68:262267. 93. Monro P, Swade C, Coppen A. Mianserin in the prophylaxis of migraine: a doubleblind study. Acta Psychiatr Scand 1985; 72:98103. 94. Noone JF. Clomipramine in the prevention of migraine. J Int Med Res 1980; 8:4952. 95. Saper JR, Silberstein SD, Lake AE, Winters ME. Double-blind trial of uoxetine: chronic daily headache and migraine. Headache 1994; 34:497502. 96. Zeeberg I, Orholm M, Nielsen JD, Honor PL, Larsen JJ. Femoxetine in the prophylaxis of migraine: a randomized comparison with placebo. Acta Neurol Scand 1981; 64:452459. 97. Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz HA, Preskorn SH, Mason J. Migraine prophylaxis. A comparison of propranolol and amitriptyline. Arch Neurol 1987; 44:486489. 98. Orholm M, Honor PF, Zeeberg I. A randomized general practice group-comparative study of femoxetine and placebo in the prophylaxis of migraine. Acta Neurol Scand 1986; 74:235239. 99. Bank J. A comparative study of amitriptyline and uvoxamine in migraine prophylaxis. Headache 1994; 34:476478. 100. Richardson JW, Richelson E. Antidepressants: a clinical update for medical practitioners. Mayo Clin Proc 1984; 59:330337. 101. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon, 1990:383435. 102. Abramowicz M. Fluoxetine (Prozac) revisited [Medical Letter]. Drugs Ther 1990:8385. 103. Barnhart ER. Physicians Desk Reference. 45th ed. Oradell: Medical Economics Inc., 1991. 104. Weilburg JB, Rosenbaum JF, Biederman J, Sachs GS, Pollack MH, Kelly K. Fluoxetine added to non-MAOI antidepressants converts nonresponders to responders: a preliminary report. J Clin Psychiat 1989; 50:447449. 105. Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, Wilkinson M. S-uoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia 1998; 18:283286. 106. Markley HG, Gasser PA, Markley ME, Pratt SM. Fluoxetine in prophylaxis of migraine: clinical experience. Cephalalgia 1991; 11:164165. 107. Solomon G, Kunkel R. Effects of uoxetine on premenstrual syndrome in chronic headache sufferers. Headache 1990; 30:301. 108. Richard D, Ferland J, Lalonde J, et al. Inuence of topiramate in the regulation of energy balance. Nutrition 2000; 16:961966. 109. Scholte HR, Busch HF, Bakker HD, Bogaard JM, Luyt-Houwen IE, Kuyt LP. Riboavin-responsive complex I deciency. Biochim Biophys Acta 1995; 1271:7583. 110. Mosniam A, Freitag FG, Ignacio R, et al. Apparent lack of correlation between tyramine and phenylethylamines content and the occurrence of food precipitated migraine. Headache Quart 1996; 7:239249. 111. Shulman KI, Walker SE. Rening the MAOI diet. Tyramine content of pizzas and soy products. J Clin Psychiat 1999; 60:191193. 112. Tollefson GD. Monoamine oxidase inhibitors: a review. J Clin Psychiat 1983; 44: 280288. 113. Raskin NH. Headache. 2nd ed. New York: Churchill-Livingstone, 1988. 114. Clary C, Schweitzer E. The treatment of MAOI hypertensive crisis with sublingual nifedipine. Clin Psychiat 1987; 48:249250. 115. Snyder SH, Reynolds IJ. Calcium-antagonist drugs: receptor interactions that clarify therapeutic effects. N Eng J Med 1985; 313:9951002.

352

Silberstein

116. Greenberg DA. Calcium channels in neurological disease. Ann Neurol 1997; 42: 275282. 117. Varadi G, Mori Y, Mikala G, Schwartz A. Molecular determinants of Ca2 channel function and drug action. TiPS 1995; 2:4349. 118. Catterall WA, Striessnig J, Snutch TP, Perez-Reyes E. International Union of Pharmacology. Compendium of voltage-gated ion channels: calcium channels. Pharmacol Rev 2003; 55:579581. 119. Miljanich GP, Ramachandran J. Antagonists of neuronal calcium channels: structure, function, and therapeutic implications. Annu Rev Pharmacol Toxicol 1995; 35:707734. 120. Wauquier A, Ashton D, Marranes R. The effects of unarizine in experimental models related to the pathogenesis of migraine. Cephalalgia 1985; 5:119120. 121. Ophoff RA, Terwindt GM, Vergouwe MN. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 channel gene CACNLA4. Cell Tiss Res 1996; 87:543552. 122. Aldeeb SM, Biary N, Bahou Y, Aljaberi M, Khoja W. Flunarizine in migraine: a double-blind placebo-controlled study (in a Saudi population). Headache 1992; 32: 461462. 123. Diamond S, Freitag FG. A double-blind trial of unarizine in migraine prophylaxis. Headache Quart 1993; 4:169172. 124. Louis P. A double-blind placebo-controlled prophylactic study of unarizine (Sibelium) in migraine. Headache 1981; 21:235239. 125. Mendenopoulos G, Mana T, Logothetis I, Bostantjopoulou S. Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation. Cephalalgia 1985; 5: 3137. 126. Pini LA, Ferrari A, Guidetti G, Galetti G, Sternieri E. Inuence of unarizine on the altered electronystagmographic (ENG) recordings in migraine. Cephalalgia 1985; 5: 173175. 127. Sorensen PS, Hansen K, Olesen J. A placebo-controlled, double-blind, cross-over trial of unarizine in common migraine. Cephalalgia 1986; 6:714. 128. Thomas M, Behari M, Ahuja GK. Flunarizine in migraine prophylaxis: an Indian trial. Headache 1991; 31:613615. 129. Frenken CW, Nuijten ST. Flunarizine, a new preventive approach to migraine: a double-blind comparison with placebo. Clin Neurol Neurosurg 1984; 86:1720. 130. Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS. Comparison of the efcacy and safety of unarizine to propranolol in the prophylaxis of migraine. Can J Neurol Sci 1992; 19:340345. 131. Lucking CH, Oestreich W, Schmidt R, Soyka D. Flunarizine vs propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients. Cephalalgia 1988; 8:2126. 132. Grotemeyer KH, Schlake HP, Husstedt IW, Rolf LH. Metoprolol versus unarizine: a double blind crossover study. Cephalalgia 1987; 7:465466. 133. Cerbo R, Casacchia M, Formisano R, et al. Flunarizine-pizotifen single-dose doubleblind cross-over trial in migraine prophylaxis. Cephalalgia 1986; 6:1518. 134. Louis P, Spierings EL. Comparison of unarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double-blind study. Cephalalgia 1982; 2:197203. 135. Rascol A, Montastruc JL, Rascol O. Flunarizine versus pizotifen: a double-blind study in the prophylaxis of migraine. Headache 1986; 26:8385. 136. Steardo L, Marano E, Barone P, Denman DW, Monteleone P, Cardone G. Prophylaxis of migraine attacks with a calcium-channel blocker: unarizine versus methysergide. J Clin Pharmacol 1986; 26:524528. 137. Agnoli A, Bussone G, Mailland F, Manzone GC, Martucci N, Nappi G. Dihydroergokryptine vs unarizine in the basic treatment of migraine without aura. Cephalalgia 1991; 11:216217.

Preventive Treatment for Migraine

353

138. Ansell E, Fazzone T, Festenstein R, et al. Nimodipine in migraine prophylaxis. Cephalalgia 1988; 8:269272. 139. Migraine-Nimodipine European Study Group (MINES). European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). Headache 1989; 29:633638. 140. Gelmers HJ. Nimodipine, a new calcium antagonist, in the prophylactic treatment of migraine. Headache 1983; 23:106109. 141. Bussone G, Baldini S, DAndrea G, et al. Nimodipine versus unarizine in common migraine: a controlled pilot trial. Headache 1987; 27:7679. 142. Formisano R, Falaschi P, Cerbo R, et al. Nimodipine in migraine: clinical efcacy and endocrinological effects. Eur J Clin Pharmacol 1991; 41:6971. 143. McArthur JC, Marek K, Pestronk A, McArthur J, Peroutka SJ. Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects. Neurology 1989; 39:284286. 144. Lamsudin R, Sadjimin T. Comparison of the efcacy between unarizine and nifedipine in the prophylaxis of migraine. Headache 1993; 33:335338. 145. Albers GW, Simon LT, Hamik A, Peroutka SJ. Nifedipine versus propranolol for the initial prophylaxis of migraine. Headache 1989; 29:215218. 146. Markley HG, Cleronis JCD, Piepko RW. Verapamil prophylactic therapy of migraine. Neurology 1984; 34:973976. 147. Diamond S, Ryan RE, Klapper JA, et al. Dotarizine in the prophylaxis of migraine headaches. Headache 1999; 39:350. 148. Riopelle R, McCans JL. A pilot study of the calcium channel antagonist diltiazem in migraine syndrome prophylaxis. Can J Neurol Sci 1982; 9:269. 149. Smith R, Schwartz A. Diltiazem prophylaxis in refractory migraine. N Engl J Med 1984; 310:13271328. 150. Coulam CB, Annagers JR. New anticonvulsants reduce the efcacy of oral contraception. Epilepsia 1979; 20:519525. 151. Hanston PP, Horn JR. Drug interaction. Newsletter 1985; 5:710. 152. Jensen R, Brinck T, Olesen J. Sodium valproate has prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology 1994; 44:241244. 153. Klapper JA. An open label crossover comparison of divalproex sodium and propranolol HCl in the prevention of migraine headaches. Headache Quart 1995; 5:5053. 154. Mathew NT, Saper JR, Silberstein SD, et al. Migraine prophylaxis with divalproex. Arch Neurol 1995; 52:281286. 155. Rompel H, Bauermeister PW. Etiology of migraine and prevention with carbamazepine (Tegretol). S Afr Med J 1970; 44:7580. 156. Stensrud P, Sjaastad O. Clonazepam (rivotril) in migraine prophylaxis. Headache 1979; 19:333334. 157. Anthony M, Lance JW, Somerville B. A comparative trial of prindolol, clonidine and carbamazepine in the interval therapy of migraine. Med J Aust 1972; 6:13431346. 158. Mathew NT. Gabapentin in migraine prophylaxis. Cephalalgia 1996; 16:367. 159. Wessely P, Baumgartner C, Klinger D, et al. Preliminary results of a double-blind study with the new migraine prophylactic drug Gabapentin. Cephalalgia 1987; 7:477478. 160. Mathew NT, Rapoport A, Saper J, et al. Efcacy of gabapentin in migraine prophylaxis. Headache 2001; 41:119128. 161. Welch KMA, Chabi E, Bartosh K, Achar VS, Meyer JS. Cerebrospinal uid gamma aminobutyric acid levels in migraine. Br Med J 1975; 3:516517. 162. Jensen R, Brinck T, Olesen J. Sodium valproate has a prophylactic effect in migraine without aura. Neurology 1994; 44:647651. 163. Rall TW, Schleifer LS. Drugs effective in the therapy of epilepsies. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilmans the pharmacologic basis of therapeutics. 8th ed. New York: Pergamon Press, 1990:436462.

354

Silberstein

164. Rimmer EM, Richens A. An update on sodium valproate. Pharmacotherapy 1985; 5:171184. 165. Chapman A, Keane PE, Meldrum BS. Mechanisms of anticonvulsant action of valproate. Prog Neurobiol 1982; 19:315359. 166. Moskowitz MA. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 1992; 13:307311. 167. Behan PO. Prophylactic treatment for migraine: a comparison of pizotifen and clonidine. Cephalalgia 1985; 5:524525. 168. Klapper JA. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 1997; 17:103108. 169. Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 1992; 12:8184. 170. Kaniecki RG. A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 1997; 54:11411145. 171. Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. For the Depakote ER Migraine Study Group. Neurology 2003; 58:16521659. 172. Sorensen KV. Valproate: a new drug in migraine prophylaxis. Acta Neurol Scand 1988; 78:346348. 173. Silberstein SD, Collins SD. Safety of divalproex sodium in migraine prophylaxis: an open-label, long-term study (for the long-term safety of depakote in headache prophylaxis study group). Headache 1999; 39:633643. 174. Silberstein SD. Divalproex sodium in headacheliterature review and clinical guidelines. Headache 1996; 36:547555. 175. Pellock JM, Willmore LJ. A rational guide to routine blood monitoring in patients receiving antiepileptic drugs. Neurology 1991; 41:961964. 176. Driefuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Meander KB. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987; 37:379385. 177. Vainionpaa LK, Rattya J, Knip M, et al. Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy. Ann Neurol 1999; 45:444450. 178. Freitag FG, Diamond S, Diamond M, Urban G. Divalproex in the long-term treatment of chronic daily headache. Headache 2001; 41:271278. 179. Shank RP, Gardocki JF, Vaught JL, et al. Topiramate: preclinical evaluation of structurally novel anticonvulsant. Epilepsia 1994; 35:450460. 180. Easterling DE, Zakszewski T, Moyer MD. Plasma pharmacokinetics of topiramate, a new anticonvulsant, in humans. Epilepsia 1988; 29:662. 181. MacDonald RL, McLean MJ. Anticonvulsant drugs: mechanisms of action. In: Escueta AD, Ward AA, Woodbury DM, Porter RJ, eds. Advances in Neurology. New York: Raven Press, 1986:713736. 182. Shank RP, Gardocki JF, Streeter AJ, Maryanoff B. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2000; 41:S3S9. 183. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efcacy with consideration of promising development stage compounds. Pharmacol Rev 1990; 42:223286. 184. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000; 41:3539. 185. DeLorenzo RJ, Sombati S, Coulter DA. Effects of topiramate on sustained repetitive ring and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Epilepsia 2000; 41:S40S44. 186. Zona C, Ciotti MT, Avoli M. Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells. Neurosci Lett 1997; 231:123126. 187. Krebs EG. The growth of research on protein phosphorylation. Trends Biochem Sci 1994; 19:439.

Preventive Treatment for Migraine

355

188. Roche KW, OBrien RJ, Mammen AL, Huganir RL. Characterization of multiple phosphorylation sites on the AMP receptor GluR1 subunit. Neuron 1996; 16: 11791188. 189. Wang JH, Kelly PT. Postsynaptic injection of CA2/CaM induces synaptic potentiation requiring CaMKII and PKC activity. Neuron 1995; 15:443452. 190. Sigel E. Functional modulation of ligand-gated GABAA and NMDA receptor channels by phosphorylation. J Receptor Signal Transduction Res 1995; 15:325. 191. Storer RJ, Goadsby PJ. Topiramate inhibits trigeminovascular trafc in the cat: a possible locus of action in the prevention of migraine [abstr]. Neurology 2003; 60:A238. 192. Shuaib A, Ahmed F, Muratoglu M, Kochanski P. Topiramate in migraine prophylaxis: a pilot study [abstr]. Cephalalgia 1999; 19:379. 193. Edwards KR, Glantz MJ, Shea P, Norton JA, Cross N. A double-blind, randomized trial of topiramate versus placebo in the prophylactic treatment of migraine headache with and without aura [abstr]. Cephalalgia 2000; 20:316. 194. Potter DL, Hart DE, Calder CS, Storey JR. A double-blind, randomized, placebocontrolled, parallel study to determine the efcacy of topiramate in the prophylactic treatment of migraine [abstr]. Neurology 2000; 54:A15. 195. Silberstein SD, Schmitt J, Neto W, Jacobs D. Topiramate in the prevention of migraine headache: a randomized, double-blind, placebo-controlled, multiple-dose study. For the MIGR-001 Study Group. Arch Neurol 2001; 61:490495. 196. Brandes JL, Saper JR, Diamond M, et al. Topirimate for migraine prevention: a randomized controlled trial. JAMA 2004; 8:965973. 197. Diener HC, Tfelt-Hansen P, Dahlof C, et al. Topiramate in migraine prophylaxis results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004; 251:943950. 198. Silberstein SD. Control of topiramate-induced paresthesias with supplemental potassium [Letter]. Headache 2002; 42:85. 199. Jones MW. Topiramate. Epilepsia 1999; 40:S71S80. 200. Burton LA, Harden C. Effect of topiramate on attention. Epilepsy Res 1997; 27: 2932. 201. Sachedo RC. Topiramate. Clin Pharm 1998; 34:335346. 202. Sachedo RC, Reife RA, Lim P, Pledger G. Topiramate monotherapy for partial onset seizures. Epilepsia 1997; 38:294300. 203. Reife R, Pledger G, Wu SC. Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. Epilepsia 2000; 41:S66S71. 204. Greenwood RS. Adverse effects of antiepileptic drugs. Epilepsia 2000; 4:S42S51. 205. York DA, Singer L, Thomas S, Bray GA. Effect of topiramate on body weight and body composition of Osborne-Mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs. Nutrition 2000; 16:967975. 206. Thomson Healthcare. Physicians Desk Reference. 57th ed. Montvale: Thomson PDR, 2003. 207. Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 2002; 59:10111014. 208. Wheeler SD. Lamotrigine efcacy in migraine prevention [abstr]. Cephalalgia 2001; 21:374. 209. Chen WT, Fuh JL, Lu SR, Wang SJ. Persistent migrainous visual phenomena might be responsive to lamotrigine. Headache 2001; 41:823825. 210. Steiner TJ, Findley LJ, Yuen AW. Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia 1997; 17:109112. 211. Drake ME, Greathouse NI, Armenthright AD, Renner JB. Zonisamide in the prophylaxis of migraine headache [abstr]. Cephalalgia 2001; 21:374. 212. Krusz JC. Zonisamide in the treatment of headache disorders [abstr]. Cephalalgia 2001; 21:374.

356

Silberstein

213. Cochran JW. Efcacy of zonisamide in prophylactic treatment of migraine headaches with or without aura: open-label experience in 7 patients [abstr]. J Pain 2002; 3:39. 214. Brewerton TD, Murphy DL, Mueller EA, Jimerson DC. Induction of migraine like headaches by the serotonin agonist m-chlorophenylpiperazine. Clin Pharmacol Ther 1988; 43:605609. 215. Gordon ML, Lipton RB, Brown SL, et al. Headache and cortical responses to m-chlorophenylpiperazine are highly correlated. Cephalalgia 1993; 13:400405. 216. Baxter G, Kennett G, Blaney F, Blackburn T. 5-HT2 receptor subtypes: a family reunited. TiPS 1995; 16:105110. 217. Fozard JR, Kalkman HO. 5-Hydroxytryptamine (5-HT) and the initiation of migraine: new perspectives. Arch Pharmacol 1994; 350:225229. 218. Fozard JR. The 5-hydroxytryptamine-nitric oxide connection: the key link in the initialization of migraine? Arch Int Pharmacodyn 1995; 329:111119. 219. Moskowitz MA. Interpreting vessel diameter changes in vascular headaches. Cephalalgia 1992; 12:57. 220. Moskowitz MA. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. TiPS 1992; 13:307311. 221. Fozard JR. 5-HT in migraine: evidence from 5-Ht receptor antagonists for a neuronal etiology. In: Sandler M, Collins GM, eds. Migraine: A Spectrum of Ideas. New York: Oxford University Press, 1990:128146. 222. Nelson DL. Proceedings from the International Business Communications Conference on Serotonin Receptors in the Central Nervous System. Philadelphia, PA, 1996; Jan:2526. 223. Muller SE. Ergot alkaloids in migraine: is the effect via 5-HT receptors. In: Olesen J, Saxena PR, eds. 5-Hydroxytryptamine mechanisms in primary headaches. New York: Raven Press, 1992:297304. 224. Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of 3H-5-hydroxytryptamine, 3H-lysergic acid diethylamide and 3H-spiroperidol. Mol Pharmacol 1979; 16:687689. 225. DenBoer MO, Villain CM, Heiligers JP, Humphrey PP, Saxena PR. The role of 5-HT1like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan. Br J Pharmacol 1991; 102:323330. 226. DenBoer MO, Villalon CM, Heiligers JP, Humphrey PP, Saxena PR. The role of 5-HT1-like receptors. Br J Pharmacol 1991; 104:183189. 227. MacLennan SJ, Martin GR. Comparison of the effects of methysergide and methylergometrine with GR 43175 on feline carotid blood ow distribution. Br J Pharmacol 1990; 99:221. 228. Saito K, Markowtiz S, Moskowitz MA. Ergot alkaloids specically block the development of neurogenic inammation within the dura mater induced by chemical or electrical stimulation. Ann Neurol 1988; 24:732737. 229. Sicuteri R. Prophylactic and therapeutic properties of 1-methylsergic acid butanolamide in migraine. Int Arch Allerg 1959; 15:300307. 230. Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med 1966; 274:360368. 231. Barrie MA, Fox WR, Weatherall M, Wilkinson MIP. Analysis of symptoms of patients with headaches and their response to treatment with ergot derivatives. Q J Med 1968; 146:319336. 232. Andersson PG. BC105 and deseril in migraine prophylaxis: a double-blind study. Headache 1973; 13:6873. 233. Cangi F, Boccuni M, Zanotti A, Mailland F, Sicuteri F. Dihydroergokryptine (DEK) in migraine prophylaxis in a double-blind study vs methysergide. Cephalalgia 1989; 9: 448449. 234. Forssman B, Henriksson KG, Kihlstrand S. A comparison between BC105 and methysergide in the prophylaxis of migraine. Acta Neurol Scand 1972; 48:204212.

Preventive Treatment for Migraine

357

235. Hudgson P, Foster JB, Newell DJ. Controlled trial of demigran in the prophylaxis of migraine. Br Med J 1967; 2:9193. 236. Lance JW, Fine RD, Curran DA. An evaluation of methysergide in the prevention of migraine and other vascular headaches. Med J Aust 1963; 1:814818. 237. Pedersen E, Moller CE. Methysergide in migraine prophylaxis. Pharmacol Ther 1966; 7:520526. 238. Presthus J. BC105 and methysergide (Deseril) in migraine prophylaxis. Acta Neurol Scan 1971; 47:514518. 239. Ryan RE. Double-blind crossover comparison of BC105, methysergide, and placebo in the prophylaxis of migraine headache. Headache 1968; 8:118126. 240. Shekelle RB, Ostfeld AM. Methysergide in the migraine syndrome. Clin Pharmacol Ther 1964; 5:201204. 241. Sicuteri F. The ingestion of serotonin precursors (L-5-hydroxytryptophan and Ltryptophan) improves migraine headache. Headache 1973; 13:1922. 242. Behan PO, Reid M. Propranolol in the treatment of migraine. Practitioner 1980; 224:201204. 243. Curran DA, Hinterberger H, Lance JW. Methysergide. Res Clin Stud Headache 1967; 1: 74122. 244. Graham J. Cardiac and pulmonary brosis during methysergide therapy for headache. Am J Med Sci 1967; 254:112. 245. Elkind AH, Friedman AP, Bachman A, Siegelman SS, Sacks OW. Silent retroperitoneal brosis associated with methysergide therapy. JAMA 1968; 206:10411044. 246. Bana DS, MacNeal PS, LeCompte PM, Shah Y, Graham JR. Cardiac murmurs and endocardial brosis associated with methysergide therapy. Am Heart J 1974; 88: 640655. 247. Barlow CF. Headaches and Migraine in Children. Philadelphia: 1984. 248. Forsythe I, Hockaday JM. Management of childhood migraine. In: Hockaday JM, ed. Migraine in Childhood. London: Butterworths, 1988:6374. 249. Curran DA, Lance JW. Clinical trial of methysergide and other preparations in the management of migraine. J Neurol Neurosurg Psychiat 1964; 27:463469. 250. Smyth GA, Lazarus L. Suppression of growth hormone secretion by melatonin and cyproheptadine. J Clin Invest 1974; 54:116121. 251. Bellavance AJ, Meloche JP. A comparative study of naproxen sodium, pizotyline, and placebo in migraine prophylaxis. Headache 1990; 30:710715. 252. Arthur GP, Hornabrook RW. The treatment of migraine with BC105 (pizotifen): a double-blind trial. N Z Med J 1971; 73:59. 253. Carroll JD, Maclay WP. Pizotifen (BC105) in migraine prophylaxis. Curr Med Res Opin 1975; 3:6871. 254. Hughes RC, Foster JB. BC 105 in the prophylaxis of migraine. Curr Ther Res Clin Exp 1971; 13:6368. 255. Krakowski AJ, Engisch R. A new agent for chemotherapy of migraine headaches: a controlled study. Psychosomatics 1973; 14:302308. 256. Lance JW, Anthony M. Clinical trial of a new serotonin antagonist, BC105, in the prevention of migraine. Med J Aust 1968; 1:5455. 257. Lawrence ER, Hossain M, Littlestone W. Sanomigran for migraine prophylaxis: controlled multicenter trial in general practice. Headache 1977; 17:109112. 258. Osterman PO. A comparison between placebo, pizotifen, and 1-isopropyl-3-hydroxy5-semicarbazono-6-oxo-2.3.5.6-tetrahydroindol (Divascan) in migraine prophylaxis. Acta Neurol Scand 1977; 56:1728. 259. Ryan RE. BC105, a new preparation for the interval treatment of migraine: a double blind evaluation compared with placebo. Headache 1971; 11:618. 260. Sjaastad O, Stensrud P. Appraisal of BC105 in migraine prophylaxis. Acta Neurol Scand 1969; 45:594600.

358

Silberstein

261. Nappi G, Sandrini G, Savoini G, Cavallini A, DeRysky C, Micieli G. Comparative efcacy of cyclandelate versus unarizine in the prophylactic treatment of migraine. Drugs 1987; 33:103198. 262. Gawel M. A double blind, cross over study of nimodipine versus pizotyline in common and classical migraine. Cephalalgia 1987; 7:453454. 263. Kangasniemi P. 1-Isopropylnoradrenochrome-5-monosemicarbazono, and pizotifen in migraine prophylaxis. Headache 1979; 19:219222. 264. Nattero G, Biale L, Savi L. Lisuride and pizotifen in the treatment of migraine without aura. Cephalalgia 1991; 11:218219. 265. Bono G, Criscuoli M, Martignoni E, Salmon S, Nappi G. Serotonin precursors in migraine prophylaxis. Adv Neurol 1982; 33:357363. 266. Havanka-Kanniainen H, Hokkanen E, Myllyla VV. Efcacy of nimodipine in comparison with pizotifen in the prophylaxis of migraine. Cephalalgia 1987; 7:713. 267. Micieli G, Trucco M, Agostinis C, Mancuso A, Papalia F, et al. Nimodipine vs pizotifen in common migraine: results of a double-blind crossover trial. Cephalalgia 1985; 5: 532533. 268. Hubbe P. The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurol Scand 1973; 49:108114. 269. Peateld R. Drugs acting by modication of serotonin function. Headache 1986; 26:129131. 270. Capildeo R, Rose FC. Single-dose pizotifen, 1.5 mg nocte: a new approach in the prophylaxis of migraine. Headache 1982; 22:272275. 271. Adam EI, Gore SM, Price WH. Double-blind trial of clonidien in the treatment of migraine in a general practice. J R Coll Gen Pract 1978; 28:587590. 272. Boisen E, Deth S, Hubbe P, Jansen J, Klee A, Leunbach G. Clonidine in the prophylaxis of migraine. Acta Neurol Scand 1978; 58:288295. 273. Bredfeldt RC, Sutherland JE, Kruse JE. Efcacy of transdermal clonidine for headache prophylaxis and reduction of narcotic use in migraine patients. A randomized crossover trial. J Fam Pract 1989; 29:153156. 274. Das SM, Ahuja GK, Narainaswamy AS. Clonidine in prophylaxis of migraine. Acta Neurol Scand 1979; 60:214217. 275. Kallanranta T, Hakkarainen H, Hokkanen E, Tuovinen T. Clonidine in migraine prophylaxis. Headache 1977; 17:169172. 276. Mondrup K, Moller CE. Prophylactic treatment of migraine with clonidine: a controlled clinical trial. Acta Neurol Scand 1977; 56:405412. 277. Ryan SRRE, Ryan JRRE. The effects of clonidine in the prophylactic treatment of migraine. Headache 1975; 15:199212. 278. Shafar J, Tallett ER, Knowlson PA. Evaluation of clonidine in prophylaxis of migraine. Double-blind trial and followup. Lancet 1972; 1:403407. 279. Sjaastad O, Stensrud P. 2-(2.6-Dichlorophenylamino)-2-imidazoline hydrochloride (ST 155 or Catapresan) as a prophylactic remedy against migraine. Acta Neurol Scand 1971; 47:120122. 280. Stensrud P, Sjaastad O. Clonidine (Catapresan)-double-blind study after long-term treatment with the drug in migraine. Acta Neurol Scand 1976; 53:233236. 281. Wilkinson M. Preliminary report on the use of clonidine (Boehringer Ingelheim) in the treatment of migraine. Res Clin Stud Headache 1970; 3:315320. 282. Elkind AH, Webster C, Herbertson RK. Efcacy of guanfacine in a double-blind parallel study for migraine prophylaxis. Cephalalgia 1989; 9:369370. 283. Louis P, Schoenen J, Hedman C. Metoprolol vs clonidine in the prophylactic treatment of migraine. Cephalalgia 1985; 5:159165. 284. Kass B, Nestvold K. Propranolol (Inderal) and clonidine (Catapressan) in the prophylactic treatment of migraine: a comparative trial. Acta Neurol Scand 1980; 61: 351356.

Preventive Treatment for Migraine

359

285. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebocontrolled, crossover study. Br Med J 2001; 322:1922. 286. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 2003; 289:6569. 287. Masel BE, Chesson AL, Peters BH, Levin HS, Alperin JB. Platelet antagonists in migraine prophylaxis: a clinical trial using aspirin and dipyridamole. Headache 1980; 20:1318. 288. Peto R, Gray R, Collins R, Wheatly K, Hennekens C, Jamrozik K. Randomized trial of prophylactic daily aspirin in British male doctors. Br Med J 1988; 296:313316. 289. Buring JE, Peto R, Hennekens CH. Low-dose aspirin for migraine prophylaxis. JAMA 1990; 264:17111713. 290. Baldratti A, Cortelli P, Proccaccianti G, Gamberini GD, et al. Propranolol and acetylsalicylic acid in migraine prophylaxis. Double-blind crossover study. Acta Neurol Scand 1983; 67:181186. 291. Pradalier A, Clapin A, Dry J. Treatment review: nonsteroid anti-inammatory drugs in the treatment and long-term prevention of migraine attacks. Headache 1988; 28:550557. 292. Sjaastad O, Spierings EL. Hemicrania continua: another headache absolutely responsive to indomethacin. Cephalalgia 1984; 4:6570. 293. Sjaastad O, Dale I. A new (?) clinical headache entity: chronic paroxysmal hemicrania. 2. Acta Neurol Scand 1976; 54:140159. 294. Bordini C, Antonaci F, Stovner LJ, Schrader H, Sjaastad O. Hemicrania Continua a clinical review. Headache 1991; 31:2026. 295. Solomon GD. Management of the headache patient with medical illness. Clin J Pain 1989; 5:9599. 296. Silberstein SD, Mathew N, Saper J, Jenkin S. Botulinum toxin type A as a migraine preventive treatment: for the Botox1 Migraine Clinical Research Group. Headache 2000; 40:445450. 297. Goldstein DJ, Offen WW, Klein EG, et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 2001; 21:102106. 298. Brandes JL, Visser H, Farmer MV, et al. Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study. On behalf of the Protocol 125 study group. Headache 2004; 44:581586. 299. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 19901997: results of a follow-up national survey. JAMA 1998; 280:15691575. 300. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efcacy of feverfew as prophylactic treatment of migraine. Br Med J 1985; 291:569573. 301. Murphy JJ, Heptinstall S, Mitchell JR. Randomized double-blind placebo controlled trial of feverfew in migraine prevention. Lancet 1988; 2:189192. 302. Palevitch D, Earon G, Carusso R. Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: a double-blind placebo-controlled study. Phytother Res 1997; 11:508511. 303. Deweerdt CJ, Bootsma HP, Hendriks H. Herbal medicines in migraine prevention: randomized double-blind placebo-controlled crossover trial of feverfew preparation. Phytomedicine 1996; 3:225230. 304. Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke HH. The efcacy and safety of Tanacetum parthenium (Feverfew) in migraine prophylaxis: a double-blind, multicenter, randomized, placebo-controlled, dose-response study. Cephalalgia 2002; 22:523532. 305. Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database of Systematic Rev 2004; 3. 306. Pittler MH, Vogler BK, Ernst E. Feverfew for preventing migraine. Cochrane Database Sys Rev 2000; 3.

360

Silberstein

307. Heptinstall S, White A, Williamson L, Mitchel JR. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leukocytes. Lancet 1985; i: 10711074. 308. Heptinstall S, Groenewegen WA, Spangenberg P, Loesche W. Extracts of feverfew may inhibit platelet behavior via neutralization of sulphydryl groups. J Pharm Pharmacol 1987; 39:459465. 309. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia 1998; 18:704708. 310. Reuter U, Chiarugi A, Bolay H, Moskowitz MA. Nuclear factor-kB as a molecular target for migraine therapy. Ann Neurol 2002; 51:507516. 311. Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology 2004; 63: 22402244. 312. Diener HC, Rahlfs VW, Danesch U. The rst placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efcacy criteria. Eur Neurol 2004; 51:8997. 313. Welch KMA, Levine SRDG, Schultz L, Helpern JA. Preliminary observations on brain energy metabolism in migraine studied by in vivo 31phosphorus NMR spectroscopy. Neurology 1989; 39:538541. 314. Montagna P, Cortelli P, Monari L, et al. 31P-magnetic resonance spectroscopy in migraine without aura. Neurology 1994; 44:666669. 315. Sangiorgi S, Mochi M, Riva R, et al. Abnormal platelet mitochondrial function in patients affected by migraine with and without aura. Cephalalgia 1994; 14:2123. 316. Watanabe H, Kuwabara T, Ohkubo M, Tsuji S, Yuasa T. Elevation of cerebral lactate detected by localized 1H-magnetic resonance spectroscopy in migraine during the interictal period. Neurology 1996; 47:10931095. 317. Arts WF, Scholte HR, Boggard JM, Kerrebijn KF, Luyt-Housen IE. NADH-CoQ reductase decient myopathy: successful treatment with riboavin. Lancet 1983; 2: 581582. 318. Penn AM, Lee JW, Thuillier P, et al. MELAS syndrome with mitochondrial tRNALEU(UUR) mutation: correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboavin. Neurology 1992; 42:21472152. 319. Antozzi C, Garavaglia B, Mora M, et al. Late-onset riboavin-responsive myopathy with combined multiple acyl coenzyme. A dehydrogenase and respiratory chain deciency. Neurology 1994; 44:21532158. 320. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998; 50:466470. 321. Rozen TD, Oshinsky ML, Gebeline CA, et al. Open label trial of coenzyme Q10 as a migraine preventive. Cephalalgia 2002; 22:137141. 322. Sandor PS, diClemente L, Coppola G, et al. Coenzyme Q10 for migraine prophylaxis: a randomized controlled trial [abstr]. Cephalalgia 2003; 23:577. 323. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multicenter, placebo-controlled and double-blind randomized study. Cephalalgia 1996; 16:257263. 324. Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in the prophylaxis of migrainea double-blind, placebo-controlled study. Cephalalgia 1996; 16:436440. 325. Silberstein SD, Lipton RB, Goadsby PJ. Migraine: diagnosis and treatment. In: Silberstein SD, Lipton RB, Goadsby PJ, eds. Headache in Clinical Practice. 1st ed. Oxford: Isis Medical Media Ltd., 1998:6190. 326. Silberstein SD. Preventive treatment of migraine: an overview. Cephalalgia 1997; 17: 6772. 327. Silberstein SD, Lipton RB, Breslau N. Migraine: association with personality characteristics and psychopathology. Cephalalgia 1995; 15:337369.

Preventive Treatment for Migraine

361

328. Mathew NT, Saper JR, Silberstein SD, et al. Prophylaxis of migraine headaches with divalproex sodium. Arch Neurol 1995; 52:281286. 329. Bowden CL, Brugger AM, Swann AC. Efcacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994; 271:918924. 330. Pascual J, Leira R, Lainez JM. Combined therapy for migraine prevention? Clinical experience with a beta-blocker plus sodium valproate in 52 resistant migraine patients. Cephalalgia 2003; 23:961962.

23
Herbal Medicines and Vitamins
Jean Schoenen and Delphine Magis
Departments of Neuroanatomy and Neurology, Headache Research Unit, `ge, Lie `ge, Belgium University of Lie

INTRODUCTION There are two major shortcomings with prophylactic therapies for migraine. The rst is that on average, efcacy rate of any prophylactic agent does not exceed 50% in most patients. The second is that most prophylactic drugs are endowed with a high prevalence of uncomfortable and sometimes intolerable adverse effects. It is therefore of clinical interest that several treatments nearly devoid of adverse effects are available for migraine prophylaxis. Among them are vitamins like riboavin and herbs, or plants like feverfew or butterbur. Other natural elements like coenzyme Q10 and thioctic acid (a-lipoic acid) have also been studied. In this chapter, we will review published data for these medications as well as for magnesium. Magnesium is also considered a soft treatment, and its preventive action in migraine has been explored in several randomized controlled trials. We will focus on efcacy data on 50% responder rates in absolute and, if available, in placebo-subtracted values, and compare the data with those published in recent trials for slow release propranolol 160 mg (1) and for valproate (2), two mainstays in preventive antimigraine treatment.

RIBOFLAVIN Rationale The rationale for using high-dose riboavin in migraine prophylaxis came from the observation made by two independent groups (3,4) that on 31P magnetic resonance spectroscopy, the mitochondrial phosphorylation potential, i.e., the energy reserve, was reduced by 25% to 30% interictally in the brain (and muscle) of migraineurs with or without aura. Riboavin (vitamin B2) is the precursor of avin mononucleotide and avin adenine dinucleotide, which are required for the activity of avoenzymes involved in the electron transport chain (Fig. 1). Given to patients with mitochondrial myopathy, encephalopathy, lactacidosis, stroke, or mitochondrial myopathies on the assumption that at large doses (300 mg/day in children) it might augment
363

364

Schoenen and Magis

Figure 1 Outline of the mitochondrial electron transport chain illustrating the potential impact of riboavin at the level of complex I (via FMN) and complex II (via FAD). Note that FAD is also a cofactor for methylene-tetrahydrofolate reductase, the metabolizing enzyme of homocystein. Abbreviations: FMN, avin mononucleotide; FAD, avin adenin dinucleotide.

activity of mitochondrial complexes I and II, riboavin was able to improve clinical and biochemical abnormalities [see Ref. (5)]. More recently, a number of alternative mechanisms of action for the effects of riboavin in migraine have been discussed. Riboavin may indeed counteract the inhibition of mitochondrial respiration by nitric oxide (NO) (6) and act as a reactive oxygen species scavenger. Another interaction between riboavin and NO could be the avin domain in the NOS gene. Riboavin can also be a precursor in the biosynthesis of vitamin B12, which, administered as intranasal hydroxycobalamin, was found to be effective as a preventive treatment of migraine in an open pilot trial (7). It can stimulate the activity of methylene-tetrahydrofolate reductase, the metabolizing enzyme of homocystein, of which the genetic polymorphism C677T could predispose to migraine (8,9). Finally, an antinociceptive effect was recently found in several B vitamins, including vitamin B2, in an animal model of chemonociception (10). Clinical Evidence After a positive open pilot study (11), the Headache Research Unit of the University ` of Liege steered a multicenter placebo-controlled, randomized parallel group trial (12). The Belgian riboavin trial was investigator initiated, sponsored by the Belgian Headache Society and included a relatively small number of patients: 27 in the placebo group and 28 in the riboavin (400 mg once per day) group. After a onemonth, single-blind placebo run-in, patients were randomized either to riboavin or to placebo as long as they had at least one attack during the run-in period. After three months of treatment with riboavin, the 50% responder rate for reduction in attack frequency was 56% [numbers-needed-to-treat (NNT): 2.8], for migraine days 59% (NNT: 2.3), and for a migraine index (headache days mean severity) 41%

Herbal Medicines and Vitamins

365

Figure 2 Fifty percent responder rates for attack frequency, headache days, and migraine index (mean severity headache days) as assessed in the third month of randomization period in riboavin (400 mg/day) and placebo groups. NNTS are indicated. Abbreviation: NNT, numbers-needed-to-treat.

(NNT: 3.1) compared with respective placebo responses of 19%, 15%, and 8%. The placebo-subtracted 50% responder rate for riboavin was 37%, which compares favorably with the 23% reported in the valproate trial by Klapper (Fig. 2) (2). Only three adverse events were recorded during the trial. One woman in the riboavin group had diarrhea two weeks after starting the drug and withdrew from the study. On follow-up, her symptoms disappeared within 72 hours. Another patient receiving riboavin complained of polyuria but completed the trial. In the placebo group, one patient mentioned recurrent abdominal cramps of moderate intensity but did not interrupt the trial. Comparing riboavin with placebo, the number of patients needed to harm was 33.3, which again compares favorably with valproate for which this number is around 2.4. Since the riboavin trial was published, riboavin has been used in several countries, both by adult and child migraineurs. Reports on favorable results were exchanged condentially, but no formal studies were conducted. Recently, Boehnke et al. (13) performed an open label study to determine the prophylactic antimigraine effect of riboavin 400 mg in a specialized tertiary headache center. In 23 patients, the results were overall in line with the Belgian riboavin trial. Median attack frequency was reduced from four attacks/month (range 35) at baseline to two attacks/month (range 23) after three months of treatment (p < 0.001) and remained at two attacks/month (range 24) after six months of treatment (p 0.005). The use of abortive antimigraine drugs signicantly decreased from 7 tablets/mo to 4.5 tablets/mo after 3 months and to 4 tablets/mo after 6 months (p 0.016 and p 0.006). Three patients experienced mild adverse effects (diarrhea, upper abdominal pain, and facial erythema) during the study. Finally, in an interesting recent randomized double-blind, placebo-controlled trial, Maizels et al. (14) studied the prophylactic antimigraine effect of a combination of three natural supplementsriboavin 400 mg, magnesium 300 mg, and feverfew 100 mg in 24 patients and compared them to 25 patients treated with a

366

Schoenen and Magis

placebo containing 25 mg riboavin. Surprisingly, after three months of treatment, there was a signicant improvement in both groups of patients. The 50% responder rate for reduction in attack frequency was 44% (40% for migraine days) for the active cocktail and 42% for the placebo (33% for migraine days). There was no signicant difference in responder rate for reduction between the two groups. These results could have different explanations: the 25 mg riboavin dose might not be inactive; the presence of magnesium (and/or feverfew) could interfere with the intestinal absorption of riboavin; the placebo effect was particularly high in this study, and none of the products tested are superior to placebo. Clinical Experience From the randomized controlled trial and our clinical experience in over 1000 patients, it seems obvious that riboavin has a slow onset of action. The maximal effect on the attack frequency does not occur before the third month of treatment. It can therefore be considered a rst choice drug only in moderately disabled patients with a low attack frequency (below four to ve attacks/month) and not in severe or chronic migraineurs. Because of its excellent efcacy/adverse effect prole, riboavin can, however, be considered as a rst line preventative drug in children. As no teratogenic effects are known for riboavin, it can also be given during pregnancy, if migraine prophylaxis is warranted. Our clinical impression is that riboavin may be more effective in migraine with aura, but this could be biased by the lower average attack frequency compared to migraine without aura. Association of riboavin with other prophylactic agents, such as beta-blockers, may allow for keeping the latter at a dose low enough to avoid side effects, but until now this has not been formally studied. Adverse events are extremely rare with riboavin at 400 mg per day. One percent of patients have gastrointestinal intolerance. We have encountered an allergic cutaneous rash in one patient, which disappeared after withdrawal and recurred after rechallenging the patient with riboavin. An important difference with most antimigraine prophylactic drugs is that riboavin does not induce weight gain. We have shown that riboavin does not inuence habituation of cortical-evoked potentials, contrary to beta-blockers and sodium valproate, which tend to normalize the decient habituation found interictally in migraineurs (15). The benecial results obtained with riboavin have initiated trials with other drugs acting on energy metabolism like coenzyme Q10 and thioctic (a-lipoic) acid. COENZYME Q10 Rationale Coenzyme Q10 is an essential element of the mitochondrial electron transport chain. It transfers electrons from mitochondrial complex I (nicotinamide adenine dinucleotide dehydrogenase) and complex II (succinate-Q-reductase) to cytochrome c (Fig. 1). It may also act as an antioxidant. Clinical Evidence After an open label trial in 31 patients, Rozen et al. (16) suggested that coenzyme Q10 (150 mg/day) could be effective in migraine prophylaxis. A greater than 50% reduction in number of days with migraine was found in 61.3% patients.

Herbal Medicines and Vitamins

367

We performed a randomized, placebo-controlled trial with a new formulation of coenzyme Q10 100 mg t.i.d. in 42 patients, using the same protocol as in our riboavin study (17). The formulation (MSE 2001, Sanomit Q10 , MSE Pharmazeutika GmBH, Germany) is a patented nanodispersion of well-characterized, very small nanoparticles containing Q10. After three months of treatment, using an intention-to-treat analysis, coenzyme Q10 was found to be superior to placebo in reducing attack frequency (p 0.01), headache days (p 0.04), and days with nausea (p 0.03). Regarding attack frequency, the proportion of patients who improved by at least 50%, i.e., responders, was 14.4% for placebo and 47.6% for coenzyme Q10 (p 0.02) and the NNT for effectiveness was 3. One of the patients in the coenzyme Q10 group withdrew due to cutaneous allergy. Because of its excellent tolerability and proven efcacy, coenzyme Q10 is an interesting option for migraine prophylaxis and a candidate for a comparative trial with an established prophylactic drug. It remains however, to be determined whether the conclusions of this trial can be extrapolated to all available coenzyme Q10 formulations.

THIOCTIC ACID (a-LIPOIC ACID) Rationale Like riboavin and coenzyme Q10, thioctic acid (a-lipoic acid) is able to stimulate mitochondrial oxygen metabolism and adenosine triphosphate (ATP) production. Thioctic acid produces a clinical and biochemical improvement in various mitochondriopathies such as Leighs encephalomyelopathy, pyruvate dehydrogenase deciency, and pyruvate carboxylase deciency (18).

Clinical Evidence In a multicenter double-blind, placebo-controlled study (19), we included 44 patients who received either thioctic acid or placebo 600 mg/day. Unfortunately the trial had to be interrupted because of slow recruitment in several centers and time limitation in drug quality. It did not demonstrate a clinically meaningful advantage of thioctic acid over placebo in migraine prophylaxis, although there was an indication for a benecial effect of thioctic acid on various secondary outcome measures. No adverse effects were reported. Larger studies are needed for this drug, which has an excellent tolerance.

FEVERFEW (TANACETUM PARTHENIUM) Rationale Feverfew (Tanacetum parthenium) has been known for its headache relief potential since medieval times (20). It has various pharmacological actions that may be relevant to migraine pathophysiology. It inhibits the interaction of platelets with collagen substrates and 5-HT release (21), prostaglandin synthesis, and nuclear factor (NF)-kappa beta. Its main sesquiterpene lactone, parthenolide, may be a nonspecic norepinephrine, serotonin, bradykinin, prostaglandin, and acetylcholine antagonist.

368

Schoenen and Magis

Figure 3 Fifty percent responder rates for attack frequency (absolute values) for the riboavin (B2), FF, coenzyme Q10 (Q10), MG, PRO, BB, and VPA trials discussed in this chapter. Abbreviations: FF, feverfew; MG, magnesium; PRO, propranolol; BB, butterbur; VPA, valproate.

Clinical Evidence A review of ve randomized controlled trials of feverfew on small samples of patients by Vogler et al. (22) concluded that the clinical efcacy of feverfew in the prevention of migraine had not been established beyond reasonable doubt (22). More recently, Pfaffenrath et al. (23) performed a large, phase II, multicenter, randomized, placebo-controlled study of three doses of a CO2 extract of tanacetum parthenium (Mig-99 ) (2.08, 6.25, 18.75 mg t.i.d.). Only the 6.25 mg t.i.d. dose was found to have some efcacy. The 50% responder rate for attack frequency was 27.8% in a sample of 36 patients (Fig. 3) but, because of a high placebo response, the placebo-subtracted 50% responder rate was negative (3.6%). Interestingly, a subanalysis of a subset of patients with at least four attacks per 28 days during the baseline period was also performed. In this conrmatory intention-to-treat sample of 49

Table 1 Subanalysis of 49 Patients Having at Least Four Migraine Attacks During the OneMonth Baseline Before Randomization Conrmatory ITT sample (23), n 49 pat. with ! 4 attacks during baseline FF 2.08 mg t.i.d. (n 9) Absolute change in attack frequency 50% responder rate 0.2 1.1 FF 6.25 mg t.i.d. (n 19) 1.8 1.5a FF 18.75 mg t.i.d. (n 8) 1.5 1.9 Placebo (n 13) 0.3 1.9

36.8%

37.5%

15.4%

a The amelioration with the 6.25 mg feverfew t.i.d. dose is signicant. Abbreviation: FF, feverfew.

Herbal Medicines and Vitamins

369

patients, the decrease in attack frequency was signicant in the 6.25 mg t.i.d. group (19) (1.8 1.5) compared to the placebo group (0.3 1.9). The 50% responder rate was 36.8% in the 6.25 mg t.i.d. group compared to 15.4% in the placebo group (Table 1). A recent update of the Cochrane Database Systematic Review (24) concluded that the overall results of ve trials that met the methodological standards did not formally establish that feverfew is efcacious in preventing migraine. Different preparations of feverfew containing various concentrations of parthenolide are available in some countries, which have occasional adverse effects, the most frequent being mouth ulcerations and oral inammation with loss of taste.

BUTTERBUR (PETASITES HYBRIDUS) Rationale Butterbur (Petasites hybridus), a plant ourishing in the moist areas of Europe has been used for centuries in medical practice for its spasmolytic and analgesic effects in conditions such as migraine, asthma, urinary tract spasms, and back pain. The mechanism of action of Petasites extract in migraine is uncertain. In laboratory studies, it has been found to have anti-inammatory properties including antileukotriene activity. Another possible mechanism of action involves an effect on the calcium channels. The active ingredient used for migraine prophylaxis is a special extract made from the underground parts (rhizome) of the plant (25). Clinical Evidence As far as clinical evidence is concerned, Diener et al. reanalyzed the outcome of a randomized, placebo-controlled parallel-group study of a special butterbur root extract 25 mg t.i.d. in migraine prophylaxis in 60 patients (26). At three months the 50% responder rate for migraine frequency was 45% in the butterbur group and 15% in the placebo group. Butterbur was well tolerated. They suggested that butterbur might be effective in migraine prophylaxis. A larger trial has recently been published (27) and largely conrms the results from previous studies. The trial was a three-arm, parallel-group, randomized trial comparing Petasites extract 75 mg b.i.d., Petasites extract 50 mg b.i.d., or placebo b.i.d. in 245 patients with migraine. Over four months of treatment, in the perprotocol analysis, migraine attack frequency was reduced by 48% for Petasites extract 75 mg b.i.d. (p 0.0012 vs. placebo), 36% for Petasites extract 50 mg b.i.d. (p 0.127 vs. placebo), and 26% for the placebo group. The proportion of patients with a !50% reduction in attack frequency after four months was 68% in the Petasites extract 75-mg arm and 49% in the placebo arm (p 0.05). Results were also signicant in favor of Petasites 75 mg at one, two, and three months based on this endpoint. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events, predominantly burping. Safety and adverse effects of butterbur extract were examined by Danesch and Rittinghausen (25), who analyzed the results of two controlled clinical trials (28,29) and reported conclusions from animal toxicity studies. In the two controlled trials, a total of 187 patients with migraine were exposed to doses of the special butterbur extract between 100 and 150 mg daily for at least three months. No signicant difference was found between placebo and butterbur regarding adverse events,

370

Schoenen and Magis

except burping, which as in Lipton et al.s study is a well-known transient adverse effect and occurred in 20% of patients. Moreover, butterbur is known to contain pyrrolizidines alkaloids (PA), substances with hepatotoxic properties that may cause liver cancer. Therefore the manufacturing process requires a complete removal of toxic PA below 0.08 ppm, i.e., the limit of detection, in the nished extract (25). To conclude, high doses of Petasites hybridus extracts (150 mg/day) seem undoubtedly effective in migraine prophylaxis. They reach a magnitude of effect that is close to that observed with classical preventive antimigraine drugs, but with less short-term adverse effects.

MAGNESIUM Rationale Low brain magnesium levels have been detected with 31P magnetic resonance spectroscopy during migraine attacks (30) and interictally in migraine with aura (31). Between attacks, low magnesium levels were also found in various other biological tissues such as erythrocytes, monocytes, serum, saliva, and cerebrospinal uid (3236). Magnesium is essential for energy metabolism and decreases neuronal excitability via blockade of N-methyl-D-aspartate receptors, decrease of intracellular calcium, and activation of Na/KATPase (37). Trial Evidence Two double-blind, placebo-controlled studies in parallel groups of patients have been performed in German-speaking countries. One study using a drinkable aspartate salt of magnesium (20 mmol) was prematurely interrupted after inclusion of 69 patients because of lack of efcacy (38). In the other trial, magnesium dicitrate was used at a 24 mmol dose in 81 patients, 43 receiving the magnesium preparation. In this study (39), the 50% responder rate for attack frequency was 52.8% (Fig. 3) which is well in the range of responder rates reported for propranolol and valproate, but the placebo-subtracted 50% responder rates was only 18.4%, which is below that estimated for the classical antimigraine prophylactics. Clinical Experience Our clinical experience with high-dose magnesium (450 mg Mg element bid) in migraine prophylaxis is limited, but we did not nd it useful as a monotherapy. Moreover, several patients complained of gastrointestinal intolerance. In the published trials, diarrhea occurred in 20% of patients and gastric irritation in 12%. It remains to be shown which combinations of high-dose magnesium and other prophylactic agents may be benecial, for example, in constipated migraineurs.

CONCLUSIONS There is convincing evidence that certain natural substances or drugs quasidevoid of adverse effects are efcacious alternatives to classical antimigraine prophylactic medications with a high incidence of side effects, such as beta-blockers or antiepileptics. The latter were developed by large pharmaceutical companies and

Herbal Medicines and Vitamins

371

Figure 4 Cost effectiveness of prophylactic antimigraine drugs as estimated by the ratio of cost in Belgium for a six-month treatment over the placebo-subtracted 50% responder rate for attack frequency.

submitted to extensive trials providing type I evidence of efcacy. The former were studied in less numerous and smaller trials by small companies or independent investigators, which is one reason why they do not reach type I evidence in evidence-based guidelines (40). Another reason why substances with proven efcacy such as riboavin, butterbur, or feverfew are not considered as rst line antimigraine treatments may be that they act slowly and are thus not ideal for patients with frequent attacks. Although high doses of riboavin and coenzyme Q10, butterbur, and to a lesser degree feverfew, were found effective in randomized controlled trials, the results cannot be extrapolated to any commercial preparation of these substances. There are indeed important differences in quality, concentrations of the active substance, and/or pharmacokinetics between available preparations. As far as pharmacoeconomic factors are concerned, most of these substances compare favorably with classic antimigraine prophylactics, but there are also cost efciency differences between them (Fig. 4). To conclude, it is unfortunate that certain unconventional prophylactic antimigraine drugs are not evaluated in supplementary and larger controlled clinical trials. Direct comparative studies with conventional drugs are also eagerly awaited. It is unlikely that the established pharmaceutical companies will ever invest in such trials. However, if sufcient funds are available, the existing headache societies should feel ethically obliged to do so.

REFERENCES
1. Diener HC, Matias-Guiu J, Hartung E, et al. Efcacy and tolerability in migraine prophylaxis of unarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia 2002; 22(3):209221. 2. Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 1997; 17(2):103108.

372

Schoenen and Magis

3. Barbiroli B, Montagna P, Cortelli P, et al. Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura. Neurology 1992; 42(6):12091214. 4. Montagna P, Cortelli P, Monari L, et al. 31P-magnetic resonance spectroscopy in migraine without aura. Neurology 1994; 44(4):666669. 5. Schoenen J. The pathophysiology of migraine: a review based on the literature and on personal contributions. Funct Neurol 1998; 13(1):715. 6. Montagna P. Back to vitamins?. Cephalalgia 2002; 22(7):489490. 7. van der Kuy PH, Merkus FW, Lohman JJ, ter Berg JW, Hooymans PM. Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study. Cephalalgia 2002; 22(7):513519. 8. Kowa H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K. The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. Am J Med Genet 2000; 96(6):762764. 9. Oterino A, Valle N, Bravo Y, et al. MTHFR T677 homozygosis inuences the presence of aura in migraineurs. Cephalalgia 2004; 24(6):491494. 10. Franca DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Eur J Pharmacol 2001; 421(3):157164. 11. Schoenen J, Lenaerts M, Bastings E. High-dose riboavin as a prophylactic treatment of migraine: results of an open pilot study. Cephalalgia 1994; 14(5):328329. 12. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998; 50(2):466470. 13. Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhaupl KM, Arnold G. High-dose riboavin treatment is efcacious in migraine prophylaxis: an open study in a tertiary care center. Eur J Neurol 2004; 11(7):475477. 14. Maizels M, Blumenfeld A, Burchette R. A combination of riboavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 2004; 44(9):885890. 15. Sandor PS, Afra J, Ambrosini A, Schoenen J. Prophylactic treatment of migraine with beta-blockers and riboavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache 2000; 40(1):3035. 16. Rozen TD, Oshinsky ML, Gebeline CA, et al. Open label trial of coenzyme Q10 as a migraine preventive. Cephalalgia 2002; 22(2):137141. 17. Sandor PS, Di Clemente L, Coppola G, et al. Efcacy of Coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology 2005; 64:713715. 18. Barbiroli B, Medori R, Tritschler HJ, et al. Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. J Neurol 1995; 242(7):472477. 19. Magis D, Deprez C, Ambrosini A, Jacquy J, Schoenen J. A randomized, double-blind placebo-controlled parallel group study of thioctic (or a-lipoic) acid, 600 mg p.o. in migraine prophylaxis. Cephalalgia 2001; 21(4):P2I29. 20. Murdoch J. Feverfew for migraine prophylaxis. Can J Hosp Pharm 1989; 42:209210. 21. Losche W, Mazurov A, Heptinstall S, Groenewegen W, Repin V, Jill V. An extract of feverfew inhibits interactions of human platelets with collagen substrates. Thromb Res 1987; 48:511518. 22. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia 1998; 18(10):704708. 23. Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke-von Zepelin HH. The efcacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxisa double-blind, multicenter, randomized placebo-controlled dose-response study. Cephalalgia 2002; 22(7):523532. 24. Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2004; (1):CD002286.

Herbal Medicines and Vitamins

373

25. Danesch U, Rittinghausen R. Safety of a patented special butterbur root extract for migraine prevention. Headache 2003; 43(1):7678. 26. Diener HC, Rahlfs VW, Danesch U. The rst placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efcacy criteria. Eur Neurol 2004; 51(2):8997. 27. Lipton R, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology 2004; 63:22402244. 28. Gobel H, Einhaupl KM, Offenhauser N, Lipton R. Spezialextrakt aus Petasitesrhizom ist wirksam in der Migraeneprophylaxe: Eine randomisierte, multizentrische, doppelblinde, placebokontrollierte Parallelgruppenstudie. Der Schmerz 2001; 15(suppl 1). 29. Grossmann M, Schmidramsl H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Int J Clin Pharmacol Ther 2000; 38(9):430435. 30. Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KMA. Low brain magnesium in migraine. Headache 1989; 29:416419. 31. Boska MD, Welch KM, Barker PB, Nelson JA, Schultz L. Contrasts in cortical magnesium, phospholipid and energy metabolism between migraine syndromes. Neurology 2002; 58:12271233. 32. Jain AC, Sethi NC, Balbar PK. A clinical electroencephalographic and trace element study with special reference to zinc, copper, and magnesium in serum and cerebrospinal uid (CSF) in cases of migraine. J Neurol 1985; 232(suppl):161. 33. Schoenen J, Sianard-Gainko J, Lenaerts M. Blood magnesium levels in migraine. Cephalalgia 1991; 11:9799. 34. Gallai V, Sarchielli P, Costa G, Firenze C, Morucci P, Abbritti G. Serum and salivary magnesium levels in migraine. Results in a group of juvenile patients. Headache 1992; 32:132135. 35. Sarchielli P, Costa G, Firenze C, Morucci P, Abbritti G, Gallai V. Serum and salivary magnesium levels in migraine and tensio-type headache. Results in a group of adult patients. Cephalalgia 1992; 12:2127. 36. Mauskop A, Altura BT, Cracco RQ, Altura BM. Deciency in serum ionized magnesium but not total magnesium in patients with migraines. Possible role of ICa2/IMg2 ratio. Headache 1993; 33:135138. 37. Welch KMA, Ramadan NM. Mitochondria, magnesium and migraine. Neurol Sci 1995; 134:914. 38. Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in the prophylaxis of migrainea double-blind placebo-controlled study. Cephalalgia 1996; 16(6):436440. 39. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia 1996; 16:257263. 40. Goadsby PJ. Herbal medicine. N Engl J Med 2003; 348(15):14981501; author reply 14981501.

24
Treatment of Migraine in Children and Adolescents
Paul Winner
Palm Beach Headache Center, and Nova Southeastern University, Fort Lauderdale, Florida, U.S.A.

INTRODUCTION Advances in the management of headache for adults have translated into improved treatment for children and adolescents. Studies conducted in children and adolescents are helping us to outline the appropriate management strategies for this population (1). Practitioners should review the causative mechanisms of headache with the patient and the parents, as well as provide a comprehensive treatment approach, including both pharmacologic and nonpharmacologic methods. The majority of childhood headache patients who are brought to a physician for evaluation will prove to have a diagnosis of migraine (2,3). To effectively treat headache (migraine), the physician initially needs to identify potential triggers and outline an acute treatment strategy with a goal of eliminating headache in one to two hours. If the initial medication is not fully effective, the physician needs to consider either repeating the initial medication or starting a possible rescue medication with the goal of eliminating all pain symptoms by four hours. In this age group, especially children under the age of 12, headache may last only for one to two hours. In this case, a more moderate approach toward treatment and pain relief can be used (17). When appropriate, preventive treatment strategies should be designed with a goal of substantially reducing headache frequency (at least 50%), with a possible reduction of the headache severity. Moreover, they should be used on an average for six-month periods, with reevaluation. Because there is a relatively high remission rate of migraine in children, it is often possible to taper a preventive regimen within six months of its initiation (1). Pharmacologic practice parameters related to the treatment of migraine in children and adolescents have been recently published, which is a helpful base in the review of treatment options (8). In this chapter, we review treatment issues related to the management of the pediatric headache patient, with special attention to pediatric migraine.

375

376

Winner

Box 1 Analgesic use limit suggested at the Palm Beach Headache Center    No more than 10 tablets of an analgesic per month for a young child No more than 20 tablets for an adolescent No more than 2 headaches treated with these parameters per week

ACUTE TREATMENT Nonspecic Analgesics In children and adolescents with mild to moderate migraine, mild analgesics, combination analgesics, and nonsteroidal anti-inammatory drugs (NSAIDs) are often quite effective. It is important to discuss the issue of medication overuse headache in young children and adolescents in an effort to avoid its occurrence. Butalbitalcontaining compounds and mild analgesics can be used safely and effectively in young children and adolescents, but some limits need to be provided. At our center, we suggest the parameters explained in Box 1. With the assistance of a parent and a diary, these parameters can be followed rather easily. In a child reporting headache at school entry, it has been noted that 24% of children had seen a doctor for their headache complaints. The medications that were taken were ibuprofen (36%), acetaminophen (30%), salicylic acid (27%), and naproxen (8%); it was noted that 47% of these children received medication for every headache (9). Ibuprofen (7.510 mg/kg) has been shown in two double-blind, placebocontrolled trials to be safe and effective in the treatment of childhood migraine (10,11). The rst study compared ibuprofen (10 mg/kg) to acetaminophen (15 mg/ kg) and placebo. Both ibuprofen and acetaminophen were signicantly more effective than placebo in providing pain relief at two hours (12). Differences between ibuprofen compared to acetaminophen were not statistically signicant at two hours. Acetaminophen was considered effective and well tolerated (12). In the second study, ibuprofen (7.5 mg/kg) was found to reduce headache severity in children aged 6 to 12, but was signicant at the two-hour primary end point only in boys. No statistically signicant adverse effects of ibuprofen or acetaminophen were reported in these studies (11,12). The Food and Drug Administration (FDA) approves the use of ibuprofen and naproxen in children over the age of two. Although Reyes syndrome is rare, salicylates should be avoided in children who are febrile and/or in whom there is concern for an underlying metabolic disorder (1,13). Opioids such as meperidine hydrochloride and codeine can be used in children over the age of six with caution and physician supervision (13). These medications can be used effectively as a rescue treatment. The dose will vary depending on the age and weight. We suggest they be limited to a maximum of two doses per week as a guide. Triptans The introduction of the 5-hydroxytryptamine (5-HT1) agonists has revolutionized the treatment of adults with moderate to severe migraine attacks. The 5-HT1 agonists are being studied in adolescents, so that they too may benet from this form of therapy when appropriate.

Treatment of Migraine in Children and Adolescents

377

Linder, in an open-label study (8), documented the effectiveness of subcutaneous sumatriptan 0.06 mg/kg and showed an overall efcacy of 72% at 30 minutes and 78% at two hours, with a recurrence rate of 6%. Because children tend to have a shorter duration of headache, a recurrence rate of 6% would seem appropriate for this study population (14). Children who prefer to avoid the parenteral route of administration now have the option of using the oral and nasal spray (NS) forms of 5-HT1 agonists (7). Oral sumatriptan has been studied in a double-blind, placebo-controlled trial of 25-, 50-, and 100-mg tablets in 302 adolescents in 35 sites (15). Sumatriptan was statistically signicant over the placebo at 25, 50, and 100 mg at the 180- and 240-minute mark showing 74% pain relief at the four-hour mark. The primary end point of the study was at two hours, and statistical signicance was not met due to a high placebo rate, which in this adolescent study may be due in part to study design. If adult placebo rates are substituted at the two-hour mark, statistical signicance could be obtained. New study designs are being implemented to address the special issues of the pediatric population, for example, the fact that children have a shorter duration of headache. The headache recurrence rates varied from 18% to 28% across all three doses and were lower than those seen in adults possibly because children tend to have a shorter duration of headache. No signicant adverse events were documented in this study of 302 patients (9). The side effects of the placebo and 25 mg of sumatriptan were almost identical. As the dose was increased to 50 mg, there was a slight increase in side effects reported, and then a further increase was reported at 100 mg. For example, the 50-mg dose side effects of a feeling of warmth, tightness, burning, stinging, numbness, strangeness, and pressure ranged from 1% to 4%. This was compared with the side effects range of 0% to 1% at the 25-mg tablet dose. The side effects of chest discomfort, tightness, pressure, and heaviness ranged from 0% to 1% for the 25-mg tablets as compared with side effects from 0% to 3% for the placebo and side effects from 3% to 4% for the 50-mg tablets. Cardiovascular palpitations, tachyarrhythmias, and hypotension were reported to be 0% to 1% for the 25- and 50-mg tablets and slightly higher for the 100-mg tablets. No such side effects were reported in the placebo group. The study demonstrated that 25-, 50-, and 100-mg oral tablets of sumatriptan were effective in treating acute migraine, with similar efcacy proles across all three dosages. Young adolescents should begin with 50-mg sumatriptan tablets for the treatment of migraine. If they do not have complete relief within two hours, the dose should be repeated. Should 50 mg not be effective, the dose needs to be increased to 100 mg as the initial dose and repeated in two hours, if needed. Rescue medication can be used at anytime for the relief of associated symptoms, but often with triptans it is not necessary. The goal, much like in adults, is to obtain a pain-free status for the child or adolescent at two hours; if this has not occurred, the same triptan medication needs to be repeated so that the patient is pain-free by four hours. Although the associated symptoms of migraine such as nausea, photophobia, or phonophobia often respond to triptan, they may not be completely relieved. Sumatriptan nasal spray was studied in a randomized, double-blind, placebo-controlled trial in which adolescents aged 12 to 17 were treated for a single attack with three NS doses: 5, 10, and 20 mg (16). At one hour, 56% of patients using the 10- or 20-mg dose of sumatriptan NS reported signicant postdose headache relief compared with 41% in the placebo group (16). All three doses were superior to the placebo with respect to the cumulative percentage of patients who obtained headache relief within two hours of administration. When reviewing the pain-free

378

Winner

data, the 20-mg sumatriptan NS provided a statistically signicant greater response of 36% at two hours postdose compared with the placebo at 25% (p < 0.05) (16). It should be noted that each dose of sumatriptan was superior to the placebo with respect to the cumulative percentage of patients reporting pain-free response two hours postdose. There was no difference in headache recurrence among the treatment groups, which ranged from 16% to 20%, and the placebo group at 20%. The recurrence rates tend to be lower in adolescent groups than in adult groups, possibly due to the shorter duration of headaches in the adolescent population. Headache recurrence was lower in the 10- and 20-mg sumatriptan NS patient groups at 8 and 8.2 hours, respectively, as compared with the placebo group at 6.7 hours (Table 1) (16). A recent sumatriptan NS study compared the efcacy and tolerability of 5 and 20 mg versus placebo in the acute treatment of migraine in adolescent subjects (10). Sumatriptan NS 20 mg provided greater headache relief than placebo at 30 minutes (42% vs. 33%, respectively; p 0.046), 1 hour (61% vs. 52%; p 0.087), and 2 hours (68% vs. 58%; p 0.025) postdose. In general, sumatriptan NS 5 mg was more effective than placebo but the differences did not reach statistical signicance. Both doses of sumatriptan NS were well tolerated. No AEs were serious or led to study withdrawal. The most common event was taste disturbance (2%, placebo; 19%, sumatriptan NS 5 mg; and 25%, sumatriptan NS 20 mg) (10). A recent study assessed the pooled efcacy and tolerability results of 5 mg and 20 mg sumatriptran NS versus placebo from two large U.S. randomized, placebocontrolled, double-blind, parallel-group studies in adolescents. The total pooled population was 1105 (placebo N 374; 5 mg N 377; and 20 mg N 354). The results for sumatriptan NS 20 mg demonstrate signicantly greater headache relief compared to placebo at 30 minutes (39% vs. 30%, p 0.016), one hour (59% vs. 48%, p 0.007), and two hours (67% vs. 57, p 0.005); for sumatriptan NS 5 mg, the study showed signicantly greater headache relief compared to placebo at two hours (64% vs. 57%, p 0.037). Sustained relief from 1 to 24 hours was greater for sumatriptan NS 5 mg (37%, p 0.041) and for sumatriptan NS 20 mg (41%, p 0.003). For the pain-free end point, the pooled results show a greater efcacy with sumatriptan NS 20 mg compared to placebo at one hour (20% vs. 14%, p 0.034) and two hours (42% vs. 28%, p 0.001). The most frequent treatmentrelated adverse events for placebo, 5 mg and 20 mg sumatriptan NS, respectively,
Table 1 Selected Triptans for the Acute Treatment of Migraine in Adolescents Triptan dose and formulation Sumatriptan (Imitrex) Tablet 25, 50, 100 mg Subcutaneous 0.06 mg/kg up to 6 mg NS 5, 20 mg Tablet 5, 10 mg Orally disintegrating tablet 5, 10 mg Tablet 2.5, 5 mg NS 5 mg

Rizatriptan (Maxalt) Zolmitriptan (Zomig)

Note: The most common adverse event reported by this patient group was taste disturbance. If this is removed from the calculations, the overall incidence of adverse events for the nasal treatment group is similar to the placebo group. No serious adverse event was reported in the sumatriptan treatment population in this study. Abbreviation: NS, nasal spray. Source: From Refs. 1719.

Treatment of Migraine in Children and Adolescents

379

were: taste disturbance (2%, 19%, and 26%), nausea (3%, 4%, and 7%), vomiting (1%, 2%, and 4%), and burning/stinging sensation (1%, 1%, and 3%). Infrequent treatment-related adverse events (1%) were pressure/tightness and chest symptoms reported in each of the treatment groups (20). These studies provide evidence of signicant headache relief compared to placebo by 30 minutes for sumatriptan NS 20 mg and two hours for sumatriptan NS 5 and 20 mg. The results also demonstrate signicant sustained headache relief from 1 to 24 hours for sumatriptan NS 5 and 20 mg. Signicantly more sumatriptan NS 20 mg subjects were pain-free beginning at one-hour postdose. Sumatriptan NS is effective and generally well tolerated in the treatment of acute migraine in adolescents (20). Overall, sumatriptan NS 20-mg provided the most rapid treatment across this adolescent population group. It also proved to be well tolerated, and the results are similar to those reported in the adult sumatriptan NS clinical trials (10,1720). The disturbance in taste may be reduced in some patients by the use of avored lozenges or hard candy after administration of the NS. Despite the reported taste disturbance by some patients, this did not discourage some adolescents from the continued use of the NS medication (1,21). The taste disturbance also may be lessened by reinstructing adolescents of the correct administration of the NS medication (16). Rizatriptan (Maxalt) 5-mg tablets have been evaluated in patients aged 12 to 17 in a double-blind, placebo-controlled, parallel-group, single-attack study. A total of 149 adolescents were treated with rizatriptan 5 mg, and 147 were treated with a placebo. The majority of patients used one dose of study medication. The percentage of adolescents receiving pain relief at two hours for the rizatriptan 5-mg group was 66%; this is similar to that seen in the adult population receiving a 5-mg dose, but is not statistically signicant because the response of the placebo group was 57%. The headache-free status at two hours was 32% for the rizatriptan 5-mg group and 28% for the placebo. There were no serious adverse events in the adolescent patient rizatriptan population. The most common adverse events reported were fatigue, dizziness, somnolence, dry mouth, and nausea. With regard to functional disability, signicantly more adolescent patients (44%) on rizatriptan 5 mg had no functional disability at two hours as compared with the placebo group (36%). Rizatriptan 5 mg is well tolerated in this adolescent population study (22). Adult patients use Rizatriptan 10 mg tablet or MLT, but presently there are no randomized, doubleblind, placebocontrolled studies in the pediatric population. At the Palm Beach Headache Center, we will often use Rizatriptan 10 mg in adolescents when Rizatriptan 5 mg is not fully effective. We have found Rizatriptan 10 mg to be well tolerated in the adolescent patient. Zolmitriptan (Zomig) has been studied in a subgroup of adolescents (1217 years). The rst two migraine subgroups were treated with 2.5 mg and subsequent attacks with 2.5 or 5 mg at each patients discretion. The overall headache response at two hours was 80% (88% and 70% with zolmitriptan, 2.5 and 5 mg, respectively). Treatment was well tolerated (23). Presently there is limited data available regarding the use of other triptans in the pediatric population. Future pediatric studies should prove helpful. Ergot Alkaloids The ergot alkaloids are a family of chemicals that have many pharmacologic effects. Their diversity results from their interaction with multiple receptors, their variable receptor afnity and intrinsic activity, and their variable organ-specicreceptor

380

Winner

access. Ergotamine tartrate (ET) was one of the rst ergot alkaloids to be isolated. Dihydroergotamine (DHE) (tradename D.H.E. 45) is a synthetic ergot with a modied pharmacologic prole. Both ET and DHE have 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1Freceptor agonist afnity. DHE exhibits a greater adrenergic antagonist activity and has less potent arterial vasoconstriction and emetic potential than ET. DHE was rst reported to be effective in migraine by Horton et al. in 1945 (24). Unfortunately, the medication fell into disuse until Raskin reintroduced it in 1986 (25). DHE offers numerous benets compared with ET because of a lower reported incidence of nausea and vomiting, as well as a lower headache recurrence and lack of rebound headache. Intravenous administration in adults provides an effective form of rapid headache relief for migraine and often is used for refractory severe migraine headache patients. Linder has studied the use of DHE in children and adolescents. Rapid administration of intravenous DHE in children can be associated with adverse effects and a more constant rate of infusion is recommended with a coadministered antiemetic, for example, promethazine hydrochloride or metoclopramide hydrochloride. In adults, the oral form of DHE is poorly absorbed and ineffective for acute migraine. Intramuscular or subcutaneous administration can be effective for moderate to severe migraine (26). Intranasal delivery vehicles also have been shown to be effective in adults. However, no studies involving intramuscular, nasal, or oral forms of DHE in children or adolescents have been done. Limited work using intravenous forms has been performed (26,27). Articles have been published outlining the use of DHE in adolescents and children in both inpatient and outpatient settings (27,28). Prior to initiating an outpatient or an inpatient protocol, a detailed history and physical and neurologic examinations are necessary to clinically dene the situation. Females must be evaluated appropriately for concerns of pregnancy when necessary. Although reports of serious adverse events on recommended doses of DHE are rare, side effects can be seen with either the antiemetic metoclopramide or DHE. In children and adolescents, the dosing of DHE is extremely important for both efcacy and the prevention of adverse events. DHE, which often needs dose adjustment depending on the patients age, can be used in an intravenous form concomitantly with an antiemetic (27):    6 to 9 years, 0.1 mg/dose; 9 to 12 years, 0.2 mg/dose; 12 to 16 years, 0.3 to 0.5 mg/dose.

The intramuscular and subcutaneous forms can be used without a concomitant antiemetic. The initial dose of DHE is recommended to be given in the emergency department or ofce at the onset of a migraine headache, and if there is incomplete relief of the headache symptoms within one hour, a second dose may be given. DHE is a medication that often requires dosage titration (27). For example, one of the more common side effects, nausea, actually may indicate that the dose is slightly high. It may be helpful to give adolescents or children a test dose of DHE on a day when they do not have a migraine to determine if the treatment causes any signicant nausea. In general, side effects can be avoided by lowering the dose or by diluting the DHE with 30 to 60 cc of saline and administering it over a period of 30 minutes to 1 hour intravenously (27). In addition, 20 to 30 minutes prior to the administration of DHE, metoclopramide should be given to prevent nausea or vomiting (27).

Treatment of Migraine in Children and Adolescents Table 2 Contraindications for the Use of Triptans, Ergot Alkaloids

381

Symptoms or ndings consistent with ischemic heart disease, coronary artery vasospasm, or other signicant underlying cardiovascular disease Uncontrolled hypertension Hemiplegic or basilar migraine Use of another 5-HT agonist or ergot-type medication (dihydroergotamine) within 24 hr of treatment Administration of monoamine oxidase inhibitors within previous 2 wk (1)
Abbreviation: 5-HT, 5-hydroxytryptamine.

The pediatric patient population tends to be sensitive to some antiemetics, including metoclopramide, and may develop extrapyramidal side effects. This is especially true when the medication is given in an intravenous form. These extrapyramidal side effects are readily reversed using diphenhydramine at a dose of 1 mg/kg up to 50 mg. The extrapyramidal side effects can also be seen using the oral form of metoclopramide, and if this is the case, it is normally seen between the fth and eighth dose, and, again, is readily reversible with diphenhydramine. If the patient has difculty with metoclopramide, promethazine hydrochloride may be substituted. DHE has been used in pediatric patients since the early 1990s as an effective treatment of moderate to severe migraine headaches. Because triptan medications have been approved for the treatment of adult migraine, DHE is used less frequently, but it still is a reliable alternative should triptans prove to be ineffective or their side effects prove intolerable. DHE also has proven to be useful for migraine headaches that last for more than two to four days (status migrainosus) (29). Both inpatient and outpatient DHE protocols may be used to break intractable migraine headaches. The use of DHE, as well as triptans, is contraindicated in patients with certain high-risk factors such as uncontrolled hypertension, carotid or peripheral artery disease, and thyrotoxicosis. Caution is advised for patients with a history of congenital heart disease or other medical problems (Table 2). Antiemetics Antiemetics, both the suppository and the oral forms, can be used in children and adolescents with acute migraine accompanied by nausea or vomiting. Promethazine hydrochloride, either the 25- or 50-mg suppository form, can prove to be quite efcacious in the younger child who has signicant vomiting associated with migraine; in children who have nausea symptoms without vomiting either the 25- or 50-mg tablet form can be used. Prochlorperazine maleate and metoclopramide can also be quite effective, although they should be used with caution because of potential extrapyramidal side effects. Antiemetics can be used effectively in conjunction with other acute therapies for treating moderate to severe migraine in children and adolescents (1). PREVENTIVE THERAPY Children or adolescents who do not respond adequately to the acute treatment of migraine and/or who are missing excessive periods of school days or have signicant disability in their life due to frequent and incapacitating migraines, should consider

382

Winner

preventive therapy. Age can play a role in the selection of appropriate therapy, and often doses need to be tailored to the individual child adolescent. The preventive therapy of migraine includes not only the pharmacologic treatment but also nonpharmacologic approaches such as the identication of migraine triggers, which may involve adjusting lifestyle. Several issues must be addressed prior to considering the use of a pharmacologic agent. These include an accurate assessment of headache frequency and severity, the effectiveness of current episodic medications, the identication of possible triggers, and most importantly, the degree of disability caused by the headache (1). There are limited well-controlled clinical trials with sufcient patient numbers to support the use of any particular agent, except unarizine, in the preventive treatment of migraine headaches in children or adolescents (8). Pertinent literature on the preventive treatment of migraine in children and adolescents, as well as dosing guidelines based on the limited data available and the clinical experience, will be reviewed (1).

Nonpharmacologic Measures in Children and Adolescents Nonpharmacologic preventive measures that may reduce headache frequency include sleep hygiene, diet, and exercise. Lack of sleep can be a signicant trigger for many children. An alteration of sleep behavior, such as going to bed late or sleeping late, may precipitate headaches. It is quite helpful if the patient arises every morning at the same time. In addition to sleep hygiene, a regular balanced diet is benecial. Frequently, adolescents concerned about weight gain may choose not to eat breakfast or lunch. This results in a relatively severe headache later in the day. In the adolescent, both sleep hygiene and diet can be signicant triggers that can be somewhat difcult to control (1). Although food triggers for migraine headache are relatively infrequent, probably occurring in less than 20% of the patients, identication of such triggers in a particular patient can be quite benecial (30). Regular physical exercise appears to reduce headache frequency. Although the value of this has never been demonstrated in children, establishing a lifestyle that includes adequate exercise, sleep, and physical activity certainly cannot be harmful to the childs overall well-being. Stress may play a signicant role in precipitating migraine events. Riback identied stress as a provoking factor in 23% of 226 children (30). Stress management using relaxation techniques and/or biofeedback can be helpful in children who are motivated to use them. Biofeedback has been demonstrated to be effective in children as young as nine years (Table 3) (31). When all of the above issues have been addressed, and yet the child continues to have disabling headaches at a signicant frequency, then a decision to initiate
Table 3 Nonpharmacologic Treatment of Migraine Education Biofeedback Stress management and relaxation exercises Elimination of triggers Sleep regulation (1)

Treatment of Migraine in Children and Adolescents Table 4 Preventive Therapy Agent Cyproheptadine (Periactin) Propranolol (Inderal) Amitriptyline (Elavil) Nortriptyline (Pamelor) Divalproex sodium (Depakote) (sprinkle) Topiramate (Topamax)
Abbreviations: bid, twice daily; hs, at bedtime.

383

Initial dosage 2 mg bid or 4 mg hs 1 mg/kg, up to 10 mg bid 0.250.5 mg/kg, up to 10 mg hs 0.250.5 mg/kg, up to 10 mg hs 10 mg/kg, up to 125 mg daily 15 or 25 mg

preventive medication needs to be considered. Headache disability, which can be assessed by a variety of headache disability scales but, more importantly, by the impact on the individual patients life, should be used to determine who should be placed on preventive medication. Certainly, a child experiencing three to four significant migraine headaches a month resulting in disability for several hours each time should be considered for preventive medication. However, even the child who experiences only one severe headache a month that results in a signicant disability may also be considered for preventive medication (1). Pharmacologic Preventive Treatment Once the decision to add a pharmacologic agent is made, there are several medications from which to choose. The appropriate dose for any of these agents has not yet been determined. The information provided herein is a summary of the literature, with dosage recommendations based on the few clinical reports as well as clinical experience (Tables 4 and 5). Anticonvulsants Several anticonvulsants have been used for migraine prevention in the pediatric population, including phenobarbital, carbamazepine, phenytoin, divalproex sodium, and topiramate. Intravenous infusion of valproate sodium (Depacon) has been reported to abort acute migraine headache (32). The divalproex sodium migraine prevention study group has shown that 500 to 1500 mg/day of divalproex sodium is effective in reducing headache frequency in adults (33). Extended-release divalproex sodium (Depakote ER) has been demonstrated to be effective and well tolerated at doses of 500 and 1000 mg once daily in adults (34). Caruso et al. treated 31 children in the age range of 7 to 16 with divalproex sodium as a preventive agent (35). Dosages
Table 5 Drugs with FDA Approval for Migraine Prevention Drug year of approval Divalproex sodium (Depakote) 1996, (DepakoteER) 2000 Timolol (Blocadren) 1990 Propranolol (Inderal) 1979 Methysergide (Sansert) 1962
Abbreviation: FDA, Food and Drug Administration.

384

Winner

ranged from 15 to 45 mg/kg/day. After four months of treatment, 76% of the patients had a greater than 50% reduction in headache frequency, 18% had a greater than 75% reduction, and 6% were essentially headache-free (36,37). Another open labeled study using divalproex sodium included children 9 to 17 years who were treated with doses between 500 and 1000 mg reported reduction in both headache frequency and severity. The mean severity using a visual analog scale was reduced from 6.8 to 0.7 (38). Mean headache attacks were reduced from 6 per month to 0.7 per month, and the mean duration from 5.5 to 1.1 hours (38). Adverse events included dizziness, drowsiness, and increased appetite, but no serious side effects were reported (38). These studies suggest that divalproex sodium may be effective as a migrainepreventive agent in children and adolescents. Clinical experience with divalproex sodium for seizures suggests that 10 mg/kg/day divided twice daily is a safe starting dose (Table 4). The dose can then be increased in the second week of treatment to 1520 mg/kg/day divided either twice or three times a day. There are no data on serum drug levels to suggest a therapeutic range for migraine prevention. The sprinkle formula, 125-mg divalproex capsules, is well tolerated and may help to decrease any potential gastrointestinal side effects. Other reported potential side effects of divalproex sodium include sedation, increased appetite, and temporary hair loss. Divalproex sodium can also reduce platelet counts in a dose-dependent manner; therefore, monitoring of platelet counts should be considered, especially when higher doses are given. Hyperammonemia can also occur from divalproex sodium without elevated transaminases; therefore serum ammonia levels should be obtained from patients who report being excessively tired. Due to the potential teratogenic effects, folic acid, 2 to 4 mg daily, can be added to the treatment for adolescent girls. Divalproex sodium (Depakote) and (Depakote ER) have been approved by the FDA as a treatment for the prevention of adult migraine (Table 5). More recent anticonvulsant data regarding the prevention of migraine in children and adolescence is from a randomized, double-blind, placebo-controlled trial evaluating topiramate (Topamax) (39). Topiramate has been demonstrated to be effective for migraine prevention in adults. Limited data is available for the efcacy and safety of topiramate in the pediatric population. Topiramate has been studied in children with migraine with or without aura (n 162; age range 615 years; 52% male, 48% female) was randomized 2:1 to topiramate (n 112) or placebo (n 50). Topiramate was initiated at 15 mg/day and titrated over eight weeks to a dose approximating 2.0 to 3.0 mg/kg/day, or their maximum-tolerated dose, whichever was less. The maximum dose allowed was 200 mg/day, this titration phase was followed by a 12-week maintenance phase (39). Topiramate reduced mean monthly migraine days by 2.6 from a baseline of 5.4 days compared to a reduction of 1.9 days for placebo from a baseline of 5.5 days, which approached statistical signicance (p 0.065). A signicantly greater percentage of patients receiving topiramate (32%) showed greater reduction in mean monthly migraine days than patients receiving placebo (14%, p 0.020). However, the percentage of topiramate-treated patients exhibiting a greater than 50% reduction in mean of monthly migraine days (55%) was not satisfactory different from that of placebo-treated patients (47%). Discontinuation rates due to adverse events were 6.5% for topiramate and 4.1% for placebo. The most common adverse events in the topiramate group were upper respiratory tract infection (19.4% topiramate vs. 6.1 placebo), anorexia (13.0% topiramate vs. 8.2 placebo), weight decrease (9.3 topiramate vs. 6.1% placebo), paresthesia (8.3% topiramate vs. 0.0% placebo), and somnolence (8.3 topiramate vs. 6.1 placebo).

Treatment of Migraine in Children and Adolescents

385

This preliminary study notes the potential utility if topiramate for the prevention of pediatric migraines, with the target dose being 100 mg daily divided bid. Topiramate was well tolerated in this pediatric population. Further studies are warranted to establish the efcacy of topiramate for the treatment of pediatric migraine (39). Although the other anticonvulsants have been used by clinicians, there are limited studies to support their use. When used in migraine prevention, the antiepileptic doses are usually prescribed.

Antidepressants The tricyclic antidepressant amitriptyline has been reported to reduce headache frequency in children (40,41). However, the efcacy of amitriptyline has not been studied in a placebo-controlled trial. Levinstein compared amitriptyline with propranolol and cyproheptadine in an open-label study (41). In that study, 30 children were randomized to receive one of the three treatments. It is not noted how many children were treated with amitriptyline. He reports a moderate 50% to 60% improvement to an excellent 80% improvement at three months of treatment with amitriptyline. Hershey et al. were more precise in reporting a reduction in headache frequency in their open-label study, but had included a mixture of headache types including headaches occurring at a frequency of greater than three per week (41). The appropriate dosage of amitriptyline has not yet been determined. Levinstein used a dosage of 15 mg/day (41). Hershey et al. suggested a standardized dosage of 1 mg/kg/day (40). This is the rst report of standardized dosing of amitriptyline based on body weight. Clinical experience suggests that a reasonable starting dosage of amitriptyline for a 5- to 10-year-old child is 0.25 to 0.5 mg/kg up to 10 mg/day administered at bedtime (Table 4). For an adolescent, 10 mg is a reasonable starting dose. A dosage ranging from 10 to 75 mg/day is usually effective in reducing headache frequency. Children may experience drowsiness with the medication in the early phases of treatment. This usually resolves over a two- to three-week period. In the rst two to four weeks, a 10-mg single daily dosage is usually maintained. At the end of a two- to four-week trial, the medication should be titrated upward to either efcacy or intolerable side effects. Because of the potential cardiac side effects, electrocardiography should be performed if dosage escalation is required. A dosage exceeding 75 mg/day is rarely needed to control headache (1). Nortriptyline also has been widely used as an alternative to amitriptyline with the belief that there are fewer side effects. The usual starting dosage is 10 mg/day administered at bedtime (Table 4). The side effects of nortriptyline are identical to those of amitriptyline (1). Serotonin selective reuptake inhibitors (SSRIs) have been studied in adults but not in children. Fluoxetine has been shown to be effective in treating mild headaches in the adult population in a limited study (42). In our center, the SSRIs are used when there is clinical suspicion of depression. The dosage is usually administered in the morning to avoid difculties with insomnia. Worsening of headache may occur in some patients. Initially, there is appetite suppression with concomitant weight loss, followed by increased appetite and weight gain. The serotonin syndrome may occur in patients on SSRIs who are treated with 5-HT1 agonists for an acute headache. There are no data to support their use in migraine prevention in children (1).

386

Winner

Antihistamines Cyproheptadine, an antihistamine with antiserotoninergic properties, was one of the earliest medications reported useful in migraine prevention in children (43). Although it has antiserotoninergic properties, its antimigraine effects may be the result of calcium channel blockade (44). Bille et al. treated 19 children with cyproheptadine for three to six months in an uncontrolled trial (43). Seventeen of the 19 children had improvement in their headache frequency, and 4 of 17 had resolution of their headaches. Dosages used ranged from 0.2 to 0.4 mg/kg/day. Although this was an uncontrolled study in a small number of children, this dosage of cyproheptadine has been quoted in several medical texts and review articles as appropriate for migraine prevention. Cyproheptadine can be used as a single daily dosage administered at bedtime, starting at 2 to 4 mg/day (Table 4). The vast majority of patients respond to a dosage between 4 and 12 mg/day. The antihistaminic effects of cyproheptadine may cause weight gain, drowsiness, dry mouth, and irritability (13).

Beta-Blockers The beta-blockers may exert their effect through antagonism of the 5-HT2 receptors or through modulation of adrenoreceptors. The evidence that propranolol is effective in migraine prophylaxis is very weak, yet propranolol remains a mainstay in the preventive treatment of migraine headaches in children. Dosing of propranolol (Inderal) has not been systemically studied. Ludvigsson studied 28 children with dosages ranging from 60 mg/day, for children weighing less than 35 kg to 120 mg/day, for children weighing greater than 35 kg (45). He concluded that a dose of 1 mg/kg/day is effective. Olness et al. in a study comparing self-hypnosis to propranolol for the treatment of classic migraine headache, used a dosage of 3 mg/kg/day (46). They found that self-hypnosis was more efcacious than propranolol in reducing headache frequency. Neither self-hypnosis nor propranolol affected subjective or objective measures of headache severity. Forsythe et al. suggested that propranolol had no impact on frequency of migraine headache and may have increased the duration of headache in some children (47). The nal dosage per kilogram used in that study was not reported. The recommended starting dosage of propranolol for the treatment of hypertension in children is 1 mg/kg/day up to 10 mg twice daily. The dosage can be titrated slowly, increasing over two to four weeks to a maximum of 3 to 4 mg/kg/ day divided twice daily, if tolerated (Table 4) (13). Adolescents may experience signicant drops in blood pressure. The beta-blockers can also reduce stamina and should be used with caution in athletes. Propranolol is contraindicated in children with a prior history of reactive airway disease or diabetes and in some children with cardiac arrhythmia. Although the majority of children have no signicant side effects from propranolol, several side effects can occur including fatigue, nausea, dizziness, vivid dreams, insomnia, nightmares, depression, and memory disturbance. One of the most signicant side effects, which can easily be missed in an adolescent, is the onset of depression. Patients should be monitored for signs of mild depression within the rst four to eight weeks of therapy initiation; the signs may be subtle. If depression symptoms are observed, the dose may need to be decreased or discontinued. If a child experiences nightmares or vivid dreams while taking propranolol, changing the dosing

Treatment of Migraine in Children and Adolescents

387

schedule so that the child receives the medication several hours before retiring usually eliminates that side effect (13). In spite of the potential for side effects, most children tolerate propranolol well. Patients should be evaluated at approximately 4 and 12 weeks into the treatment phase to determine if the medication has been effective and well tolerated. It is important to remember that beta-blockers may take several weeks for full effect. A minimum of 12 weeks of treatment at appropriate doses is needed to determine if the medication has been efcacious. Although other beta-blockers have been used clinically for several years, there are no studies to demonstrate their usefulness in children. Noronha reported that the beta-blocker timolol is not effective as a preventive medication in children (48). However, this was a very small study involving only 17 children. Nadolol has been reported to be as equally efcacious as propranolol in adult studies (49). However, the data must be interpreted with respect to the assessment of Ramadan et al. concerning the scientic merit of many of these studies (50). Propranolol (Inderal) and timolol maleate (Blocadren) have been approved by the FDA for the treatment of migraine prevention (Table 5). Calcium Channel Blockers Calcium channel blockers have been used quite extensively in the adult population (51). Flunarizine, a calcium channel blocker, is available in Europe but not in the United States. It has been shown to be effective as a preventive medication in children (8,5256). In the double-blind, placebo-controlled crossover study performed by Sorge et al., patients were crossed over from active drug to placebo following a four-month active treatment phase (52). The baseline mean number of headache attacks per month was 3 for both groups. In the unarizine-treated group, the mean number of attacks per month decreased progressively to as low as 1.3 per month. Thus, the actual change in the number of headache attacks was small but statistically signicant. No data are presented beyond four months; thus, it is unknown if treatment beyond that point would have demonstrated a continued clinical efcacy. All studies of unarizine report similar outcomes (5356). The efcacy of unarizine should not be generalized to suggest that all calcium channel blockers would be effective. Only nimodipine, a class-2 (nifedipine-like) calcium entry blocker for slow calcium channels, has been reported to reduce the frequency of migraine headache in children (57). However, in the rst phase of this double-blind, placebo-controlled crossover trial, there was an identical reduction in headache frequency in both the placebo and the active drug group. After crossover, the initial placebo group responded to nimodipine with a reduction in headache frequency greater than the second placebo group. The authors conclude that nimodipine is efcacious as a migraine preventive agent. However, the data do not appear to support their conclusions (8,57). Clinical experience suggests that calcium channel blockers are not more efcacious than other classes of agents. Calcium channel blocker side effects include constipation, hypotension, AV block, nausea, weight gain, and occasionally, depression. The side effects of the calcium channel blockers may prove limiting in some patients (1). Nonsteroidal Anti-inammatory Drugs The NSAIDs such as naproxen sodium are known to be efcacious in the treatment of acute migraine headache and have been reported to be effective as a migraine

388

Winner

preventive medication. Lewis et al. treated 19 children with naproxen sodium, 250 mg twice daily, in a double-blind, placebo-controlled crossover trial (58). Ten of the 19 patients completed the study, and of these, six reported a signicant reduction in the frequency and severity of their headaches. Of the 50% reported, 50% reduction in headache frequency, 2 a greater than 70% reduction, and 1 a greater than 90% reduction. Thus, this relatively small study suggests that naproxen sodium may be effective. Our clinical experience indicates that naproxen sodium is an effective preventive medication. A starting dosage of 10 mg/kg twice daily reduces migraine headache frequency and lessens the severity of breakthrough headaches. Long-term use of NSAIDs may not be advisable because of their effects on the gut and on renal function. However, for some patients who have difculty tolerating the other treatments, this may be a reasonable short-term alternative for up to four to eight weeks (1). Other Agents Reports on the use of trazodone and pizotifen in a small number of children suggest that these agents may be effective in preventing migraine (59,60). However, no conrmatory data are available. Clonidine has been studied in a single double-blind, placebo-controlled trial involving 57 children. There was no signicant difference in headache frequency between treatment and placebo groups. Clonidine was most helpful in a subset of patients with visual aura and a positive family history of migraine. Ergotamine compounds such as methylergonovine maleate (Methergine) and methysergide have not been studied in the adolescent or pediatric population. As these compounds have a long-term potential to cause retroperitoneal brosis, their use, even in the adult population, is somewhat limited (1). Treatment PeriodWhen to Discontinue Preventive Treatment A difcult and unanswered question is how long should a patient be treated with preventive medication? Treatment periods with preventive medication typically range from as short as 3 months to as long as 18 months, with 6 months being the mean (1). Treatment periods of 6 to 12 months generally result in a signicant reduction in frequency and a persistent effect after withdrawal of preventive medication. Children started on preventive medications in the beginning of the school year should continue the medications throughout the school year. If signicant headache control has been achieved, the medication may be withdrawn preferably the following summer. If, on the other hand, the childrens medication is begun late in the school year, it may be discontinued either through a prolonged break or through the following year and withdrawn the following summer depending on the clinical situation (1).

CONCLUSIONS Treatment options are improving for both children and adolescents with regard to the acute and preventive management of migraine and headache in general. The combined use of nonpharmacologic and pharmacologic modalities can prove to be quite efcacious in the complete relief of migraine headaches in this patient

Treatment of Migraine in Children and Adolescents

389

population (1). A signicant need exists for well-designed studies evaluating the efcacy and safety, as well as tolerability, for this patient population.

REFERENCES
1. Winner P, Rothner AD. Headache in Children and Adolescents. Hamilton: B.C. Decker, 2001:87125. 2. Sillanpaa M. Changes in the prevalence of migraine and other headaches during the rst seven school years. Headache 1983; 23:1519. 3. Gladstein J, Holden EW, Peralta L, Raven M. Diagnoses and symptom patterns in children presenting to a pediatric headache clinic. Headache 1993; 33:497500. 4. Seshia SS, Wolstein JR, Adams C, et al. International Headache Society criteria and childhood headache. Dev Med Child Neurol 1994; 36:419428. 5. Winner P, Martinez W, Mate L, Bello L. Classication of pediatric migraine: proposed revision of the IHS criteria. Headache 1995; 35:407410. 6. Winner P, Gladstein S, Hamel R, et al. Multicenter prospective evaluation of proposed pediatric migraine revisions to the IHS criteria. American Association for the Study of Headache Scientic Meeting, San Diego, CA, May, 1996. 7. Hamalainen M, Hoppu K, Santavuori P. Sumatriptan for migraine attacks in children: a randomized, placebo-controlled study. Do children with migraine respond to oral sumatriptan differently from adults? Neurology 1997; 48:11001103. 8. Lewis D, Ashwal S, Hershey A, et al. Practice parameter: pharmacological treatment of migraine headache in children and adolescents. Neurology 2004; 63:22152224. 9. Bille B, Ludvigsson J, Sanner G. Prophylaxis of migraine in children. Headache 1977; 17:6163. 10. Winner P, Rothner D, Wooen J, Webster B, Ames M. Randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in adolescent migraineurs. Neurology 2004; 62(suppl 5):A148. 11. Lewis D, Kellstein D, Burke B, et al. Childrens ibuprofen suspension for the acute treatment of migraine headache. Headache 2002; 42:780786. 12. Hamalainen M, Hoppu K, Valkeila E, et al. Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, crossover study. Neurology 1997; 48:102107. 13. Winner P, Visser WH, Lines CR. Headaches in children. Postgrad Med 1995; 101(5): 8190. 14. Linder SL. Subcutaneous sumatriptan in the clinical setting. The rst 50 consecutive patients with acute migraine in a pediatric neurology ofce practice. Headache 1996; 36:419422. 15. Winner P, Pensky A, Linder S. Efcacy and safety of oral Sumatriptan in adolescent migraines. American Association for the Study of Headache Scientic Meeting, Chicago, IL, May, 1996. 16. Winner P, Rothner AD, Saper J, et al. Sumatriptan nasal spray in the treatment of acute migraine in adolescent. Pediatrics 2000; 106(5P):989997. 17. MacDonald J. Treatment of juvenile migraine with subcutaneous sumatriptan. Headache 1994; 34:581582. 18. Diamond S, Elkind A, Jackson R, et al. Multiple-attack efcacy and tolerability of sumatriptan nasal spray in the treatment of migraine. Arch Fam Med 1998; 7:234240. 19. Ryan R, Elkind A, Baker C, et al. Sumatriptan nasal spray for the acute treatment of migraine. Results of two clinical studies. Neurology 1997; 49:12251230. 20. Winner P, Rothner A, Webster C, Ames M. Overall efcacy of Sumatriptan Nasal Spray in Adolescent Migraineurs: Pooled Results from US Placebo-Controlled Trials. Headache 2004; 44(5):465.

390

Winner

21. Schoenen J, Bulcke J, Caebeke J. Self-treatment of acute migraine with subcutaneous sumatriptan using an auto-injector device: comparison with customary treatment in an open, longitudinal study. Cephalalgia 1994; 14:5563. 22. Winner P. Clinical prole of Rizatriptan 5 mg in adolescent migraineurs. American Academy of Neurology Annual Meeting, San Diego, CA, April, 2000. 23. Linder SL, Dowson AJ. Zolmitriptan provides effective migraine relief in adolescents. Int J Clin Prac 2000; 54:466469. 24. Horton BT, Peters GA, Blumenthal LS. A new product in the treatment of migraine; a preliminary report. Mayo Clin Proc 1945; 20:241248. 25. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intra migraine. Neurology 1986; 36:995997. 26. Winner P, Ricalde O, Le Force B, et al. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol 1996; 53:180184. 27. Linder SL. Treatment of childhood headache with dihydroergotamine mesylate. Headache 1994; 34:578580. 28. Linder SL. Treatment of acute childhood migraine headaches. Cephalalgia 1991; 11(suppl 2):120121. 29. Practice parameter: appropriate use of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainosus (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1995; 45:585587. 30. Riback PS. Factors precipitating migraine headache in children. Ann Neurol 1999; 46:541. 31. Winner P. Pediatric headaches: whats a new? Curr Opin Neurol 1999; 12:269272. 32. Edwards KR, Santarcangelo V. Intravenous valpropate for acute treatment of migraine headache. Headache 1999; 39:353. 33. Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 1997; 17:103108. 34. Freitag F, Saper J, Winner P, Collins D. Depakote ER in migraine prophylaxis. 52nd Annual Meeting of the American Academy of Neurology, Montreal, Canada, May 1, 2000. 35. Caruso JM, Ferri R, Exil G, et al. The efcacy of divalproex sodium in the prophylactic treatment of migraine. Ann Neurol 1998; 44:567. 36. Matthew N, Saper J, Silberstein S, et al. Migraine prophylaxis with divalproex. Arch Neurol 1995; 52:281286. 37. Silberstein S. Divalproex sodium in headache: literature review and clinical guidelines. Headache 1996; 9:547555. 38. Serdaroglu G, Rhan E, Tekgul, et al. Soduim valproate prophylaxis in childhood migraine. Headache 2002; 42:819822. 39. Winner P, Pearlman E, Linder S, Jordon D, Fisher A, Hulihan J. Topiramate for the prevention of migraines in children and adolescence: a randomized, double-blind, placebo-controlled trial. Headache 2004; 44(5):481. 40. Hershey AD, Powers SW, Brenntti AL, et al. Standard dosing of amitriptyline is highly effective in a pediatric headache center population. Headache 1999; 39:357358. 41. Levinstein B. A comparative study of cyproheptadine, amitriptyline, and propranolol in the treatment of adolescent migraine. Cephalalgia 1991; 11(suppl 11):122123. 42. Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxis of migraine. Headache 1992; 32:101104. 43. Bille B, Ludvigsson J, Sanner G. Prophylaxis of migraine in children. Headache 1977; 17:6163. 44. Peroutka SJ, Allen GS. The calcium antagonist properties of cypropheptadine: implications for anti-migraine action. Neurology 1984; 34:304309.

Treatment of Migraine in Children and Adolescents

391

45. Ludvigsson J. Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 1974; 50:109115. 46. Olness K, MacDonald JT, Ulden DL. Comparison of self-hypnosis and propranolol in treatment of juvenile class migraine. Pediatrics 1987; 79:593597. 47. Forsythe JI, Gillies D, Sills MA. Propanolol (Inderal) in treatment of childhood migraine. Dev Med Child Neurol 1984; 26:737741. 48. Noronha MJ. Double-blind randomized cross-over trial of timolol in migraine prophylaxis in children. Cephalalgia 1985; 5(suppl 3):174175. 49. Olerud B, Gustausson CL, Furberg B. Nadolol and propranolol in migraine management. Headache 1986; 26:490493. 50. Ramadan NM, Shultz LL, Gilkey SJ. Migraine prophylactic drugs: proof of efcacy, utilization and cost. Cephalalgia 1997; 17:7378. 51. Toda N, Tfelt-Hansen P. Calcium antagonists. In: Oleson J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York, NY: Raven Press, 1993:383390. 52. Sorge F, DeSimone R, Marano E, et al. Flunarizine in prophylaxis of childhood migraine. Cephalalgia 1988; 8:16. 53. Pothman R. Calcium-antagonist unarizine vs. low-dose acetylsalicylic acid in children migrainea double-blind study. Cephalalgia 1987; 7(suppl 6):385386. 54. Martinez-Lage JM. Flunarizine (Sibelium) in the prophylaxis of migraine. An open, long-term multicenter trial. Cephalalgia 1988; 8(suppl 8):1520. 55. Sorge F, Marano E. Flunarizine V. placebo in childhood migraine. A double-blind study. Cephalalgia 1985; 5(suppl 2):145148. 56. Guidetti V, Moscato D, Ottauiano S, et al. Flunarizine and migraine in childhood. Cephalalgia 1987; 7:263266. 57. Battistella PA, Ruflli R, Moro R, et al. A placebo-controlled crossover trial of nimodipine in pediatric migraine. Headache 1990; 30:264268. 58. Lewis DW, Middlebrook M, Mehallick M, et al. Naproxen for migraine propphylaxis. Ann Neurol 1994; 36:542. 59. Salmon M. Pizotifen. (B.C. 105 Sandomigran) in prophylaxis of childhood migraine. Headache 1995; 35:174. 60. Battistella PA, Ruflli R, Cernetti R, et al. A placebo-controlled crossover trial using trazodone in pediatric migraine. Headache 1993; 33:3639.

25
Inpatient Management and Invasive Treatment Strategies for Migraine and Chronic Daily Headaches
Frederick G. Freitag
Diamond Headache Clinic, Chicago and Department of Family Medicine, Chicago College of Osteopathic Medicine, Downers Grove and Department of Family Medicine, Rosalind Franklin University of Medicine and Science/Chicago Medical School, North Chicago, Illinois, U.S.A.

INTRODUCTION While the treatment of migraine is commonly delivered in an outpatient environment, there are patients who are refractive to standard pharmacological and nonpharmacological treatment. Many of them can be treated with more aggressive modalities of treatment. Some of these therapies are described in this chapter, which is divided into two subsections. First we describe the inpatient management of migraine. Most of the strategies described can also be used, and often are, for the treatment of chronic daily headaches. We then describe some invasive treatment strategies for migraine and the chronic daily headaches (some of which require hospitalization, while others can be used in the outpatient setting).

INPATIENT TREATMENT Historical Background and Economic Considerations The evolution of specialized treatment of headache has progressed from the rst headache clinic in the United States established in 1945 at Monteore Medical Center in New York (1) to the use of dedicated inpatient treatment units for those whose headaches require intensive multidisciplinary therapy. The concept of inpatient treatment for headache may have been fostered by Fordyce (2,3) in the treatment of other chronic pain conditions. Inpatient pain specialty assessment and treatment units have, for severely disabled headache sufferers, superior outcomes compared with alternative treatment programs as demonstrated in a recent controlled clinical trial (4). This study found that patients who received the initial treatment on an inpatient basis had greater improvement in their pain, were able to maintain control of the pain more effectively over one year, and utilized overall health-care services less than those
393

394

Freitag

patients matched for type, severity, and duration of pain treated as outpatients. The rst inpatient headache clinic was established in the late 1970s in Michigan. Currently, there are three dedicated inpatient headache treatment programs in the United States, and several others existing as part of other chronic pain programs. Essentially, all patients who are treated in the hospital environment have daily or near daily headache, often associated with signicant disability. This severity of illness produces signicant health-care costs, and is responsible for a major impact on businesses and the economy. In a study (5) conducted at a managed care organization, migraine patients generated nearly twice as many medical claims in comparison to other group patients, and their pharmacy claims were almost 2.5 times greater. The migraineurs, when compared to other patients, used more emergency services. In another study, treatment of headache patients in primary care costs 87% more than those without headache (6). A review of hospitalization costs in the year of 2000 showed that for migraine there was a mean length of stay of 5.1 days and at a cost of almost $7000 (7). A Swedish study (8) examined headache in the private and public sector. The prevalence of headache in this survey, returned by 71.5% of the 800 distributed, was 64% of the private sector employees and 78% of those in the public sector. The frequency of headache that still permitted employees to work was similar in the two groups, with approximately two days per month of headache. During the headache attacks, employees had a mean of 25% reduction in their effectiveness at work. These migraine-specic costs are only a portion of the overall medical costs of caring for patients with migraine. Beyond the headache itself, there are additional factors that may contribute to the severity of the illness in the form of coexisting medical and psychiatric disease. These comorbid medical issues may impact the treatments available for headache, and, conversely, the treatments necessary for headache may have an impact on the optimal management of the comorbid medical condition (9,10). In many cases, factors that inuence the severity of the treatment situation include, medication overuse (1115), psychiatric issues such as depression, insomnia, and stressful or traumatic life events, and head injury (1621). Furthermore, evidence demonstrates that comorbid disorders increase the burden on individuals with headache and on society (22) by compounding the effect on the impact of headache and increase loss of productivity in the workplace (23,24). Among the comorbid medical issues present in the migraine population may be a congenital anomaly that has been recently linked to migraine. A study of patients being assessed for closure of patent foramen ovale (25,26) found roughly twice the prevalence of migraine among these patients as would have been expected based on population prevalence studies. Closure of the patent foramen ovale produced a 54% reduction in migraine attacks in this population. Further study of this situation is necessary. All of the patients in this study have been referred for closure because of apparent paradoxical cerebral embolism. The role of this embolism on the migraine situation is unclear. Reports from other countries that do not have dedicated inpatient treatment lend support to other options for the treatment of headache. These reports have suggested that aggressive outpatient treatment is an option in headache management. However, even with the progress in migraine-specic pharmacologic treatments and the increased use of nonpharmacologic approaches, there are patients who fail at outpatient treatment (27). In a longitudinal study of patients with headache in a primary care setting, Von Korff et al. found that 60% of the patients

Inpatient Management and Invasive Treatment Strategies

395

had continued disability at one year, with 20% continuing with signicant pain and disability at two years (28). These patients cause an important economic burden to society, with a disproportional contribution from those with high-frequency refractive headaches (29). Inpatient TreatmentGeneral Considerations Inpatient headache treatment occurs in two different hospital environments: community/regional hospitals and specialty headache treatment units. The choice of the setting for this inpatient care may also to a degree depend upon these same considerations and aid in determining the need for referral to a center with a dedicated inpatient headache unit. Several convenience surveys have been conducted to assess criteria for hospitalization. One survey was conducted in 174 physicians with an interest in headache selected from the membership of the American Headache Society (known as American Association for the Study of Headache at the time of the study). Inpatient treatment was viewed as necessary for at least a portion of all patients requiring detoxication from opioids, barbiturates, or prescription analgesics (30). A second survey (Table 1) involved both clinicians and the insurance industry and surprisingly had a number of areas of similar views and criteria for inpatient treatment (31). Additionally, criteria from inpatient programs substantially overlapped in their guidelines, as did those of community/regional physicians treating in the community setting. Previously, there had been two sets of published criteria for admission to headache treatment centers (Tables 2 and 3) (32,33). Currently, these criteria are being excerpted by a section of the Department of Health and Human Services as recognized evidence-based criteria for inpatient treatment of headache. Inpatient treatment will differ based on the facility and type of headache. Community/regional inpatient treatment and dedicated headache inpatient treatment units may all share the common elements of treatment protocols; signicant differences may exist in the sophistication of other aspects of medical management, the multidisciplinary services offered, and the recidivism of the patients in treatment. Dedicated inpatient treatment units are characterized by the broad availability of a multidisciplinary team (Table 4). In the evaluation of the patient clinically, there are a number of considerations that need to be entertained in determining the appropriate treatment setting. Seven major factors have been identied for this consideration of care (Table 5) (34). These factors, which inuence both the need for hospitalization and the type of care rendered, include  intractability of the patients pain;  the refractoriness of the patient and the headache to established preventative treatment regimens;  the medical stability of the patient;  presence of coexisting medical illness;  the occurrence of medication overuse headache and associated drug dependency issues;  psychological and psychiatric comorbidities;  need for patient monitoring during administration of medical therapies. One of the primary goals of an inpatient headache treatment program is pain control, but achieving this goal is often complicated by patients who come in with medication overuse headache. These patients require addressing the medication

396

Freitag

Table 1 Results of Survey of Physicians Interested in Inpatient Treatment of Headache and Available Admission Criteria from Insurance Companies Number of physicians (total N 21), % 3, 14.2 5, 23.8 5, 23.8 1, 4.7 1, 4.7 8, 38.0 2, 9.4 2, 9.4 1, 4.7 1, 4.7 12, 57.0 7, 33.3 0, 0.0 1, 4.7 4, 18.8 6, 28.5 8, 38.0 4, 19.0 3, 14.1 1, 4.7 1, 4.7 1, 4.7 5, 23.5 2, 9.4 Number of insurance companies (total N 7), % 1, 14.3 5, 71.5 5, 71.5 0, 0.0 1, 14.3 3, 42.9 0, 0.0 0, 0.0 0, 0.0 0, 0.0 4, 57.2 0, 0.0 6, 85.8 0, 0.0 0, 0.0 0, 0.0 3, 42.9 1, 14.3 0, 0.0 1 (with loss of consciousness), 14.3 0, 0.0 0, 0.0 0, 0.0 0, 0.0

Reason for admission Change in headache pattern Organic disease Clinically signicant nausea and vomiting Frequent parenteral medications Complicated migraine Status migraine Patients at risk from triptan use or other observation needed Failed acute therapy Failed outpatient dihydroergotamine-45 Severe drug allergies Medication overuse headache/drug dependency Failed prophylaxis Failed outpatient treatment Copharmacy management issues Prolonged pain state Chronic daily headache Comorbid medical and/or psychiatric disease Disability Intractable cluster headaches Trauma related acute or chronic Distance Comprehensive treatment program Refer for admit elsewhere No interest or no guidelines

overuse component as a rst step in bringing pain control to the patient. Medication overuse includes not only analgesics but also migraine-specic therapy such as the triptans. Differing therapeutic approaches may be needed to address the control of patients pain based on the withdrawal of the offending acute agent.

Other Reasons for Inpatient Treatment Risk of Serotoninergic Syndrome Rapid transitions in medical therapies control the patients headaches in a timely fashion. This would not normally require close monitoring. However, the use of a combination of different serotonergic agents, from different families [triptans, selective serotonin reuptake inhibitors (SSRIs), etc.] in high doses, may increase the potential for the development of serotonin syndrome. This is especially the case in the patient who needs to undergo a rapid transition between SSRI antidepressants and monoamine oxidase inhibitors (MAOI). Product labeling species that in almost all of these cases, a drug-free interval of 10 to 14 days is required before starting the new agent. This is not a practical solution for patients with disabling headaches,

Inpatient Management and Invasive Treatment Strategies Table 2 Admission Criteria of Michigan Headache and Neurological Institute for Inpatient Headache Treatment Program at Chelsea Hospital

397

Presence of moderate-to-severe intractable headache that fails to respond to appropriate and aggressive outpatient or emergency department measures and requires repetitive sustained parenteral treatment (e.g., dihydroergotamine) Presence of continuing nausea, vomiting, or diarrhea Need to detoxify and treat toxicity, dependency, or rebound phenomena and/or monitor protectively against withdrawal symptoms, including seizures, in cases in which this cannot be achieved effectively or safely on an outpatient basis Presence of dehydration, electrolyte imbalance, and prostration that requires monitoring and intravenous uids Presence of unstable vital signs Presence of repeated previous emergency department treatments Likely presence of serious disease (e.g., subarachnoid hemorrhage, intracranial infection, cerebral ischemia, severe hypertension) Need to rapidly develop both immediate pain reduction and an effective pharmacologic prophylaxis in order to sustain improvement achieved by parenteral therapy (aggressive daily drug manipulation, requiring careful monitoring and drug level evaluation) Need to urgently address other comorbid conditions contributing to or accompanying the headache, including medical and/or psychological illness Presence of concurrent medical and/or psychological illnesses requiring careful monitoring in high-risk situations
Source: From Ref. 32.

and a more rapid transition with a shorter transition period may be used. Close observation of the patient for warning signs of a serotonin syndrome with elevated temperature, agitation, and other serotonergic indications is required. Untreated, a potentially morbid situation could occur.
Table 3 Admission Criteria of the National Headache Foundation for Treatment of Headache Severe dehydration for which inpatient parenteral therapy may be necessary Diagnostic suspicion (conrmed by appropriate diagnostic testing) of organic etiology such as an infectious disorder involving the central nervous system (e.g., brain abscess, meningitis), acute vascular compromise (e.g., aneurysm, subarachnoid hemorrhage), structural disorder with accompanying symptoms (e.g., brain tumor) Prolonged unrelenting headache with associated symptoms such as nausea and vomiting which, if allowed to continue, would pose a further threat to the patients welfare Status migraine or dependence on analgesics, ergots, opiates, barbiturates, or tranquilizers Pain that is accompanied by serious adverse reactions or complications from therapy continued use of such therapy aggravates or induces further illness Pain that occurs in the presence of signicant medical disease, but appropriate treatment of headache symptoms aggravates or induces further illness Failed outpatient detoxication for which inpatient pain and psychiatric management may be necessary Intractable and chronic cluster headache for which inpatient administration of histamine or dihydroergotamine may be necessary Treatment requiring copharmacy with drugs that may cause a drug interaction, thus necessitating careful observation (e.g., monoamine oxidase inhibitors and beta-blockers)
Source: From Ref. 33.

398 Table 4 Typical Treatment Modalities in a Multidisciplinary Inpatient Headache Treatment Program Detoxication Pharmacologic therapy Nursing intervention Physical therapy Dietary management and education Stress management Exercise programs Biofeedback and relaxation therapy Cognitive-behavioral treatment Group psychotherapy Individual and family psychotherapy Family groups Interactions between patients Lifestyle management Discharge planning

Freitag

Cyproheptadine may be given preventatively to reduce the risk and is one of the treatments of choice should a serotonergic syndrome manifest. Cyproheptadine is given as a preventative for serotonin syndrome during rapid transitions between SSRI and other novel newer antidepressants and MAOI. Patients are started on 4 mg of cyproheptadine four times a day, and their current antidepressant treatment is discontinued. The patient is maintained on the cyproheptadine while other appropriate treatments for the headache disorder are initiated other than the new antidepressant class. Five days after the patient has been off the MAOI or SSRI and while still taking the cyproheptadine, the patient will be started on the new agent in the alternative class. After three to ve days on the new agent, if the patient is tolerating it well, cyproheptadine is discontinued over the course of the next 4 to 10 days while monitoring the patient for symptoms of a serotonin syndrome. The patient undergoes the latter stage almost invariably as an outpatient, but the rst several days of the initiation of the new antidepressant medication class agent, the patient will be under close observation as an inpatient. Need of Politherapy In patients with difcult-to-treat headache, monotherapy may not have provided adequate preventative effects in the past. Complicated regimens may be needed to produce an effective therapeutic response. These more complex regimens may also be necessitated by the coexisting and comorbid medical and psychiatric illnesses of
Table 5 Outpatient vs. Inpatient Treatment Factors Degree and intractability of pain Refractoriness to established regimens Need for supportive medical measures Degree of toxicity and drug dependence Psychological health considerations Comorbid medical disease considerations Need for close patient monitoring

Inpatient Management and Invasive Treatment Strategies

399

many of these patients. This, however, can increase the likelihood of adverse effects and drug interactions. Initial observation and management within the hospital environment facilitate prompt treatment of complications that may result from copharmacy. Close monitoring of the clinical response and tolerability of the treatment are necessary to optimize the outcome without substantially compromising the patients functional abilities during the initiation of therapy. Presence of Symptomatic Comorbid Diseases Chronic headache may be exacerbated by psychological problems. Long-term followup research has found that patients with multiple psychiatric diagnoses have a poorer long-term prognosis than patients with little or no psychiatric disturbance (3537). Accurate diagnosis by qualied psychologists and psychiatrists and appropriate treatment are essential if development of a long-term treatment program is indicated. Psychological intervention may be undertaken in the hospital. Group therapy sessions and individual counseling is initiated during the hospitalization. Continuation of this treatment after hospitalization is often necessary. After an initial assessment and basic psychological intervention, long-term treatment is imperative to establish a pain management program to help these patients deal with the psychological aspects of their condition. Biofeedback has demonstrated efcacy in the treatment of migraine in combination with these other psychological therapies. The Inpatient Treatment of Medication Overuse The outpatient treatment of medication overuse headache is beyond the scope of this chapter. Treatment of medication overuse headache is crucial, because preventive therapy often does not work to control the underlying chronic headaches that contributed to the development of the overuse situation. It may take as long as 12 weeks to reverse the effects of medication overuse (38). Failure to achieve successful detoxication of the patient with medication overuse as an outpatient occurs due to the increased pain during the initial period of withdrawal, unmasking of the underlying headaches, and acute withdrawal symptoms typically associated with butalbital and opioid use. The use of clonidine for opiate withdrawal (39) may be of benet in the outpatient arena especially, but may be needed in those with signicant toxicity from these agents in the inpatient setting as well. While there are no dened criteria for establishing when a patient will have toxicity from opioids, it has been my personal experience that it would be unusual at dose equivalents to 200 mg of meperidine parenteral per day. Clonidine is given either orally once or twice a day or as a long-acting patch that may be used in place of the tablets. The dose is based on the weight and sex of the patient, with doses from 0.1 to 0.3 mg/day in divided doses. During this initial phase of treatment, concomitant use of tricyclic antidepressants is withheld to avoid blocking of the alpha-adrenergic effects of the clonidine to suppress the withdrawal symptoms. Phenobarbital can be used for the withdrawal of short-acting barbiturates (40). Our protocol is based on the amount of butalbital-containing medication the patient is taking. The patient who has been using only several tablets per day of these agents is most unlikely to require a phenobarbital taper in my experience. As the amounts the patient uses increase or if the patient has used small amounts of this type of medication but for periods in excess of a year, then the likelihood of withdrawal phenomenon begins to increase substantially. This may be veried in

400

Freitag

many episodes of case-history taking with the patient, where they relate withdrawal symptoms occurring when they missed doses of their pain medication for more than a day or two. We will administer a dose of 100 mg of phenobarbital when it has been at least six hours but not more than 24 hours from their last dose of butalbital-containing medication. The patient is reevaluated in one hour, and if the patient is awake and alert then they will be started on phenobarbital 60 mg three times a day. If, however, the patient is lethargic or asleep, then an initial phenobarbital treatment would not be started. Patients who subsequently show signs of agitation or tremor while on phenobarbital or those who have not been treated will have 30 mg/day of phenobarbital added to their regimen. Dosing adjustments may be made for excessive sedation, but, in general, are continued with a gradual taper over up to three months. The primary benet of this adjunct beyond minimizing the acute withdrawal symptoms is the prevention of butalbital withdrawal seizures. In the inpatient unit, abrupt withdrawal or rapid tapering of the offending analgesic is used in most patients, because prolonging the withdrawal period only delays the time until the effectiveness of the preventative therapies can be achieved. Withdrawal of triptans and ergotamine compounds necessitates the use of analgesics to control the headache pain during this phase. The intravenous use of diverse agents including antidopaminergic, muscle relaxants, nonopioid analgesics, propofol (41,42), and valproic acid may be required to provide interim control of headaches while initiating treatment with preventive medications. There are several situations in which intravenous administration of dihydroergotamine (DHE) may be appropriate in patients with severe headache in a headache unit. In patients with medication overuse headache, the administration of a course of IV DHE over two or three days may provide adequate control of the underlying migraine, minimizing the need for additional adjunctive approaches to pain management. Another scenario in which parenteral administration of DHE over several days is useful may be as an adjunctive in terminating the chronic phase of migraine. Its use, coupled with appropriate preventative medications, often may produce substantial resolution of the daily headache to allow the patient to regain functional ability related to their headaches in the matter of days versus weeks or months. Repetitive intravenous DHE used for more than two days has been recognized by the American Academy of Neurology in their practice parameter as an indication for inpatient headache monitoring (43). The basic protocol rst proposed by Raskin (44) has undergone modication to suit specic treatment needs of patients and improve the tolerability of the treatment. Among the variations on this basic protocol (Table 6) are dose reductions in patients with response to the initial test dose as well in those with adverse events. Diluting the DHE in normal saline and giving it over 15 to 30 minutes also improves the adverse events associated with the treatment. A variety of antinauseant agents have also been adapted for this treatment in those, where nausea and vomiting constitute signicant components of the migraine attack or in those with adverse effects to the treatment. Corticosteroids in the Inpatient Treatment of Migraine and Chronic Daily Headaches There are several reports that have suggested the usefulness of corticosteroids in the treatment of refractive migraine. Lobo et al. noticed that corticosteroids can

Inpatient Management and Invasive Treatment Strategies Table 6 Inpatient Treatment Unit Protocol for IV DHE

401

Establish IV access Premedicate with antinausent (e.g., trimethobenzamide 200 mg IM or trimethobenzamide 250 mg PO; metoclopramide 10 mg IM or PO; promethazine 50 mg IM or PO; ondansetron 4 mg IV or PO) 30 min after premedicating: administer 0.5 mg DHE by slow IV push Vital signs should be monitored and adverse effects assessed prior to dose and for 30 min postdose Subsequent doses should be given every eight hours for a total of nine doses If headache responds to 0.5 mg DHE continue this dose If headache continues with 0.5 mg DHE then increase doses 29 to DHE 1 mg If patient has adverse events with IV slow push administration of DHE then dilute additional doses in 50 mL normal saline and administer over 30 min If patient has nausea with administration of DHE after dilution then change to alternative antinauseant or reduce dose of DHE for subsequent doses by 50% Adverse effects may be reduced by dilution of DHE in 50 cc normal saline and administering as IV drip over 30 min
Abbreviation: DHE, dihydroergotamine.

be used as rescue therapy in patients who have failed to achieve adequate relief of their acute migraine attacks with specic agents such as triptans and DHE (45). Rozen (46) suggests the same approach but also points out that it can be used as a treatment for status migraine, that is, migraine that has persisted for more than 72 hours. This is one of the rst steps in the treatment of difcult migraine headache before a patient is considered for an inpatient hospital treatment in the absence of other treatment issues. Another potential use of corticosteroids is for the patient with medication overuse headache. Here, much like in the situation that occurs with the use of DHE for patients with medication overuse headache, upon withdrawal of the overused medication not only do subjects have the headache occurring from the overused drug but they also have the underlying chronic migraine headache present, which is what set the stage for the patient to enter into the scenario of overusing acute medication in the rst place. Therefore a course of corticosteroids as part of a comprehensive treatment program should be considered (47). Because there are no dened trials of these agents, the choice of agents is of personal preference and familiarity than scientic foundation. My personal preferences include the use of oral dexamethasone or methylprednisolone in migraine and prednisone in patients with cluster headache. If a parenteral formulation is needed then either a depot form of intramuscular or the intravenous formulation of methylprednisolone is used.

Outcome MeasuresAssessing the Benets of Inpatient Treatment There is no class I evidence for inpatient treatment outcomes (31). Numerous outcome studies have been published in article and abstract form (4867). Of the 14 published peer-reviewed papers describing the outcome of inpatient treatment for chronic daily headache, seven papers (totaling 561 patients) gave sufcient information to be included in the analysis of short-term outcomes. These seven papers were

402

Freitag

used to construct a meta-analysis by Lake and coworkers (31). The proportion of patients with 50% improvement was 81% with short-term follow-up and 62.5% with long-term follow-up. The remaining reports cited involved peer-reviewed abstracts only and while presenting similar ndings did not provide sufcient information to include in a meta-analysis. Several reports have provided additional outcome information reecting on treatment issues in this patient population. An abstract by Diamond et al. (61) assessed health-care utilization in 66 patients and found that, by comparing the one-year period following the discharge with the year prior to admission, there was a marked reduction in emergency room visits (from 0.3 to 0.1 per month), a reduction in hospital admissions (from 39 to 10 per year), and reduced use of analgesic and other abortive medications. Lake et al. assessed changes in headache activity as well other relevant measures (68). Mean number of dysfunctional days in a twoweek period (where the patient was disabled from normal function due to head-pain) declined from 6.30 prior to hospitalization to 2.38 at the two-week follow-up, and 1.94 at eight months. Clinically signicant depression on the Beck Depression Inventory dropped from 46% at admission to 6% at two-week follow-up and remained low (14%) at eight months. Thirty-one percent of these patients were on medical leave due to headache at the time of admission. At eight months, only 4% remained on medical leave. The number of patients with reduced work status resulting from headache dropped from 51% at admission to 22% at follow-up. The number of patients engaged in full- or part-time employment rose from 31% on admission to 53% after eight months (65) (Table 7). There have only been three papers that have attempted to assess outcomes for patients in a comparative fashion between outpatient treatment and inpatient treatment. Casaly and coworkers in an abstract (66) reported similar reduction in outcomes in patients, using a headache disability questionnaire. However, the inpatient and outpatient groups were not comparable with twice as many inpatients as outpatients having analgesic abuse and a substantial difference in the occurrence of daily versus episodic headache. Suhr et al. compared drug withdrawal for analgesic and abortive medications for inpatient and outpatient headache (69). Long-term follow-up (average of six years following treatment) was conducted only in the subset of patients who had resolution of their daily headache following withdrawal. For both groups, this was approximately one-third of the original group. Both groups had similar improvement in their headaches, though 25% of the inpatients and 15% of the outpatients contacted had relapsed to daily acute medications. A shorter study with differing results was done by Pini et al. (70) in Italy. Here, both treatments show signicant headache improvement but there was a higher rate of relapse in those treated on an outpatient basis. Assessing outcomes across these various studies is further complicated by the changing health-care environment for inpatient treatment and even for patient referral to headache centers. Saper and Lake (65,68), comparing outcome data from the early to the late 1990s, found similar efcacy outcome and hospital lengths of stay, but found that frequency of severe headaches had increased from a mean of 3.13 per week to 4.91 per week in the patients prior to treatment. They also found a 50% increase in the number of patients coming from outside their immediate geographic region. Similarly, Weeks noted increasing comorbid psychiatric conditions, complicated medical histories, and greater detoxication challenges along with more complex treatment strategies, comparing patients from the early and late 1990s (31).

Table 7 Outcomes of Inpatient Headache Treatment Lost days 39 20 19 Retrospective Retrospective Prospective 12 mo 36 mo 16 mo N Method Follow-up interval Pct. with headache improvement >50% 50% 81% improved 71% with sustained benets

Outcome study

Treatment program

Tfelt-Hansen and Krabbe (48) Ala-Hurula et al. (49) Raskin (45)

Diamond et al. (59) 14 14 7.4 8.5 Prospective Retrospective Retrospective Prospective 16.8 mo 35 mo Discharge

Pharmacological only 9 Pharmacological only 4.4 Pharmacological only (repetitive DHEmetoclopramide vs. diazepam) Multidisciplinary Retrospective 6.8 mo 57 66 38

Baumgartner et al. (50)

Multidisciplinary

Diener et al. (51) Silberstein et al. (52)

Pharmacological only Multidisciplinary

Inpatient Management and Invasive Treatment Strategies

Lake et al. (68)

Multidisciplinary

103 42 214 100

Silberstein and Silberstein (53)

Multidisciplinary

7.3

50

Retrospective

2 wk 8.3 mo 8.3 mo 3 mo 6 mo 12 mo 24 mo 48 Prospective Discharge 3 wk

Schnider et al. (54)

Pharmacological only

1011

50% (freq) 60% (freq duration) 61% (dened as signicant relief) 67% 86% 92% 67% 68% 87% 72% follow-up 72% limited to pts 83% who were 87% HA-free at discharge 51% 62% (Continued)

403

404

Table 7 Lost days 14 75 Retrospective Discharge 38 Retrospective 5 yr N Method Follow-up interval

Outcomes of Inpatient Headache Treatment (Continued ) Pct. with headache improvement >50% 50% (<8 days/mo) 47% (only mild HA)

Outcome study

Treatment program

Schnider et al. (55)

Multidisciplinary

Ford and Ford (56)

Comparison of two forms of 4 DHE-45: repetitive vs. continuous 2 6 96 32 32 Prospective Prospective 3 mo 3 mo 12 mo

Pringsheim and Howse (57) Monzon and Lainez (59)

Pharmacological only Pharmacological only

82% 57%

Abbreviation: DHE, dihydroergotamine. Source: From Ref. 31.

Freitag

Inpatient Management and Invasive Treatment Strategies

405

INVASIVE TREATMENT OF MIGRAINE AND CHRONIC DAILY HEADACHES Therapeutic Blocks and Radiofrequency Stimulation In a recidivist population of patients, other adjunctive approaches to pain management may be needed. Long-standing effects of trauma to the cervical spine can produce changes in mechanical contributions to headache. Input from upper cervical segments may act directly on trigeminal centers impacting the migraine headache situation as well as serving as a focal source of pain. A study of eight patients with chronic migraine who had a positive response to implanted suboccipital stimulators was recently conducted (71). Positron emission tomography scans were performed using regional cerebral blood ow (rCBF) as a marker of neuronal activity. There were signicant changes in rCBF in the dorsal rostral pons. The activation pattern was highly suggestive of a role for this structure in chronic migraine. The localization and persistence of activity during stimulation were consistent with that seen in episodic migraine, and with a similar treatment response as seen in migraine. Assessment of this contribution can include the use of diagnostic/therapeutic blocks of the greater occipital nerve (72) as well as the facet joints of the upper cervical spine or epidural steroid injections. The therapeutic value of greater occipital and supraorbital nerve blockade was studied in 27 patients with migraine. Patients received repetitive blocks. Outcome was determined by a pain index, the number of migraine attacks, and analgesic consumption. Twenty-three patients (85%) responded and maintained a favorable response for as long as six months. Anthony (73), however, has suggested that patients diagnosed with migraine and responding to occipital nerve block and or division of the greater occipital nerve instead had greater occipital neuralgia. Successful outcomes with these procedures may lead to the use of radiofrequency procedures to produce longer treatment effects. Local trigger point injections in painful cervical and scalp muscles can help to address these mechanisms in headache. Botulinum Toxin Although its mechanism of action is still to be determined, the use of botulinum toxin type A injections may not only produce effects on the muscular components contributing to chronic headache but also alter underlying trigeminal nerve contributions to the chronic migraine state. Binder (74) rst reported his results with botulinum toxin type A in an uncontrolled study. Subsequently there have been a number of studies conducted with this agent. The largest of the placebo-controlled trials in migraine was a study on 122 patients (75). Patients were randomized to receive placebo injection, 25 units of botulinum toxin type A, or 75 units of the toxin. Although baseline headache frequency was unequally distributed between the three groups, the difference was not statistically signicant. The 25-unit but not the 75-unit treatment group had statistically signicant improvement compared to the placebo. The authors attribute the relative lack of response by the 75-unit treatment group to the reduced baseline numbers of headaches in this group. The efcacy of botulinum toxin type A in the treatment of chronic daily headache was rst studied in a double-blind trial of 56 patients (76). The results of this trial suggested possible efcacy with improvements in headache duration and frequency. Two recent studies have added (77,78) support to the potential applicability of botulinum toxin type A in the population of patients with migraine headache and

406

Freitag

daily or near daily headache. These studies have veried much of what has been the clinical impression with the use of botulinum toxin type A. The use of 100 to 200 units of botulinum toxin type A, given as multiple injections in the face, head, and neck, with repetitive injections every three months appeared to produce the greatest efcacy. Many variables may play a role in determining outcome including the concomitant use of preventive medications and acute medication overuse. Despite these uncertainties that still exist, the progress that has occurred and the clinical experience that has been gained allow us to utilize this agent with safety and efcacy in many of our most challenging patients with highly favorable results. There are several approaches to administering botulinum toxin type A, regarding the selection of injection sites. One has been termed a xed site approach. The other is termed a follow the pain approach. With a xed site approach, all patients receive botulinum toxin in the same locations in the head and neck region, regardless of the location of their pain or its relative intensity. In the follow the pain approach, the administration, the amount used, the number of injections, and their locations is based on the location of the patients pain and even its relative intensity in one location versus another. A number of sites have been chosen as demonstrated in Figures 13, which are designed to target the muscles in the distribution of the rst branch of the trigeminal nerve, covering the region above and between the eyebrows and extending to the hairline and also including the temporalis muscles. Masseter injections are occasionally included for those patients who have signicant bruxism. In the posterior regions of the scalp and neck, again the muscle innervated primarily by branches of the rst three cervical rami is injected; so this commonly includes the occipitalis, semispinalis, and splenius capitus muscles; in some patients, portions of the trapezius muscle may be injected as may the sternocleidomastoid muscle unilaterally, if the patient has spasticity. While relief of muscle spasticity may be important in the mechanism of botulinum toxin type A, there may also be effects modulated directly via the afferent nerves, so neuronal distribution may be of importance as well. The potential overlap between the upper cervical segments and the trigeminal nucleus caudalis may explain the need to treat this region in patients with chronic daily headache, even if the pain is not appreciated in the cervical region.

Figure 1 Possible posterior locations for injection of botulinum toxin type A. Source: Courtesy of Drs. Joseph Tsui, Ian Finkelstein, Sylvain Chouinard, and Anna McCormick.

Inpatient Management and Invasive Treatment Strategies

407

Figure 2 Possible anterior cervical and facial location for injection of botulinum toxin type A. Source: Courtesy of Drs. Joseph Tsui, Ian Finkelstein, Sylvain Chouinard, and Anna McCormick.

Typically I will use 100 units of botulinum toxin type A, but may occasionally use lesser amounts in patients with an extremely tight scalp aponeurosis. Larger quantities may also be used in patients based on their response to treatment at 100 units. Dilutions of 2 cc to 4 cc in normal saline and injection with a ne scale subcutaneous needle is my preference. Electromyogram needle placement is not needed in this type of treatment for chronic headache. Injections in the face should be kept within the midpupillary lines and directed superiorly. Multiple injections of small quantities should be used preferentially to a single injection of a large quantity in areas of the face. These techniques will reduce the likelihood of eyelid ptosis. The application of ice packs and the use of a nonsteroidal anti-inammatory agent for a day may reduce the discomfort associated with the injections. While not recommended on the package label, the use of preservative-containing normal saline solution also reduces discomfort, acting as a mild local anesthetic agent. Whereas some patients demonstrate an improving duration of response with repeated injections of botulinum toxin type A, most patients require reinjection on a schedule on average

Figure 3 Lateral cervical and lower facial areas for possible injection of botulinum toxin type A. Source: Courtesy of Drs. Joseph Tsui, Ian Finkelstein, Sylvain Chouinard, and Anna McCormick.

408

Freitag

of every 12 weeks. The onset of activity takes several days to occur and develops progressively. The loss of effect as the toxins action is physiologically reversed, may be abrupt, and may dissipate from maximal effect to loss of effect in less than a week in some patients. These treatment characteristics make establishment of scheduled treatments important in minimizing loss of effect. The use of botulinum toxin type A to identify trigger sites for migraine has been suggested (79). Those responding to the injections underwent surgical procedures involving the nasal septum and turbinate or forehead surgery. Substantial improvement occurred on a wide variety of parameters in follow-up over a year. Adverse events while not uncommon were not severe. Another study used corrugator muscle resection (80), based on the previous study. These authors found that those with less-frequent migraine were more likely to have a favorable outcome. Recurrence of headache in the rst month occurred in one of six patients. Another approach that has been suggested as being efcacious in treatment resistant migraine involves those with small nasal passages may beneting from reconstructive surgery according to Novak (81). Implanted Devices Recently, there has been limited use of implanted devices for pain management. The use of occipital stimulators may be appropriate in those who respond to local block procedures of the greater occipital nerve or trigger point injections in this region. We have patients with repeated successful blocks and or radiofrequency rhizotomy, before progressing to a temporary occipital stimulator implant. Those who nd this device producing acceptable results and comfort have a permanent stimulator implanted. A study by Popeney and Alo (82) examined the effect of occipital stimulation in a population of patients diagnosed with transformed migraine. The 25 patients were followed for an average of approximately 18 months, with the vast majority having at least a 50% reduction in their pain. Vagal nerve stimulation (83,84) has been used in a limited fashion for intractable headache following its successful use in refractive epilepsy. This parasympathetic nerve inputs via the solitary tract nucleus and hence to other brain stem nuclei that act upon trigeminal vascular responses. CONCLUSION Inpatient hospital treatment of headache continues to be an important component of the practice of specialty headache management. There are challenging patients who have refractive headache problems in the traditional outpatient milieu who are candidates for comprehensive inpatient headache treatment programs. Many of the individual components of inpatient treatment utilized in these specialty centers, however, have applicability in the treatment of less-challenging patients in the community level amongst physicians familiar with headache management. While controlled trials do not exist, the evidence strongly suggests and the clinical experience of specialty headache management continues to demonstrate specic rationales for this approach. These groups of patients whose headache histories, treatment histories, coexisting disease processes, and disease impact on quality of life and work productivity have been shown to achieve the greatest levels of improvement in disability and expensive health-care utilization. Appropriateness for inpatient treatment is dictated by the intensity of the treatments being rendered, the routes of administration complexity of regimens, safety issues related to drug therapies, and coexisting illness.

Inpatient Management and Invasive Treatment Strategies

409

Comprehensive multidisciplinary management is also needed by patients with longterm refractive disorders for headache, and selected centers exist for these situations. Alternative approaches to management of refractive headache continue to be explored. These approaches involve the use of injections of a variety of agents from corticosteroids to botulinum toxin type A as alternative approaches for the management of challenging headaches. Trigger point injections, facet blocks, and other invasive procedure may even lead to the use of implantation of device to block pain or alter its regulation centrally. Surgical approaches have again come to the fore as possible therapeutic approach in migraine. The long-term success and implications of surgical approaches and these other interventions have yet to stand the tests of time of many of the traditional medical approaches.

REFERENCES
1. Saper JR. Perspectives from a headache center with an inpatient unit. In: Adler C, Adler SM, Packard RC, eds. Psychiatric Aspects of Headache. Baltimore: Williams and Wilkins, 1987:340384. 2. Fordyce WE, Fowler RS Jr, Lehmann JF, et al. Operant conditioning in the treatment of chronic pain. Arch Phys Med Rehabil 1973; 54:399. 3. Fordyce WE. Behavior Methods for Chronic Pain and Illness. St Louis: CV Mosby, 1976. 4. Williams ACdeC, Richardson PH, Nicholas MK, et al. Inpatient versus outpatient pain management: results of a randomized controlled trial. Pain 1996; 66:1322. 5. Clouse JC, Osterhaus JT. Healthcare resource use and costs associated with migraine in a managed healthcare setting. Pharmacoeconomics 1994; 28:659664. 6. Fishman P, Von Korff M, Lozano P, et al. Chronic care costs in managed care. Health Affairs 1997:239247. 7. Cady R, Schreiber C. Pharmacoeconomics implication of migraine and migraine therapies. Pharmacoeconomics 2001; 19:231244. 8. Raak R, Raak A. Work attendance despite headache and its economic impact: a comparison between two workplaces. Headache 2003; 43:10971101. 9. Essink-bot ML, Van Roen L, Krabbe P, Bonsel GJ, Rutten FFH. The impact of migraine on health status. Headache 1995; 35:200206. 10. Elston Lafata J, Moon C, Leotta C, Kolodner K, Poisson L, Lipton RB. The medical care utilization and costs associated with migraine headache. J Gen Intern Med 2004; 10:10051012. 11. Mathew NT. Transformed migraine. Cephalalgia 1993; 13(suppl 12):7883. 12. Silberstein SD, Lipton RB, Sliwinski M. Classication of daily and near daily headaches: eld trial of revised IHS criteria. Neurology 1996; 47:871875. 13. Mathew NT. Chronic daily headache: clinical features and natural history. In: Nappi G, ed. Headache and Depression: Serotonin Pathways as a Common Clue. New York: Raven Press, 1991. 14. Koenig MA, Gladstein J, McCarter RJ, Hershey AD, Wasiewski W. Chronic daily headache in children and adolescents presenting to tertiary headache clinics. Headache 2002; 42:491500. 15. Sandrini G, Manzoni GC, Zanferrari C, Nappi G. An epidemiological approach to the nosology of chronic daily headache. Cephalalgia 1993; 13(suppl 12):7277. 16. Sanin LC, Mathew NT, Bellmeyer LR, Ali S. The International Headache Society (IHS) headache classication as applied to a headache clinic population. Cephalalgia 1994; 14:443446. 17. Rothrock J, Patel M, Lyden P, Jackson C. Demographic and clinical characteristics of patients with episodic migraine versus chronic daily headache. Cephalalgia 1996; 16:4449.

410

Freitag

18. Mathew NT, Reuveni U, Perez F. Transformed or evolutive migraine. Headache 1987; 27: 102106. 19. Silberstein SD. Tension type and chronic daily headache. Neurology 1993; 43:16441649. 20. Mathew NT, Stubits E, Nigam MP. Transformation of episodic migraine into daily headache: analysis of factors. Headache 1982; 22:6668. 21. Zwart JA, Dyb G, Hagen K, Odegard KJ, Dahl AA, Bovim G, Stovner LJ. Depression and anxiety disorders associated with headache frequency. The Nord Trondelag Health Study. Eur J Neurol 2003; 10(2):147152. 22. Lipton RB, Silberstein SD, Stewart WF. An update on the epidemiology of migraine. Headache 1994; 34:319328. 23. Kessler RC, Frank RG. The impact of psychiatric disorders on work loss days. Psychol Med 1997; 27:861873. 24. Villareal SS. A comparative study of selected patient variable risk factors in hospitalization for chronic headache. Headache 1995; 35:349354. 25. Schwerzmann M, Wiher S, Nedeltchev K, et al. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology 2004; 62(8):13991401. 26. Yankovsky AE, Kuritzky A. Transformation into daily migraine with aura following transcutaneous atrial septal defect closure. Headache 2003; 43(5):496498. 27. Rome HP, Rome JD. Limbically augmented pain syndrome (LAPS): kindling, corticolimbic sensitization, and the convergence of affective and sensory symptoms in chronic pain disorders. Pain Med 2000; 1:723. 28. Von Korff M, Ormel J, Keefe FJ, Dworkin SF. Grading the severity of chronic pain. Pain 1992; 50:133149. 29. Von Korff M, Stewart WF, Simon DJ, Lipton RB. Migraine and reduced work performance: a population based diary study. Neurology 1998; 50:17411745. 30. Rapoport A, Stang P, Gutterman DL, et al. Analgesic rebound headache in clinical practice: data from a physician survey. Headache 1996; 36:1419.29. 31. Freitag FG, Lake A, Lipton R, Cady R, on behalf of the US Headache Guidelines Consortium, Section on Inpatient Treatment Chairpersons: Seymour Diamond, MD; Stephen Silberstein, MD. Inpatient treatment of headache: an evidence-based assessment. Headache 2004; 44:119. 32. Saper JR, Silberstein S, Gordon CD, Hamel RL, Swidan S, Handbook of Headache Management. A Practical Guide to Diagnosis of Head, Neck and Facial Pain. 2nd ed. Philadelphia: Lippincott, Williams and Wilkins, 1999. 33. Freitag F, Cady R. The National Headache Foundation Standards of Care. 3rd. Chicago, Illinois: National Headache Foundation, 2004. 34. Freitag FG. Headache Clinics and Inpatient Treatment Units for Headache. In: Diamond S, Dalessio DJ, eds. The Practicing Physicians Approach to the Treatment of Headache. 6th ed. Baltimore: ML Diamond, G Solomon, Williams & Wilkins. 35. Guidetti V, Galli F, Fabrizi P, et al. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia 1998; 18:455462. 36. Page L, Howard L, Husain K, et al. Psychiatric morbidity and cognitive representations of illness in chronic daily headache. J Psychosom Res 2004; 57:549555. 37. Smith R. Impact of migraine on the family. Headache 1998; 38:423426. 38. Mathew NT, Kurman R, Perez F. Drug induced refractory headacheclinical features and management. Headache 1990; 30:634638. 39. Dalessio DJ. The clonidine protocol. Headache Q 1991; 2:133134. 40. Silberstein SD, McCrory DC. Butalbital in the treatment of headache: history, pharmacology and efcacy. Headache 2001; 41:953967. 41. Mendes PM, Silberstein SD, Young WB, Rozen TD, Paolone MF. Intravenous propofol in the treatment of refractory headache. Headache 2002; 42:638641. 42. Krusz JC, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable migraine. Headache 2000; 40:224230.

Inpatient Management and Invasive Treatment Strategies

411

43. American Academy of Neurology. Practice parameter: appropriate use of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainous [summary statement]. Report of the Quality Standard Subcommittee of the American Academy of Neurology. Neurology 1995; 45:585587. 44. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986; 36:995997. 45. Lobo BL, Cooke SC, Landy SH. Symptomatic pharmacotherapy of migraine. Clin Ther 1999; 21(7):11181130. 46. Rozen TD. Migraine headache: immunosuppressant therapy. Curr Treat Options Neurol 2002; 4(5):395401. 47. Diamond S, Freitag FG. Headache. Am Acad Family Physicians Monogr 1985; 69:154. 48. Tfelt-Hansen P, Krabbe AA. Ergotamine abuse. Do patients benet from withdrawal? Cephalalgia 1981; 1:2932. 49. Ala-Hurula V, Myllyla V, Hokkanen E. Ergotamine abuse: results of ergotamine discontinuation, with special reference to the plasma concentrations. Cephalalgia 1982; 2:189195. 50. Baumgartner C, Wessely P, Bingol C, Maly J, Holzner F. Long-term prognosis of analgesic withdrawal in-patients with drug induced headache. Headache 1989; 29:510514. 51. Diener HC, Dichgans J, Scholz E, Geiselhart S, Gerber WD, Bille A. Analgesic-induced chronic headache: long-term results of withdrawal therapy. J Neurol 1989; 236:914. 52. Silberstein SD, Schulman EA, Hopkins MF. Repetitive intravenous DHE in the treatment of refractory headaches. Headache 1990; 30:334339. 53. Silberstein SD, Silberstein JR. Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE. Headache 1993; 32:439445. 54. Schnider P, Maly J, Grunberger J, Aull S, Zeiler K, Wessely. Improvement of decreased critical icker frequency (CFF) in headache patients with drug abuse after successful withdrawal. Headache 1995; 35:269272. 55. Schnider P, Auall S, Baumgartner C, et al. Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: ve-year follow-up. Cephalalgia 1996; 16: 481485. 56. Ford RG, Ford KT. Continuous intravenous dihydroergotamine in the treatment of intractable headache. Headache 1997; 37:129136. 57. Pringsheim T, Howse D. In-patient treatment of chronic daily headache using dihydroergotamine: a long-term follow-up study. Can J Neurol Sci 1998; 25:146150. 58. Monzon MJ, Lainez JM. Chronic daily headache: long-term prognosis following inpatient treatment. Headache Q 1998; 9:326330. 59. Diamond S, Freitag FG, Maliszewski M, Prager J, Gandhi S. Treatment of headache in an inpatient headache unit: long-term results [abstract]. Cephalalgia 1985; 5(suppl 3): 440441. 60. Saper JR. Treatment of ergotamine dependency: techniques, outcome, and recidivism [abstract]. Headache 1987; 27:306. 61. Diamond S, Freitag FG, Solomon GD. Impact of in-patient headache treatment on subsequent medical care [abstract]. Headache 1988; 28:317. 62. Lake AE III, Saper JR. Prospective outcome evaluation of an accredited inpatient headache program [abstract]. Headache 1988; 28:315. 63. Wall DJ, Haugh MJ. Biofeedback as an adjunct to repetitive intravenous dihydroergotamine in the treatment of refractory headache [abstract]. Headache 1993; 33:285. 64. Weeks RE, Baskin SM, Rapoport AM, Sheftell FD. A prospective analysis of repetitive intravenous DHE in the treatment of refractory headache [abstract]. Headache 1993; 33:286. 65. Saper JR, Lake AE III, Madden S, Kreeger C. Comprehensive inpatient treatment for intractable head pain: patient factors associated with outcome [abstract]. Headache 1994; 34:514.

412

Freitag

66. Loughner BA, Dawson GA, Casaly JS. Inpatient treatment of chronic daily headache: outcome measures [abstract]. Headache 1995; 35:306. 67. Weeks RE, Baskin SM, Rapoport AM, Sheftell FD. Neurology 1995; 45(suppl 4):A379 [abstract]. 68. Lake AE III, Saper JR, Madden SF, Kreeger C. Comprehensive inpatient treatment for intractable migraine: a prospective long-term outcome study. Headache 1993; 33:5562. 69. Suhr B, Evers S, Bauer B, Gralow I, Grotemeyer KH, Hussted TIW. Drug-induced headache: long-term results of stationary versus ambulatory withdrawal therapy. Cephalalgia 1999; 19:4449. 70. Pini LA, Bigarelli M, Vitale G, Sternieri E. Headache associated with chronic use of analgesics: a therapeutic approach. Headache 1996; 36:433439. 71. Matharu MS, Bartsch T, Ward N, Frackowiak RS, Weiner R, Goadsby PJ. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 2004; 127(Pt 1):220230. 72. Caputi CA, Firetto V. Therapeutic blockade of greater occipital and supraorbital nerves in migraine patients. Headache 1997; 37:174179. 73. Anthony M. Headache and the greater occipital nerve. Clin Neurol Neurosurg 1992; 94:297301. 74. Binder WJ, Brin MF, Blitzer A, Schoenrock LD. Botulinum toxin type A (BOTOX ) for the treatment of migraine headaches: an open label study. Otolaryngol Head Neck Surg 2000; 123:669676. 75. Silberstein SD, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000; 40:445450. 76. Klapper JA, Mathew NT, Klapper A, Kailasam J. Botulinum toxin type A (BTX-A) for the prophylaxis of chronic daily headache. Cephalalgia 2000; 20:291292. 77. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX ) for the prophylactic treatment of chronic daily headache a randomized double-blind placebo-controlled trial. Headache 2005; 45:293307. 78. Dodick DW, Mauskop A, Elkind AH, DeGryse R, Brin MF, Silberstein SD. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebocontrolled study. Headache 2005; 45:315324. 79. Guyuron B, Kriegler JS, Davis J, Amini SB. Comprehensive surgical treatment of migraine headaches. Plast Reconstr Surg 2005; 115:19. 80. Dirnberger F, Becker K. Surgical treatment of migraine headaches by corrugator muscle resection. Plast Reconstr Surg 2004; 114:652657. 81. Novak VJ. Pathogenesis and surgical treatment of neurovascular primary headaches. Ital J Neurol Sci 1995; 16(8 suppl):4955. 82. Popeney CA, Alo KM. Peripheral neurostimulation for the treatment of chronic disabling transformed migraine. Headache 2003; 43:369375. 83. Mauskop A. Vagal nerve stimulation for refractory migraine. Neurology 2001; 56(suppl 3):65. 84. Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patients with intractable epilepsy. Cephalalgia 2002; 22:482484.

26
Migraine in the Emergency Department
Merle Diamond
Diamond Headache Clinic and Rosalyn Finch School of Medicine, Chicago, Illinois, U.S.A.

Benjamin W. Friedman
Department of Emergency Medicine, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, U.S.A.

INTRODUCTION Headache is a common emergency department (ED) complaint, representing around 2% of visits to American EDs (13). More than ve million ED patients report headache as one of three chief reasons for the ED visit (4). The vast majority of these headaches are primary headaches or headaches due to benign systemic illness such as upper respiratory infections and other febrile illnesses (5,6). The vast majority of primary headaches in the ED are migraines, with tension-type headaches comprising a small, but signicant minority (5,6). The goals for emergency physicians and neurologists consulting in EDs on headache patients are to facilitate the correct diagnosis, initiate migraine-abortive therapy when appropriate while controlling pain in the ED, and provide the patient with an appropriate discharge plan that includes a diagnosis, a disease-specic education sheet, prescriptions, referrals, and reasonable expectations. There have been few in-depth scientic assessments of the clinical features of migraine in the ED, so a thorough description of these patients is not possible. ED migraine patients probably represent a heterogeneous population including some patients with very signicant headache-related disability scores and some with minimal or no disease-related disability. It is not uncommon for migraineurs to come to an urban ED without having taken any medication at all for their headache (3,7). In urban EDs, a signicant percentage of migraineurs are probably uninsured or underinsured (3), in contrast to health maintenance organizations and rural community hospitals where patients are very likely to have insurance (8). It is often true that an ED migraine visit represents a failure of the health care system. If patients were adequately diagnosed and treated, the majority would not need to come to the ED. Two-thirds of female migraineurs and one-half of male migraineurs, who visited an ED at least once for migraines report that they have not used a prescription medication (9). In general, migraineurs do not use EDs for emergency carein an insured and
413

414

Diamond and Friedman

healthy population, migraineurs used the ED only slightly more often than nonmigraineurs (10). In a sample of the general population, only 20% of female migraineurs and 13% of male migraineurs reported a lifetime ED visit for headache (9). One of the most important questions is why headache patients come to the ED. One model describes two distinct groups: a rst or worst syndrome and a last straw syndrome (11). Patients with the rst or worst syndrome present with their rst severe headache or the worst headache of their lives. These patients require a diagnostic work-up in the ED. The last straw syndrome presents with an acute, unbearable exacerbation of a chronic intermittent headache. These patients require effective treatment and appropriate discharge planning. An important subpopulation of the last straw patients is the repeaters patients who make multiple ED visits within a short time period (12). Although comprising less than 15% of the headache population, these patients accounted for 43% to 50% of all ED visits or urgent clinic headache visits (3,8,12). A Canadian categorization reported that the repeaters were predominantly female and tended not to use multiple EDs (13). The repeaters represent a problematic population because multiple ED visits represent an expensive and ineffective route for the delivery of health care. Further, repeaters tend to rely on opiates for migraine relief and often request a particular medication and a particular dosage. In general, ED health care providers often view the repeater with irritation and suspicion because of concern about their motivation for being there. This creates frustration and ineffective disease management. At times, the emergency physicians frustration with the repeater is transferred to other migraineurs.

HOW TO APPROACH A PATIENT WITH ACUTE HEADACHE IN THE ED Of late, the need to exclude potentially lethal causes of headaches has been discussed (14). As the availability, speed, and sensitivity of modern computed tomography (CT) scanners for space-occupying lesions continues to increase, the reasons not to perform a CT, particularly in ED headache patients who have never had one, become less and less compelling. Experts recommend performing a lumbar puncture in all patients with a rst, worst, or changed headache (14). As yet, there is no way to exclude a subarachnoid bleed completely short of performing a lumbar puncture to evaluate for xanthrochromia. The patients history should guide the clinician, and testing to exclude other lethal causes of headache should be performed as needed, especially in immunocompromised or thrombophilic patients, or in those patients with fever and meningismus. Patients at extremes of age are at risk for specic organic causes of headache as well. The questions below can help the emergency physician screen for secondary causes of headache:      Do you have recurrent headaches like this? Is this your rst headache? Is this your worst headache? What evaluation have you had done in the past for these headaches? How often do you take medicine for your headaches?

It tends to be more apparent when an evaluation for secondary headache is needed than when it is not. Typical red ag features, which usually indicate the need for a diagnostic work-up, are listed in Table 1. Certainly, thunderclap

Migraine in the Emergency Department Table 1 Red Flags for Secondary Headaches in the ED Red ag Thunderclap headache Acute signs of increased intracranial pressure Fever Comment

415

Immunocompromised patient

Thrombophilic patient

Thrombocytopenic or anticoagulated patient Acute focal neurologic signs

Incidence of subarachnoid hemorrhage in this population 1020% (1517) Papilledema or loss of venous pulsations mandates a work-up Although intercurrent upper respiratory infections and other viral illnesses can exacerbate migraines, meningitis should be considered as an etiology of the fever Cryptococcal meningitis or sinusitis are not uncommon in patients with AIDS and can present subtly In gravid patients, the recently postpartum, and others with a history of hypercoaguable state, venous sinus thrombosis should be considered Intracranial bleeds should be considered Although migraine with aura causes focal neurologic signs, this should be a diagnosis of exclusion in an ED Classically, the indication to evaluate for subarachnoid hemorrhage. The actual test characteristics of these descriptions of headache are unknown Intracranial hemorrhage and concussion should be considered if clinically relevant These patients are at increased risk of temporal arteritis and cerebrovascular accidents Consider carbon monoxide poisoning during winter months

First, worst, or changed headache

Blunt trauma Elderly patient

Others in household with similar symptoms

Abbreviation: ED, emergency department.

headaches, i.e., headaches that reach a severe peak in intensity in less than one minute, suggest worrisome causes. Similarly, persistent focal neurologic decits, visual complaints in the elderly, and stigmata of elevated intracranial pressure should generate an ED work-up. After secondary causes of headache have been excluded, the diagnosis of migraine should be considered in any patient with painful or debilitating recurrent headaches. Although a complete headache history may be difcult to obtain in a bright and busy ED, an accurate diagnosis of migraine will allow the initiation of migraine-specic treatment in the ED and the creation of an appropriate discharge plan. A correct initial diagnosis will allow appropriate initial treatment. As we will discuss in the section on Treatment, the goal of therapy is to avoid nonspecic analgesia. An accurate diagnosis will allow the initiation of migraine-specic medication. This also allows the patient to undergo follow-up for a specic condition and form realistic expectations about the disease itself.

416

Diamond and Friedman

When diagnosing migraines, the emergency or consulting physician should consider tension-type headaches, which typically are not as severe or disabling as migraines. The prevalence of pure tension-type headaches in North American EDs has not been well documented, but European and South American EDs report that tension-type headaches represent 18% to 44% of all their primary headaches (5,6). Medication-rebound headaches, possibly represent a signicant percentage of emergency headaches, though this has not been well studied in the ED setting. Physicians should not exclude migraines as the diagnosis because of the presence of sinusitis or viremia, because either of these conditions could coexist with, be confused by, or exacerbate an acute migraine. Once a patient has already been diagnosed with an alternative type of headache, they are less likely to receive the diagnosis of migraine. The original diagnosis becomes the default diagnosis (i.e., chronic sinusitis) and the patient never receives migraine-appropriate medication (18). Similarly, the pain associated with a migraine headache could cause an elevation in blood pressure. A patients migraine should not be called a hypertensive headache, merely because the blood pressure is elevated. The epidemiology of hypertensive headaches in the ED has not yet been established. Whether and how often hypertension causes headache is uncertaineven more so at levels of hypertension that are considered moderate. We believe that known migraineurs who present with an acute migraine attack and associated moderate hypertension should be treated with a migraine-appropriate analgesic medication prior to an antihypertensive agent if there is no evidence of end-organ damage. Physicians should be careful not to cause an unnecessary precipitous drop in blood pressure. The dilemma for the emergency physician is whether or not to use a triptan medication or ergotamine, both contraindicated in hypertensive patients, when a patient comes in with a severe migraine headache and an associated rise in blood pressure. A reasonable approach would be the use of a dopamine receptor antagonist, or a parenteral nonsteroidal, until the head pain and blood pressure have been controlled and a more complete history taken. Chronic migraines and status migrainosus need to be diagnosed because they could dictate a different disposition for the patient. The patient in status migrainous needs admission and the patient with chronic migraines needs an expedited referral to a neurologist or headache specialist. Although 72 hours is used as the formal cut-off for status migrainosus, a patient with persistent pain after several hours of appropriate and aggressive ED treatment, for all intents and purposes, has status migrainosus and needs admission for further aggressive parenteral therapy. When determining appropriate and aggressive ED treatment, it does behoove the emergency physician to determine which medications the patient has already used unsuccessfully during the acute attack and which medications have been used previously with success. Routine neuroimaging and blood work are likely to be of no benet in a patient with a typical migraine attackdehydration and evidence of infection can usually be diagnosed based on history and physical exam. Pregnancy should be actively determined in migraine patients because teratogenicity and aborticant properties are a concern with certain migraine-abortive medications. Acetaminophen is safe for use in pregnancy and can be administered to a pregnant patient, especially if the patient has taken nothing for her headache. Metoclopramide has a favorable pregnancy rating and is commonly used in pregnant patients for hyperemesis gravidarum.

Migraine in the Emergency Department

417

TREATMENT Goals of Treatment As with outpatient headache medicine, the goals of therapy should be rapid alleviation of pain with a minimum of side effects and an eye toward preventing recurrence of headache.

General Approach In outpatient headache medicine, previous headache-related disability dictates the most appropriate class of medication for a patient, using the stratied care plan (19). The optimal treatment paradigm has not yet been reported for the ED however, a stepwise approach in which stronger medications are used successively will likely not be tolerated by a very uncomfortable ED patient. These patients likely need the best medication up front. As many as 55% of migraine patients do not take any medication prior to presentation to an urban ED (3,7). A stepwise treatment approach in these patients, using cheap oral nonsteroidals, might sometimes be acceptable in patients who have not yet taken any medication at all. More research is needed. For now, pain intensity and a patients ability to tolerate oral medication should dictate management. Initial emergency treatment should be based on medications that have worked well for the patient previously. The exception to this statement is patients who request their usual dose of opiate medicationmethods to address the concerns of these patients are discussed in the section on Opiates. Redosing the same class of medication already used by a patient at home is unlikely to provide relief to a patient.

General Interventions The role of routine intravenous (IV) uids in ED migraineurs is unknown. Although likely to be of benet, especially in patients with pronounced nausea and vomiting, it is not always needed. A clinical assessment of uid status should be performed in all migraineurs. Most patients in an ED should receive parenteral medications. This is important for several reasons. First, migraineurs in the middle of an acute attack suffer from gastroparesis. Thus, the bioavailability of oral medications is often limited. Second, migraineurs in an ED are often suffering severe attacksparenteral medications will usually relieve the migraine pain more rapidly. Third, many migraineurs are nauseated or vomiting and unable to tolerate oral medication. For these reasons, we will limit the discussion in the following section to parenteral medications.

Specic Classes of Medications Triptans Although well established in outpatient headache medicine, these medications are not commonly used in North American EDs (4,20). That they are of benet in ED migraineurs is not in doubta well-done multicenter ED trial has clearly shown the benet of subcutaneous sumatriptan versus placebo (Table 2) (21).

418 Table 2 Commonly Used Medications Medication Triptans Sumatriptan Dose 6 mg subcutaneous

Diamond and Friedman

Main utility in the ED Early arrivers, considered rst line prior to onset of allodynia Considered rst line

Cautions/ contraindications Hypertension and atherosclerotic vascular disease

Ergotamines DHE

0.51.0 mg IV/IM (with metoclopramide 10 mg)

Hypertension, renal or hepatic disease, atherosclerotic vascular disease, sepsis, pregnancy, and use of triptan

Phenothiazines/dopamine receptor antagonists Metoclopramide 1080 mg IV/IM Monitor for Commonly used akathisias, as rst line in drowsiness, and EDs, usually in hypotension combination with other products Effective for episodic Monitor for akathisias, tension-type drowsiness, and headaches and hypotension migraine Commonly used as Monitor for rst line in EDs akathisias, drowsiness, and hypotension Check EKG prior to Black box warning administration. should not preclude Monitor for use in intractable akathisias, headaches drowsiness, and hypotension Useful adjuvant therapy Caution in patients with peptic ulcer disease or renal insufciency and the elderly Must be given rapidly (under 10 min)

Chlorpromazine

2550 mg IV/IM

Prochlorperazine

510 mg IV/IM

Droperidol

2.5 mg IV/IM

Nonsteroidals Ketorolac

30 mg IV/60 mg IM

Other Valproic acid

500 mg IV

Magnesium

12 g IV

Failure to respond to rst-line medications Failure to respond to rst-line medications

Abbreviations: DHE, dihydroergotamine; ED, emergency department; EKG, electrocardiogram.

Migraine in the Emergency Department

419

It is unclear why emergency physicians in North American EDs favor opiates over triptans and other migraine-specic medications. A useful paradigm to understand this issue divides reasons into patient-centered factors and physician-centered factors (4). The former include failure to respond or a history of nonresponse or allergy/ intolerance to nonopioid medications; or, a preference for opioids, either because of a history of relief with this class of medication or a desire for the associated euphoria. Physician-centered factors include a lack of knowledge, fear of side effects or contraindications, lack of willingness to change practice, or a disagreement with recommendations based on personal experience; or, a desire to appease or please the patient because of a desire to avoid confrontation or prevent complaints to administration. Although triptans do not seem to cause cardiovascular morbidity in healthy young patients (22), their contraindication in patients with atherosclerotic vascular disease and their relative contraindication in patients with poorly managed hypertension, likely give many emergency physicians pause. Added to the difculty of treating a patient in pain about whom not much is known, the dilemma of the emergency physician is compounded by the fact that patients in pain often have an elevated blood pressure at triage. If fear of administering a triptan to a patient with an elevated blood pressure prevents the emergency physicians from using this medication, then a triptan can be added to another analgesic once the patients pain has slightly abated, the blood pressure has gone down, and a more complete history has been obtained. The form of triptan that is to be used is not clear. Most ED patients have missed the boat for early intervention, so it is likely that a parenteral form will be most useful. To date, the only injectable form is the rst-generation sumatriptan. However, by the time patients present to an ED, central sensitization most likely has already set induration of headache prior to ED presentation is rarely less than eight hours (see Chapter X) (3,2325). In triptan-naive patients and over-the-counter (OTC) users, injectable sumatriptan is likely to produce more success than in patients with frequent migraine attacks on multiple analgesics, whose brains are more sensitized to frequent migraine attacks. Other parenteral triptan choices are the nasal spray formulations of zolmitriptan and sumatriptan. Ergotamines Ergotamines have a long history of successful use in select migraine patients (26). However, unlike the triptans, the efcacy of parenteral ergotamines has not been clearly demonstrated in clinical trials (26,27). Subcutaneous dihydroergotamine, though not quite as efcacious in the short term as subcutaneous sumatriptan has better pain-relief results at 24 hours (28). Dihydroergotamine is often combined with a dopamine receptor antagonist, and this combination has efcacy (29,30). Dihydroergotamine is often a useful tool for patients with a prolonged migraine attack because of its sustained action. Dihydroergotamine, like the triptans, should not be used in patients with coronary artery disease, peripheral vascular disease, or poorly managed hypertension. This drug also should not be used in patients on retroviral agents or with signicant intercurrent infection. Dopamine Receptor Antagonists/Phenothiazines Although not widely used as a primary migraine-abortive therapy in the outpatient population, these medications have taken hold in North American EDs. Their

420

Diamond and Friedman

mechanism of action in migraine patients is unknown but is possibly related to the inhibition of dopamine hypersensitivity (31,32). There have been no large-scale studies demonstrating the efcacy of the parenteral version of these medications. Dose-nding studies have not occurred and the class of medication received adverse publicity when a black box warning was added to droperidol for causing QTc prolongation. However, this class of medication is old, cheap, widely used for a variety of indications, and known to be safe in considerably higher doses than used in emergency medicine or neurology practice (33). Further, when the parenteral versions of these medications have been compared to the triptans, their efcacy and tolerability has been at least as good as the more expensive medications (7,34,35), though concerns still linger about their ability to allow the return of patients to normal daily activities as rapidly as the triptans. It is difcult to summarize conclusions about this class of medications because there are multiple small trials, each with different enrollment criteria, outcomes, and comparative agents. However, the data consistently demonstrates that this class of medications is effective and safe for migraine headaches. Dopamine receptor antagonists have efcacy in tension-type headaches as well (36). By using this class of medication, the burden of differentiating severe tensiontype headaches from migraines is removed from the emergency physician. Common adverse effects of these medications include akathisias and other extrapyramidal side effects. Some authors report rate of akathisias as high as 44% with IV administration of a dopamine antagonist (37,38). To prevent akathisias, diphenhydramine can be coadministered with the dopamine antagonists (39). Despite the sedative effect of each of these two centrally acting classes of medication, the ability to perform activities of daily living after receiving the combination of IV metoclopramide and diphenhydramine is probably no worse than migraineurs administered subcutaneous sumatriptan (7), though this has not yet been consistently demonstrated in large-scale studies. Chlorpromazine. In individual double-blind clinical trials, chlorpromazine has been shown to have two-hour pain-free rates signicantly better than placebo (40,41) and as good as sumatriptan (34). Some data suggest that chlorpromazine might be a better monotherapy than dihydroergotamine (42). This drug is now available again after a recent short-term absence. Metoclopramide. Metoclopramide has been shown to be better than placebo and nonsteroidals (43) and at least as good as sumatriptan (7,35). The optimal dose of this medication for migraines has not yet been established and might be considerably higher than commonly used (7,44). Metoclopramide is pregnancy category B and is commonly used during pregnancy. In the gravid, or potentially gravid patient, this medication should be considered rst line, perhaps in combination with another category Bdrug diphenhydramine. Prochlorperazine. It has been shown to be better than placebo (45), ketorolac (46), and metoclopramide (45,47). Droperidol. It has been shown to be better than placebo (48), and at least as efcacious as prochlorperazine (49,50). There is no apparent benet from dosing more than 2.5 mg (48). Because of safety concerns expressed by the Food and Drug Administration, this medication should be used with caution. Nonsteroidals Ketorolac has enjoyed some efcacy as a parenteral treatment for migraines, although it tends not to be as efcacious as the other medications discussed above

Migraine in the Emergency Department

421

(29,46,51,52). There might be a role for this medication as part of a multidrug cocktail for migraines (53). Because of the efcacy of this medication in tension-type headache (54), the emergency physician can use ketorolac when uncertain whether the diagnosis is migraine or tension-type headache. Valproate Multiple open-label, nonrandomized trials demonstrated benet of IV valproate for the treatment of acute migraines, with headache response of about 60% with 300 to 500 mg of IV valproate (55,56). However the only blinded, randomized controlled trial that we could nd reported that IV valproate has no benet for acute migraines (pain intensity scale did not change before and after treatment) and demonstrated that parenteral prochlorperazine is signicantly better for acute migraines (57). More research should be done before this medication is used clinically as rst-line ED migraine therapy. When rst-line therapy fails, this treatment might be tried as rescue therapy. This medication might also have a role for the treatment of admitted patients with chronic headaches (58). Magnesium IV magnesium has demonstrated benet when used alone against placebo (59), but trended toward less efcacy when coadministered with metoclopramide (44). The role of this medication in the ED treatment of migraine is unclear. Some evidence suggest that one gram of IV magnesium sulfate reduces the duration of migrainerelated photophobia and phonophobia (59). It is also a benign and perhaps useful treatment in the pregnant migraineur. Caffeine Although some data suggest that caffeine has efcacy for the treatment of postlumbar puncture headache (60), we could nd no literature discussing the utility of IV caffeine for migraines. Caffeine is commonly used in OTC migraine preparations, but an oral form of caffeine combined with a nonsteroidal was comparable to a nonsteroidal without caffeine (61). It is possible that it has primary efcacy, it serves to enhance the efcacy of other analgesics by increasing absorption or gastric motility, or it merely treats a caffeine-withdrawal headache in certain patients. Further study is warranted, but until then, caffeine should not be used as a rst-line migraine therapy. Corticosteroids Dexamethasone is likely to have benet in decreasing the incidence of recurrence (24,62), and should be considered in all discharged migraineurs. Corticosteroids are commonly used in intractable migraines. The role of corticosteroids for the acute attack is unknown. Opiates This class of medication is commonly used in North American EDs (4,20), although considerable practice variation exists among different EDs (8). In general, opiates should not be used as rst-line migraine therapy because they do not modify the underlying disease mechanism.

422

Diamond and Friedman

Patients who receive opiates as rst-line therapy tend to have a shorter duration of headache prior to ED presentation and are more likely to have taken a prescription headache medication prior to ED presentation (20), suggesting that these patients are more familiar with their headaches. However, patients who receive opiates as rst-line therapy do not have higher pain scores than patients who do not receive opiates (20). Some evidence suggests that patients who use opiates for their migraines might be at increased risk of developing chronic headaches (63,64). Use of controlled substances is a common feature of ED repeaters (12). Despite guideline recommendations not to use opiates as rst-line therapy, emergency physicians are often placed in a difcult situation when a patient presents with a headache and demands an opiate medication by name, refuses to accept any other treatment, and often improves after one or two doses of the opiate medication. By administering the opiate, the emergency physician avoids a confrontation and eventually discharges a satised patient. With this in mind, we present strategies to deal with migraineurs with regard to opiates:  Newly diagnosed migraineurs. Do not use opiates as rst or second line of therapy in this population. Opiates should be used as a therapy of last resort. Be particularly careful in populations at risk of habituation, for example teenagers and patients with substance-abuse histories.  Migraineurs usually treated with opiates but amenable to migraine-specic therapy. Consider coadministration of a triptan or a dopamine antagonist along with the opiate. Find an alternate therapy that allows the gradual removal of opiates from the migraineurs regimen.  Migraineurs usually treated with opiates and unwilling to try another medication. This population represents the most difcult of the three groups. Some hospitals and regions have attempted to deal with this patient group by removing meperidine from the hospitals formulary. Whether this maneuver is effective is unknown, but it seems likely that the migraineur will merely switch their rst choice of therapy to a different opiate. If the emergency physician is fortunate enough to practice in a health care system with extensive resources, then a comprehensive disease management program might be of benet (65). Patients, in general, should not be allowed to self-prescribe, and there are numerous alternatives that can be given. Care of all opiate-seeking migraineurs should be coordinated with the neurologist or headache specialist.

SPECIFIC SITUATIONS Pregnancy The latter half of pregnancy and the immediate postpartum period is known to be a thrombophilic period. Patients who present with headache during this time period should arouse concerns in their physicians. Of the medications discussed earlier in this chapter metoclopramide and magnesium are safe and commonly used during pregnancy. If a patient has not taken acetaminophen, this too can be used. IV uids will not cause harm and might be of benet. Judicious and infrequent use of opiates is appropriate for pregnant patients when absolutely necessary (Table 3).

Migraine in the Emergency Department Table 3 Specic Situations Category Pregnancy Reason for concern Teratogenic or laborinducing effects of medication Tolerability Recommended medication Metoclopramide, magnesium Phenothiazines diphenhydramine, triptans, ergotamines Comments

423

Nonsteroidals okay in early pregnancy Medical comorbidities less of an issue in this group. Patient preference and tolerability should dictate management Need to weigh side effects prole against potential benet. Ideal medication in the elderly has not yet been established Superiority of this class of mediation in these patients has not been established

Pediatric

Elderly

Increased incidence of atherosclerotic vascular disease, renal insufciency,

Nauseated

Unable to tolerate oral medication

Phenothiazines/ dopamine antagonists

Elderly As in late pregnancy, the concern for secondary headaches rises substantially in the elderly patient. Similarly, the prevalence of hypertension and coronary artery disease increases with age. Nonetheless, elderly patients are at risk of oligoanalgesia (66) and their migraine pain should not be ignored. This is a population in which dopamine receptor antagonists might have a more important role. We know of no data that specically reports the efcacy and adverse-effect prole of antimigraine agents in the elderly. Pediatrics Scant data are available to guide the pediatric emergency physician. Migraines are a common chief complaint in the pediatric ED, though they represent a smaller percentage of all ED headaches (67), probably because of the increased frequency of presentation of headaches associated with viral syndromes. In the only pediatric clinical trial we could locate, parenteral prochlorperazine proved superior to ketorolac (51). In the absence of more data, pediatric emergency physicians are encouraged to use the medications discussed above. Nasal spray forms of medication might be better tolerated by the youngest migraineurs.

DISPOSITION Migraineurs should be discharged once their pain has been adequately controlled and any necessary work-up completed.

424

Diamond and Friedman

Data from several clinical trials suggest that ED migraine patients often suffer from headaches after discharge (24,25,44,68). Recurrent or persistent 24-hour headaches rated as moderate or severe in intensity occurred in 14% to 43% of subjects. One observational cohort study reported a rate of headache-related functional impairment of 45% in subjects within 24 hours of ED discharge (69). Migraineurs who are going home should be warned about recurrence or persistence of headache and given appropriate medication to deal with it when it occurs. The patients who have never received a diagnosis of migraine should be given standard educational material, available on the American Headache Society website.

Figure 1 Status migrainosus/intractable migraines. Abbreviation: DHE, dihydroergotamine.

Migraine in the Emergency Department

425

Some data exist to suggest that parenteral corticosteroids substantially decrease the recurrence of migraines after ED discharge. This intervention should be considered in all discharged migraineurs (24). Migraineurs need to be admitted to the hospital in the following situation: Status Migrainosus Intractable Pain. STATUS MIGRAINOSUS/INTRACTABLE PAIN Patients with intractable migraine headaches unresponsive to appropriate ED treatment and rehydration should be admitted to a neurology service for aggressive management of their headache, regardless of how long their headache has lasted (Fig. 1). Medicationrebound headache should be considered and excluded as the diagnosis in these patients. It is unclear which inpatient regimen should be used, however, adequately dosed medications that have not proved effective should not be continued. Opiates should not be withheld on principle, especially in a patient with a migraine severe enough for

Figure 2 Raskin protocol for status migrainosus/intractable migraines. Abbreviations: DHE, dihydroergotamine; EKG, electrocardiogram, PRN. Source: Refs. 70, 71.

426

Diamond and Friedman

admission. The Raskin IV dihydroergotamine/metoclopramide protocol (Fig. 2) has long been used with success in these patients (70), though rigorous clinical trials are lacking. Use of any of the medications discussed in this chapter the primary treatment section is possibly benecial. Some data and clinical experience support the use of corticosteroids (24,62) and dopamine antagonists (72,73) in these patients. REFERENCES
1. Dhopesh V, Anwar R, Herring C. A retrospective assessment of emergency department patients with complaint of headache. Headache 1979; 19:3742. 2. Leicht MJ. Non-traumatic headache in the emergency department. Ann Emerg Med 1980; 9:404409. 3. Salomone JA III, Thomas RW, Althoff JR, Watson WA. An evaluation of the role of the ED in the management of migraine headaches. Am J Emerg Med 1994; 12:134137. 4. Vinson DR. Treatment patterns of isolated benign headache in US emergency departments. Ann Emerg Med 2002; 39:215222. 5. Luda E, Comitangelo R, Sicuro L. The symptom of headache in emergency departments. The experience of a neurology emergency department. Ital J Neurol Sci 1995; 16:295301. 6. Bigal M, Bordini CA, Speciali JG. Headache in an emergency room in Brazil. Sao Paulo Med J 2000; 118:5862. 7. Friedman B, Corbo J, Lipton R, et al. Metoclopramide versus sumatriptan for the ED treatment of migraines. Neurology 2005. 8. Vinson DR, Hurtado TR, Vandenberg JT, Banwart L. Variations among emergency departments in the treatment of benign headache. Ann Emerg Med 2003; 41:9097. 9. Celentano DD, Stewart WF, Lipton RB, Reed ML. Medication use and disability among migraineurs: a national probability sample survey. Headache 1992; 32:223228. 10. Elston Lafata J, Moon C, Leotta C, Kolodner K, Poisson L, Lipton RB. The medical care utilization and costs associated with migraine headache. J Gen Intern Med 2004; 19:10051012. 11. Edmeads J. Emergency management of headache. Headache 1988; 28:675679. 12. Maizels M. Health resource utilization of the emergency department headache repeater. Headache 2002; 42:747753. 13. Chan BT, Ovens HJ. Chronic migraineurs: an important subgroup of patients who visit emergency departments frequently. Ann Emerg Med 2004; 43:238242. 14. Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000; 342:2936. 15. Morgenstern LB, Luna-Gonzales H, Huber JC Jr, et al. Worst headache and subarachnoid hemorrhage: prospective, modern computed tomography and spinal uid analysis. Ann Emerg Med 1998; 32:297304. 16. Lledo A, Calandre L, Martinez-Menendez B, Perez-Sempere A, Portera-Sanchez A. Acute headache of recent onset and subarachnoid hemorrhage: a prospective study. Headache 1994; 34:172174. 17. Landtblom AM, Fridriksson S, Boivie J, Hillman J, Johansson G, Johansson I. Sudden onset headache: a prospective study of features, incidence and causes. Cephalalgia 2002; 22:354360. 18. Diamond ML. The role of concomitant headache types and non-headache co-morbidities in the underdiagnosis of migraine. Neurology 2002; 58:S3S9. 19. Lipton RB, Stewart WF, Stone AM, Lainez MJ, Sawyer JP. Stratied care vs step care strategies for migraine: the Disability in Strategies of Care (DISC) Study: a randomized trial. JAMA 2000; 284:25992605. 20. Colman I, Rothney A, Wright SC, Zilkalns B, Rowe BH. Use of narcotic analgesics in the emergency department treatment of migraine headache. Neurology 2004; 62: 16951700.

Migraine in the Emergency Department

427

21. Akpunonu BE, Mutgi AB, Federman DJ, et al. Subcutaneous sumatriptan for treatment of acute migraine in patients admitted to the emergency department: a multicenter study. Ann Emerg Med 1995; 25:464469. 22. Hall GC, Brown MM, Mo J, MacRae KD. Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 2004; 62:563568. 23. Friedman BW, Corbo J, Lipton RB, et al. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Neurology 2005; 64:463468. 24. Innes G, Macphail I, Dillon E. Dexamethasone prevents relapse after emergency department treatment of acute migraine: a randomized clinical trial. Can J Emerg Med 1999:1. 25. Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache. Acad Emerg Med 1995; 2:597602. 26. Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and efcacy. Headache 2003; 43:144166. 27. Tfelt-Hansen P, Saxena PR, Dahlof C, et al. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 2000; 123(Pt 1):918. 28. Winner P, Ricalde O, Le Force B, Saper J, Margul B. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol 1996; 53:180184. 29. Klapper JA, Stanton JS. Ketorolac versus DHE and metoclopramide in the treatment of migraine headaches. Headache 1991; 31:523524. 30. Klapper JA, Stanton J. Current emergency treatment of severe migraine headaches. Headache 1993; 33:560562. 31. Fanciullacci M, Alessandri M, Del Rosso A. Dopamine involvement in the migraine attack. Funct Neurol 2000; 15(suppl 3):171181. 32. Mascia A, Afra J, Schoenen J. Dopamine and migraine: a review of pharmacological, biochemical, neurophysiological, and therapeutic data. Cephalalgia 1998; 18:174182. 33. Tsavaris NB, Koufos C, Katsikas M, Dimitrakopoulos A, Athanasiou E, Linardaki G. Antiemetic prophylaxis with ondansetron and methylprednisolone vs metoclopramide and methylprednisolone in mild and moderately emetogenic chemotherapy. J Pain Symptom Manage 1999; 18:218222. 34. Kelly AM, Ardagh M, Curry C, DAntonio J, Zebic S. Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine. J Accid Emerg Med 1997; 14:209211. 35. Esteban-Morales A, Chavez PT, Martinez CGR, Zuniga AS. Respuesta clinica de metoclopramida en comparacion con sumatriptan en el tratamiento de ataques agudos de migrana. Revista de la Sanidad Militar Mexico 1999; 53:3640. 36. Bigal ME, Bordini CA, Speciali JG. Intravenous chlorpromazine in the acute treatment of episodic tension-type headache: a randomized, placebo controlled, double-blind study. Arq Neuropsiquiatr 2002; 60:537541. 37. Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 1999; 34:469475. 38. Olsen JC, Keng JA, Clark JA. Frequency of adverse reactions to prochlorperazine in the ED. Am J Emerg Med 2000; 18:609611. 39. Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med 2004; 26:265270. 40. McEwen JI, OConnor HM, Dinsdale HB. Treatment of migraine with intramuscular chlorpromazine. Ann Emerg Med 1987; 16:758763. 41. Bigal ME, Bordini CA, Speciali JG. Intravenous chlorpromazine in the emergency department treatment of migraines: a randomized controlled trial. J Emerg Med 2002; 23:141148. 42. Bell R, Montoya D, Shuaib A, Lee MA. A comparative trial of three agents in the treatment of acute migraine headache. Ann Emerg Med 1990; 19:10791082. 43. Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Ann Emerg Med 1990; 19:10831087.

428

Diamond and Friedman

44. Corbo J, Esses D, Bijur PE, Iannaccone R, Gallagher EJ. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Ann Emerg Med 2001; 38:621627. 45. Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996; 14:262264. 46. Seim MB, March JA, Dunn KA. Intravenous ketorolac vs intravenous prochlorperazine for the treatment of migraine headaches. Acad Emerg Med 1998; 5:573576. 47. Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995; 26:541546. 48. Silberstein SD, Young WB, Mendizabal JE, Rothrock JF, Alam AS. Acute migraine treatment with droperidol: a randomized, double-blind, placebo-controlled trial. Neurology 2003; 60:315321. 49. Weaver CS, Jones JB, Chisholm CD, et al. Droperidol vs prochlorperazine for the treatment of acute headache. J Emerg Med 2004; 26:145150. 50. Miner JR, Fish SJ, Smith SW, Biros MH. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med 2001; 8:873879. 51. Brousseau DC, Duffy SJ, Anderson AC, Linakis JG. Treatment of pediatric migraine headaches: a randomized, double-blind trial of prochlorperazine versus ketorolac. Ann Emerg Med 2004; 43:256262. 52. Shrestha M, Singh R, Moreden J, Hayes JE. Ketorolac vs chlorpromazine in the treatment of acute migraine without aura. A prospective, randomized, double-blind trial. Arch Intern Med 1996; 156:17251728. 53. Peroutka SJ. Beyond monotherapy: rational polytherapy in migraine. Headache 1998; 38:1822. 54. Harden RN, Rogers D, Fink K, Gracely RH. Controlled trial of ketorolac in tensiontype headache. Neurology 1998; 50:507509. 55. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache 2001; 41:976980. 56. Mathew NT, Kailasam J, Meadors L, Chernyschev O, Gentry P. Intravenous valproate sodium (depacon) aborts migraine rapidly: a preliminary report. Headache 2000; 40: 720723. 57. Tanen DA, Miller S, French T, Riffenburgh RH. Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective, randomized, double-blind trial. Ann Emerg Med 2003; 41:847853. 58. Schwartz TH, Karpitskiy VV, Sohn RS. Intravenous valproate sodium in the treatment of daily headache. Headache 2002; 42:519522. 59. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia 2002; 22:345353. 60. Yucel A, Ozyalcin S, Talu GK, Yucel EC, Erdine S. Intravenous administration of caffeine sodium benzoate for postdural puncture headache. Reg Anesth Pain Med 1999; 24:5154. 61. Peroutka SJ, Lyon JA, Swarbrick J, Lipton RB, Kolodner K, Goldstein J. Efcacy of diclofenac sodium softgel 100 mg with or without caffeine 100 mg in migraine without aura: a randomized, double-blind, crossover study. Headache 2004; 44:136141. 62. Krymchantowski AV, Barbosa JS. Dexamethasone decreases migraine recurrence observed after treatment with a triptan combined with a nonsteroidal anti-inammatory drug. Arq Neuropsiquiatr 2001; 59:708711. 63. Lipton RB, Bigal ME. Opioid therapy and headache: a cause and a cure. Neurology 2004; 62:16621663.

Migraine in the Emergency Department

429

64. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62:788790. 65. Maizels M, Saenz V, Wirjo J. Impact of a group-based model of disease management for headache. Headache 2003; 43:621627. 66. Jones JS, Johnson K, McNinch M. Age as a risk factor for inadequate emergency department analgesia. Am J Emerg Med 1996; 14:157160. 67. Kan L, Nagelberg J, Maytal J. Headaches in a pediatric emergency department: etiology, imaging, and treatment. Headache 2000; 40:2529. 68. Blumenthal HJ, Weisz MA, Kelly KM, Mayer RL, Blonsky J. Treatment of primary headache in the emergency department. Headache 2003; 43:10261031. 69. Ducharme J, Beveridge RC, Lee JS, Beaulieu S. Emergency management of migraine: is the headache really over? Acad Emerg Med 1998; 5:899905. 70. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986; 36:995997. 71. Raskin NH. Treatment of status migrainosus: the American experience. Headache 1990; 30(suppl 2):550553. 72. Wang SJ, Silberstein SD, Young WB. Droperidol treatment of status migrainosus and refractory migraine. Headache 1997; 37:377382. 73. Kabbouche MA, Vockell AL, LeCates SL, Powers SW, Hershey AD. Tolerability and effectiveness of prochlorperazine for intractable migraine in children. Pediatrics 2001; 107:E62.

27
Progression Forms of Migraine
Marcelo E. Bigal
Department of Neurology, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A.

Richard B. Lipton
Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Monteore Headache Center, New York, New York, U.S.A.

INTRODUCTION Chronic daily headache (CDH) of long duration is a clinical syndrome dened by headaches that occur for four hours a day or more, on 15 days a month or more, over more than three months (1,2). CDH is one of the most common and disabling headache presentations in neurology centers; it aficts 4% to 5% of the general population (3,4). Many patients with CDH are severely impaired (5). CDH sufferers usually have higher disability than those with episodic migraine (6). CDH disorders may be primary or secondary. For the secondary disorders, classication is based on the underlying pathology. For the primary CDH disorders, classication has been controversial (7,8). As a consequence, several separate proposals for the classication of CDH have emerged. The Silberstein and Lipton (S-L) criteria have been most widely used (2). The S-L criteria divide primary CDH into transformed migraine (TM), chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua (HC), and subclassify each of these into subtypes with medication overuse or without medication overuse (Table 1). Of these, the rst edition of the International Classication of Headache Disorders (ICHD)-1 (7) included only CTTH, while the second edition (ICHD-2) (8) has detailed diagnostic criteria for all four types of primary CDH of long duration. The term chronic migraine (CM) was introduced in place of TM, and has a very different denition, as discussed below. Although vastly improved, recent studies show that the ICHD-2 remains cumbersome for the classication of adults with CDH (9). More recently, the ICHD-2 has been considering revising the CM criteria, moving it to the appendix. CTTH (Chapter 30), HC, and NDPH (Chapter 31) are covered in detail elsewhere. In this chapter we focus on TM. We discuss TM as the result of episodic

431

432

Bigal and Lipton

Table 1 The Classication of the Chronic Daily Headaches According to the Silberstein and Lipton Criteria Daily or near-daily headache lasting more than 4 hr for more than 15 days/mo 1.8 Transformed migraine 1.8.1 With overuse 1.8.2 Without overuse 2.2 Chronic tension-type headache 2.2.1 With overuse 2.2.2 Without overuse 4.7 New daily persistent headache 4.7.1 With overuse 4.7.2 Without overuse 4.8 Hemicrania continua 4.8.1 With overuse 4.8.2 Without overuse

migraine that progressed over time. We highlight the strategies for the treatment of TM, and potential strategies to avoid its development. EPIDEMIOLOGY OF THE CDHS The epidemiology of CDH has been described in a number of population samples based in Europe, the Far East, and the United States (Table 2) (10). The prevalence of CDH is remarkably consistent among studies, ranging from 2.4% (Norway) to 4.7% (Spain) (4,11). In the United States, the prevalence is 4.1%. From 35% to 50% of CDH sufferers in the population have TM (3). The incidence of CDH was investigated in a prospective study in the United States. Among subjects with episodic headaches at baseline, 3% developed CDH within one year (12). The incidence among migraine sufferers in subspecialty care is 13% (13). Clinic-based studies show that CDH response occurs in 10% to 20% of the patients in European headache clinics, although this is likely an underestimation (14). In the United States, studies show that 50% to 80% of the patients presenting in a headache clinic have TM (1518). In this setting, TM is by far the most common type of CDH. In a study by Mathew et al. (16), 77% of the patients with CDH had TM. In a large study conducted at a U.S. headache center, TM represented 87.4% of the cases of CDH (15). The relative frequency of the different headache subtypes presenting in a headache clinic is different in adults and in adolescents. CTTH and NDPH are more common in adolescents than in adults (10% vs. 0.9% and 20% vs. 10%, respectively), TM is more common in adults, and HC is equally rare. Furthermore, the clinical presentation, as we will discuss in the following section, of TM is different in adolescents than in adults. Adolescents with TM have a higher frequency of migraine attacks than adults (19). TRANSFORMED MIGRAINE Most patients with TM report a past history of episodic migraine. Sufferers usually report a process of transformation over months or years, and as headache increases

Table 2 Prevalence of Very Frequent Headaches in Adult Populations Using SilbersteinLipton Criteria (Ordered by Date of Publication) Prevalence (%) N 2.2 2.2 2.7 1.3 2.4 1.0 Case denition Age range Total CTTH TM F:M 1.8 8.7 3.1 1.6 1.7 1.6 2.1 2.3 2.4 2.6 Analgesic overuse (%) 25 25

Progression Forms of Migraine

Author (year of publication)

Country

Scher (1998) Castillo (1999) Wang (1999) Hagen (2000) Ho (2001) Lu (2001) Prencipe (2001) Lanteri-Minet (2003) Takeshima (2004) 1.4 2.5

United States Spain China Norway Singapore Taiwan Italy France Japan

13,343 1883 1533 51,383 2096 3377 833 10,585 5758

15/mo 15/mo, 4hr/day 15/mo 15/mo >180/yr 15/mo, 4hr/day 15/mo Daily CTTH only

1865 14 65 20 12 15 65 15 20

4.1 4.7 3.9 2.4 3.3 3.2 4.4 3.0

34 38

Analgesic overuse based on Silberstein (45) criteria. Abbreviations: CTTH, chronic tension-type headache; TM, transformed migraine; F:M, female to male prevalence ratio. Source: Modied from Ref. 43.

433

434

Bigal and Lipton

in frequency, associated symptoms become less severe and frequent (1417). The process of transformation frequently ends in a pattern of daily or nearly daily headache that resembles CTTH, with some attacks of full migraine superimposed (2). In the clinical setting, migraine transformation most often is related to acute medication overuse, but transformation may occur without overuse (18). In the population, most cases of TM are not related to medication overuse (12). Multiple risk factors may be involved in these cases (see chapters for risk factors for CDH). Revising the denition of CM: The terms TM and CM have been used synonymously in the past but this is no longer appropriate: CM has a specic denition in the ICHD-2, which does not recognize TM as a separate entity. Two main differences exist between the S-L (TM) and ICHD-2 (CM) systems. First, the ICHD-2 criteria for CM require that headaches meeting criteria for migraine without aura occur on 15 days a month or more. To classify TM, the S-L criteria require 15 days or more of headache (not necessarily migraine) and one link to migraine. Second, the ICHD-2 reserves the diagnosis of CM from patients overusing acute medications (simple analgesics on 15 days a month or more or ergotamine, triptans, opioids, or combination analgesics on 10 days a month or more), applying instead probable CM plus probable medication-overuse headache, and coding of the antecedent episodic migraine (Table 3). We have recently proposed that CM is classied in those subjects with headache lasting more than four hours, on more than 15 days per month, for at least three months, where at least eight of the days ll criteria for migraine or probable migraine. If the headache begins abruptly, a diagnosis of NDPH should be assigned (data in press). The Phenotype of TM Is Not the Same in Adolescents and Adults Differences exist regarding the clinical presentation of TM in adolescents and adults. Most adults with TM have less than 15 days of full-blown migraine per month, and more days of headache resembling tension-type headache than of migraine. TM in adolescents is replete with migraine attacks. Second, most adults with TM are overusing acute medication (84%), while most adolescents (58.9%) are not (19). CM Is the Early Stage of TM In a recent study of 402 subjects with TM, the proportion of migraine attacks decreased with age (with a proportional increase of tension-type headache attacks), from 71% below the age of 30 years to 22% aged 60 or above, it was higher in those with shorter interval from the onset of migraine to the onset of CDH (less than ve years, p 0.003), and in those with a more recent onset of CDH (less than six years, p < 0.0001). These ndings suggest that CM (15 or more days of migraine per month) is the rst stage of migraine chronication in most patients. Subsequently, the frequency of migraine attacks diminishes, and most attacks will lack migraine features. Thus, CM is the earlier stage of TM, and both are different evolutive stages of migraine chronication. These ndings have implications for the classication of CDH and for our understanding of the natural history of migraine and biology of the transformation process (20). The ndings of this study support what is seen in clinical practice and has been taught by headache specialists for many years (Saper et al., personal communication). The concept that early in the process of transformation most headache days ll criteria for migraine, and as disease evolves, the headache attacks get less typical,

Table 3 Diagnostic Criteria for Transformed/Chronic Migraine Current ICHD-2 Chronic migraine

Headache

Proposed Criteria (Bigal et al.)

Progression Forms of Migraine

Transformed migraine/ chronic migraine

Transformed migraine

Description: Migraine headache more than or equal to 15 days/mo for more than or equal to 3 mo and no drug overuse Diagnostic criteria: A. Headache fullling criteria C and D for 1.1 migraine without aura on more than or equal to 15 days/mo for over 3 mo B. Not attributed to another disordera

A. Headache frequency of more than or equal to 15 days/mo for 3 mo B. Average headache duration of more than 4 hr/day (if untreated) C. Headache fullling IHS criteria for 1.1 migraine without aura, 1.2 migraine with aura, or 1.6 probable migraine, on greater than or equal to 8 headache days D. Does not meet criteria for IHS chronic tensiontype headache (2.3), hypnic headache (4.5), hemicrania continua (4.7), or new daily persistent headache (4.8) E. Not attributed to another disorder

When medication overuse is present (i.e., fullling criterion B for any of the subforms of 8.2 Medicationoveruse headache), the default rule is to code such patients according to the antecedent migraine subtype (usually 1.1 Migraine without aura) plus 1.6.5 Probable chronic migraine plus 8.2.7 Probable medicationoveruse headache. Abbreviations: ICHD, International Classication of Headache Disorders; IHS, International Headache Society.

435

436

Bigal and Lipton

Figure 1 Evolution of the frequency of headache in subjects that stopped (group 1) or continued analgesic overuse (group 2) after 1 year of follow-up.

was also supported by an adolescent study, where those with recent onset CDH were much more likely to have 15 or more migraine days per month (74.5% vs. 25.8%, p < 0.001) (21).

PathophysiologyTM as the Result of Progression of Disease General Considerations Although the source of pain in primary TM is unknown and may be dependent on the subtype, recent work suggests that the following mechanism, alone or in combination, contribute to the process (22): (i) Abnormal excitation of peripheral nociceptive afferent bers in the meninges; (ii) Enhanced responsiveness of trigeminal nucleus caudalis neurons; (iii) Decreased pain modulation from higher centers such as the periaqueductal gray (PAG) matter; (iv) Spontaneous central pain generated by activation of the on cells in the medulla; (v) Decreased serotonin levels; and (vi) Central sensitization. An imaging study has shown that iron deposition occurs in the PAG area in subjects with chronic headaches (23). The PAG area is related to descending analgesic network and is important in controlling pain and providing endogenous analgesia. It is closely related to the trigeminal nucleus. In this study, the iron levels were increased in migraine sufferers, compared with controls, and in CDH headache sufferers compared with migraineurs. These ndings may be directly attributable to iron-catalyzed, free-radical cell damage. The authors suggested that iron deposition may reect progressive neuronal damage related to recurrent migraine attacks. It can be hypothesized that repetitive central sensitization of the trigeminal neurons correlate with iron deposition in the PAG area and, therefore, migraine attacks predispose to disease progression. Evidence of migraine progression also comes from a recent neuroimaging study (24). Kruit et al. used a cross-sectional design to study Dutch adults aged 30 to 60 years. They showed that male subjects with migraine with aura were at an increased risk of posterior circulation infarct. Additionally, women with migraine with or without aura were at a higher risk of deep white matter lesions, compared with controls. The white matter lesions increased with attack frequency, possibly demonstrating progression of the disease.

Progression Forms of Migraine

437

Finally, in a longitudinal epidemiologic study, Scher et al. (12) showed that 3% of individuals with episodic headache (headache frequency of 2 to 104 days/yr) progressed to CDH over the course of one year. The authors concluded that the incidence of CDH in subjects with episodic headache is 3% per year. Burstein et al. showed that around 75% of migraine sufferers develop central sensitization (sensitization of the second-order trigeminal neuron, which is clinically manifested by the development of cutaneous allodynia) during the course of a migraine attack (25). Central sensitization appears to be associated with triptan refractoriness. Central sensitization not only explains the progression of attacks, but also may play a role in the progression of the disease itself. It is suggested that repeated central sensitization episodes are associated with permanent neuronal damage, preventive treatment refractoriness, and disease progression (26). Risk Factors for the Development of CDH Limited evidence exists about risk factors for migraine progression. A study found that the prevalence of CDH decreased slightly with age and increased in women [Odds Ratio (OR) 1.65 (1.32.0)] and divorced, separated, or widowed individuals [OR 1.50 (1.21.9)] (12). CDH prevalence was inversely associated with educational level. Having less than a high-school education was associated with more than a threefold risk of CDH compared with those with a graduate schoollevel education [OR 3.56 (2.353.6)]. CDH was also associated with a self-reported physician diagnosis of arthritis [OR 2.50 (1.93.3)] or diabetes [OR 1.51 (1.012.3)], with previous head trauma, and with medication overuse (12). Importantly, the risk of new-onset CDH increased nonlinearly with baseline headache frequency; elevated risk was primarily limited to controls with more than about two headaches per month. Finally, the strongest risk factor for the development of CDH was obesity [OR 5.53 (1.421.8)]. We recently have shown that although obesity is not a risk factor for migraine, it is for CDH. Furthermore, compared to normal-weighted subjects, obese migraine sufferers have more severe and frequent headache attacks, which, per se, are risk factors for migraine progression. We also found that although not a risk factor for migraine development, obesity was comorbid to TM (27). TM and Medication Overuse In most clinical studies of CDH, overuse of analgesics or other acute-care medications gures prominently (4,12,14,15). There are a number of issues with this association that evoke controversy. Is overuse a signicant factor in transforming episodic headache into TM? Or is the frequently observed overuse merely a response to chronic pain itself? Although medication rebound has not been demonstrated in placebo-controlled trials, withdrawal headache has been shown in a controlled trial of caffeine withdrawal (28). Katsarava et al. (13), using individual studies plus meta-analysis, found that the time required for the development of CDH was approximately ve years of exposure to medication and a history of primary headache for ten years prior to that. A patient develops CDH, then, after consuming a critical dose of a single medication or a combination of medications for an extended period of time, which is shortest for triptans (one to two years), longer for ergots (three years) and longest for analgesics (ve years). Acute withdrawal of the offending medications worsens headache for a nite time, usually from three days to three weeks. Both preventive and acute-care treatment for

438

Bigal and Lipton

the primary headache usually fail if the offending medication or medications are not terminated (13,2931). In an attempt to better understand the relationship between medication overuse and refractory headaches, Wilkinson et al. looked for CDH in 28 patients who underwent total colectomy for ulcerative colitis (28). All migraineurs who overused opioids developed CDH (19%), whereas no nonmigraineurs who overused opioids did so. Recently, Bahra, et al. showed that when nonsteroidal antiinammatory agents are used daily in large doses for medical conditions, such as rheumatoid arthritis, they do not induce CDH in subjects without preexisting primary headache disorders (32). Both studies established two principles of medication overuse headache: (i) Even when the overused medication is used for reasons other than headache, it may still be associated with the development of TM; (ii) Acute medication overuse induces TM only in those predisposed (i.e., those with preexisting episodic migraine). The Treatment of TM Principles of Treatment As with other lifelong illness, several fundamental management considerations are important for treatment success in patients with TM (33). Patients suffering from long-duration TM often present not only with acute medication overuse, but also with psychiatric and somatic comorbidity, low frustration tolerance, as well as physical and emotional dependence. In patients with primary TM, it is important to identify the subtype of TM and evaluate for the presence of analgesic overuse and comorbidities. A combination of pharmacologic, nonpharmacologic, behavioral, and sometimes physical interventions is usually necessary for a favorable outcome. The essential features of an effective treatment regimen include a combination of the following steps: 1. Educate the patient, establish expectations and a follow-up plan 2. Use nonpharmacologic therapies when appropriate:      Biofeedback and relaxation therapy Cognitive behavioral therapy Individual/family counseling as necessary Dietary instructions, chronobiologic therapy, and sleep hygiene Daily exercise program

3. Identify, address, and treat psychiatric and somatic comorbidities 4. Discontinue all potentially offending medications and caffeine by outpatient or inpatient detoxication procedures 5. Institute a program of acute care and preventive pharmacologic therapy Discussing the nonpharmacologic treatment of TM, as well as the treatment of comorbid disorders, is beyond the scope of this chapter. Herein we focus on the outpatient treatment of medication overuse, and basic prospects to treat and prevent the development of TM. Treatment of Medication Overuse Most studies suggest the benet and necessity of detoxifying the patient from the overused medication (when present), followed by an intensive, long-term treatment plan (3437). If patients discontinue their overused medications, they

Progression Forms of Migraine

439

frequently improve considerably, and if they do not, they are usually difcult to treat effectively (Fig. 1). Basically, there are three outpatient approaches to detoxication. One approach is to taper the overused medication gradually while an effective preventive therapy is established. The second strategy is to abruptly discontinue the overused drug, institute a transitional medication (medication bridge) to break the cycle of headache, and subsequently taper the transitional medication. The third approach is to combine the two strategies by eliminating the rebound medication rapidly, adding a preventive medication rapidly, but also supplying a temporary bridge, to give the patient the maximum chance to improve without drastically worsening rst. No mater what medication is being tapered, a very useful technique is to use a three- to seven-day taper of oral steroids, prednisone starting at 60 mg/day, dexamethasone starting at 4 to 12 mg/day, or methylprednisolone. The mechanism of action is unknown, but presumed to be related to decreased neurogenic inammation in the meninges. A second adjunctive therapy is to use a short course of daily triptans in patients who are not overusing them. For example, one could use daily naratriptan (2.5 mg, b.i.d.) for seven days. A recent study showed that transitional therapy with naratriptan was as effective as transitional therapy with prednisone, and both were more effective than just tapering off the overused medication (37). For medications containing butalbital compounds or opioids, abrupt discontinuation may be followed by severe abstinence syndrome. Thereby, for patients suspected of overusing butalbital compounds, it is important to calculate the average daily dose of medication in order to slowly taper over time. One approach is to reduce the dose of one tablet every three to ve days. A more controlled approach is to change the overused butalbital to longer-acting phenobarbital, which is easier to withdraw. For each 100 mg butalbital, an equivalent dose would be 30 mg phenobarbital in divided doses throughout the day. Once this switch has been made, phenobarbital can be tapered 15 to 30 mg/day, thereby avoiding withdrawal (33). For opioids, one approach is to taper the opioid 10% to 15% every day over 7 to 10 days. It usually helps to add clonidine 0.05 or 0.1 mg b.i.d. or t.i.d. during opiod withdrawal. This will prevent withdrawal symptoms (probably by decreasing the release of norepinephrine) and if given in high-enough doses, can speed the detoxication process. Clonidine can be given either by tablet or transcutaneously. During opioid withdrawal, lack of ability to fall and stay asleep may prevent appropriate medication reduction. Various sleep-promoting medication may help, including tricyclic antidepressants, atypical antipsychotics, tizanidine, benzodiazepines, and zolpidem (33). Establishing an Effective Preventive Treatment Most of the commonly used preventive agents for TM have not been evaluated in well-designed, double-blind studies. They are usually the same medications tried for migraine prevention. Table 4 summarizes the medications commonly used in TM. The choice of a preventive drug is done based on its proven efcacy, the patients preferences and headache prole, the drugs side effects, and the presence or absence of coexisting or comorbid disease. The clinician should select the drug with the best risk-to-benet ratio for the individual patient and minimize the side effects that are most important to the patient. Table 5 summarizes an assessment

440

Bigal and Lipton

Table 4 Selected Preventive Therapies for Migraine That May Be Used in the Treatment of CDH Generic treatment doses Alpha2-agonists Clonidine tablets Anticonvulsants Divalproex sodium tabletsa Gabapentin tabletsa Levetiracetam tablets Topiramate tabletsa Zonisamide capsules Antidepressants MAOIs Phenelzine tablets TCA Amitriptyline tabletsa Nortriptyline tablets SSRIs Fluoxetine tablets Sertraline tablets Paroxetine tablets Venlafaxine tabletsa Mirtazapine tablets Beta-blockers Atenolol tabletsa Metoprolol tablets Nadolol tablets Propranolol tabletsa Timolol tabletsa Calcium-channel antagonists Verapamil tabletsa Nimodipine tablets Diltiazem tablets Nisoldipine tablets Amlodipine tablets Flunarizine Serotonergic agents Methysergide tabletsa Cyproheptadine tablets Pizotifen tabletsa Miscellaneous Monteleukast sodium tablets Lisinopril tablets Botulinum toxin A injection Feverfew tablets Magnesium gluconate tablets Riboavin tablets Petasites 75 mga
a

0.050.3 mg/day 5001500 mg/day 3003000 mg/day 15004500 mg/day 50200 mg/day 100400 mg/day

3090 mg/day 30150 mg/day 30100 mg/day 1040 mg/day 25100 mg/day 1030 mg/day 37.5225 mg/day 1545 mg/day 25100 mg/day 50200 mg/day 20200 mg/day 30240 mg/day 1030 mg/day 120720 mg 40 mg t.i.d. 3060 mg t.i.d. 1040 mg/day 2.510 mg/day 10 mg/day 212 mg/day 216 mg/day 1.53 mg/day 520 mg/day 1040 mg/day 25100 units (IM)/3 month 5082 mg/day 400600 mg/day 400 mg/day 75 mg b.i.d.

Evidence for moderate efcacy from at least two well-designed placebo-controlled trials. Abbreviations: CDH, chronic daily headache; IM, intramuscular; MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants.

Progression Forms of Migraine Table 5 Choices of Preventive Treatment for Transformed Migraine* Efcacy in the treatment of migraine 4 Adverse events 2 Relative contraindication Asthma, depression, congestive heart failure, Raynauds disease, and diabetes Obesity Angina and vascular disease

441

Drug Beta-blockers

Relative indication based on comorbidity Hypertension and angina

Antiserotonin Pizotifen Methysergide Calcium-channel blockers Verapamil

4 4

2 4

Orthostatic hypotension

Constipation and hypotension Parkinsons and depression Mania, urinal retention, and heart block Mania Unreliable patient

Flunarizine Antidepressants TCAs

Aura, hypertension, angina, and asthma Dizziness and vertigo Depression, anxiety, insomnia, and pain Depression and OCD Refractory depression Mania, epilepsy, and anxiety Mania, epilepsy, and anxiety Obesity, mania, epilepsy, and anxiety

SSRIs MAOIs Anticonvulsants Divalproex/ Valproate Gabapentin Topiramate

2 4

1 4

4 2 4

2 2 2

Liver disease and bleeding disorders Liver disease and bleeding disorders Kidney stones

Based on studies for migraine. Ratings are on a scale from 1 (lowest) to 4 (highest) based on the strength of evidence. Abbreviations: SSRIs, selective serotonin reuptake inhibitors; MAOI, monoamine oxidase inhibitors. Source: From Ref. 31.

of the efcacy, safety, and evidence for a number of agents that may be useful in the preventive treatment of TM based on the efcacy for episodic migraine. PROSPECTS FOR PREVENTING HEADACHE PROGRESSION Based on recent data, some episodic headaches (i.e., migraine and episodic tensiontype headache) are now conceptualized not just as an episodic disorder, but as a chronic episodic and sometimes chronic progressive disorder. Ongoing research and new emerging therapeutic strategies should consider this change in the conceptual model of migraine and TM. Preventing disease progression in migraine has already been added to the traditional goals of relieving pain and restoring

442

Bigal and Lipton

Table 6 Risk Factors for TM Development and Strategies to Address Them Not readily modiable Sex: female Low education/socioeconomic status Head injury Modiable Attack frequency Central sensitization Obesity Strategies to address modiable risk factors Preventive treatment Early acute migraine interventions Diet; using preventive medications that do not increase the weight Limiting the consumption of acute medications; preventive treatment; detox protocols Relaxation techniques; biofeedback; addressing depression when present Assessing sleep disturbances; treating sleep apnea when present

Medication overuse

Stressful life events

Snoring

Abbreviation: CDH, chronic daily headache.

patients ability to function. Emerging treatment strategies to prevent disease progression include risk factor modication, use of preventive therapies, and possibly the use of triptans as early as possible in the course of a migraine attack (Table 6). REFERENCES
1. Silberstein SD, Lipton RB, Solomon S, Mathew NT. Classication of daily and neardaily headaches: proposed revisions to the IHS criteria. Headache 1994; 34:17. 2. Silberstein SD, Lipton RB, Sliwinski M. Classication of daily and near-daily headaches: eld trial of revised IHS criteria. Neurology 1996; 47:871875. 3. Scher AI, Stewart WF, Liberman J, et al. Prevalence of frequent headache in a population sample. Headache 1998; 38:497506. 4. Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache 1999; 38:497506. 5. Spierings ELH, Ranke AH, Schroevers M, Honkoop PC. Chronic daily headache: a time perspective. Headache 2000; 40:306310. 6. Bigal ME, Rapoport A, Lipton RB, Tepper SJ, Sheftell FD. Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache 2003; 43(4):336342. 7. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain. Cephalalgia 1988; 8(suppl 7):196. 8. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Second Edition. Cephalalgia 2004; (suppl 1):1160. 9. Bigal ME, Tepper SJ, Sheftell FD, Rapoport AM, Lipton RB. Chronic daily headache: correlation between the 2004 and the 1988 International Headache Society diagnostic criteria. Headache 2004; 44(7):684691.

Progression Forms of Migraine

443

10. Scher AI, Lipton RB, Stewart W. Risk factors for chronic daily headache. Curr Pain Headache Rep 2002; 6(6):486491. 11. Zwart JA, Dyb G, Hagen K, Svebak S, Holmen J. Analgesic use: a predictor of chronic pain and medication overuse headache: the Head-HUNT Study. Neurology 2003; 61(2):160164. 12. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003; 106(12):8189. 13. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62:788790. 14. Dowson AJ, Dodick DW, Limmroth V. Medication overuse headache in patients with primary headache disorders: epidemiology, management and pathogenesis. CNS Drugs 2005; 19(6):483497. 15. Bigal ME, Sheftell FD, Rapoport AM, Lipton RB, Tepper SJ. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia; 22(6):432438. 16. Mathew NT, Reuveni U, Perez F. Transformed or evolutive migraine. Headache 1987; 27:102106. 17. Spierings EL, Schroevers M, Honkoop PC, Sorbi M. Presentation of chronic daily headache: a clinical study. Headache 1998; 38:191196. 18. Silberstein SD, Dodick D, Lipton RB, et al. Classifying migraine patients with primary chronic daily headache consensus statement from the American Headache Society. Headache. In press. 19. Bigal ME, Lipton RB, Tepper SJ, Rapoport AM, Sheftell FD. Primary chronic daily headache and its subtypes in adolescents and adults. Neurology 2004; 63(5):843847. 20. Bigal ME, Liberman J, Lipton RB. Chronic migraine is the early stage of transformed migraine. Neurology. In press. 21. Bigal ME, Sheftell FD, Tepper SJ, Rapoport AM, Lipton RB. Migraine days decline with duration of illness in adolescents with transformed migraine. Cephalalgia 2005; 25(7):482487. 22. Welch KM, Goadsby PJ. Chronic daily headache: nosology and pathophysiology. Curr Opin Neurol 2002; 15(3):287295. 23. Welch KMA, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001; 41:629637. 24. Kruit MC, van Buchem MA, Hofman PA, et al. Migraine as a risk factor for subclinical brain lesions. JAMA 2004; 291:427434. 25. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47:614624. 26. Burstein R, Jakubowski M. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol 2004; 55:2736. 27. Bigal M, Liberman M, Lipton R. Body mass index and headache: associations with attack frequency, severity and disability. Neurology. In press. 28. Wilkinson SM, Becker WJ, Heine JA. Opioid use to control bowel motility may induce chronic daily headache in patients with migraine. Headache 2001; 41:303309. 29. Diener HC, Limmroth V. Medication-overuse headache: a worldwide problem. Lancet Neurol 2004; 3(8):475483. 30. Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001; 57(9):16941698. 31. Migraine days decline with duration of illness in adolescents with transformed migraine. Cephalalgia 2005; 25(7):482487. 32. Bahra A, Walsh M, Menon S, Goadsby PJ. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache 2003; 43:179190.

444

Bigal and Lipton

33. Tepper SJ, Rapoport AM, Sheftell FD, Bigal M. Chronic daily headachean update. Headache Care 2004; 1:233245. 34. Krymchantowski AV. Overuse of symptomatic medications among chronic (transformed) migraine patients: prole of drug consumption. Arq Neuropsiquiatr 2003; 61:4347. 35. Grazzi L, Andrasik F, DAmico D, et al. Behavioral and pharmacologic treatment of transformed migraine with analgesic overuse: outcome at 3 years. Headache 2002; 42:483490. 36. Diener HC, Haab H, Peters C, et al. Subcutaneous sumatriptan in the treatment of headache during withdrawal from drug-induced headache. Headache 1991; 31:205209. 37. Krymchantowski AV, Moreira PF. Out-patient detoxication in chronic migraine: comparison of strategies. Cephalalgia 2003; 23(10):982993. 38. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Transformed migraine and medication overuse in a tertiary headache centerclinical characteristics and treatment outcomes. Cephalalgia 2004; 24(6):483490. 39. Scher AI, Stewart WF, Lipton RB. Migraine and headache. A meta-analytic approach. In: Crombie IK, ed. Epidemiology of Pain. Seattle, Washington: IASP Press, 1999: 159170.

28
The Future of Migraine Therapies
Todd Schwedt
Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

David Dodick
Mayo Clinic College of Medicine, Scottsdale, Arizona, U.S.A.

INTRODUCTION Attempts to alleviate the suffering caused by migraine span millennia and encompass treatments as primitive as trepanation of the skull to increasingly specic medications. Ergots, which were introduced in 1884, were the rst class of medications that targeted what at that time was felt to be the etiology of migraine painvasodilation of the cerebral and extracranial vasculature. Ergotamine tartrate, a pure ergot alkaloid that was isolated in 1920, was the mainstay of acute migraine therapy until the introduction of the triptans approximately 15 years ago (1). Triptans were developed as cranial vasoconstrictors to mimic the desirable effects of serotonin while avoiding its unfavorable adverse effects (2). The developmental rationale was based on the clinical efcacy of serotonin and methysergide, and the scientic rationale that selective constriction of cranial arteriovenous anastomoses would correct the underlying cause of the pain of migraine headache (24). However, triptans not only changed the way clinicians managed acute migraine attacks, but also revolutionized in our understanding of the fundamental anatomy, physiology, and molecular mechanisms involved in the initiation and transmission of pain associated with migraine headache. It is now generally accepted that migraine is a disorder where the initial dysfunction occurs centrally in the brain, with the vascular changes being secondary to neuropeptide transmission at the trigeminovascular junction (5). The understanding that the common nal denominator of migraine pain is the activation and, in many cases, the sensitization of peripheral and central trigeminal nociceptive pathways has led to the development of highly selective compounds designed to inhibit the release or antagonize the downstream effects of neuropeptides released at the trigeminovascular junction or at the central trigeminal synapse (Fig. 1). Advances in our understanding of the receptors expressed on trigeminal afferents and the neuropeptides most important in initiating and maintaining the pain of migraine has led to the development of highly selective receptor targets whose modulation would inhibit the release of these neuropeptides. In this way, the transmission of nociception along
445

446

Schwedt and Dodick

Figure 1 Trigeminal receptor targets at the trigeminovascular junction. The same receptor targets exist at the central synapse within the trigeminal nucleus caudalis. The majority of novel receptor targets for acute migraine therapy reside on the trigeminal nerve terminal endings and are devoid of vasoconstrictor effects. CGRP receptors are located on smooth muscle cells of blood vessels. CGRP antagonists inhibit neurogenic vasodilation mediated by CGRP release from trigeminal nerve terminals. Nitric oxide release from the vascular endothelium may be stimulated by activation of 5HT-2B receptors, but also by activation of inducible and neuronal nitric oxide synthase. Abbreviations: CGRP, calcitonin generelated peptide; serotonin, 5-HT; A1, adenosine A1; ORL-1, opioid receptorlike receptor; VR1, vanilloid receptor; NO, nitric oxide; NMDA/GluR5, ionic and metabotropic glutamate receptors.

peripheral and central trigeminal pathways would be interrupted and pain would be ameliorated or terminated without the need for drugs or the inherent risks associated with drugs that cause vasoconstriction. This discussion will focus on some of these highly selective compounds. In the future, as we learn the mechanisms involved in activating or disinhibiting the trigeminal system, we will unquestionably move closer to the ultimate goal of developing safe and effective compounds to prevent the initiation of migraine attacks.

TRIGEMINAL RECEPTOR TARGETS Serotonin (5-HT) Receptor Triptans, which are 5-HT1B/1D/(1F) agonists, are thought to terminate migraine through neuronal and vascular effects along the trigeminal vascular system. Vasoconstriction of cranial blood vessels is believed to be mediated through the 5-HT1B receptor subtype. Inhibition of neuropeptide [calcitonin generelated peptide

The Future of Migraine Therapies

447

(CGRP)] release, neurogenic inammation, and ring of trigeminal afferents is likely mediated by the agonist activity of triptans at 5-HT1D and 5-HT1F receptors located on the presynaptic nerve terminal endings at the trigeminovascular junction and central synapse (5,6). Because of the presence of 5-HT1B receptors on peripheral and coronary vascular beds, the potential for serious adverse vascular events limits the broad utility of triptans by posing safety concerns in certain populations (7). Consequently, drug discovery programs were established to search for compounds that selectively act at the 5-HT1D and 5-HT1F receptor systems while being devoid of activity at the 5-HT1B receptor.

5-HT1D Receptor PNU-142633 is a highly selective 5-HT1D agonist with at least 1000-fold selectivity for the 5-HT1D receptor compared to the 5-HT1B receptor (8). Preclinical study of PNU-142633 in animal models suggests that the drug is effective in blocking neurogenic inammation and the increase in trigeminal nucleus blood ow normally elicited by stimulation of trigeminal afferents. There is no evidence of a vasoconstrictive effect of the drug on carotid, meningeal, and coronary arteries (8). The safety and tolerability of PNU-142633 was established in a phase I, single-dose, doubleblind, dose-escalation study in which 39 subjects received doses from 1 to 100 mg (9). The most common adverse effects were headache and dizziness with no serious adverse events reported. A randomized, double-blind, placebo-controlled study using a 50 mg oral dose of PNU-142633 for the acute treatment of migraine with or without aura failed to show a signicant treatment effect compared to placebo (10). Two of 34 patients receiving the study medication reported chest pain and three had QTc prolongation on electrocardiography. As this compound was developed using gorilla 5-HT1D receptors, it was a relatively weak agonist when compared to sumatriptan in in vitro studies, and was a poor brain penetrant (11). Therefore, the clinical failure of this compound may reect the use of a poor 5-HT1D agonist at the human receptor than a failure to terminate migraine by agonizing the 5-HT1D receptor. Although this was a failed trial, the preclinical efcacy of 5-HT1D agonists supports continued development of this class of compounds.

5-HT1F Receptor Most of the triptans currently used for the treatment of migraine are potent agonists at the cloned human 5-HT1F receptor (12). Selective 5-HT1F agonists have been shown to inhibit neurogenic inammation in animal models of migraine (1315). The selective 5-HT1F receptor agonist LY334370 has a high afnity for the 5-HT1F receptor with a more than 50-fold binding selectivity over all other serotonin receptors except 5-HT1A (16). Initial in vivo tests suggested that LY334370 exhibits high selectivity for the 5-HT1F receptor with no signicant 5-HT1A agonist activity (17,18). Phase I trials of orally and intravenously administered LY334370 showed its safety and tolerability (19,20). Adverse events with oral doses up to 200 mg and IV doses up to 20 mg included transient and mild to moderate asthenia, dizziness, somnolence, and paresthesias. There was no electrocardiographic evidence of cardiac ischemia after administration of the drug. A placebo-controlled, double-blinded study randomized migraine patients to receive 20, 60, or 200 mg of LY334370 versus placebo for the acute treatment of migraine (21). Headache response, pain-free,

448

Schwedt and Dodick

sustained response, and sustained pain-free rates after two hours were signicantly better in the 60 and 200 mg treatment groups as compared to the placebo group. The 200 mg treatment group showed the most benet with 15 of 21 (71%) patients showing response, 11 of 21 (52%) having sustained response, 8 of 21 (38%) pain-free, and 7 of 21 (33%) with a sustained pain-free response at two hours. Adverse events were similar to those recorded in phase I trials. Eighty percent of patients who received the 200 mg dose of LY334370 reported at least one adverse event, a rate higher than that seen with conventional triptans. Unfortunately, further study of this compound was halted due to systemic toxicity of the drug in animals. These early studies suggest that agonists specic for 5-HT1F receptors are effective for the acute treatment of migraine, and support the concept that drugs with a neuronal mechanism of action, which are devoid of vasoconstrictor activity, may be effective acute antimigraine agents. ADENOSINE RECEPTORS Adenosine has an established antinociceptive effect in humans. Recent ndings suggest that the analgesic effect of adenosine may be mediated by the adenosine A1 receptor (22). The relevance of these ndings to human migraine is based on the recent observations that the A1 receptor protein is localized in human trigeminal ganglia and two selective A1 receptor agonists, GR79236 (23) and GR190178 (24) have been shown to inhibit the peripheral release of CGRP in the cranial circulation as well as at the central trigeminal synapse, thereby preventing activation of central trigeminal neurons (25). The lack of an effect on resting vascular tone and the inhibition of the nociceptive blink reex make A1 receptor agonists potentially feasible for the acute treatment of migraine. DRUGS TARGETING THE ORL-1 RECEPTORS A novel neurotransmitter receptor referred to as opioid receptorlike (ORL)-1 receptor has been identied. Due to structural similarities with the other known opioid receptors, particularly dynorphin A, it has been suggested that it be included in the opioid receptor family with the name of NOP1 (26), although opioid ligands do not activate the ORL-1 receptor (27). The heptadecapeptide nociceptin/orphanin FQ (N/OFQnociceptin) has been identied as the endogenous ligand for the ORL-1 (NOP1) receptor. However, it does not bind to opioidergic m-, d-, or k-receptors (28), nor are the effects of nociceptin antagonized by naloxone (29). Nociceptin seems to be involved in several biological systems and may play a role in central nociceptive processing (29). Nociceptin immunoreactivity and ORL-1 mRNA have been detected in human and cat trigeminal ganglia where it was shown to be colocalized with CGRP, substance P, nitric oxide synthase (NOS), and pituitary adenylate-cyclase activating peptide, suggesting a role in trigeminal sensory transmission and trigeminovascular regulation (30). Furthermore, nociceptin inhibits neurogenic dural vasodilatation (31) elicited by stimulation of trigeminal sensory nerve endings innervating meningeal vessels (32), and nocistatin, an N/OFQ antagonist, has been shown to reverse nociceptin-induced analgesia (33). Neurogenic vasodilation is mediated predominantly by CGRP release from trigeminovascular nerve terminals, and appears to be a predictive preclinical animal model for effective acute antimigraine compounds.

The Future of Migraine Therapies

449

The ORL-1 receptor may therefore offer another selective trigeminal receptor target for acute antimigraine drug development.

VANILLOID RECEPTORS Vanilloid type 1 (VR1) receptors are activated by capsaicin, located on small and medium-sized neurons that are either unmyelinated C-bers or thinly myelinated Ad-bers, and are present on neurons in the human trigeminal ganglia (34). Intravenous capsaicin promotes the release of the proinammatory neuropeptides from trigeminal neurons and has been shown to cause dural extravasation and dural vessel dilation in the rat (35). Capsaicin-induced dural vessel dilation is antagonized by capsazepine (VR1 antagonist) and a CGRP receptor blocker (CGRP837) (36). This nding suggests that VR1 receptor activation may lead to CGRP-induced vasodilation at the trigeminovascular junction, and therefore, the VR1 receptor is potentially a feasible target for the development of antimigraine compounds.

GLUTAMATE RECEPTORS Glutamate, the most abundant excitatory neurotransmitter in the central nervous system, has been implicated in the pathogenesis of migraine. There is an emerging body of preclinical and human evidence to suggest that glutamate may play a pivotal role in the pathogenesis of acute migraine attacks. In animal models, l-glutamate excites trigeminal nucleus caudalis (TNC) neurons (37). Furthermore, glutamate levels rise in the extracellular substrate of the TNC following noxious stimuli to the trigeminal nerve (38). Also in animal studies, a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), kainate (KA), N-methyl-D-aspartate, and metabotropic glutamate receptors have been identied on peripheral and central trigeminal pathways (3941). The discovery that 5-HT1B/D/F receptorpositive neurons in the trigeminal ganglion (TG) are also glutamate-positive suggests that 5-HT1 agonists may inhibit the presynaptic release of glutamate (42). While the evidence for elevated levels of glutamate in migraine sufferers is conicting, several studies have reported higher glutamate plasma levels in migraineurs compared to controls, especially during attacks, and particularly in those with migraine with aura (43,44). In addition, the central role of glutamate in the development of central sensitization supports a role for this excitatory neurotransmitter in acute migraine attacks, given the recent evidence suggesting that approximately 70% of migraine sufferers experience central sensitization during acute migraine attacks (45). LY293558 is an AMPA/KA receptor antagonist and has been tested for the treatment of migraine and pain (4648). The potential role of LY293558 specically in migraine has been investigated in a small pilot study in patients with moderate to severe migraine attacks (47). This was a multicenter, randomized, single-attack study where patients received LY293558 1.2 mg/kg IV (n 13), 6 mg subcutaneous sumatriptan (n 15), or placebo (n 16). Of 45 patients who were enrolled in the study, 44 completed it. Two-hour headache response rates were 69% for LY293558 (p 0.017 vs. placebo), 86% for sumatriptan 6 mg SC, and 25% for placebo. Painfree rates were high for LY293558 (54%) and sumatriptan 6 mg (60%), and low for placebo (6%). In the clinical studies done to date, adverse events reported with LY293558 included mild, transient dizziness, visual distortion, and sedation.

450

Schwedt and Dodick

Collectively, this preclinical, human, and clinical trial data suggest a pathogenetic role for glutamate in acute migraine attacks and supports future research into the clinical effects of glutamate receptor modulators for the treatment of migraine. CGRP RECEPTOR ANTAGONISTS CGRP is one of the several neuropeptides found within the sensory terminals of the trigeminal nerve. In animals, stimulation of TG bers results in release of CGRP, leading to neurogenic vasodilation (49). CGRP levels are increased in the external jugular venous blood during spontaneous migraine attacks with normalization of levels after treatment with sumatriptan (50,51). In migraine sufferers, infusion of human CGRP induces migraine-like headache (50). In a double-blind, placebo-controlled, crossover study, the effect of human CGRP infused intravenously was studied in 10 patients with frequent migraine headache (52). All patients were headache free at the time of infusion. All 10 patients receiving CGRP, but only one patient in the placebo group, experienced headache within 12 hours of infusion. This data suggests that antagonizing the effect of CGRP may provide acute relief of migraine headache. BIBN 4096 BS is the rst, highly potent, nonpeptide CGRP receptor antagonist with a high afnity and specicity for the human CGRP-receptor(53). Animal studies and in vitro studies of human cerebral arteries have shown BIBN 4096 BS to be an effective antagonist at the CGRP receptor (54). The safety and tolerability of BIBN 4096 BS was established in a double-blinded, placebo-controlled, randomized, single-rising dose design study of healthy volunteers (55). Intravenous doses between 0.1 and 10 mg were administered to 41 volunteers. There were no clinically relevant changes in blood pressure, pulse rate, respiratory rate, electrocardiogram, laboratory tests, or forearm blood ow. Eight of the 41 volunteers reported at least one adverse event, two-thirds of which occurred after the 10 mg dose. Adverse events consisted of paresthesias and fatigue. Overall, the safety and tolerability of BIBN 4096 BS was favorable, although tolerated best at doses below 10 mg. A multicenter, randomized, double-blind trial examined the effectiveness of BIBN 4096 BS for the acute treatment of migraine (56). A group-sequential adaptive treatment assignment design was used to minimize exposure of patients to nonefcacious doses and to identify the lowest dose superior to placebo evidenced by a rate of response of at least 60%. Response was dened as the reduction of severe or moderate headache at baseline to mild or no headache at two hours. The 2.5 mg dose was chosen, with a response rate of 66% as compared to 27% for the placebo. BIBN 4096 BS was also found to be superior to placebo in regards to: the pain-free rate at two hours; the rate of sustained response over 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. Adverse events were reported in 25% of patients receiving the 2.5 mg dose, were considered mild to moderate in severity, and consisted mostly of paresthesias. There were no serious adverse events. NOS INHIBITORS Nitric oxide (NO) is an endogenously synthesized short-lived vasodilator, weak oxygen radical, and neurotransmitter that has been implicated in the pathogenesis of migraine headache (57). Platelet levels of cyclic guanosine monophosphate, the second messenger of NO, and NO metabolites such as nitrate/nitrite are increased

The Future of Migraine Therapies

451

at baseline in migraine sufferers and rise further during attacks (58,59). Intravenous infusions of glyceryl trinitrate (GTN), an exogenous NO donor, and histamine, a stimulator of NO release from vascular endothelium, have been demonstrated to cause a delayed (four to six hours) but typical migraine headache in migraine patients (60,61). While the mechanism underlying the ability of NO to induce migraine is unclear, the induction of dural mast cell degranulation and dural plasma protein extravasation (neurogenic inammation) has been demonstrated in animal models after an infusion of GTN (62). This occurs because of delayed induction of gene and cytokine expression with the production of inammatory mediators such as interleukin (IL)-1b and IL-6 (62). The effect of NOS inhibition on neuronal activity in the trigeminal nucleus has been studied in the rat (63). Extracellular impulse activity was recorded from neurons in the rat spinal trigeminal nucleus, with afferent input from the dura mater. As compared to placebo, infusion of an NOS inhibitor signicantly reduced neuronal activity, suggesting that NO plays a role in the ongoing activity of sensitized neurons in the trigeminal nucleus. The effect of an NOS inhibitor, L-NG methylarginine hydrochloride (546C88), was tested in a controlled study in which 15 patients received the experimental therapy and were compared to historical placebo controls (64). The treatment group received intravenous infusion of 546C88, at 6 mg/kg, during an acute attack of migraine without aura. Two hours after infusion, 10 of 15 patients who had received the NOS inhibitor experienced headache relief as compared to 2 of 14 placebo-treated patients. Three of the 10 patients in the treatment group who responded by two hours required rescue medication for headache after two hours. Four of the remaining seven patients in the initial response group had headache recurrence within 4 to 16 hours after infusion. Although patients reported only minimal symptomatic adverse effects after infusion of 546C88, there were signicant but asymptomatic increases in mean arterial pressures (maximum 17%) and decreases in heart rate (maximum 21%). This study suggests that NOS inhibitors may be effective in the acute treatment of migraine. However, signicant alterations in the systemic arterial blood pressure and heart rate would be unacceptable. It is noteworthy that 546C88 is a nonspecic NOS inhibitor acting on all three types of NOS: endothelial, neuronal, and inducible (65). The development of more specic NOS inhibitors that target inducible NOS, present to a large extent in dural macrophages and responsible for the delayed neurogenic inammatory response seen after GTN infusion, is desirable and may prove to be effective for the treatment of migraine.

PHARMACOGENOMICS Migraine is a complex genetic disorder, likely governed by multiple genetic factors that may differ from patient to patient. Identication of genetic variants that increase susceptibility to migraine and specic migraine subtypes will lend further knowledge regarding the pathophysiology of migraine headache and the most effective treatment options. Understanding molecular mechanisms of migraine at an individual level will allow for the development of new classes of more specic acute and prophylactic migraine therapies. Familial hemiplegic migraine, the only known autosomal dominant migraine subtype, has been mapped to the CACNA1A gene on chromosome 19 (66), encoding a brain-specic P/Q-type calcium channel gene, and the ATP1A2 gene on chromosome 1,

452

Schwedt and Dodick

encoding a sodiumpotassium adenosine triphosphatase pump. Both of these mutations cause disturbances in ionic ux across neuronal membranes, alterations in resting membrane potential, and abnormalities in neuronal excitability. The neuronal voltagegated P/Q calcium channel also regulates the release of serotonin and excitatory neurotransmitters such as glutamate. Multiple gain-of-function phenotypes result from the creation of a knock-in mouse model carrying the human mutation in the CACNA1A gene (67). The mice were noted to have enhanced neurotransmission at the neuromuscular junction, as well as a reduced threshold and increased velocity of cortical spreading depression. This nding implies a possible role for this gene and its product in the pathogenesis of cortical spreading depression. Although the contribution of CACNA1A mutations in more common forms of migraine awaits further study, it can be postulated that pharmacotherapy targeting voltage-gated PQ calcium channels may be effective for the treatment of migraine. As gene proling becomes more available, migraine treatment may become individualized according to a patients likelihood of responding to specic medications. Polymorphisms of the serotonin receptor have been hypothesized to alter the effectiveness of serotonin agonists. A pharmacogenomic study of a possible relation between 5-HT1B polymorphisms (G801C and T-261G) and effectiveness of sumatriptan in migraine treatment showed no signicant difference (68). Other polymorphisms have been shown to negatively affect binding of dihydroergotamine (DHE) and sumatriptan (69,70). From such data, one could not postulate that DHE and sumatriptan would have differing effects in patients with these polymorphisms. As genetic mutations are better dened and testing becomes more cost effective, genetic proling may become part of the standard diagnostic protocol for migraine patients. This will allow for more informed decisions regarding optimal prevention and acute treatment of migraine.

SUMMARY The foundation for advances in migraine therapy has been laid by a better understanding of the underlying anatomy and pathophysiology of this disorder over the past two decades. Migraine is an inherited brain disorder characterized by, among other features, headaches that are due to recurrent activation of peripheral and central trigeminovascular pathways. The discovery of receptor subtypes located on trigeminovascular afferents and their pharmacology, as well as the neuropeptides involved in neurogenic vasodilation and central trigeminal activation, has led to a host of molecular targets for acute migraine therapy that may not only prove effective, but also be devoid of vasoconstrictor activity and therefore the potential for adverse vascular effects. An understanding of the mechanisms by which the trigeminovascular system becomes abnormally activated or disinhibited will undoubtedly lead to novel prophylactic therapies. Compounds that block cortical spreading depression may prove useful in those patients who have migraine with aura, while molecules that selectively inhibit the ring of central trigeminovascular neurons may provide effective prevention for those with or without aura. The identication of genetic mutations in familial hemiplegic migraine, loci associated with increased susceptibility to migraine, and receptor polymorphisms altering the binding of migraine medications have been important discoveries in the realm of pharmocogenomics. Future research in the pharmacogenomics of migraine may uncover novel therapeutic targets and the ultimate possibility of individualized treatment strategies (71,72).

The Future of Migraine Therapies

453

REFERENCES
1. Villalon CM, Centurion D, Valdivia LF, De Vries P, Saxena PR. An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy [Review]. Proc West Pharmacol Soc 2002; 45:199210. 2. Humphrey PPA, Feniuk W, Perren MJ, Beresford IJM, Skingle M, Whalley ET. Serotonin and migraine. Ann New York Acad Sci 1990; 600:587598. 3. Lance JW, Fine RD, Curran DA. An evaluation of methysergide in the prevention of migraine and other vascular headache. Med J Aust 1963; 1:814818. 4. Johnston BM, Saxena PR. The effect of ergotamine on tissue blood ow and the arteriovenous shunting of radioactive microspheres in the head. Br J Pharmacol 1978; 63:541549. 5. Goadsby PJ, Lipton RB, Ferrari MD. Migraine-current understanding and treatment. N Engl J Med 2002; 346:257270. 6. Humphrey PPA, Goadsby PJ. Controversies in headache. The mode of action of sumatriptan is vascular? A debate. Cephalalgia 1994; 14:401410. 7. Maassen VanDenBrink A, Reekers M, Bax WA, et al. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 1998; 98:2530. 8. McCall RB, Huff R, Chio CL, et al. Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633. Cephalalgia 2002; 22(10):799806. 9. Fleishaker JC, Pearson LK, Knuth DW, et al. Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F. Int J Clin Pharmacol Ther 1999; 37(10):487492. 10. Gomez-Mancilla B, Cutler NR, Leibowitz MT, et al. Safety and efcacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine.[see comment]. Cephalalgia 2001; 21(7):727732. 11. Pregenzer JF, Alberts GL, Im WB, et al. Differential pharmacology between the guineapig and the gorilla 5-HT1D receptor as probed with isochromans (5-HT1D-selective ligands). Br J Pharmacol 1999; 127:468472. 12. Adham N, Kao HT, Schecter LE, et al. Cloning of another human serotonin receptor (5-HT1F): a fth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci USA 1993; 90(2):408412. 13. Shepheard S, Edvinsson L, Cumberbatch M, et al. Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370. Cephalalgia 1999; 19(10):851858. 14. Johnson KW, Schaus JM, Durkin MM, et al. 5-HT1F receptor agonists inhibit neurogenic dural inammation in guinea pigs. Neuroreport 1997; 8(910):22372240. 15. Phebus LA, Johnson KW, Zgombick JM, et al. Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding afnities, brain penetration and activity in the neurogenic dural inammation model of migraine. Life Sci 1997; 61(21): 21172126. 16. Bouchelet I, Case B, Olivier A, Hamel E. No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery. Br J Pharmacol 2000; 129(3):501508. 17. Ramadan NM, Skljarevski V, Phebus LA, Johnson KW. 5-HT1F receptor agonists in acute migraine treatment: a hypothesis [Review]. Cephalalgia 2003; 23(8):776785. 18. Overshiner CD, Adham N, Zgombick JM, Brancheck JA, Calligaro DO, Phebus LA. LY334370 is selective for the cloned 5-HT1F receptor. Soc Neurosci 1996; 22(Abstr):1331. 19. Pereira A, Granier LA, Vandenhende F, de Suray JM, Onkelinx C. Safety and pharmacokinetics of high doses of LY334370, a selective serotonin 1F receptor agonist (SSOFRA), during and outside an acute migraine attack. Cephalalgia 1999; 19(Abstr):368. 20. Granier LA, Gossen D, Vandenhende F. Safety, pharmacokinetics, and efcacy of intravenous LY334370. Cephalalgia 2000; 20(Abstr):351352. 21. Goldstein DJ, Roon KI, Offen WW, et al. Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial [see comment]. Lancet 2001; 358(9289):12301234.

454

Schwedt and Dodick

22. Sawynok J, Sweeney MI, White TD. Classication of adenosine receptors mediating antinociception in the rat spinal cord. Br J Pharmacol 1986; 88:923930. 23. Gurden MF, Coates J, Ellis F, et al. Functional characterization of three adenosine receptor types. Br J Pharmacol 1993; 109:693698. 24. Sheehan MJ, Wilson DJ, Cousins R, Giles H. Relative intrinsic efcacy of adenosine A1 receptor agonists measured using functional and radioligand binding. Br J Pharmacol 2000; 131:34P. 25. Goadsby PJ, Hoskin KL, Storer RJ, Edvinsson L, Connor HE. Adenosine (A1) receptor agonists inhibit trigeminovascular nociceptive transmission. Brain 2002; 125:13921401. 26. Mogil JS, Pasternak GW. The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 2001; 53:381415. 27. Reinscheid RK, Nothacker HP, Bourson A, et al. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 1995; 270:792794. 28. Darland T, Grandy DK. The orphanin FQ system: an emerging target for the management of pain? Br J Anaesth 1998; 81:2937. 29. Xu X, Grass S, Hao J, Xu IS, Wiesenfeld-Hallin Z. Nociceptin/orphanin FQ in spinal nociceptive mechanisms under normal and pathological conditions. Peptides 2000; 21: 10311036. 30. Hou M, Tajti J, Uddman R, Edvinsson L. Demonstration of nociceptin positive cells and opioid-receptor like-1 in human trigeminal ganglion. Cephalalgia 2001; 21:402. 31. Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural blood vessel diameter in the anaesthetized rat. Cephalalgia 1997; 17:518524. 32. Bartsch T, Akerman S, Goadsby PJ. The ORL-1 (NOP1) receptor ligand nociceptin/ orphanin FQ (N/OFQ) inhibits neurogenic vasodilatation in the rat. Neuropharmacology 2002; 43:991998. 33. Okuda-Ashitaka E, Minami T, et al. Nocistatin, a peptide that blocks nociceptin action in pain transmission. Nature 1998; 392:286289. 34. Hou M, Uddman R, Tajti J, Kanje M, Edvinsson L. Capsaicin receptor immunoreactivity in the human trigeminal ganglion. Neurosci Lett 2002; 330:223226. 35. Markowitz S, Saito K, Moskowitz MA. Neurogenically mediated leakage of plasma proteins occurs from blood vessels in dura mater but not brain. J Neurosci 1987; 7: 41294136. 36. Akerman S, Kaube H, Goadsby PJ. Vanilloid type 1 receptor (VR1) evoked CGRP release plays a minor role in causing dural vessel dilation via the trigeminovascular system. Br J Pharmacol 2003; 140:718724. 37. Hill RG, Salt TE. An ionophoretic study of the responses of rat caudal trigeminal nucleus neurons to non-noxious mechanical sensory stimuli. J Physiol 1982; 327:6578. 38. Bereiter DA, Benetti, AP. Excitatory amino acid release within spinal trigeminal nucleus after mustard oil injection into the temporomandibular joint region of the rat. Pain 1996; 67:451459. 39. Sahara Y, Noro N, Iida Y, Soma K, Nakamura Y. Glutamate receptor subunits GluR5 and KA-2 are coexpressed in rat trigeminal ganglion neurons. J Neurosci 1997; 17:66116620. 40. Quartu M, Serra MP, Ambu R, Lai ML, Del Fiacco M. AMPA-type glutamate receptor subunits 2/3 in the human trigeminal sensory ganglion and subnucleus caudalis from prenatal ages to adulthood. Mech Ageing Dev 2002; 123:463471. 41. Tallaksen-Greene SJ, Young AB, Penney JB, Beitz AJ. Excitatory amino acid binding sites in the trigeminal principal sensory and spinal trigeminal nuclei of the rat. Neurosci Lett 1992; 141:7983. 42. Ma QP. Co-localization of 5-HT (1B/1D/1F) receptors and glutamate in trigeminal ganglia in rats. Neuroreport 2001; 12:15891591. 43. Alam Z, Coombes N, Waring RH, Williams AC, Steventon GB. Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache. J Neurol Sci 1998; 156:102106.

The Future of Migraine Therapies

455

44. Ferrari MD, Odink J, Bos KD, Malessy MJ, Bruyn GW. Neuroexcitatory plasma amino acids are elevated in migraine. Neurology 1990; 40:15821586. 45. Burstein R, Jakubowski M, Collins B. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol 2004; 55:1926. 46. Sang CN, Hostetter MP, Gracely RH, et al. AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Anesthesiology 1998; 89:10601067. 47. Sang CN, Ramadan NM, Wallihan RG, et al. LY293558, a novel AMPA/GluR5 antagonist, is efcacious and well-tolerated in acute migraine. Cephalalgia 2004; 24: 596602. 48. Gilron I, Max MB, Lee G, et al. Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain. Clin Pharmacol Ther 2000; 68(3):320327. 49. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23(2):193196. 50. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28(2):183187. 51. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33(1):4856. 52. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia 2002; 22(1):5461. 53. Doods H, Hallermayer G, Wu D, et al. Pharmacological prole of BIBN4096BS, the rst selective small molecule CGRP antagonist. Br J Pharmacol 2000; 129(3):420423. 54. Moreno MJ, Abounader R, Hebert E, Doods H, Hamel E. Efcacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment. Neuropharmacology 2002; 42(4):568576. 55. Iovino M, Feifel U, Young CL, Wolters JM, Wallenstein G. Safety, tolerability and pharmacokinetics of BIBN 4096 BS, the rst selective small molecule calcitonin generelated peptide receptor antagonist, following single intravenous administration in healthy volunteers. Cephalalgia 2004; 24(8):645656. 56. Olesen J, Diener HC, Husstedt IW, et al. BIBN 4096 BS Clinical Proof of Concept Study Group. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine [see comment]. N Engl J Med 2004; 350(11):11041110. 57. Olesen J, Thomsen LL, Lassen LH, Olesen IJ. The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia 1995; 15(2):94100. 58. Shimomura T, Murakami F, Kotani K, Itawa S, Kono S. Platelet nitric oxide metabolites in migraine. Cephalalgia 1999; 19:218222. 59. Stepian A, Chalimoniuk M. Level of nitric-oxide dependent cyclic GMP in patients with migraine. Cephalalgia 1998; 18:631634. 60. Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1994; 1:7380. 61. Lassen LH, Thomsen LL, Olesen J. Histamine induces migraine via the H1-receptor. Support for the NO hypothesis of migraine. Neuroreport 1995; 6(11):14751479. 62. Reuter U, Bolay H, Jansen-Olesen I, et al. Delayed inammation in rat meninges: implications for migraine pathophysiology. Brain 2001; 124:24902502. 63. De Col R, Koulchitsky SV, Messlinger KB. Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport 2003; 14(2):229232. 64. Lassen LH, Ashina M, Christiansen I, et al. Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia 1998; 18(1):2732.

456

Schwedt and Dodick

65. Lassen LH, Iversen HK, Olesen J. A dose-response study of nitric oxide synthase inhibition in different vascular beds in man. Eur J Clin Pharmacol 2003; 59:499505. 66. Ducros A, Tournier-Lasserve E, Bousser MG. The genetics of migraine. Lancet Neurol 2002; 1(5):285293. 67. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, et al. A CACNA1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004; 41(5):701710. 68. Maassen VanDerBrink A, Vergouwe MN, Ophoff RA, Saxena PR, Ferrari MD, Frants RR. 5-HT1B receptor polymorphisms and clinical response to sumatriptan. Headache 1998; 38:288291. 69. Bruss M, Bonisch H, Buhlen M, Nothen MM, Propping P, Gothert M. Modied ligand binding to the naturally occurring Cys-124 variant of the human serotonin 5-HT1B receptor. Pharmacogenetics 1999; 9(1):95102. 70. Lappalainen J, Zhang L, Dean M, et al. Identication, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Genomics 1995; 27(2):274279. 71. Honey AC, Bland-Ward PA, Connor HE, Feniuk W, Humphrey PP. Study of an adenosine A1 receptor agonist on trigeminally evoked dural blood vessel dilation in the anaesthetized rat. Cephalalgia 2002; 2002; 22:260264. 72. Moskowitz MA. Neurogenic inammation in the pathophysiology and treatment of migraine [Review]. Neurology 1993; 43(6 suppl 3):S16S20.

29
Tension-Type Headache
Rigmor Jensen
Department of Neurology, The Danish Headache Center, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark

INTRODUCTION Tension-type headache (TTH) is the most prevalent primary headache (1) and is usually considered a normal headache type both by patients and their doctors. Furthermore, in specialized headache clinics, the vast majority of patients present with migraine or secondary headaches as their main problem and due to very little academic or pharmaceutical interest, less disabling headaches, such as TTH, are frequently missed. Nevertheless, TTH is a substantial problem in the general population and represents a major confounder in the diagnostic and therapeutic process of the complicated headache patient. In a comparative study by Russell et al. where headache diagnosis from a clinical interview was compared to the diagnosis from a prospective headache diary, less than 50% of the patients who reported episodic TTH during the clinical interview were actually identied. The opposite pattern was seen with migraine (2). Because very recent epidemiological data clearly demonstrate a poor prognosis and a very high socioeconomic impact in patients with coexisting migraine and TTH compared to that in patients with pure migraine, the correct diagnosis and the precise treatment of TTH are very important (3). Several instruments have been developed to help in the recognition of TTH both by doctors and their patients, but specic diagnostic tests are still lacking for the complicated headache patient with several different headache disorders. The rst edition of the International Classication of Headache Disorders (ICHD-1) (4) clearly delineated and dened the disorder, and distinguished between an episodic type that occurs in less than half of all days and a chronic type that occurs in half of all days or more and in the majority of cases daily. The second edition of the ICHD (ICHD-2) (5) subdivided episodic TTH into an infrequent form (happening less than 1 day per month or less than 12 days per year) and a frequent episodic form (occurring between 12 to 180 days per year) (Table 1) (5). Where infrequent episodic TTH can be regarded as an irritant, not a disease, frequent episodic TTH and especially the chronic TTH may be disabling disorders, sometimes associated with medication overuse, poorer prognosis, higher socioeconomic impact, and decrease in the quality of life (3,610).
457

458 Table 1 Episodic TTH: Headache Types Infrequent episodic TTH Infrequent episodic TTH associated with pericranial tenderness Infrequent episodic TTH not associated with pericranial tenderness Frequent episodic TTH Frequent episodic TTH associated with pericranial tenderness Frequent episodic TTH not associated with pericranial tenderness
Abbreviation: TTH, tension-type headache.

Jensen

The classication of frequent headaches by the ICHD-1 has been most controversial, and much effort has been spent with various attempts to improve the diagnostic criteria of frequent headaches (3,9,1113). In 1994, Silberstein et al. introduced the term chronic daily headache (CDH) to designate headaches lasting for four hours or more and occurring 15 days or more per month (12). The CDHs are discussed in Chapter 3 of this book. As originally proposed, the CDHs are subdivided into transformed migraine, chronic TTH, new daily-persistent headache, and hemicrania continua (12). It is our opinion that the denition of CDH is broad and unspecic without implying any possible etiology, just as arterial hypertension is a common broad term irrespective of the underlying cause. The CDH denition proposed by Silberstein et al. (12) has become quite popular, especially in clinical practice, where it is easy to use but is not included in ICHD-2 (4). Herein we focus on the TTH as dened by the ICHD-2. THE EPIDEMIOLOGY OF TTH Several epidemiological studies of various aspects of TTH have been published (1429), all based on the diagnostic criteria of ICHD-1 (3). It is meaningless to discuss the prevalence of TTH if the frequency of attacks is not considered. In the Danish epidemiological studies, the vast majority of the general population (namely 5159%) had infrequent TTH (one day per month or less) and did not require specific medical attention (29,30). In most studies, 18% to 37% had TTH several times a month, 10% to 25% had it weekly, and 2% to 6% of the population had chronic TTH usually lasting for the greater part of their lifetime (16,20,27,28,31). Thus, when subjects with infrequent TTH are excluded, comparison of the studies reveals a high degree of concordance between the prevalence of frequent episodic and chronic TTH. A very recent population study of adults reported an increase in frequent episodic and chronic TTH in accordance with a similar study from Sweden (29,32). Daily or near daily headaches account for 40% to 50% of the patients in specialized headache clinics (9,23,33,34), although the prevalence in the general population is much lower, between 4% and 5% (18,23). There is considerable debate regarding terminology, and this affects the denition used in the epidemiological studies (35). The terms chronic daily headache or CDH are widely used in the literature but are not internationally accepted and are not included in either version of the ICHD. Many prefer to only designate the daily occurrence of various subgroups of headache. The vast majority of these patients may also have medication overuse headache (MOH). Distinguishing chronic tension-type headache (CTTH) from migraine and CTTH from MOH is a substantial, diagnostic challenge. It is, however, of importance because management of these headaches is completely different (35).

Tension-Type Headache

459

Sex and Age Distribution of TTH The average age for the onset of TTH is between 20 and 30, slightly older than what is seen in migraine (2730). The prevalence seems to peak in the third to fourth decennium between the age of 20 and 39 and then declines with increasing age in both genders (2730). The male:female ratio of TTH is 4:5 indicating that, unlike migraine, females are only slightly more affected (2730). Studies of younger children have shown an equal prevalence in males and females, with the female preponderance starting in adolescence (32). Natural History of TTH There is little information on the prognosis of TTH. The mean duration of TTH was 10.3 years in the German population study (28) and 17 to 20 years in clinical studies of chronic TTH (36,37), illustrating the life-time consistency of this disorder. In a Danish 12-year epidemiological follow-up study, the prognosis was fairly favorable, with reduced frequency or remission in 47% of subjects with chronic TTH (5). On the other hand, the vast majority of patients with chronic TTH had evolved from the episodic form over many years (5,38). This is conrmed by pathophysiological studies indicating that peripheral and central sensitization play a prominent role, and patients with frequent episodes of headache are at risk of developing the chronic and more treatment-resistant form of TTH (39,40). Depression, anxiety, coexisting active migraine, sleeping problems, and medication overuse are usually considered as predictors for a poor outcome, but only few of these can be conrmed in a follow-up study (5). Sociodemographic Factors Related to TTH A number of demographic factors besides sex and age have been studied in TTH. European population studies have shown a fairly uniform prevalence of TTH in various social groups (41,42), whereas a large U.S. study has reported an increased risk for chronic tension-type headache (CTTH) in less-educated or lower-income groups (27). There are at least two plausible reasons for a link between headache disorders and income. Poor living conditions, stress, or poor access to health care could lead to an increased prevalence of headache disorders. Alternatively frequent headaches might lead to difculties with work or career advancement. This could lead to a downward drift in socioeconomic status. Racial differences have also been reported in the U.S. study and prevalence of TTH was signicantly higher in whites than in African-Americans, in both men and women (27). Overall, the prevalence of CTTH is fairly uniform among races. Socioeconomic Impact of TTH The socioeconomic burden of headaches includes direct costs associated with health care utilization and indirect costs associated with missed work due to sickness absence or reduced efciency. In most studies, TTH is not separately listed, but because of its high prevalence, it probably accounts for at least some of the disability due to headache disorders in general. Functional impairment and abolished working capacities were described by at least 60% of persons with TTH and accounted for 64% of the reduction in working capacity due to headaches, whereas migraineurs usually had higher rates of absence from work (1,27,4347).

460

Jensen

Utilization of Medical Services Only 16% of patients with TTH have been in contact with their general practitioner for headache, in contrast to 56% of migraineurs (46). When the data are corrected for the markedly higher prevalence of TTH, the total use of medical services is however 54% higher for TTH. In Chile, consultation rates in TTH sufferers were 39% compared to 63% in migraineurs, and younger age or moderate-to-severe pain intensity increased the likelihood of medical consultation (21). Although TTH is not the most visible syndrome, it is one of the most costly to the society, costing roughly four times more than that for epilepsy and more than twice the cost for migraine. Estimates of socioeconomic loss due to TTH should therefore include direct costs as well as indirect costs associated with lost workplace productivity.

THE CLINICAL PRESENTATION OF TTH Most patients with the episodic forms of TTH report that their headaches usually are mild in intensity and relatively short lasting, lack the migraine-associated incapacitating symptoms of nausea and vomiting, and usually respond to simple analgesics, whereas the patients with the chronic forms report a constant pressing, moderate headache that is unrelated to daily hassles, stress, and holidays, and completely refractory to most analgesics (Table 2). As patients in headache clinics tend to focus on their most severe and most recent headaches, usually their migraines, the clinical picture of TTH is therefore not as well described as it is for most other primary headache disorders. Characteristics of Pain Patients usually describe their pain as a dull, nonpulsating headache, and terms such as a sensation of tightness, pressure, or soreness are often employed; some patients refer to it as a band or a cap compressing their head, while others
Table 2 Diagnostic Criteria for Frequent Episodic TTH A. B. C. At least 10 episodes occurring on !1 but <15 days per month for at least three months (!12 and <180 days/year) and fullling criteria BD Headache lasting from 30 mins to 7 days Headache has at least two of the following characteristics: Bilateral location Pressing/tightening (nonpulsating) quality Mild or moderate intensity Not aggravated by routine physical activity such as walking or climbing stairs Both of the following: No nausea or vomiting (anorexia may occur) No more than one of photophobia or phonophobia Not attributed to another disordera

D.

E.
a

History and physical and neurological examinations do not suggest any of the disorders listed in groups 5 to 12, or history and/or physical and/or neurological examinations do suggest such a disorder, but it is ruled out by appropriate investigations, or such a disorder is present but headache does not occur for the rst time in close temporal relation to the disorder. Abbreviation: TTH, tension-type headache.

Tension-Type Headache Table 3 Diagnostic Criteria for Probable Frequent Episodic TTH Probable frequent episodic TTH Diagnostic criteria: Episodes fullling all but one of criteria AD for 2.2 Frequent episodic TTH Episodes do not fulll criteria for 1.1 Migraine without aura Not attributed to another disorder
Abbreviation: TTH, tension-type headache.

461

mention a big weight over their head and/or their shoulders (48). The pressing quality was conrmed in later studies, because it was present in 78% of 488 subjects with episodic tension-type headache (ETTH) from the general population (49). A pulsating character occurs seldom or never in 80% to 86% of the patients from clinical populations (50,51). The most frequent pain quality in TTH is thus nonpulsating and pressing, although, it may be experienced as periodically pulsating during severe pain episodes. Subjects that ll all but one criterion for TTH should be classied as having probable TTH (Table 3). Severity of Pain According to the ICHD, the pain of TTH is typically of mild or moderate intensity (3,4,49). In a population-based study, the pain was mild or moderate in 87% to 99% of subjects with ETTH (49). This corresponds well with a recent clinical study of Zeeberg et al. where the mean intensity was 1.2 on a 0 to 3 scale (52). The severity of TTH increases markedly with increasing frequency, as 76% of subjects with more than 30 days of headache per year report moderate or severe intensity compared to 50% of those with less frequent headache (49,53,54). These data would appear to conrm the clinical impression that TTH is a graded phenomenon with headache intensity increasing as headache frequency increases, in contrast to a migraine attack, which is an all-or-none phenomenon that runs its course once started. The clinical characteristics of TTH in migraineurs and in nonmigraineurs were compared in a large epidemiological study of 4000 subjects (54). The one-year prevalence of TTH and the male:female ratio were similar in migraineurs and in nonmigraineurs, whereas the frequency of TTH attacks was higher and the episodes lasted signicantly longer in the migraineurs compared to those who have never had migraine. It must also be kept in mind that for the primary headache disorders such as migraine and episodic TTH, there is still no gold standard for diagnosis and, especially, the severity criteria is debated because an early treatment may have a signicant inuence on the pain intensity. In the Spectrum Study after diary review, 32% of patients with disabling episodic TTH were reclassied as having ICHD migraine (55). Even after careful diary review, however, 63% of the original 75 subjects with disabling episodic TTH retained their diagnosis (55). Thus, it seems clear that a signicant proportion of people who have TTH suffer important disability as a result of their headache, and that many patients may suffer from both TTH and from migraine. The Location of Pain The pain of TTH is typically bilateral, and this was reported by 90% of subjects in a Scandinavian population study (25). Nevertheless, pain does not always occur in the

462

Jensen

same location; varying pain sites associated with varying intensities are often reported by the patients. A band-like topography including frontal and occipital areas is however common. Lack of aggravation of the pain by physical activities is typical of TTH. This criterion has been shown to be one of the best pain criteria to distinguish TTH from migraine, as 72% to 83% of subjects with the episodic form in population studies (25,28) and 84% in a prospective diary study (56) reported no aggravation of pain by routine physical activity, in contrast to only 4% of migraineurs (25). Accompanying Symptoms Presence of nausea and vomiting actually rules out the diagnosis of infrequent or frequent episodic TTH, and yet there are no studies analyzing the frequency of such symptoms in relation to ICHD-2 (4). Nevertheless, 18% of subjects with TTH according to the ICHD-1 have reported mild or moderate anorexia during the headache episode and only 2% were excluded due to nausea (25,49). Photophobia or phonophobia may be present, while presence of both symptoms is not allowed. Mild photophobia was present in 10% and mild phonophobia in 7% of episodic TTH subjects, although in most subjects, their appearance was occasional (25,49). Nevertheless, the presence of these accompanying symptoms had no inuence on the pain characteristics, as not only two, but more frequently, three or all four pain characteristics were fullled in subjects with episodic TTH irrespective of accompanying symptoms. In the large epidemiological study, the pain characteristics and the accompanying symptoms of the episodes of TTH were very similar in those with and without migraine, and therefore it was concluded that TTH and migraine are separate disorders and not part of a continuum, although they may coexist in many patients (49,52,54). However, migraine may aggravate or even precipitate TTH, conrming the impression from headache clinics, where the vast majority of migraine patients also have coexisting TTH (52).

PHYSICAL EXAMINATION IN SUBJECTS WITH TTH The diagnosis of TTH requires exclusion of other causative disorders. Therefore, it is mandatory to base the diagnosis on an extensive history of the evolution of the patients pain and other symptoms, and a careful physical and neurological examination. The physical examination should also include a manual palpation of the pericranial muscles to identify tender points and trigger points. Tender points are areas where manual pressure induces local pain, and trigger points are areas of localized deep tenderness where sustained pressure also induces referred pain in another area in the region. At a minimum, pericranial tenderness should be assessed by manual palpation of the temporal, lateral pterygoid, masseter, sternocleidomastoid, and trapezius muscles. The muscle insertion areas such as the mastoid process and the neck muscle insertions should also be palpated (39,56,57). Pain sensitivity assessed by pressure algometer and electromyography (EMG) recordings has been widely used in research, but due to high intersubject variability, plays no role in routine practice and has now been omitted from ICHD-2 (4). In patients with TTH, increased tenderness in pericranial muscles is the most consistent abnormal nding and increases with increasing frequency and intensity of TTH. Subjects with the episodic form have

Tension-Type Headache

463

increased total tenderness score (TTS) score compared to migraineurs and healthy controls, but are less tender than subjects with CTTH (5658). The cervical spine should be examined for restricted and painful movements, whereas (59,60) cervical radiological examination should not be recommended unless local pathology is suspected clinically, because the prevalence of organic cervical spine lesions in TTH is equivalent to other headache disorders (60). PSYCHOLOGICAL ASPECTS OF TTH TTHs are generally reported to occur in relation to emotional conict and psychosocial stress but the causeeffect relation is still unclear. In most studies, stress and mental tension were the most frequently reported precipitating factors, but occurred with similar frequency in TTH and migraine (54,61). These results are in keeping with the ndings of largely normal personality proles in subjects with episodic TTH (41,61). In both epidemiological and clinical studies, the most important predictor for depression and psychopathology was chronicity, and a fairly high prevalence of depression and anxiety has been identied in chronic TTH. In conclusion, some of the psychosocial and personality factors suspected in the past to cause headache may be the result of specic coping strategies or the result of recurrent pain rather than the primary cause of the headache. In a controlled study, Holroyd et al. reported that a number of personality factors such as depression, anxiety, and somatization, which were highly abnormal during ongoing pain, normalized again when patients were retested outside the pain period (45,62). In general, psychological abnormalities in most TTH sufferers may be viewed as secondary to headache, but the exact causeeffect relationship suggests further studies. PATHOPHYSIOLOGY It has been suggested that TTH and migraine share some common biology as they frequently coexist in severely affected individuals. In population studies, TTH and migraine, however, differ in gender ratio, age distribution, and clinical presentation (25,27). Therefore, it could be argued that the continuum theory is an artifact of referral bias in headache clinics. It is most likely that migraine and TTH are closely linked but biologically different disorders. Some traits are shared also in migraine and cluster headache, but no headache specialists will claim that migraine and cluster headache are part of a continuum just because both headaches often are unilateral or respond to triptans. It may, therefore, be proposed that migraine may be a precipitating factor to TTH in genetically predisposed individuals, and probably also vice versa. A detailed genetic characterization of the headache patient may help us to improve the clinical description and perhaps also lead to a specic individualized treatment strategy. The most likely explanation of the pathophysiological similarities between migraine and TTH is that activation of the trigeminal system may be of pivotal importance in both the disorders. In migraine, activation may predominantly be induced by stimuli from e.g., pericranial vessels and brainstem structures, while nociceptive or non-nociceptive stimuli from pericranial tissues may be most important in TTH. Thus, the pain pathways may be shared in the two disorders. Likewise, central sensitization may play an important role for both primary headaches because it has been suggested that very frequent migraine attacks may induce a permanent central sensitization in

464

Jensen

the trigeminal system, and as early as 1996, such sensitization has been demonstrated to play a major role in CTTH (39,40,63). As most patients with CTTH have started with ETTH one or two decades earlier, the process of central sensitization may be a common denominator for both migraine and TTH in their chronic manifestations. To summarize, peripheral myofascial sensitization is probably of importance in ETTH, whereas sensitization of pain pathways in the central nervous system due to prolonged nociceptive stimuli from pericranial myofascial tissues or a genetic predisposition seems to be responsible for the conversion of episodic to chronic TTH. This hypothesis may lead to future understanding of pathophysiology and treatment. TREATMENT Nonpharmacological Techniques It is an absolute prerequisite for successful treatment to establish an accurate diagnosis where the individual headache episode is identied and separated from migraine or a secondary headache, most frequently medication-overuse headache. In particular, identication of a high intake of analgesics is essential because other treatments are usually ineffective in the presence of medication overuse. Second, avoidance of any possible trigger factors such as nonphysiological working positions, psychosocial stress, unbalanced meals, and inadequate sleep is also important. Furthermore, identication and treatment of signicant comorbidities, e.g., anxiety or depression, should also be done. Another important element in treating TTH patients is to take their complaints seriously, to show empathy, to examine them thoroughly, and to inform them about their headache because many of the patients have been met with medical ignorance and lack of interest for years. The present treatment strategy is largely empiric and can be divided into nonpharmacological treatment, acute pharmacological treatment, and pharmacological prophylaxis. Nonpharmacological treatment is widely used for TTH but is rarely evidence based. Physical therapy is the most common therapy and includes relaxation and exercise programs, improvement of posture, hot and cold packs, and ultrasound and electrical stimulation, but the majority of these modalities have not been properly evaluated. A recent controlled study reported the modest effect of a standardized eight-week physiotherapy program, which included relaxation techniques and smooth stretching and daily muscle exercise at home (64). Spinal manipulation and acupuncture have also been extensively used but the amount of evidence is insufcient for nal conclusion (65). Relaxation training is a self-regulation strategy that aims to provide patients with signicant stress with an ability to consciously reduce muscle tension and general arousal, which can precipitate headaches. Cognitive-behavioral therapy (stress management) aims also to reduce emotional and physiologic arousal, which can precipitate and exacerbate headache, and typically includes relaxation training, cognitive restructuring, and problem-solving methods (66,67). A well-conducted, placebo-controlled study demonstrated signicant and comparable efcacy of stress management therapy and amitriptyline with a tendency for greater improvement when the two treatments were combined (66). Pharmacological Treatment Pharmacological treatment of the acute episode of TTH is most often done with the simple analgesics, aspirin and acetaminophen, both of which have proved to

Tension-Type Headache

465

be effective in several placebo-controlled trials (68,69). Steiner et al. recently demonstrated that aspirin (500 mg and 1000 mg) and acetaminophen (1000 mg but not 500 mg) were superior to placebo (70). Frequent intake of simple analgesics or nonsteroidal anti-inammatory drugs (NSAIDs), e.g., for more than 15 days per month, and use of combination analgesics should generally be avoided because of the risk of MOH and the patients should be thoroughly informed about this. The triptans do not have a clinically relevant effect in patients with ETTH (71). Nevertheless, sumatriptan may have some effect on coexisting TTHs in patients with migraine but not in those with pure TTH (55,71,72). To summarize, simple analgesics and NSAIDs are still the mainstays in the acute pharmacotherapy of TTH. Thorough information on an upper monthly limit of analgesics and NSAIDs is crucial to avoid medicationoveruse headache. Prophylactic pharmacotherapy should be considered in all patients with CTTH without medication overuse and who do not respond sufciently to nonpharmacological treatment. Since 1964, the tricyclic antidepressant amitriptyline has been the mainstay in the treatment of nondepressed patients with chronic TTH, and several subsequent studies have conrmed this nding (7380). Amitriptyline probably elicits its analgesic effect in TTH by reducing the transmission of painful stimuli from myofascial tissues and by reducing the increased excitability in the central nervous system (7478). Although amitriptyline generally is fairly tolerated, the majority of patients experience some side effects, especially weight gain. Other tricyclic and tetracyclic antidepressants may also be effective but there is insufcient evidence for this. Recently mirtazapine, which is a relatively new so-called nonadrenergic and specic serotonergic antidepressant with a better tolerability prole than the tricyclic antidepressants, was reported effective in chronic TTH (37). Mirtazapine 15 to 30 mg/day had an effect similar to amitriptyline compared with placebo in nondepressed, difcult-to-treat patients with chronic TTH. Mirtazapine was effective also in some patients who had not responded to amitriptyline and was generally well tolerated, although weight gain and drowsiness were also reported (37). Muscle relaxants have often been used in TTH, but only the centrally acting drug tizanidine has been tested with conicting results (8184). Likewise there is no clear evidence of an effect of Botulinum toxin in TTH (85). So it can be summarized that there is an urgent need for more efcacious drugs for the treatment of TTH without signicant side effects. In conclusion, TTH represents a wide variety of frequency and intensity, not only between patients but also within the individual over long time. As most cases of chronic TTH had evolved from the episodic forms, it is very important to study the long-term history and to try and identify risk factors for chronicity. As in migraine, it is yet unknown whether early intervention may prevent development of chronicity and large longitudinal studies in well-described populations are needed. Nevertheless, identication of frequent episodic TTH is very important in the patient with coexisting migraine as different headaches within the same individual complicate the treatment and outcome. It is especially important to identify MOH, and to develop more focused and specic treatment strategies for TTH. REFERENCES
1. Rasmussen BK. Epidemiology and socio-economic impact of headache. Cephalalgia 1999; 19(suppl 25):2023. 2. Russell MB, Rasmussen BK, Brennum J, Iversen HK, Jensen RA, Olesen J. Presentation of a new instrument: the diagnostic headache diary. Cephalalgia 1992; 12(6):369374.

466

Jensen

3. Lyngberg AC, Rasmussen BK, Jrgensen T, Jensen R. Favorable prognosis for the majority with migraine and tension-type headache. Neurology 2005; 65:580585. 4. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders. Cranial Neuralgias Facial Pain 1988; 8 (suppl 7):196. 5. Headache classication subcommitee of IHS. The International Classication of Headache Disorders 2nd Edition. Cephalalgia 2004; 24 (suppl 1):1160. 6. Manzoni GC, Torelli P. International Headache Society classication: new proposals about chronic headache. Neurol Sci 2003; 24(suppl 2):S86S89. 7. Mongini F, Deregibus A, Raviola F, Mongini T. Conrmation of the distinction between chronic migraine and chronic tension-type headache by the McGill Pain Questionnaire. Headache 2003; 43(8):867877. 8. Wang SJ, Fuh JL, Lu SR, Juang KD. Quality of life differs among headache diagnoses: analysis of SF-36 survey in 901 headache patients. Pain 2001; 89(23):285292. 9. Bigal ME, Sheftell FD, Rapoport AM, Lipton RB, Tepper SJ. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002; 22(6):432438. 10. Cassidy EM, Tomkins E, Hardiman O, OKeane V. Factors associated with burden of primary headache in a specialty clinic. Headache 2003; 43(6):638644. 11. Levin M. Chronic daily headache and the revised international headache society classication. Curr Pain Headache Rep 2004; 8(1):5965. 12. Silberstein SD, Lipton RB, Solomon S, Mathew NT. Classication of daily and neardaily headaches: proposed revisions to the IHS criteria. Headache 1994; 34:17. 13. Olesen J, Rasmussen BK. The International Headache Society classication of chronic daily and near-daily headaches: a critique of the criticism. Cephalalgia 1996; 16(6): 407411. 14. Abdul JM, Ogunniyi A. Sociodemographic factors and primary headache syndromes in a Saudi community. Neuroepidemiology 1997; 16(1):4852. 15. Ayatollahi SM, Moradi F, Ayatollahi SA. Prevalences of migraine and tension-type headache in adolescent girls of Shiraz (southern Iran). Headache 2002; 42(4):287290. 16. Cheung RT. Prevalence of migraine, tension-type headache, and other headaches in Hong Kong. Headache 2000; 40(6):473479. 17. Jensen R. Diagnosis, epidemiology, and impact of tension-type headache. Curr Pain Headache Rep 2003; 7(6):455459. 18. Kavuk I, Yavuz A, Cetindere U, Agelink MW, Diener HC. Epidemiology of chronic daily headache. Eur J Med Res 2003; 8(6):236240. 19. Lainez MJ, Monzon MJ. Chronic daily headache. Curr Neurol Neurosci Rep 2001; 1(2):118124. 20. Lavados PM, Tenhamm E. Epidemiology of tension-type headache in Santiago, Chile: a prevalence study. Cephalalgia 1998; 18(8):552558. 21. Lavados PM, Tenhamm E. Consulting behaviour in migraine and tension-type headache sufferers: a population survey in Santiago, Chile. Cephalalgia 2001; 21(7):733737. 22. Mitsikostas DD, Gatzonis S, Thomas A, Kalfakis N, IIias A, Papageoergiou C. An epidemiological study of headaches among medical students in Athens. Headache 1996; 36(9):561564. 23. Pascual J, Colas R, Castillo J. Epidemiology of chronic daily headache. Curr Pain Headache Rep 2001; 5(6):529536. 24. Pop PH, Gierveld CM, Karis HA, Tiedink HG. Epidemiological aspects of headache in a workplace setting and the impact on the economic loss. Eur J Neurol 2002; 9(2):171174. 25. Rasmussen BK, Jensen R, Schroll M, Olesen J. Interrelations between migraine and tension-type headache in the general population. Arch Neurol 1992; 49(9):914918. 26. Rasmussen BK, Olesen J. Epidemiology of migraine and tension-type headache. Curr Opin Neurol (13507540) 1994; 7:264271.

Tension-Type Headache

467

27. Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998; 279(5):381383. 28. Gobel H, Petersen-Braun M, Soyka D. The epidemiology of headache in Germany: a nationwide survey of a representative sample on the basis of the headache classication of the International Headache Society. Cephalalgia 1994; 14:97106. 29. Lyngberg AC, Rasmussen BK, Jrgensen T, Jensen R. Has the prevalence of migraine and tension-type headache changed over a 12-year period? Eur J Epidemiol 2005; 20:243249. 30. Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of headache in a general populationa prevalence study. J Clin Epidemiol 1991; 44(11):11471157. 31. Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in Chinese elderly: prevalence, risk factors, and biannual follow-up. Neurology 2000; 54(2):314319. 32. Laurell K, Larsson B, Eeg-Olofsson O. Headache in schoolchildren: agreement between different sources of information. Cephalalgia 2003; 23(6):420428. 33. Krymchantowski AV. Primary headache diagnosis among chronic daily headache patients. Arq Neuropsiquiatr 2003; 61(2B):364367. 34. Solomon S, Lipton RB, Newman LC. Clinical features of chronic daily headache. Headache (00178748) 1992; 32:325329. 35. Jensen R, Bendtsen L. Is chronic daily headache a useful diagnosis? J Headache Pain 2004; 5:8793. 36. Jensen R, Olesen J. Initiating mechanisms of experimentally induced tension-type headache. Cephalalgia 1996; 16:175182. 37. Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 2004; 62(10):17061711. 38. Langemark M, Olesen J, Poulsen DL, Bech P. Clinical characterization of patients with chronic tension headache. Headache (00178748) 1988; 28(9):590596. 39. Bendtsen L, Jensen R, Olesen J. Qualitatively altered nociception in chronic myofascial pain. Pain 1996; 65(23):259264. 40. Bendtsen L. Sensitization: its role in primary headaches. Curr Opin Invest Drugs 2002; 3(3):449453. 41. Rasmussen BK. Migraine and tension-type headache in a general population: psychosocial factors. Int J Epidemiol 1992; 21(6):16. 42. Boardman HF, Thomas E, Croft PR, Millson DS. Epidemiology of headache in an English district. Cephalalgia 2003; 23(2):129137. 43. Bigal ME, Bigal JM, Betti M, Bordini CA, Speciali JG. Evaluation of the impact of migraine and episodic tension-type headache on the quality of life and performance of a university student population. Headache 2001; 41(7):710719. 44. Edmeads J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson RF, Murray TJ. Impact of migraine and tension-type headache on life-style, consulting behaviour, and medication use: A Canadian Population Survey. Can J Neurol Sci 1993; 20:131137. 45. Holroyd KA, Stensland M, Lipchik GL, Hill KR, ODonnell FS, Cordingley G. Psychosocial correlates and impact of chronic tension-type headaches. Headache 2000; 40(1): 316. 46. Rasmussen BK, Jensen R, Olesen J. Impact of headache on sickness absence and utilisation of medical services: A Danish Population Study. J Epidemiol Community Health (0143005X) 1992; 46:443446. 47. Schwartz BS, Stewart WF, Lipton RB. Lost workdays and decreased work effectiveness associated with headache in the workplace. J Occup Environ Med (10762752) 1997; 39:320327. 48. Friedman AP. Characteristics of tension headache: A prole of 1420 cases. Psychosomatics 1979; 20(7):451461. 49. Rasmussen BK, Jensen R, Olesen J. A population-based analysis of the diagnostic criteria of the International Headache Society. Cephalalgia 1991; 11:129134.

468

Jensen

50. Iversen HK, Langemark M, Andersson PG, Hansen PE, Olesen J. Clinical characteristics of migraine and episodic tension-type headache in relation to old and new diagnostic criteria. Headache 1990; 30(8):514519. 51. Roh JK, Kim JS, Ahn YO. Epidemiologic and clinical characteristics of migraine and tension-type headache in Korea. Headache 1998; 38(5):356365. 52. Zeeberg P, Olesen J, Jensen R. Efcacy of multidisciplinary treatment in a tertiary referral headache center. Cephalalgia. In press. 53. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003; 106(12):8189. 54. Ulrich V, Russell MB, Jensen R, Olesen J. A comparison of tension-type headache in migraineurs and in non-migraineurs: a population-based study. Pain 1996; 67:501506. 55. Lipton RB, Stewart WF, Cady R, et al. 2000 Wolfe Award. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study. Headache 2000; 40(10):783791. 56. Jensen R, Rasmussen BK, Pedersen B, Olesen J. Muscle tenderness and pressure pain thresholds in headache. A Population Study. Pain 1993; 52:193199. 57. Jensen R, Bendtsen L, Olesen J. Muscular factors are of importance in tension-type headache. Headache 1998; 38:1017. 58. Jensen R. Tension-type Headache. Curr Treat Options Neurol 2001; 3(2):169180. 59. Ylinen J, Takala EP, Nykanen M, et al. Active neck muscle training in the treatment of chronic neck pain in women: a randomized controlled trial. JAMA 2003; 289(19): 25092516. 60. Wober-Bingol C, Wober C, Zeiler K, et al. Tension headache and the cervical spineplain X-ray ndings. Cephalalgia 1992; 12:152154. 61. Rasmussen BK. Migraine and tension-type headache in a general population: precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain (03043959) 1993; 53:6572. 62. Holroyd KA, France JL, Nash JM, Hursey KG. Pain state as artifact in the psychological assessment of recurrent headache sufferers. Pain 1993; 53:229235. 63. Ursin H, Endresen IM, Haaland EM, Mjellem N. Sensitization: a neurobiological theory for muscle pain. Elsevier 1993:413427. 64. Torelli P, Jensen R, Olesen J. Physiotherapy for tension-type headache: a controlled study. Cephalalgia 2004; 24(1):2936. 65. Vernon H, McDermaid CS, Hagino C. Systematic review of randomized clinical trials of complementary/alternative therapies in the treatment of tension-type and cervicogenic headache. Complement Ther Med 1999; 7(3):142155. 66. Holroyd KA, ODonnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW. Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA 2001; 285(17):22082215. 67. Marhold C, Linton SJ, Melin L. A cognitive-behavioral return-to-work program: effects on pain patients with a history of long-term versus short-term sick leave. Pain 2001; 91(12):155163. 68. Dahlof CGH, Jacobs LD. Ketoprofen, paracetamol and placebo in the treatment of epi sodic tension-type headache. Cephalalgia 1996; 16:117123. 69. Lange R, Lentz R. Comparison ketoprofen, ibuprofen and naproxen sodium in the treatment of tension-type headache. Drugs Exp Clin Res 1995; 21(3):8996. 70. Steiner TJ, Lange R, Voelker M. Aspirin in episodic tension-type headache: placebocontrolled dose-ranging comparison with paracetamol. Cephalalgia 2003; 23(1):5966. 71. Brennum J, Brinck T, Schriver L, et al. Sumatriptan has no clinically relevant effect in the treatment of episodic tension-type headache. Eur J Neurol 1996; 3:2328. 72. Brennum J, Kjeldsen M, Olesen J. The 5-HT1-like agonist sumatriptan has a signicant effect in chronic tension-type headache. Cephalalgia 1992; 12:375379.

Tension-Type Headache

469

73. Cerbo R, Barbanti P, Fabbrini G, Pascali MP, Catarci T. Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogenetic implications. Headache 1998; 38(6):453457. 74. Ashina S, Ashina M. Current and potential future drug therapies for tension-type headache. Curr Pain Headache Rep 2003; 7(6):466474. 75. Ashina S, Bendtsen L, Jensen R. Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition. Pain 2004; 108(12): 108114. 76. Bendtsen L, Jensen R, Olesen J. A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. J Neurol Neurosurg Psychiatry 1996; 61:285290. 77. Bendtsen L, Jensen R, Olesen J. Amitriptyline, a combined serotonin and noradrenaline re-uptake inhibitor, reduces exteroceptive suppression of temporal muscle activity in patients with chronic tension-type headache. Electroencephalogr Clin Neurophysiol 1996; 101:418422. 78. Bendtsen L, Jensen R. Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache. Cephalalgia 2000; 20(6):603610. 79. Boline PD, Kassak K, Bronfort G, Nelson C, Anderson AV. Spinal manipulation vs. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial. J Manipulative Physiol Ther 1995; 18:148154. 80. Gobel H, Hamouz V, Hansen C, et al. Chronic tension-type headache: amitriptyline reduces clinical headache-duration and experimental pain sensitivity but does not alter pericranial muscle activity readings. Pain (03043959) 1994; 59:241249. 81. Fogelholm R, Murros K. Tizanidine in chronic tension-type headache: a placebo controlled double-blind cross-over study. Headache (00178748) 1992; 32:509513. 82. Nakashima K, Tumura R, Wang Y, Shimoda M, Sakuma K, Takahashi K. Effects of tizanidine administration on exteroceptive suppression of the temporalis muscle in patients with chronic tension-type headache. Headache (00178748) 1994; 34:455457. 83. Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache 2002; 42(6):470482. 84. Shimomura T, Awaki E, Kowa H, Takahashi K. Treatment of tension-type headache with tizanidine hydrochloride: its efcacy and relationship to the plasma MHPG concentration. Headache (00178748) 1991; 31:601604. 85. Gobel H, Heinze A, Heinze-Kuhn K, Austermann K. Botulinum toxin A in the treatment of headache syndromes and pericranial pain syndromes. Pain 2001; 91(3):195199.

30
Trigeminal Autonomic Cephalgias
David Dodick
Mayo Clinic College of Medicine, Scottsdale, Arizona, U.S.A.

INTRODUCTION Trigeminal autonomic cephalgias (TACs), a term coined by Goadsby and Lipton (1), represent a group of primary headache disorders manifested by pain in the somatic distribution of the trigeminal nerve and by autonomic signs that reect activation of the cranial parasympathetic pathways. The headache disorders within this group include cluster headache, paroxysmal hemicrania, and the short-lasting unilateral neuralgiform pain with conjunctival injection and tearing (SUNCT) syndrome. The TACs are characterized by discrete, stereotyped, and relatively short-lasting (seconds to three hours) episodes of severe unilateral pain that is often conned or maximal in the orbital/periorbital region. The attacks are separated by pain-free intervals, but often recur on a daily basis either continuously (chronic) or for a dened period of time (episodic) with intervening remission periods. They are differentiated from each other based on the duration of the individual attacks, the daily frequency of attacks, and the response to various medications (Fig. 1, Table 1). Hemicrania continua is a continuous headache that should be considered in the differential diagnosis of other chronic daily headache disorders of longer duration (more than four hours). These disorders must also be differentiated from a variety of other primary headache disorders and organic causes that can mimic the phenotype of any one of these disorders. These disorders are highly disabling and eminently treatable, underscoring the importance of an accurate diagnosis.

PATHOPHYSIOLOGY Although the underlying genesis of the TACs is not completely known, the anatomic and pathophysiologic basis continues to be elucidated. The clinical manifestations are thought to reect activation of the trigeminal and cranial autonomic (parasympathetic) pathways. The central origin of the trigeminal and cranial parasympathetic pathways reside, respectively, in the caudal trigeminal nucleus and superior salivatory nucleus (Fig. 1). The cell bodies in the superior salivatory nucleus give rise to parasympathetic preganglionic efferents that course within the facial nerve (cranial
471

472

Dodick

Figure 1 Differentiating the trigeminal autonomic cephalgias.

Trigeminal Autonomic Cephalgias Table 1 Differential Diagnosis of Trigeminal Autonomic Cephalgias Feature Sex ratio (M:F) Attack duration Attack frequency Autonomic features Indomethacin response Cluster headache 4:1 60 min (15180 min) 18/day Paroxysmal hemicrania 1:3 20 min (245 min) 140/day SUNCT 2.1:1 40 sec (5250 sec) 1/day to 30/hr

473

Abbreviations: SUNCT, short-lasting unilateral neuralgiform pain with conjunctival injection and tearing; , precipitates headache; , no effect on headache.

nerve VII). These bers pass through the geniculate ganglion and synapse in the sphenopalatine and otic ganglia. Postganglionic bers travel in the greater supercial petrosal nerve to provide the vasomotor innervation of the cerebral blood vessels and the secretomotor innervation of the lacrimal glands and nasal mucosa. Activation of either the trigeminovascular or parasympathetic pathway can lead to reex activation of the other pathway through a functional connection in the brainstem. Each pathway can presumably be independently activated, which accounts for patients who experience autonomic symptoms without pain or vice versa. The evidence that these anatomical pathways become activated in these disorders comes not only from the clinical phenotype of pain within the rst division of the ophthalmic nerve and hypersecretion from lacrimal and nasal mucosal glands, but by a series of animal and human experiments that have demonstrated the local release of trigeminal [calcitonin generelated peptide (CGRP)] and parasympathetic [vasoactive intestinal polypeptide (VIP)] marker peptides during acute attacks. Signicant elevations of CGRP and VIP within cranial venous blood have been measured in the ipsilateral external jugular vein during attacks of cluster headache or chronic paroxysmal hemicrania (CPH) (2,3). Furthermore, these peptide levels return to baseline after the headache is terminated with medication. Although the mechanism by which the pathways are activated is unclear, recent evidence from functional neuroimaging studies has demonstrated activation in the periventricular hypothalamic gray matter in patients with cluster headache, SUNCT syndrome, and hemicrania continua (46). This region contains the suprachiasmatic nucleus (the human biological pacemaker), which may explain the rhythmic periodicity of these disorders.

CLUSTER HEADACHE Clinical Features Cluster headache is aptly named because of the tendency for attacks to occur in groups or clusters separated by periods of remissions (freedom from symptoms). The mean age at onset is 28 to 30 years, but the disorder can occur in both the young and old (79). In episodic cluster headache, attacks of pain occur daily for weeks or months (cluster period) before an attack-free period or remission occurs that can last from weeks to years (Table 2). On average, a cluster period lasts 6 to 12 weeks and remissions last for 12 months (7). Chronic cluster headache is less common and is

474 Table 2 Diagnostic Criteria of Cluster Headache According to the International Classication of Headache Disorders-2 (ICHD-2)

Dodick

Diagnostic criteria A. At least ve attacks fullling criteria BD B. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15180 min if untreated C. Headache is accompanied by at least one of the following: 1. Ipsilateral conjunctival injection and/or lacrimation 2. Ipsilateral nasal congestion and/or rhinorrhea 3. Ipsilateral eyelid edema 4. Ipsilateral forehead and facial sweating 5. Ipsilateral miosis and/or ptosis 6. A sense of restlessness or agitation D. Attacks have a frequency from one every other day to 8 per day E. Not attributed to another disorder

characterized by attacks of pain that occur for more than a year without a remission period that lasts longer than two weeks (10). The chronic form may develop spontaneously or evolve from episodic cluster headache. Whether the disease is in the episodic or chronic phase, the attacks of pain are highly stereotyped. Nocturnal predilection is common and patients are often aroused from sleep by an attack, which characteristically occurs during rapid eye movement (REM) sleep. A cluster headache attack lasts on average 45 to 90 minutes (15180 minutes) and occurs one to three times daily (up to eight attacks per day). The pain is strictly unilateral and almost always remains on the same side of the head during cluster periods. Rarely, the pain may occur on the opposite side in a subsequent period and, even less frequently, attacks may switch to the opposite side within the same cluster period. Typically, the pain is maximal in the retro-orbital and periorbital region of the affected side, and may radiate into the forehead, temple, cheek, jaw, and occiput. The onset of pain is abrupt or preceded by a brief sensation of pressure or mild discomfort. Aura symptoms, though uncommon, have been described in association with the cluster attack (11,12). A prospective study of the clinical and epidemiological characteristics of cluster-headache sufferers noted that 14% of patients reported migraine aura symptoms (12). In contrast to migraine, patients are restless during the pain of cluster headache. In a recent study, nearly 93% of patients during a cluster attack reported that they were restless (12). The autonomic signs and symptoms that accompany the pain can help establish the diagnosis of cluster headache. Generally, the autonomic features are short lived, lasting only for the duration of the attack, except for a partial Horner syndrome that manifests itself by ptosis or miosis (or both) and may persist after acute attacks. It is important to note that autonomic signs and symptoms may be absent in up to 3% of patients with cluster headache (13). Migrainous features may also accompany the cluster attack. In a recent study, 50% of patients reported nausea during an acute attack, 56% photophobia, 43% phonophobia, and 36% osmophobia (12). Once a cluster period begins, alcohol almost invariably triggers a cluster attack within minutes. The mechanism underlying the provocative action of alcohol is not understood. Other compounds, namely nitroglycerin and histamine, also act as potent triggers. Stress, depression, allergies, food sensitivities, and hormonal changes appear to have little role in the pathogenesis of cluster headache. Head trauma has

Trigeminal Autonomic Cephalgias

475

been recognized legally as a cause of cluster headache, but whether there is medical merit to this remains to be determined (14,15). Neurological examination ndings in patients with cluster headache are normal except for the possibility of an ipsilateral partial Horner syndrome. During an attack, there often is prominent ipsilateral conjunctival injection, tearing, and nasal rhinorrhea and obstruction, as well as an ipsilateral Horner syndrome. Ipsilateral facial sweating and ushing and ipsilateral swelling of the temple, cheek, and palate are relatively rare. Differential Diagnosis The main diagnostic considerations in patients with presumed cluster headache are other TACs, migraine, hypnic headache, and secondary causes of cluster-like syndromes. Symptomatic cluster headaches, although rare, are cluster-like attacks that are presumed to be caused by a structural lesion. Examples of these lesions are included in Box 1 (16,17). Clues that may indicate a symptomatic cluster headache include (18)  absence of periodicity  a low-grade background headache that does not subside between attacks  inadequate or incomplete response to therapy Cluster headache may be confused with migraine. The confusion is in part due to the fact that migraine is characteristically unilateral and up to 50% of migraine sufferers report cranial autonomic symptoms. In addition, cluster patients frequently report symptoms that are perceived to be migrainous (nausea, photophobia, phonophobia, etc.) and some even describe aura symptoms. The features that are most useful in distinguishing cluster from migraine include the rapid peak in pain severity (often less than ve minutes), abbreviated duration (45180 minutes), circadian periodicity with the potential for multiple attacks within a 24-hour period, circannual periodicity with attacks occurring daily for periods of weeks or months, motor restlessness and pacing during attacks, and very prominent cranial autonomic symptoms. Hypnic headache typically occurs in elderly persons (above 60 years of age), is often bilateral, and only occurs during sleep (19). Patients often prefer not to lie at, but may not necessarily pace. There are no cranial autonomic features, and the headache is mild to moderate in intensity, or certainly not of the same intensity as cluster headache.

Box 1 Differential diagnosis of cluster headache Adenoma of the pituitary Arteriovenous malformation Carotid artery aneurysm Impacted molar teeth Meningioma of the upper cervical cord Metastatic lung cancer Nasopharyngeal carcinoma Parasellar meningioma Vertebral artery aneurysm

476

Dodick

Treatment of Cluster Headache Acute (Symptomatic) Therapy Because of the sudden onset and short time to peak intensity, acute attacks of cluster headache necessitate the use of fast-acting symptomatic therapy. Oxygen inhalation, sumatriptan (subcutaneous and intranasal), octreotide (subcutaneous), dihydroergotamine, zolmitriptan, and local anesthetics have provided acute relief from cluster headache attacks. Oxygen. Oxygen inhalation is one of the most effective symptomatic treatments for cluster headache. In an open-label study, 39 of 52 patients (75%) given 100% oxygen via facemask at 7 L/min experienced complete or near-complete relief within 15 minutes (class 3) (20). In the only double-blind, controlled study of oxygen versus air inhalation, oxygen inhalation was also shown to be effective for the symptomatic treatment of a cluster attack (class 1) (21). In some patients, however, oxygen inhalation may merely delay, rather than abort the attack. In a small placebo-controlled study, hyperbaric oxygen (2 atm for 30 minutes) was effective within 5 to 13 minutes in six of seven patients (class 2) (22). The use of hyperbaric oxygen in the treatment of cluster headache has practical limitations. Sumatriptan. Subcutaneous sumatriptan is a highly effective acute treatment for cluster headache. In a double-blind, placebo-controlled study, 6 mg of sumatriptan administered subcutaneously was signicantly more effective than placebo, with 74% of patients having complete relief within 15 minutes compared with 26% of those given placebo (class 1) (23). In several long-term open-label studies, sumatriptan was still effective after continued use for several months (class 3) (24,25). Sumatriptan has not been demonstrated to be effective when used in a preemptive manner, nor has it been effective when used as a prophylactic agent (class 1) (26). In an open, randomized study that compared the effectiveness and satisfaction of subcutaneous sumatriptan 6 mg with intranasal sumatriptan 20 mg, 49 of 52 treatments provided complete relief of pain within 15 minutes, with a mean time to pain relief of 9.6 minutes after subcutaneous injection (class 3) (27). In only 7 of 52 treatments with nasal spray in the nostril ipsilateral to the head pain was complete relief noted within 15 minutes. The benecial effects of intranasal sumatriptan, however, have been further corroborated by a recent study demonstrating its efcacy in cluster attacks lasting longer than 45 minutes (28). A benecial response was noted within 30 minutes in 57% of the attacks treated with sumatriptan 20 mg nasal spray, compared with the placebo response of 26% (class 1) (28). Sumatriptan is generally well tolerated, but it is contraindicated in patients with ischemic heart disease or uncontrolled hypertension. Thus, caution must be exercised because cluster headache predominates in middle-aged men who often have coexisting risk factors for cardiovascular disease, particularly tobacco abuse. Zolmitriptan. Zolmitriptan is an effective oral agent for the acute treatment of episodic cluster headache (class 1) (29). In a placebo-controlled study that evaluated the efcacy and tolerability of oral zolmitriptan 5 and 10 mg in comparison with placebo in cluster headache, zolmitriptan was an effective oral agent for the acute treatment of episodic cluster headache (class 1). Headache response rates at 30 minutes, dened as a 2-point or greater decrease from baseline on a 5-point pain intensity scale, were 29%, 40%, and 47% for placebo and 5 and 10 mg of zolmitriptan, respectively. The difference was statistically signicant only for 10 mg zolmitriptan compared with placebo. Mild or no pain at 30 minutes was reported by 60%, 57%, and 42% of patients given zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo, respectively.

Trigeminal Autonomic Cephalgias

477

Zolmitriptan nasal spray may prove to be a more useful alternative than the tablet in patients with cluster headache. The pharmacokinetics of zolmitriptan nasal spray are consistent with a fast onset of action; following intranasal administration, zolmitriptan is detected in the plasma at two minutes postdose and in the brain at ve minutes postdose (3033). Intranasal absorption has been shown to account for approximately 70% of the total exposure to zolmitriptan in the rst hour postdose (34). Correspondingly, in a recent single-blind observation trial involving ve patients who treated 36 attacks of cluster headache with 5 mg zolmitriptan nasal spray, a pain-free response was observed in 27 of 36 attacks at 15 minutes (35). Conclusive evidence for the efcacy and safety of zolmitriptan nasal spray will, however, await the results from a randomized, placebo-controlled trial. Dihydroergotamine. Dihydroergotamine administered intravenously has been shown to provide relief in less than 10 minutes (36). An intranasal preparation is now widely available. A double-blind crossover trial compared intranasal dihydroergotamine (1 mg) with placebo and found no change in the frequency or duration of the attacks, but pain intensity was markedly reduced with the drug compared with placebo (class 1) (37). Thus, with a bioavailability of 40%, the currently available 2-mg commercial preparations of dihydroergotamine nasal spray may be effective (38). Because of the low, slow, erratic bioavailability of oral ergotamine tartrate, it has not been particularly useful in the acute treatment of a cluster attack. Contraindications for all ergotamine derivatives include coexisting coronary artery disease, uncontrolled hypertension, peripheral vascular disease, kidney failure, or liver failure. Octreotide. Somatostatin has been shown to inhibit the release of CGRP and VIP based on the results of two small, randomized, double-blind trials that suggested efcacy of intravenous somatostatin in cluster headache (39,40). A recent randomized double-blind placebo-controlled crossover study evaluated the use of octreotide, a somatostatin analogue for the acute treatment of cluster headache (class 1) (41). Patients were instructed to treat two attacks of at least moderate pain severity using subcutaneous octreotide 100 mg or matching placebo. The headache response rate with subcutaneous octreotide was 52% compared to a placebo-response rate of 36% ( p < 0.01). Octreotide was well tolerated with no reports of serious side effects. The main side effect observed was gastrointestinal upset in eight patients treated with octreotide compared with four patients treated with placebo. All side effects resolved spontaneously and were generally short lived and mild in nature. Topical Local Anesthetics. The intranasal administration of local anesthetic agents such as cocaine (class 3) or lidocaine (class 3) has been reported to be effective (42,43). Nonetheless, intranasal lidocaine applied by spray bottle or by dropping 4% viscous lidocaine in the nostril ipsilateral to the pain does not render the patient pain-free and produces only a modest decrease in pain in fewer than one-third of patients (class 3).

Prophylactic Therapy The primary goals of preventive therapy are to produce a rapid suppression of attacks and to maintain this remission over the expected duration of the cluster period. The principles of preventive pharmacotherapy are to  begin treatment early in the cluster period  continue the treatment until the patient has been headache-free for at least two weeks

478

Dodick

 taper the dose of the drug rather than abruptly withdraw it  restart treatment with the drug at the beginning of the next cluster period Herein we divide the prophylactic therapy into transitional therapy and maintenance prophylaxis.

Transitional Prophylaxis Transitional prophylaxis refers to the short-term use of corticosteroids, ergotamine, or greater occipital nerve (GON) blocks. Prednisone. Corticosteroids (prednisone and dexamethasone) are the most rapidly acting prophylactic agents. A response typically occurs within one to two days after therapy is initiated. These agents are the most effective initial prophylactic options to break the cycle of headache rapidly while waiting for longer-acting maintenance prophylactic agents to take effect (18). The literature supporting the use of corticosteroids is sparse and does not include the results of controlled trials. While strategies vary, a common method involves initiating treatment with prednisone 60 mg daily for three days, followed by 10-mg decrements every three days, over an 18-day period. Dexamethasone at a dose of 4 mg twice daily for two weeks, followed by 4 mg daily for one week, is a strategy that is also employed (class 3) (38). As with prednisone, when the dose of dexamethasone is tapered, cluster attacks invariably recur. Thus, corticosteroids are useful primarily for inducing rapid remission in patients with episodic cluster headache. Because of the adverse effects associated with corticosteroids, long-term treatment should be avoided. Most clinicians limit the use of prednisone or dexamethasone to no more than two or three cycles per year. Ergotamine Tartrate. Ergotamine tartrate (2 mg) is also an effective agent for achieving rapid suppression of attacks when administered daily for a short period. Ergotamine tartrate taken at bedtime may prevent attacks at night, allowing for more restful sleep. For periods shorter than two months, ergotamine may be taken once or twice daily to a maximal daily dose of 3 to 4 mg. Ergotamine tartrate is contraindicated within 24 hours of taking sumatriptan, and it generally is not administered with methysergide because of the risk of potentiating the vasoconstrictive effects of both these drugs. GON Blockade. GON blockade was initially reported by Anthony as an effective means of providing temporary relief from cluster attacks (44). More recently, Peres et al. have demonstrated that GON blockade in cluster headache patients can provide good to moderate short-term relief in 64% of patients (45). In a recent double-blind, placebo-controlled study involving 23 patients with episodic cluster headache and seven patients with chronic cluster headache, 92% of patients who received an injection of betamethasone 9.06 mg/dL and 0.3 mL 2% xylocaine in the region of the GON on the side ipsilateral to the pain experienced at least a 50% reduction in attack frequency in the rst postinjection week compared with the preinjection week, whereas only one patient in the placebo group had a similar improvement ( p 0.0004) (46). Four weeks after the injection, nine patients who received the corticosteroid injection were attack-free, without any other preventive therapies. GON blockade provides clinicians with an alternative therapeutic option for the transitional treatment of cluster headache.

Trigeminal Autonomic Cephalgias

479

Maintenance Prophylaxis Maintenance prophylaxis refers to the use of preventive medications throughout the anticipated duration of the cluster period. Often, maintenance prophylaxis is started at the onset of the cluster period and is given in combination with either corticosteroids or an ergotamine derivative, but it is continued after treatment with these initial suppressive agents has been discontinued. Calcium-Channel Blockers. Calcium-channel blockers are a group of chemically heterogeneous drugs developed as cardiovascular agents that interact with L-type calcium channels. Their mechanism of action in cluster headache has not been explained. Verapamil. Most clinicians consider verapamil the preventive therapy of choice for both episodic and chronic cluster headache. Verapamil has a benign side-effect prole and can be given safely in conjunction with ergotamine derivatives, sumatriptan, zolmitriptan, and other preventive agents. In an open-label trial involving 48 patients, 69% reported improvement by more than 75% during treatment with verapamil (mean daily dose, 360 mg) (class 3) (47). A double-blind, placebocontrolled trial evaluated the efcacy of verapamil (120 mg t.i.d.) over 14 days. The drug markedly decreased the frequency of attacks and the consumption of analgesics during the 14 days and was well tolerated (class 1) (48). The initial dose of verapamil is generally 80 mg three times daily or 240 mg sustained-release daily. Dosages range from 240 to 720 mg daily in divided doses. Although most clinicians believe that both the regular and extended-release preparations are equally efcacious, no direct comparative trials have been conducted. Nimodipine (30 mg four times daily) has been shown in two open trials to be effective (class 3) (49,50); however, it is not widely used to treat cluster headache. Methysergide. Although methysergide is no longer available in the United States, given its continued use worldwide, a brief review is warranted. Methysergide is a prodrug of methylergonovine. It is widely distributed throughout the body, crosses the bloodbrain barrier, and binds to serotonin (5-HT2) receptors in the brain (38). Methysergide has been reported to be effective for the prophylaxis of episodic cluster headache in approximately 30% to 70% of patients (class 3) (51,52). The daily dose generally is 2 mg three times daily, but up to 12 mg may be given if tolerated. The short-term side effects include nausea, abdominal pain, diarrhea, muscle cramps, and pedal edema. Long-term side effects include brotic reactions (retroperitoneal, pulmonary, pleural, and cardiac), and this complication, which occurs in about 1 out of 1500 patients, has signicantly curtailed its use. When used in patients with cluster headache, most clinicians abide by the recommendations of a one-month drug holiday between six-month treatment periods, and recommend periodic imaging and laboratory studies [e.g., chest radiography, echocardiography, computed tomography or magnetic resonance imaging (MRI) of the abdomen, and general screening laboratory tests] when methysergide is given for a prolonged period. Lithium Carbonate. Lithium carbonate has been reported in open-label studies to be effective primarily for the treatment of chronic cluster headache. Response rates from 38% to 82% have been reported (class 3) (5355). A double-blind, placebo-controlled trial failed to demonstrate superiority of lithium (800 mg sustained release) over placebo (56) (class 2). However, the study was terminated one week after treatment began, which was too short for the results to be conclusive. The initial starting dose of lithium is either 300 mg twice daily or 450 mg sustained-release, but higher doses may be needed. A therapeutic response frequently

480

Dodick

occurs within one month and often at serum concentrations of 0.4 to 0.8 mEq/L, less than those required for the treatment of bipolar disorders. Lithium has a narrow therapeutic window and has the potential for numerous side effects, which seriously limits its long-term use in cluster headache sufferers. Adverse effects include weakness, nausea, diarrhea, polyuria, tremor, nystagmus, confusion, ataxia, extrapyramidal signs, and seizures. Renal and thyroid toxicity are well-known complications with this drug. Caution must be exercised when other drugs such as diuretics or nonsteroidal anti-inammatory agents are given concomitantly. Polymorphonuclear leukocytosis may occur in patients taking lithium and may be mistaken for occult infection. The serum concentration should be measured 12 hours after the last dose and should not exceed 1.0 mEq/L. Kidney and thyroid function studies must be performed before treatment and periodically during treatment. Divalproex Sodium/Sodium Valproate. In an open-label study of 26 patients (21 with chronic and 5 with episodic cluster headache), treatment with divalproex sodium (mean dose, 838 mg/day) resulted in mean decreases in headache frequency of 59% and 54%, respectively (57). In a retrospective assessment of 49 patients with cluster headache who received divalproex sodium daily (5001500 mg), either as monotherapy (13 patients) or as an add-on therapy (36 patients), 73% of patients reported improvement (58). However, 22% of cluster patients reported negative side effects, including nausea, weight gain, somnolence, bloating, alopecia, disequilibrium, and rash. The effectiveness of sodium valproate (6002000 mg/day in two divided doses) for the prevention of cluster headache was assessed in a second, small open-label study of 15 patients (59). Nine patients reported complete remission of cluster headache and two patients reported marked improvement. Unfortunately, in a recent double-blind, placebo-controlled study, sodium valproate was not shown to effectively prevent cluster headache (60). Side effects associated with sodium valproate included nausea, vomiting, and somnolence. Weight gain, tremor, and alopecia are other side effects, which may limit the use of valproate in clinical practice. Other rare but concerning side effects associated with its use include pancreatitis, thrombocytopenia, and hepatic dysfunction. In general, when treating patients with cluster headache, valproate sodium or divalproex sodium should be started at 250 mg b.i.d. and titrated up in 250 mg increments according to clinical response and tolerability. In the open-label studies described, the effective dose ranged between 500 and 2000 mg/day. Topiramate. Several open-label studies suggest that topiramate may be an effective prophylactic therapy for patients with episodic or chronic cluster headache. In an open-label study involving 10 patients (seven with episodic cluster headache, two with chronic cluster headache, and one with clustertic syndrome), topiramate was associated with cluster remission in nine patients within three weeks of treatment initiation (61). The mean dose of topiramate for cluster remission was 83.3 mg/day. In another open-label study, 26 patients (12 with episodic and 14 with chronic cluster headache) were treated with topiramate at a mean dose of 100 mg/day (range 25200 mg/day) (62). Cluster remission was observed in six patients (50%) with episodic and nine patients (64%) with chronic cluster headache. The mean time to remission was 14 days, but several patients had complete headache cessation within the rst few days of treatment. Reported side effects included paresthesia, altered taste, memory impairment, weight loss, and drowsiness. Conicting results on the efcacy of topiramate for cluster headache were found in a study of 33 patients. No signicant differences in the median number

Trigeminal Autonomic Cephalgias

481

of daily attacks were found between the run-in and treatment periods (63). However, in seven patients (21%), the daily number of attacks was reduced by more than 50%. Clearly, randomized controlled trials are needed, given the conicting results of some of these studies. In addition to the side effects described above, topiramate also causes kidney stones in 1% of patients, and patients must be alert to the rare but concerning adverse events including acute myopia, oligohidrosis, and metabolic acidosis. Gabapentin. In an open-label trial, 12 patients previously shown to be refractory to other preventive therapies were treated with gabapentin initiated at 100 mg t.i.d. and increased in three days to 300 mg t.i.d. All patients were pain-free after a maximum of eight days following the initiation of gabapentin (64). In the patients with episodic cluster headache, no relapse had occurred in the three months following discontinuation of therapy. Those patients suffering from chronic cluster headache were instructed to continue gabapentin at 300 mg t.i.d. for six months. At four months after the start of therapy, none of them reported new attacks. During this study, two patients reported mild drowsiness. Further studies are warranted to verify the effectiveness of gabapentin for the prevention of cluster headache. Capsaicin. Capsaicin, a constituent of hot peppers, depletes sensory neurons of substance P. In a double-blind, placebo-controlled study, capsaicin was applied topically twice daily for seven days to the nostril ipsilateral to the pain and was shown to be superior to placebo in reducing the frequency and severity of the attacks (class 2) (65). Fusco et al. demonstrated that capsaicin applied to the nostril ipsilateral to the pain produced marked improvement in 70% of 70 patients (51 with episodic headache and 19 with chronic cluster headache) (66). No improvement was noted in patients in whom capsaicin was applied to the nostril contralateral to the pain (class 2). Capsaicin is not widely used for the treatment of cluster headache because other more easily administered and effective agents are available. Melatonin. Melatonin is the most sensitive surrogate marker of circadian rhythm in humans and is under the control of the suprachiasmatic nucleus. The efcacy of 10 mg of oral melatonin was evaluated in a double-blind, placebo-controlled trial (class 1) (67). Remission of cluster headache was noted within three to ve days in 5 of 10 patients who received melatonin compared with none of the 10 patients who received placebo. Other Drugs. Several other drugs are being investigated for the treatment of cluster headache. Small open-label studies and case reports have indicated that the following drugs are effective for cluster headache: methylphenidate (class 3) (68), baclofen (class 3) (69), tizanidine (class 3) (70), clonidine (class 3) (71), pizotifen (class 3) (72), chlorpromazine (class 3) (73), histamine (class 3) (74), leuprolide (class 3) (75), eletriptan (class 3) (76), and frovatriptan (7786). The experience with these drugs and several others such as botulinum toxin, cyproheptadine, diltiazem, and tamoxifen is too limited to support their routine use in the treatment of cluster headache. Refractory Cluster Headache Approximately 10% to 20% of patients with cluster headache experience chronic cluster headache that fails to respond to monotherapy. However, patients with episodic cluster headache with frequent cluster periods may develop relative drug resistance, intolerance, or contraindications to abortive or prophylactic medications. Thus, many of these patients require rational polypharmacy or may be candidates for ablative neurosurgical procedures.

482

Dodick

Before a surgical procedure is considered, it is incumbent on the clinician to exhaust all potential medical options. Some patients have a response to medications used in combination rather than to the maximal dosage of a single medication. Although verapamil is the only drug for which there is placebo-controlled evidence for efcacy, the debilitating nature of this disorder, combined with the potential for serious morbidity associated with destructive surgical procedures, justies the use of each of the drug options listed above, sometimes in combination. In addition to a combination of prophylactic therapies, dihydroergotamine administered intravenously every eight hours over three days has been reported to be effective for some patients with intractable cluster headache (class 3) (87). A recent study, also suggests that outpatient intravenous dihydroergotamine is a safe and effective treatment for cluster headache (class 3) (88). Surgical Therapy Surgical therapy is a consideration only for patients with medically intractable cluster headache, in whom outpatient and inpatient therapy has failed, or patients in whom contraindications or intolerance sufciently limits the use of effective prophylactic therapy given sequentially and in combination. Criteria for patient selection for deep brain stimulation have recently been proposed, and these criteria can be generalized to the selection of patients for any surgical procedure (Table 3) (89). Over the past few decades, various surgical procedures have been used to treat chronic cluster headache that is refractory to medical therapy. Procedures aimed at lesioning or decompressing the trigeminal ganglion or nerve have been better evaluated. Radiofrequency lesions have been utilized more than glycerol rhizotomy or balloon compression. The results of radiofrequency rhizotomy are somewhat
Table 3 Patient Selection Criteria for Invasive Cluster Headache Surgery IHS-dened CCH for at least 24 mo Attacks should normally occur on daily basis Attacks must have always been strictly unilateral Patients must be hospitalized to witness attacks and document their characteristics All state of the art drugs for CH prophylaxis must have been tried in sufcient dosages (unless contraindicated or have unacceptable side effects) alone and in combination, where applicable. These comprise verapamil, lithium carbonate, methysergide, valproate, topiramate, gabapentin, melatonin, indomethacin, and steroids Normal psychological prole No recent medical/neurological conditions contraindicating surgery including Normal neurological examination except for symptoms characteristic of CH (e.g., persistent Horners syndrome) Normal CT scan (base of the skull window). Normal cerebral MRI including foramen magnum MRI angiography and venography Experienced neurosurgical team Patient not pregnant Ethics Committee/Institutional Review Board approval Patient quits smoking and drinking alcohol Patient informed and gives written consent
Abbreviations: IHS, International Headache Society; CCH, chronic cluster headache; CH, cluster headache; CT, computed tomography. Source: From Ref. 89.

Trigeminal Autonomic Cephalgias

483

encouraging, with nearly 75% of patients having good-to-excellent results (class 3) (9092). The best results have been noted in patients with complete analgesia or dense hypoalgesia. Some patients have remained pain-free for up to 20 years. The recurrence rate is about 20% (class 3). Transient complications may include diplopia, hyperacusis, ice-pick pain, and jaw deviation. Longer-term complications include corneal anesthesia and, in fewer than 4% of patients, anesthesia dolorosa. Accordingly, aggressive long-term ophthalmologic follow-up is critical for all patients having radiofrequency rhizotomy. In a recent study, radiofrequency lesioning of the sphenopalatine ganglion via an infrazygomatic approach was performed in 66 patients (class 3) (93). The results were marginal, with 40% of the patients experiencing relief and only 30% of those with chronic cluster headaches obtaining complete relief. Complications included epistaxis (12%), cheek hematoma (17%), and partial maxillary nerve lesion in 6% of patients. Most clinicians hesitate to recommend this procedure. Gamma-knife radiosurgery was shown to be effective in six patients with medically refractory cluster headache (class 3) (94). The time to effective relief was either immediate or within one week. Four patients remained pain-free beyond eight months. Because this study has not been duplicated, the overall efcacy, safety, and durability of the procedure are not clear. Microvascular decompression of the trigeminal nerve, with or without section of the intermediate nerve, for chronic cluster headache was recommended by Lovely et al. as a rst-line surgical treatment (95). In their series, 28 patients (two with bilateral cluster headache) underwent 39 operations of the trigeminal nerve, alone or in combination with microvascular decompression or section of the intermediate nerve. An initial postoperative benet (greater than 90% relief) was noted by 50% of patients and relief greater than 50% was noted by 73% of rst-time surgical patients. Long-term follow-up (5.3 years) demonstrated a decrease in the good-to-excellent relief to 46%. Repeat procedures were ineffective. These procedures require an experienced surgical team. Additional studies are needed before microvascular decompression can be considered as a rst-line operative treatment for chronic cluster headache. Several authors have reported favorable results in patients with refractory chronic cluster headache after section of the sensory trigeminal nerve at the root exit zone (class 3). In one, Kirkpatrick et al. reported complete or near-complete relief of pain in 12 of 14 patients who had a sensory trigeminal rhizotomy through the posterior fossa approach (class 3) (96). The mean duration of follow-up was 5.6 years. It is noteworthy that 7 of the 14 patients who had a partial nerve root section required a second procedure for complete relief. Kirkpatrick et al. concluded that complete section was more likely to provide sustained relief than partial section of the root. In a recent observational study, 15 of 17 patients who underwent sectioning of the trigeminal sensory root at the level of the brainstem experienced complete or nearcomplete relief in the immediate postoperative period, and 76% went on to have long-term benet (mean follow-up period 6.7 years) (97). Satisfaction with the procedure was reported by 10 of the 17 of those patients who did not require preventive medications after surgery. Stroke, death, weakness of the masticatory muscles, and painful facial dysesthesias or anesthesia dolorosa are potential adverse events. Given the results of recent functional imaging data, which suggest that the cluster headache generator is located in the posterior inferior hypothalamic gray matter, Leone et al. were prompted to employ deep-brain stimulation of this area, in selected medically refractory cases (class 3) (98). A total of 19 patients have received

484

Dodick

deep-brain stimulation with favorable results in 18 (class 3) (99,100). One patient died of an intracranial hemorrhage after the surgery. The mechanism by which stimulation of this area is able to suppress attacks from occurring is not well understood. Larger series will be needed to determine the safety and long-term efcacy of this procedure. Occipital nerve stimulation has recently been demonstrated to be efcacious in a 45-year-old man with chronic cluster (101). The procedure may provide clinicians an alternative option to more aggressive procedures with less neurologic morbidity. The durability of this procedure remains to be further elucidated (class 3).

PAROXYSMAL HEMICRANIAS Paroxysmal hemicranias are characterized by frequent, short-lasting unilateral headaches (Table 4 ). The female-to-male ratio is approximately 2:1, and the disorder usually begins in adulthood, at a mean age of 34 (102). However, the age at onset varies from 6 to 81 years. The clinical proles of CPH and episodic paroxysmal hemicrania (EPH) are similar, with the only difference being that EPH has pain-free remissions. The pain occurs predominantly in the anterior region of the head (orbital or temporal) and usually lasts between 2 and 45 minutes. In a recent report of 78 patients, the headaches lasted less than 30 minutes in more than half of the patients (103). In a retrospective study of 84 patients, the mean duration of the attack was 21 minutes and the mean frequency of attacks was 11 per day (range, 640) (102). In a prospective study of 105 attacks, the mean duration of the attack was 13 minutes (range, 346 minutes) and the mean frequency of attacks was 14 per day (range, 438) (104). This is in contrast to cluster headache, in which fewer than 6% of headaches last less than 30 minutes and more than 90% of patients have fewer than three attacks per day (104108). The pain is strictly unilateral in most patients, although in some, the pain may alternate sides or, more rarely, occur bilaterally. The pain is described as a throbbing, boring, pulsatile, or stabbing pain that ranges from moderate to excruciatingly severe in intensity. During attacks, one or more ipsilateral autonomic symptoms or signs occur. Lacrimation and nasal congestion are the most common
Table 4 Diagnostic Criteria of Paroxysmal Hemicranias According to the International Classication of Headache Disorders-2 Diagnostic criteria A. At least 20 attacks fullling criteria BD B. Attacks of severe unilateral orbital, supraorbital, or temporal pain lasting 230 min C. Headache is accompanied by at least one of the following: 1. Ipsilateral conjunctival injection and/or lacrimation 2. Ipsilateral nasal congestion and/or rhinorrhea 3. Ipsilateral eyelid edema 4. Ipsilateral forehead and facial sweating 5. Ipsilateral miosis and/or ptosis D. Attacks have a frequency above 5 per day for more than half of the time, although periods with lower frequency may occur E. Attacks are prevented completely by therapeutic doses of indomethacin F. Not attributed to another disorder

Trigeminal Autonomic Cephalgias

485

accompanying features and are often robust. Conjunctival injection and rhinorrhea also occur in upto one-third of patients. Similar to episodic cluster headache, EPH differs from CPH in having attack phases that are interrupted by longer lasting remission phases. The headache phase can last from 2 weeks to 4.5 months; remissions range from 1 to 36 months. About one-third of attacks occur during nocturnal sleep in both disorders, and attacks have been reported to occur in association with REM sleep. Indomethacin is the treatment of choice for paroxysmal hemicranias, and the marked response to this drug has been considered the sine qua non for establishing the diagnosis. Treatment is usually initiated at a dosage of 25 mg three times daily with meals. After an appropriate dose has been attained, the response to treatment is invariably swift. The average interval between drug ingestion and relief of pain in patients with hemicrania continua is approximately 30 minutes and for those with CPH, 48 hours (109). Most patients report complete headache relief within 24 hours and frequently within eight hours. Interindividual differences exist in the dose and timing needed to abolish the headaches and likely are due to differences in bioavailability and individual sensitivity. If headache relief is not obtained within 48 hours after initiation of treatment, the dosage should be increased to 50 mg three times daily. Patients may have a partial response but not complete relief if the dose is not optimal. Treatment failure should be considered only if a patient has not had a response to a dosage of 300 mg/day. Maintenance doses between 25 and 100 mg are usually adequate for suppressing the headache. It is recommended that after an effective dose has been established for several weeks, it should be decreased gradually to ascertain the lowest effective dose. In a recent study of 26 patients with hemicrania continua or CPH, who were followed for an average of 3.8 years, 42% experienced a mean decrease of 56% in the dosage of indomethacin (41 mg 619 mg/day) required to maintain a pain-free state (110). Occasionally, dose adjustments are necessary to treat the clinical uctuations that occur sometimes in these disorders. Because nocturnal attacks or exacerbations are frequent, a bedtime dose of sustained-release indomethacin may be useful to prevent these attacks. Some patients are so exquisitely sensitive to indomethacin that skipping even one dose will allow the headache to recur. In patients with EPH, indomethacin is usually continued for approximately two weeks beyond the expected duration of the headache period. Although longterm, indenite treatment is often required for patients with CPH or hemicrania continua, a periodic attempt to withdraw the medication is useful because long-term remissions have been described (103,109111). If the headache is refractory to indomethacin therapy, the diagnosis should be reconsidered. However, typical cases of CPH have been described in which the headache was unresponsive to indomethacin (103,112). Patients who require a continuous high dose of indomethacin and those who require increasing doses after an initial response to a lower dose may have an underlying lesion and need careful evaluation (113). Some patients with symptomatic CPH due to intracranial or pulmonary lesions have been reported to have a response to modest doses of indomethacin (114,115), highlighting the need for a careful clinical evaluation of patients who otherwise appear to have a typical clinical picture and response to medication. In subjects with a phenotype that resembles CPH, but who fail to or cannot tolerate indomethacin, several drugs have been reported effective, including other nonsteroidal anti-inammatory drugs, dihydroergotamine, methysergide, corticosteroids, acetaminophen with caffeine, lamotrigine, gabapentin, and lithium carbonate (116120). Therefore, from the perspective of a clinician evaluating and treating

486

Dodick

patients in routine clinical practice, a response to indomethacin should not be considered either necessary or sufcient to make a diagnosis of CPH or hemicrania continua or of any primary headache disorder.

SUNCT SYNDROME SUNCT is a rare primary headache disorder that is more common in males (2:1) and usually begins between the ages of 40 and 70 years (range 1077 years) (Table 5). The individual attacks of pain are very brief, lasting less than 40 seconds on average (5200 seconds), moderate or severe, exclusively unilateral, maximal in the orbital, periorbital, or frontal location, and often described as an electric shock or as a stabbing, piercing, or burning pain (121). The pain peaks and resolves abruptly (122). Most patients are completely pain-free between attacks, although some report a persistent dull interictal discomfort (123). The attack frequency between and among individual sufferers varies considerably, occurring as infrequently as once a day or less to more than 30 attacks an hour. Unlike cluster headache, nocturnal attacks are seldom reported. Like other TACs, the cranial autonomic symptoms occur in synchrony with the pain, and are often robust. Ipsilateral conjunctival injection and lacrimation are almost always present, while nasal congestion, rhinorrhea, eyelid edema, ptosis, miosis, and facial redness or sweating are less commonly reported. Nausea, vomiting, photophobia, and phonophobia are not normally associated with SUNCT syndrome. Unlike in CPH, restlessness is not a feature of SUNCT syndrome (124). The temporal pattern of SUNCT is quite erratic, with no predictable timing between symptomatic and remission periods. Symptomatic periods generally last from a few days to several months and occur once or twice annually. Remissions typically last a few months, though these periods can range from one week to seven years. Like trigeminal neuralgia, the majority of patients can trigger attacks by touching the face or scalp, washing, shaving, eating, chewing, brushing teeth, talking, or coughing, or with certain neck movements (124). However, in contrast to trigeminal neuralgia, most patients have no refractory period between successive triggering stimuli.

Differential Diagnosis Secondary SUNCT has been reported in several patients with lesions in the posterior fossa or pituitary gland (125,126). All patients, therefore, with a presumptive
Table 5 Diagnostic Criteria of SUNCT According to the International Classication of Headache Disorders-2 Diagnostic criteria A. At least 20 attacks fullling criteria BD B. Attacks of unilateral orbital, supraorbital, or temporal stabbing or pulsating pain lasting 5240 sec C. Pain is accompanied by ipsilateral conjunctival injection and lacrimation D. Attacks occur with a frequency from 3 to 200 per day E. Not attributed to another disorder
Abbreviations: SUNCT, short-lasting unilateral neurogliform pain with conjunctival injection and tearing.

Trigeminal Autonomic Cephalgias

487

diagnosis of SUNCT should have an MRI of the brain with attention to the sellar/ parasellar region and posterior fossa. SUNCT can be differentiated from paroxysmal hemicrania by the brevity of attacks (seconds) and by a trial of indomethacin. Primary stabbing headache (PSH), which may be mistaken for SUNCT, differs in that the attacks last only one to three seconds and they are not usually conned to the orbital/periorbital region, nor are they usually exclusive to one side. In addition, patients with PSH do not report cranial autonomic symptoms. Because of the considerable overlap in the clinical phenotype, differentiating SUNCT from trigeminal neuralgia can be very challenging. Both are characterized by frequent unilateral stabbing or electric-like shocks of pain of brief duration, which are associated with trigger zones in the face and occur in middle or old age. However, the pain of trigeminal neuralgia is rarely conned to the ophthalmic division of the trigeminal nerve or accompanied by robust cranial autonomic features (124,127).

Treatment Unlike other TACs, patients with SUNCT syndrome do not respond to indomethacin or medications typically effective for patients with cluster headache. Triptans, ergotamine, dihydroergotamine, beta-blockers, tricyclic antidepressants, calcium-channel antagonists (verapamil and nifedipine), methysergide, lithium, prednisolone, phenytoin, and baclofen have been reported to be ineffective (128). Partial improvement with carbamazepine has been observed in several patients (128). Open-label lamotrigine 100 to 200 mg has been reported to be highly effective in seven patients, and until results for randomized controlled trials become available, it is considered the treatment of rst choice (6870). Gabapentin and topiramate have also been reported in isolated cases to be effective and should be considered as alternative therapeutic options for patients with SUNCT (7174). It has been recently demonstrated that intravenous lidocaine can completely suppress attacks of SUNCT (74), suggesting that treatment with lidocaine can be considered when acute intervention is required to suppress a severe exacerbation of SUNCT, and further broaden the therapeutic and clinical background of this syndrome. For patients with medically intractable SUNCT, microvascular decompression and percutaneous trigeminal ganglion compression have been reported to be effective in three patients (75,76). However, two patients with SUNCT were reported to have failed to respond to similar decompressive or ablative procedures, including trigeminal nerve root section (129). Given the uncertain efcacy of trigeminal procedures together with the potential for complications, surgery should only be considered as a last resort in patients who are truly refractory to medical therapy.

REFERENCES
1. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic features, including new cases. Brain 1997; 120:193209. 2. Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache: neuropeptide changes and effects of acute attacks therapies. Brain 1994; 117:427434.

488

Dodick

3. Goadsby PJ, Edvinsson L. Neuropeptide changes in a case of chronic paroxysmal hemicraniaevidence for trigemino-parasympathetic activation. Cephalalgia 1996; 16:448450. 4. May A, Bahra A, Buchel C, et al. Hypothalamic activation in cluster headache attacks. Lancet 1998; 352:275278. 5. May A, Bahra A, Buchel C, et al. Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 1999; 46:791794. 6. Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RS, Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004; 44(8):747761. 7. Ekbom K. A clinical comparison of cluster headache and migraine. Acta Neurol Scand 1970; (suppl 41):1. 8. Manzoni GC, Terzano MG, Bono G, et al. Cluster headacheclinical ndings in 180 patients. Cephalalgia 1983; 3:2130. 9. DCruz OF. Cluster headaches in childhood. Clin Pediatr (Phila) 1994; 33:241242. 10. Ekbom K. Patterns of cluster headache with a note on the relations to angina pectoris and peptic ulcer. Acta Neurol Scand 1970; 46:225237. 11. Silberstein SD, Niknam R, Rozen TD, et al. Cluster headache with aura. Neurology 2000; 54:219221. 12. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology 2002; 58:354361. 13. Nappi G, Micieli G, Cavallini A, et al. Accompanying symptoms of cluster attacks: their relevance to the diagnostic criteria. Cephalalgia 1992; 12:165168. 14. Reik L Jr. Cluster headache after head injury. Headache 1987; 27:509510. 15. Turkewitz LJ, Wirth O, Dawson GA, et al. Cluster headache following head injury: a case report and review of the literature. Headache 1992; 32:504506. 16. Campbell JK. Diagnosis and treatment of cluster headache. J Pain Symptom Manage 1993; 8:155164. 17. Mendizabal JE, Umana E, Zweier RM. Cluster headache: Hortons cephalalgia revisited. South Med J 1998; 91:606617. 18. Dodick DW, Rozen TD, Goadsby PJ, et al. Cluster headache. Cephalalgia 2000; 20:787803. 19. Evers S, Goadsby PJ. Hypnic headache: clinical features, pathophysiology, and treatment. Neurology 2003; 60:905909. 20. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache 1981; 21:14. 21. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation. Arch Neurol 1985; 42:362363. 22. Di Sabato F, Fusco BM, Pelaia P, et al. Hyperbaric oxygen therapy in cluster headache. Pain 1993; 52:243245. 23. Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group. N Engl J Med 1991; 325:316321. 24. Ekbom K, Krabbe A, Micieli G, et al. Cluster headache attacks treated for up to three months with subcutaneous sumatriptan (6 mg). Cephalalgia 1995; 15:230236. 25. Gobel H, Lindner V, Heinze A, et al. Acute therapy for cluster headache with sumatriptan: ndings of a one-year long-term study. Neurology 1998; 51:908911. 26. Monstad I, Krabbe A, Micieli G, et al. Preemptive oral treatment with sumatriptan during a cluster period. Headache 1995; 35:607613. 27. Hardebo JE, Dahlof C. Sumatriptan nasal spray (20 mg/dose) in the acute treatment of cluster headache. Cephalalgia 1998; 18:487489. 28. van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan in cluster headache: randomized placebo-controlled double-blind study. Neurology 2003; 60:630633.

Trigeminal Autonomic Cephalgias

489

29. Bahra A, Gawel MJ, Hardebo J, et al. Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology 2000; 54:18321839. 30. Yates R, Nairn K, Dixon R, et al. Preliminary studies of the pharmacokinetics and tolerability of zolmitriptan nasal spray in healthy volunteers. J Clin Pharmacol 2002; 42:12371243. 31. Uemura N, Charlesworth B, Onishi T, et al. Zolmitriptan is detectable in plasma 2 to 5 minutes after administration by nasal spray. Headache 2003; 43:S159. 32. Bergstrom M, Wall A, Gedal M, et al. An open label positron emission tomography study to investigate the distribution of intranasally administered [11C] zolmitriptan into the CNS. Neurology 2004; 62:A80A81. 33. Gedal M, Duvauchelle T, Hovsepian L, et al. Zolmitriptan demonstrates good pharmacokinetic consistency between and within individuals following intranasal administration. Br J Clin Pharmacol 2004; 57:679680. 34. Zingmark PH, Yates R, Hedlund C, et al. True nasopharyngeal absorption of zolmitriptan following administration of zolmitriptan nasal spray. Eur J Neurol 2003; 10:76. 35. Mathew NT, Kailasam J, Seifer T, et al. Zolmitriptan (Zomig) nasal spray in cluster headache attacks: a single-blind observationa preliminary report. Headache 2004; 44:483. 36. Mathew NT. Cluster headache. Neurology 1992; 42:2231. 37. Andersson PG, Jespersen LT. Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. A double-blind trial versus placebo. Cephalalgia 1986; 6:5154. 38. Silberstein SD. Pharmacologic management of cluster headache. CNS Drugs 1994; 2(3):199207. 39. Sicuteri F, Geppetti P, Marabini S, et al. Pain relief by somatostatin in attacks of cluster headache. Pain 1984; 18:359365. 40. Pfaffenrath V, Lundberg PO, Sjaastad O. Updating in Headache. Berlin, New York: Springer-Verlag, 1985:xxv, 331 p. 41. Matharu MS, Levy MJ, Meeran K, et al. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Ann Neurol 2004; 56: 488494. 42. Barre F. Cocaine as an abortive agent in cluster headache. Headache 1982; 22:6973. 43. Kittrelle JP, Grouse DS, Seybold ME. Cluster headache. Local anesthetic abortive agents. Arch Neurol 1985; 42:496498. 44. Anthony M. Arrest of attacks of cluster headache by local steroid injection of the occipital nerve. In: Rose CF, ed. Migraine: Clinical and Research Advances. Basel: Karger, 1985:169173. 45. Peres MF, Stiles MA, Siow HC, et al. Greater occipital nerve blockade for cluster headache. Cephalalgia 2002; 22:520522. 46. Ambrosini A, Van den Heede M, Rossi P, et al. Suboccipital (GON) injection with long-acting steroids in cluster headache: a double-blind placebo-controlled study. Cephalalgia 2003; 23:734. 47. Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. Headache 1989; 29:167168. 48. Leone M, DAmico D, Frediani F, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 2000; 54:13821385. 49. Meyer JS, Hardenberg J. Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headaches. Headache 1983; 23:266277. 50. de Carolis P, Baldrati A, Agati R, et al. Nimodipine in episodic cluster headache: results and methodological considerations. Headache 1987; 27:397399. 51. Curran DA, Hinterberger H, Lanie JW. Methysergide. Res Clin Stud Headache 1967; 1:74122. 52. Krabbe A. Limited efcacy of methysergide in cluster headache: a clinical experience. Cephalalgia 1989; 9(suppl 10):404405.

490

Dodick

53. Kudrow L. Lithium prophylaxis for chronic cluster headache. Headache 1977; 17: 1518. 54. Ekbom K. Lithium for cluster headache: review of the literature and preliminary results of long-term treatment. Headache 1981; 21:132139. 55. Manzoni GC, Bono G, Lanfranchi M, et al. Lithium carbonate in cluster headache: assessment of its short- and long-term therapeutic efcacy. Cephalalgia 1983; 3:109114. 56. Steiner TJ, Hering R, Couturier EG, et al. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia 1997; 17:673675. 57. Freitag FG, Diamond S, Diamond ML, Urban G, Peepr B. Divalproex sodium in the preventive treatment of cluster headache. Headache 2000; 40:408. 58. Gallagher RM, Mueller LL, Freitag FG. Divalproex sodium in the treatment of migraine and cluster headaches. J Am Osteopath Assoc 2002; 22:205208. 59. Hering R, Kuritzky A. Sodium valproate in the treatment of cluster headache: an open clinical trial. Cephalalgia 1989; 9:195198. 60. El Amrani M, Massiou H, Bousser MG. A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia 2002; 22:205208. 61. Wheeler SD, Carrazana EJ. Topiramate-treated cluster headache. Neurology 1999; 53:234236. 62. Lainez MJA, Pascual J, Pascual AM, Santonja JM, Ponz A, Salvador A. Topiramate in the prophylactic treatment of cluster headache. Headache 2003; 43:784789. 63. Leone M, Dodick D, Rigamonti A, et al. Topiramate in cluster headache prophylaxis: an open trial. Cephalalgia 2003; 23:10011002. 64. Leandri M, Luzzani M, Cruccu G, Gottlieb A. Drug-resistant cluster headache responding to gabapentin: a pilot study. Cephalalgia 2001; 21:744746. 65. Marks DR, Rapoport A, Padla D, et al. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993; 13:114116. 66. Fusco BM, Marabini S, Maggi CA, et al. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain 1994; 59:321325. 67. Leone M, DAmico D, Moschiano F, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16:494496. 68. DAndrea G, Granella F, Cadaldini M. Possible usefulness of lamotrigine in the treatment of SUNCT syndrome. Neurology 1999; 53:1609. 69. Leone M, Rigamonti A, Usai S, et al. Two new SUNCT cases responsive to lamotrigine. Cephalalgia 2000; 20:845847. 70. DAndrea G, Granella F, Ghiotto N, et al. Lamotrigine in the treatment of SUNCT syndrome. Neurology 2001; 57:17231725. 71. Graff-Radford SB. SUNCT syndrome responsive to gabapentin. Cephalalgia 2000; 20:515517. 72. Hunt CH, Dodick DW, Bosch EP. SUNCT responsive to gabapentin. Headache 2002; 42(6):525526. 73. Matharu MS, Boes CJ, Goadsby PJ. SUNCT syndrome: prolonged attacks, refractoriness and response to topiramate. Neurology 2002; 58(8):1307. 74. Matharu MS, Cohen AS, Goadsby PJ. SUNCT syndrome responsive to intravenous lidocaine. Cephalalgia 2004; 24(11):985992. 75. Lenaerts M, Diederich N, Phuoe D. A patient with SUNCT cured by the Jannetta procedure. Cephalalgia 1997; 17:460. 76. Gardella L, Viruega A, Rojas H, et al. A case of a patient with SUNCT syndrome treated with Jannetta procedure. Cephalalgia 2001; 21:996999. 77. Mellick GA, Mellick LB. Cluster headache management with methylphenidate (Ritalin). Headache 1998; 38:710712. 78. Hering-Hanit R, Gadoth N. Baclofen in cluster headache. Headache 2000; 40:4851. 79. DAlessandro R. Tizanidine for chronic cluster headache [letter]. Arch Neurol 1996; 53:1093.

Trigeminal Autonomic Cephalgias

491

80. Leone M, Attanasio A, Grazzi L, et al. Transdermal clonidine in the prophylaxis of episodic cluster headache: an open study. Headache 1997; 37:559560. 81. Speight TM, Avery GS. Pizotifen (BC-105): a review of its pharmacological properties and its therapeutic efcacy in vascular headaches. Drugs 1972; 3:159203. 82. Caviness VS Jr, OBrien P. Cluster headache: response to chlorpromazine. Headache 1980; 20:128131. 83. Diamond S, Freitag FG, Prager J, et al. Treatment of intractable cluster. Headache 1986; 26:4246. 84. Nicolodi M, Sicuteri F, Poggioni M. Hypothalamic modulation of nociception and reproduction in cluster headache. I. Therapeutic trials of leuprolide. Cephalalgia 1993; 13:253257. 85. Zebenholzer K, Wober C, Vigl M, et al. Eletriptan for the short-term prophylaxis of cluster headache. Headache 2004; 44:361364. 86. Siow HC, Pozo-Rosich P, Silberstein SD. Frovatriptan for the treatment of cluster headaches. Cephalalgia 2004; 24(12):10451048. 87. Mather PJ, Silberstein SD, Schulman EA, et al. The treatment of cluster headache with repetitive intravenous dihydroergotamine. Headache 1991; 31:525532. 88. Magnoux E, Zlotnik G. Outpatient intravenous dihydroergotamine for refractory cluster headache. Headache 2004; 44:249255. 89. Leone M, May A, Franzini A, et al. Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection. Cephalalgia 2004; 24(11):934937. 90. Onofrio BM, Campbell JK. Surgical treatment of chronic cluster headache. Mayo Clin Proc 1986; 61:537544. 91. Mathew NT, Hurt W. Percutaneous radiofrequency trigeminal gangliorhizolysis in intractable cluster headache. Headache 1988; 28:328331. 92. Taha JM, Tew JM Jr. Long-term results of radiofrequency rhizotomy in the treatment of cluster headache. Headache 1995; 35:193196. 93. Sanders M, Zuurmond WW. Efcacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12- to 70-month follow-up evaluation. J Neurosurg 1997; 87:876880. 94. Ford RG, Ford KT, Swaid S, et al. Gamma knife treatment of refractory cluster headache. Headache 1998; 38:39. 95. Lovely TJ, Kotsiki SX, Jannetta PJ. The surgical management of chronic cluster headache. Headache 1998; 38:590594. 96. Kirkpatrick PJ, OBrien MD, MacCabe JJ. Trigeminal nerve section for chronic migrainous neuralgia. Br J Neurosurg 1993; 7:483490. 97. Jarrar RG, Black DF, Dodick DW, et al. Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Neurology 2003; 60:13601362. 98. Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 2001; 345:14281429. 99. Leone M, Franzini A, DAmico D, et al. Long-term followup of hypothalamic stimulation to relieve intractable chronic cluster headache. Neurology 2004; 62:A355 [Abstract]. 100. Van denheeden, Naertens AS, Renacle JN, et al. Deep brain stimulation of posterior hypothalamus in chronic cluster headache. Neurology 2004; 62:A356 [Abstract]. 101. Dodick DW. Occipital nerve stimulation for chronic cluster headache. Adv Stud Med 2003; 3:S569S571. 102. Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache 1989; 29:648656. 103. Boes C, Dodick DW. The clinical spectrum of chronic paroxysmal hemicrania seen at the Mayo Clinic from 1976 to 1996 (abstract). Cephalalgia 2000; 20:289. 104. Russell D. Chronic paroxysmal hemicrania: severity, duration and time of occurrence of attacks. Cephalalgia 1984; 4:5356.

492

Dodick

105. Newman LC, Lipton RB, Soloman S. Hemicrania continua: ten new cases and a review of the literature. Neurology 1994; 44:21112114. 106. Peres MF, Silberstein SD, Nahmias S, et al. Hemicrania continua is not that rare. Neurology 2001; 57:948951. 107. Peres MF, Siow HC, Rozen TD. Hemicrania continua with aura. Neurology 2001; 56(suppl 3):A452. 108. Bordini C, Antonaci F, Stovner LJ, et al. Hemicrania continua: a clinical review. Headache 1991; 31:2026. 109. Pareja J, Sjaastad O. Chronic paroxysmal hemicrania and hemicrania continua. Interval between indomethacin administration and response. Headache 1996; 36:2023. 110. Sanchez del Rio M, Caminero AB, Pascual J, Pareja JA. Dose and efcacy of long-term indomethacin treatment of chronic paroxysmal hemicrania and hemicrania continua (abstract). Cephalalgia 2001; 21:507508. 111. Sjaastad O, Antonaci F. Chronic paroxysmal hemicrania (CPH) and hemicrania continua: transition from one stage to another. Headache 1993; 33:551554. 112. Kuritzky A. Indomethacin-resistant hemicrania continua. Cephalalgia 1992; 12:5759. 113. Sjaastad O, Stovner LJ, Stolt-Nielsen A, et al. CPH and hemicrania continua: requirements of high indomethacin dosagesan ominous sign? Headache 1995; 35:363367. 114. Eross EJ, Swanson JW. Hemicrania continua: an indomethacin-responsive case with an underlying malignant etiology. Neurology 2001; 56(suppl 3):A452. 115. Antonaci F, Sjaastad O. Hemicrania continua: a possible symptomatic case, due to mesenchymal tumor. Funct Neurol 1992; 7:471474. 116. Young WB, Silberstein SD. Hemicrania continua and symptomatic medication overuse. Headache 1993; 33:485487. 117. Pascual J. Hemicrania continua. Neurology 1995; 45:23022303. 118. Wheeler SD. Lamotrigine efcacy in migraine prevention (abstract). Cephalalgia 2001; 21:374. 119. Mariano HS, Alcantara MC, Bordini CA, Speciali JG. Relief of continuous hemicrania by gabapentin: a case report (abstract). Cephalalgia 2001; 21:508. 120. Joubert J. Hemicrania continua in a black patientthe importance of the non-continuous stage. Headache 1991; 31:480482. 121. Pareja JA, Ming JM, Kruszewski P, et al. SUNCT syndrome: duration, frequency and temporal distribution of attacks. Headache 1996; 36:161165.http://jnnp.bmjjournals. com/cgi/external_ref?access_num8984088&link_typeMED. 122. Pareja JA, Sjaastad O. SUNCT syndrome. A clinical review. Headache 1997; 37: 195202. 123. Pareja JA, Joubert J, Sjaastad O. SUNCT syndrome. Atypical temporal patterns. Headache 1996; 36:108110. 124. Sjaastad O, Kruszewski P. Trigeminal neuralgia and SUNCT syndrome: similarities and differences in the clinical picture. An overview. Funct Neurol 1992; 7:103107. 125. Matharu MS, Levy MJ, Merry RT, Goadsby PJ. SUNCT syndrome secondary to prolactinoma [Case Reports. Journal Article]. J Neurol Neurosurg Psychiatr 2003; 74(11):15901592. 126. Matharu MS, Cohen AS, Boes CJ, Goadsby PJ. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome: a review. Curr Pain Headache Rep 2003; 7(4):308318. 127. Goadsby PJ, Matharu MS, Boes CJ. SUNCT syndrome or trigeminal neuralgia with lacrimation. Cephalalgia 2001; 21:8283. 128. Pareja JA, Kruszewski P, Sjaastad O. SUNCT syndrome: trials of drugs and anesthetic blockades. Headache 1995; 35:138142. 129. Black DF, Dodick DW. Two cases of medically and surgically intractable SUNCT: a reason for caution and an argument for a central mechanism. Cephalalgia 2002; 22(3):201204. 130. Noronha A, Appelbaum J. Symptomatic cluster. Neurology 1993; 43:1270.

Trigeminal Autonomic Cephalgias

493

131. Mathew NT, Kailasam J, Meadors L. Prophylaxis of migraine, transformed migraine, and cluster headache with topiramate. Headache 2002; 42:796803. 132. Hering-Hanit R. Efcacy of topiramate for the prevention of cluster headache. Presented at 8th Congress of the European Federation of Neurological Societies, September 47, Paris, France, 2004. Poster P1233. 133. Wheeler SD. Rofecoxib-responsive hemicrania continua (abstract). Headache 2000; 40:436437. 134. Trucco M, Antonaci F, Sandrini G. Hemicrania continua: a case responsive to piroxicam-beta-cyclodextrin. Headache 1992; 32:3940. 135. Coria F, Claveria LE, Jimenez-Jimenez FJ, de Seijas EV. Episodic paroxysmal hemicrania responsive to calcium channel blockers. J Neurol Neurosurg Psychiatr 1992; 55:166. 136. Shabbir N, McAbee G. Adolescent chronic paroxysmal hemicrania responsive to verapamil monotherapy. Headache 1994; 34:209210. 137. Hannerz J, Ericson K, Bergstrand G. Chronic paroxysmal hemicrania: orbital phlebography and steroid treatment. A case report. Cephalalgia 1987; 7:189192. 138. Sjaastad O, Antonaci F. A piroxicam derivative partly effective in chronic paroxysmal hemicrania and hemicrania continua. Headache 1995; 35:549550. 139. Warner JS, Wamil AW, McLean MJ. Acetazolamide for the treatment of chronic paroxysmal hemicrania. Headache 1994; 34:597599.

31
Other Primary Headaches
Lawrence C. Newman, Susan W. Broner, and Christine L. Lay
The Headache Institute, Roosevelt Hospital Center, New York, New York, U.S.A.

INTRODUCTION Although migraine and tension-type headaches are the most common headache disorders encountered in clinical practice, recognition of other less common primary headache syndromes is important, because the sufferers tend to be desperate, often misdiagnosed and mismanaged. Although included under the rubric of other primary headaches, some of the syndromes listed within this classication may in fact have secondary etiologies. As noted in the criteria for these disorders in the second edition of the International Classication of Headache Disorders (ICHD-2) (1), the diagnosis of the primary headache can only be given after secondary causes have been excluded. Furthermore, the proper treatment of these disorders is predicated upon establishing the correct diagnosis; some of the conditions described in this chapter respond dramatically to therapy with indomethacin but not to agents typically prescribed for the other more common primary headaches. This chapter reviews the clinical features and treatment options for several of these rarer disorders.

PRIMARY STABBING HEADACHE (ICHD-2 CODE 4.1) Primary stabbing headache, the new ICHD-2 (1) term for idiopathic stabbing/icepick headache, is a benign headache disorder, often coming on in middle or later years of life, with a lifetime prevalence of 2% (2). It typically is described as a paroxysmal, very brief (110 seconds) sharp/stabbing pain, which may be bilateral or unilateral and may vary in location. The pattern and frequency of attacks are quite variable and in more than 50% of cases, this headache is associated with other headache disorders, such as migraine, hemicrania continua (HC), chronic paroxysmal hemicrania and cluster (3). The ICHD-2 criteria (1) for primary stabbing headache are listed in Table 1. Women are more commonly affected than men and although the attacks are usually self-limiting, some patients develop repetitive volleys of painful attacks, up to 50 times/day, lasting days at a time (4). Indomethacin 25 to 50 mg t.i.d brings relief in most, but not all, cases (4,5). Secondary stabbing headache has been associated with intracerebral meningiomas and temporal arteritis (6,7). In patients
495

496 Table 1 ICHD-2 Criteria for Primary Stabbing Headache

Newman et al.

Description Transient and localized stabs of pain in the head, which occur spontaneously in the absence of organic disease of underlying structures of the cranial nerves Diagnostic criteria Head pain occurring as a single stab or a series of stabs and fullling criteria B and C Exclusively or predominantly felt in the distribution of the rst division of the trigeminal nerve Stabs last for up to a few seconds and recur with irregular frequency ranging from one to many per day No accompanying symptoms Not attributed to another disorder
Note: History and physical and neurological examinations do not suggest any of the disorders listed in groups 512 and/or neurological examinations do suggest such disorder but it is ruled out by appropriate investigations, or such disorder is present, but attacks do not occur for the rst time in close temporal relation to the disorder. Abbreviation: ICHD, International Classication of Headache Disorders.

unable to tolerate indomethacin, success has been reported with melatonin, in doses ranging from 3 to 12 mg daily (8).

PRIMARY COUGH HEADACHE (ICHD-2 CODE 4.2) Primary cough headache typically affects men over 40 years of age and while often described as a severe headache of sudden onset, it is by denition benign. Within seconds of coughing, sneezing, straining or other Valsalva maneuvers an immediate headache is experienced. The headache usually subsides within minutes, however, some sufferers may continue to experience a dull ache for several hours afterward. Often bilateral in location, the throbbing pain is maximally felt at the vertex, frontal, occipital or temporal areas and associated neurological features or nausea/vomiting are absent. The criteria for primary cough headache are listed in Table 2. While the precise etiology is unknown, it may relate to a sudden increase
Table 2 ICHD-2 Criteria for Primary Cough Headache Previously used terms: Benign cough headache, Valsalva-maneuver headache Description Headache precipitated by coughing or straining in the absence of any intracranial disorder Diagnostic criteria Headache fullling criteria B and C Sudden onset, lasting one second to 30 min Brought on by and occurring only in association with coughing, straining and/or Valsalva maneuver Not attributed to another disorder
Note: Cough headache is symptomatic in about 40% of cases, and the large majority of these present Arnold-Chiari malformation type I. Other reported causes of symptomatic cough headache include carotid or vertebrobasilar diseases and cerebral aneurysms. Diagnostic neuroimaging plays an important role in differentiating secondary cough headache from 4.2 Primary cough headache. Abbreviation: ICHD, International Classication of Headache Disorders.

Other Primary Headaches

497

in intracranial pressure with traction on pain-sensitive structures from a downward displacement of cerebellar tonsils. When cough headache occurs in a younger patient, is of long duration, is strictly unilateral or is associated with other features, the diagnosis must be questioned. Secondary cough headache has been described in Chiari malformation, brain tumor [both malignant and benign (meningioma/acoustic neuroma)], cerebral aneurysm and carotid or vertebrobasilar disease (9). Neuroimaging is mandatory in distinguishing the secondary causes from primary cough headache. Indomethacin is the treatment of choice in those patients who frequently experience cough headache and the sustained release formulation (75 mg q.i.d. or b.i.d.) is often the best choice. A positive response to indomethacin may be seen in secondary cases and is therefore not diagnostic of primary cough headache. In a small case series, lumbar puncture provided prompt relief (10).

PRIMARY EXERTIONAL HEADACHE (ICHD-2 CODE 4.3) Primary exertional headache, not surprisingly, occurs with exertional effort as may occur during physical exercise, weight-lifting, straining or bending over. While cough and exertional headache are often linked as Valsalva maneuver headache, they remain distinct entities in the ICHD-2 classication (1). The headache is of sudden onset and often bilateral in location, but unlike cough headache, the pain is often pulsatile and of longer duration (5 minutes to 48 hours). The ICHD-2 criteria for primary exertional headache are listed in Table 3. As in cough headache, neuroimaging to rule out a posterior fossa or craniocervical junction abnormality should be undertaken in a patient presenting with new exertional headache, particularly when the headache is unilateral (9). In addition to unilaterality, secondary exertional headache often begins later in life, lasts longer (24 hours to weeks) and in cases of subarachnoid hemorrhage (SAH), the headache is associated with neurological features such as meningismus. Other secondary causes include Chiari malformation, subdural hematoma, neoplasm (primary and metastatic) and platybasia (9). A rst-ever presentation of exertional headache requires a work-up to rule out SAH or arterial dissection. While the pathophysiology of primary exertional headache is unknown, it is theorized that venous distention following exercise or arterial distention as a result of exercise (especially in a warm environment) may be at the root of the cause, with subsequent release of vasoactive peptides leading to downstream neurogenic
Table 3 ICHD-2 Criteria for Primary Exertional Headache Description Headache precipitated by any form of exercise Diagnostic criteria Pulsating headache fullling B and C Lasting 5 min to 48 hr Brought on by and occurring only during or physical exertion Not attributed to another disorder
Note: On rst occurrence of this headache type it is mandatory to exclude subarachnoid hemorrhage and arterial dissection. Abbreviation: ICHD, International Classication of Headache Disorders.

498

Newman et al.

inammation (11). Treatment with indomethacin or ergotamine around 30 minutes prior to exercise may be helpful. Other NSAIDs may be empirically tried.

PRIMARY HEADACHES ASSOCIATED WITH SEXUAL ACTIVITY (ICHD-2 CODE 4.4) Headaches with sexual activity affect men more often than women; it has also been reported to occur more commonly during illicit sexual encounters (12,13). These headaches have also been referred to as benign sex headache, coital cephalalgia, benign vascular sexual headache, or benign orgasmic headaches. As they are not solely precipitated by sexual intercourse (similar headaches provoked by masturbation and during nocturnal emissions have been reported) or with orgasm, the ICHD2 (1) has classied these as primary headaches associated with sexual activity (1214). Three varieties of these headaches were described in the rst edition of the ICHD (15); a dull type, an explosive type, and a postural type. In ICHD-2, however, these subtypes are not classied as such. Rather, primary headache associated with sexual activity is now separated into preorgasmic and orgasmic headaches (1). These criteria are listed in Table 4. Preorgasmic headaches (previously classied as the dull subtype) occur in approximately 20% of sufferers. These headaches resemble tension-type headaches in that they are characterized by a dull ache in the muscles of the head and neck. Some patients describe an awareness of tightness of the muscles of the jaw and neck occurring during sexual activity. Preorgasmic headaches are bilateral, beginning as sexual excitement builds, and can be prevented or reduced by deliberate muscle relaxation. Orgasmic headaches (previously called the explosive subtype) are the most common, accounting for approximately 75% of cases. It is estimated that 50% of these sufferers also have preexisting migraine headaches (16). These headaches begin abruptly, at the moment of orgasm, and may be caused by an increase in blood pressure. The pain is excruciatingly severe, most often described as explosive or throbbing, and may be frontal, occipital, or generalized. On occasion this type of
Table 4 Criteria of Primary Headache Associated with Sexual Activity Description Headache precipitated by sexual activity, usually starting as a dull bilateral ache as sexual excitement increases and suddenly becoming intense at orgasm, in the absence of any intracranial disorder Preorgasmic headache Dull ache in the head and neck associated with awareness of neck and/or jaw muscle contraction and fullling criterion B Occurs during sexual activity and increases with sexual excitement Not attributed to another disorder Orgasmic headache Sudden severe (explosive) headache fullling criterion B Occurs at orgasm Not attributed to another disorder
Note: On rst onset of orgasmic headache it is mandatory to exclude conditions such as subarachnoid hemorrhage.

Other Primary Headaches

499

headache may be associated with nausea and vomiting. These headaches typically last from one minute to three hours. The postural variety is the least common subtype, affecting approximately 5% of sufferers. This headache resembles the headache that follows lumbar puncture in that it worsens with sitting or standing and is relieved by recumbency. It may be caused by a rent in the dura, which spontaneously develops during sexual activity. This rare subtype is no longer included in the ICHD classication of headaches associated with sexual activity. Instead, these headaches are now classied as headaches attributed to spontaneous low cerebrospinal uid (CSF) pressure. The diagnosis of primary headache associated with sexual activity is predicated upon the exclusion of secondary causes such as SAH, arterial dissection and lesions of the posterior fossa, CSF pathways, and cervical spine (9,17). The mainstay of treatment of the primary forms of headaches associated with sexual activity is reassurance, both of the patient and their partner. For most patients, these are self-limited disorders; however, the course may be unpredictable. Headaches often recur during several encounters over a brief period of time and never return again, while other patients experience them at infrequent intervals throughout their lifetime. Often patients can lessen the severity of an impending attack by stopping the sexual activity as soon as the headache begins. For patients who suffer from frequent, recurrent episodes preventive strategies should be employed. Indomethacin 25 mg t.i.d. with meals often prevents attacks. Other options include the use of oral ergotamine tartrate taken a few hours prior to when sexual activity is planned, or prophylaxis with the b-blocker propranolol 40200 mg daily, which unfortunately may interfere with sexual function (18,19). One patient has been reported in whom treatment with the calcium channel blocker diltiazem 60 mg t.i.d. was successful (20).

THE HYPNIC HEADACHE SYNDROME (ICHD-2 CODE 4.5) The hypnic headache (HH) is a rare, recurrent, sleep-related, primary headache disorder that usually begins after 50 years of age. Raskin (21) rst described the disorder in 1988; more than 90 cases have been subsequently reported (2225). In the largest case study HH was diagnosed in 0.07% of all headache patients assessed annually at a specialty clinic reecting the rarity of this syndrome (23). HH usually begins late in life with a mean age at onset of 61 10 years (range 3083 years). A report of a nine-year-old girl with probable HH has been reported, although the headache frequency did not meet International Headache Society (HIS) criteria (26). The condition is more prevalent in women (65%) than in men. Table 5 lists the ICHD-2 criteria for HH. The headaches of HH occur at a consistent time each night, usually between 1:00 to 3:00 AM, and may on rare instances occur during a daytime nap (24,28). The headaches begin abruptly, are diffuse and throbbing, and spontaneously resolve in 15 to 180 minutes. Rarely, the headache is hemicranial (2830). The pain in HH is usually localized anteriorly and less often involves the lateral aspects of the head or felt as a diffuse headache. On occasion it involves the occiput or radiates into the neck. The duration of an untreated attack and in-between attacks varies among patients. Usually the pain resolves within one to two hours (range 15180 minutes), but longer attacks of up to 10 hours have been reported. The frequency of the attacks is high. More than four attacks per week occurred in 70% of the cases and about half of them had daily attacks (range one per week to six per night) (24).

500 Table 5 IHS Criteria for Hypnic Headache

Newman et al.

Description Attacks of dull headache that always awaken the patient from sleep Diagnostic criteria Dull headache fullling criteria BD Develops only during sleep, and awakens patient At least two of the following characteristics: Occurs >15 times/mo Lasts !15 min after waking First occurs after the age of 50 No autonomic symptoms and no more than one of nausea, photophobia, or phonophobia Not attributed to another disorder
Note: Intracranial disorders must be excluded. Distinction from one of the trigeminal autonomic cephalgias is necessary for effective management. Abbreviation: IHS, International Headache Society.

No associated autonomic symptoms accompany the pain, but nausea, photophobia and phonophobia may rarely be present. Two reports of probable secondary HH have been described. In one, the patient had a nine-month history of typical HH, but also reported brief episodes of giddiness. A brain magnetic resonance imaging revealed a large posterior-fossa meningioma. Following tumor resection, there was complete resolution of the headache (31). In the second report, HH-like headaches occurred in the setting of intracranial hypotension. Headaches remitted following a spinal blood patch (32). Lithium was the rst, and remains the most indicated treatment for HH (21,22,24,33). Treatment is initiated with 300 mg at bedtime and can be increased to 600 mg at bedtime within a week. Renal and thyroid function should be assessed prior to initiating therapy, and periodically during treatment. Lithium serum concentrations should be monitored as well to avoid toxicity. Side effects include tremor, diarrhea, increased thirst, and polyuria. Although lithium has higher efcacy rates than other medications, it is often poorly tolerated. By reassuring the patients of the benign nature of the headache, some will choose to delay usage of medications (23). Other agents that have been reported to effectively treat HH include bedtime doses of caffeine (4060 mg tablet, or as a cup of coffee) (23,33), unarizine 5 mg (22,33), and indomethacin 25 to 75 mg (3335). Indomethacin appears to be of utility for patients in whom attacks are strictly unilateral (34).

PRIMARY THUNDERCLAP HEADACHE (ICHD-2 CODE 4.6) Primary thunderclap headache (PTCH) is a severe headache of sudden onset that may persist for several hours. Severe headaches with abrupt onset are often associated with a sinister underlying secondary cause; that thunderclap headache (TCH) exists as a primary subtype is controversial, but criteria have been suggested in the ICHD-II (1) and are listed in Table 6. The disorder was rst described in 1984 (36). In 1986, Day and Raskin coined the term thunderclap headache when describing a patient with a severe, rapidly developing headache who had normal computed tomography (CT) of the brain

Other Primary Headaches Table 6 Diagnostic Criteria for Thunderclap Headache Severe head pain fullling criteria B and C Both of the following characteristics Sudden onset, reaching maximum intensity in <1 min Lasting from 1 hr to 10 days Does not recur regularly over subsequent weeks or monthsa Not attributed to another disorderb
Headache may recur within the rst week after onset. Normal CSF and normal brain imaging are required. Abbreviation: CSF, cerebrospinal uid.
b a

501

and lumbar puncture, but in whom angiography revealed an unruptured aneurysm with diffuse vasospasm (37). Patients often describe TCH as the worst headache of their life. It comes on suddenly, peaks in intensity within one minute, and typically lasts several hours. Patients may experience repeated bouts in the rst two weeks; rarely, the headache may linger at a lower level. PTCH is often self-limiting, although one-third of patients may experience recurrent PTCH over the following months to years. It may occur spontaneously while at rest, although in one-third of reported cases, the headache was precipitated by exertion (38). PTCH may be part of the migraine continuum. Some patients have a prior history of migraine; in others it may presage the development of migraine. Clinically, a consistent location or quality of pain has not been described. The headache may be associated with light and sound sensitivity, neck stiffness, nausea, and/or vomiting. The majority patients have a normal neurological examination, although rarely, focal decits have been reported (39). According to ICHD-2 criteria (1), cerebrospinal uid and brain imaging must be normal. These criteria make no mention of the need for angiography, yet two subtypes of PTCH may exist: one with no angiographic abnormalities and a second subtype with diffuse segmental vasospasm (37,39,40). As mandated by the ICHD-2 criteria, PTCH is a diagnosis of exclusion. Secondary causes of TCH should be aggressively sought. The differential diagnosis includes SAH (12% of patients with SAH present with the worst headache of their life), cerebral venous sinus thrombosis, pituitary apoplexy, and arterial dissection amongst others. In patients with angiographic evidence of segmental vasospasm, central nervous system vasculitis should be considered. Initial work-up should include a head CT, lumbar puncture, and when appropriate, magnetic resonance imaging and conventional, CT, or magnetic resonance angiography of the brain. Because PTCH is usually a self-limited disorder, there are no treatment recommendations. Long-term follow-up in patients with PTCH and unruptured aneurysms thus far has not revealed a tendency to bleed (41,42), but this remains controversial (43). Recurrent TCH with vasospasm leading to stroke has been reported (44); nimodipine may lessen the risk (45,46).

HEMICRANIA CONTINUA (ICHD-2 CODE 4.7) HC is another primary headache that is responsive to treatment with indomethacin. The disorder was rst described in 1981 (5) and ofcially named in 1984 (47). There

502 Table 7 Diagnostic Criteria for HC

Newman et al.

Headache for >3 mo fullling criteria BD All of the following characteristics Unilateral pain without side-shift Daily and continuous, without pain-free periods Moderate intensity, but with exacerbations of severe pain At least one of the following autonomic features occurs during exacerbations and ipsilateral to the side of pain Conjunctival injection and/or lacrimation Nasal congestion and/or rhinorrhoea Ptosis and/or miosis Complete response to therapeutic doses of indomethacin Not attributed to another disordera
History and physical and neurological examinations do not suggest any of the disorders listed in groups 512, or history and/or physical and/or neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations, or such disorder is present but headache does not occur for the rst time in close temporal relation to the disorder. Abbreviation: HC, hemicrania continua.
a

are now more than 100 reports of HC in the literature. HC was not included in the rst edition of the ICHD guidelines (15). Because of the presence of autonomic features that accompany the painful exacerbations, HC was considered to be one of the trigeminal autonomic cephalgias (25). However, the ICHD-2 (1) includes HC within the other primary headaches section. Criteria for HC are listed in Table 7. HC is thought to be under-recognized in the general population, but is a common cause of refractory, unilateral, chronic daily headaches in sub-specialty practices (48). The disorder demonstrates a female predominance with a femaleto-male ratio of approximately 2:1. The age of onset ranges from 11 to 58 years (mean 34 years). Clinically, HC is characterized by a unilateral, continuous headache of mild-to-moderate intensity. Patients usually describe this baseline discomfort as dull, aching, or pressing, and it is not associated with other symptoms. The pain is maximal in the ocular, temporal, and maxillary regions. Superimposed upon this background discomfort, exacerbations of more severe pain, lasting 20 minutes to several days are experienced by the majority of sufferers. Although signicantly more intense than the baseline pain, these painful exacerbations never reach the level experienced by cluster headache sufferers. During these are-ups, one or more autonomic symptoms (ptosis, conjunctival injection, lacrimation, and nasal congestion) occur ipsilateral to the pain. These exacerbations may occur at any time and frequently awaken the patient from sleep. Migrainous symptoms, such as nausea, vomiting, photophobia, and phonophobia may also accompany the exacerbations of pain. Many patients report primary stabbing headaches (stabs and jabs), and a feeling of sand or an eyelash in the affected eye (foreign body sensation) (49). Most patients experience strictly unilateral headaches without side shift, although three patients in whom attacks alternated sides (5052), and three bilateral cases have been described (5355). Two temporal proles of HC exist: an episodic form with distinct headache phases separated by pain-free remissions, and a chronic form in which headaches persist without remissions (25,56,57). HC is chronic from onset in 53% of patients; in 35% the disorder began as the episodic subtype and evolved into the chronic

Other Primary Headaches

503

form, in 12% it begins and remains episodic (48). Two atypical presentations of HC, one in whom an initially chronic course evolved into the episodic form, and a patient with episodic HC with a clear seasonal pattern have been described (48,58). HC is frequently misdiagnosed as another primary headache syndrome. If the physician focuses on the ipsilateral autonomic features that accompany the painful exacerbations, the disorder may be incorrectly diagnosed as cluster headache. Similarly, by focusing on the associated photophobia, phonophobia, nausea, and vomiting that may occur during exacerbations, HC may be misdiagnosed as migraine. HC is distinguished from cluster and migraine by the presence of a continuous baseline headache of mild-to-moderate severity; neither the ipsilateral autonomic features of cluster, nor the associated phenomena typically reported with migraine accompany this baseline pain. Organic mimics of HC have been reported: a mesenchymal tumor involving the sphenoid bone, clinoid process, and skull base created symptoms of HC (25). The diagnosis of HC may be masked by medication overuse headache (59); with discontinuation of the overused agents, an unremitting headache will remain, and the diagnosis of HC can then be made. Indomethacin is the treatment of choice for HC, and response to therapy with indomethacin is necessary for establishing the diagnosis (1). Therapy is usually initiated at a dose of 25 mg t.i.d. and increased to 50 mg t.i.d. in one week if there is no response or only partial benet. Headache resolution is usually prompt, occurring within one to two days after the effective dosage is reached, although response may take as long as two weeks. Maintenance with doses ranging from 25 to 100 mg usually sufces; however, at times doses as high as 300 mg daily may be required. Dosage adjustments are occasionally necessary to treat the clinical uctuations that are sometimes seen with HC; nighttime dosing with sustained-release indomethacin often prevents nocturnal exacerbations. During the active headache cycle, patients report that skipping or even delaying doses of indomethacin may result in the prompt re-emergence of symptoms. In patients suffering from the episodic form of HC, indomethacin should be given for slightly longer than the usual headache phase and then gradually tapered. In patients with the chronic sub-type, long-term indomethacin dosing is required. The gastrointestinal side effects of indomethacin can be mitigated with antacids, misoprostel, or histamine H2 receptor antagonists. These agents should always be considered for those patients requiring long-term therapy. Although the ICHD-2 requires indomethacin responsiveness as a diagnostic criterion, other agents have been reported to induce a partial response. These include naproxen, paracetamol, and paracetamol with caffeine, ibuprofen, piroxicam (25), rofecoxib (60), and celecoxib (61). Patients who have otherwise met, criteria for HC but failed to respond to indomethacin or other agents have been described (62). This has been termed indomethacin-resistant hemicrania continua but as such would not meet ICHD-2 criteria (1) for the disorder.

NEW DAILY-PERSISTENT HEADACHE (ICHD-2 CODE 4.8) New daily-persistent headache (NDPH) is a headache that develops de novo, either acutely or over a maximum of three days, and then persists as a daily, unremitting headache. It has features of both migraine and tension-type headache: it is usually bilateral, pressure-like, of mild-to-moderate intensity without worsening by physical activity, and may be accompanied by photophobia, phonophobia, or mild nausea.

504 Table 8 Diagnostic Criteria for NDPH

Newman et al.

Headache for >3 mo fullling criteria BD Headache is daily and unremitting from onset or from <3 days from onseta At least two of the following pain characteristics: Bilateral location Pressing/tightening (non-pulsating) quality Mild or moderate intensity Not aggravated by routine physical activity such as walking or climbing stairs Both of the following: No more than one of photophobia, phonophobia, or mild nausea Neither moderate or severe nausea nor vomiting Not attributed to another disorderb
Headache may be unremitting from the moment of onset or very rapidly build up to continuous and unremitting pain. Such onset or rapid development must be clearly recalled and unambiguously described by the patient. Otherwise code as 2.3 Chronic tension-type headache. b History and physical and neurological examinations do not suggest any of the disorders listed in groups 512 (including 8.2 Medication-overuse headache and its subforms), or history and/ or physical and/or neurological examinations do suggest such a disorder but it is ruled out by appropriate investigations, or such disorder is present but headache does not occur for the rst time in close temporal relation to the disorder. Abbreviation: NDPH, new daily-persistent headache.
a

The patient typically can recall the day of onset and, in fact, an unambiguous description of this recollection is part of the criteria. The current ICHD criteria are listed in Table 8. NDPH was rst described in 1986 (63). The initial report described 45 patients with no previous headache history who developed daily headaches from onset. These headaches were usually bilateral, continuous, and associated with nausea, vomiting, and photo- and phonophobia. Over subsequent years, further cases were identied and various investigators published proposed criteria (64,65). NDPH appears to be a relatively rare disorder with a female predominance. The age of onset in women ranges from 13 to 73, with the peak age in the second to fourth decades. In men, the age of onset ranges from 14 to 67, with the peak age in the third to fth decades (62,66,67). Additionally, a signicant number of adolescents with chronic daily headache have been found to meet criteria for NDPH (68,69). No consistent pain location is described in the reported cases of NDPH. A high percentage of patients have features typical of migraine. Neck pain, lightheadedness, blurred vision, and concentration difculties are also described (63,65). There is some data suggesting an infectious etiology to the disorder. Two studies have found elevated EpsteinBarr Virus titers in these patients, invoking a possible autoimmune etiology or even perhaps direct, virally-induced trigeminal nerve damage (66,70). Secondary mimics of NDPH include low- or high-pressure CSF headaches, cerebral venous sinus thrombosis, postinfectious headache, posttraumatic headache, SAH, chronic meningitis, neoplasm, and giant cell arteritis (65,7173). Whereas the initial report of NDPH suggested a benign outcome, with most patients becoming headache-free regardless of treatment (63), subsequent descriptions suggest a more intractable course (65). Indeed, there may be two forms of NDPH: a self-limited subtype and a refractory, persistent subtype (65). Medications reported to have some efcacy include topiramate and gabapentin (65), tizandine, baclofen, amitriptyline, valproic acid, uvoxamine and paroxetine (67), and phenelzine (72).

Other Primary Headaches

505

CONCLUSION The disorders discussed in this chapter are by denition, primary headaches. Clinicians must, however, remain vigilant as many of these syndromes may have an underlying secondary cause. Indeed, each of the headaches included within this subcategory have as part of their diagnostic criteria the mandate that their diagnosis can only be made after secondary causes have been appropriately excluded. Many of the syndromes discussed here demonstrate a unique response to treatment with indomethacin; proper diagnosis and treatment signicantly improves the lives of patients with these disorders, and is especially rewarding for the health-care professional as well.

REFERENCES
1. Headache Classication Committee of the International Headache Society. The International Classication of Headache Disorders. 2nd ed. Cephalalgia 2004; Suppl 1:1160. 2. Ramussen BK. Epidemiology of headache. Cephalalgia 1995; 15:4568. 3. Dodick D. Indomethacin-responsive headache syndromes. Current Pain Headache Rep 2004; 8:1926. 4. Pareja JA, Rujiz J, Deisla C, et al. Idiopathic stabbing headache (jabs and jolt syndrome). Cephalalgia 1996; 16:9396. 5. Medina JL, Diamond S. Cluster headache variant: spectrum of a new headache syndrome. Arch Neurol 1981; 38:705709. 6. Mascellino AM, Lay CL, Newman LC. Stabbing headache as the presenting manifestation of intracerebral meningioma: a report of two patients. Headache 2001; 41:599601. 7. Raskin NH, Schwartz RK. Icepick-like pain. Neurology 1980; 30:203205. 8. Rozen TD. Melatonin as treatment for idiopathic stabbing headache. Neurology 2003; 61:865866. 9. Pascual J, Iglesias F, Oterino A, Vazquez-Baquero A, Berciano J. Cough, exertional and sexual headaches: an analysis of 72 benign and symptomatic cases. Neurology 1996; 46:15201524. 10. Raskin NH. The cough headache syndrome: treatment. Neurology 1995; 45:1784. 11. Buzzi MG, Bonamini M, Moskowitz MA. Neurogenic model of migraine. Cephalalgia 1995; 15:277280. 12. Robbins L. Masturbatory-orgasmic pain. Headache 1994; 34:214216. 13. Lance JW. Headaches related to sexual activity. J Neurol Neurosurg Psychiat 1976; 39:12261230. 14. Jacome DE. Masturbatory-orgasmic extracephalgic pain. Headache 1998; 38:138141. 15. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):1160. 16. Silbert PL, Edis RH, Stewart-Wynn EG, Gubbay SS. Benign vascular sexual headache and exertional headache: inter-relationships and long term prognosis. J Neurol Neurosurg Psychiat 1991; 54:417421. 17. Selwyn DL. A study of coital related headaches in 32 patients. Cephalalgia 1985; 5(suppl 3):300301. 18. Kumar KL, Reuler JB. Uncommon headaches: diagnosis and treatment. J Gen Int Med 1993; 8:333341. 19. Porter M, Jancovic J. Benign coital cephalalgia. Differential diagnosis and treatment. Arch Neurol 1981; 38:710712. 20. Akpunonu BE, Ahrens J. Sexual headaches: case report, review, and treatment with calcium channel blocker. Headache 1991; 31:141145. 21. Raskin NH. The hypnic headache syndrome. Headache 1988; 28:534536.

506

Newman et al.

22. Newman LC, Lipton RB, Solomon S. The hypnic headache syndrome: a benign headache disorder of the elderly. Neurology 1990; 40:19041905. 23. Dodick DW, Mosek AC, Campbell JK. The hypnic (alarm clock) headache syndrome. Cephalalgia 1998; 18:152156. 24. Newman LC, Mosek AC. The hypnic headache syndrome. In: Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA, eds. The Headache. 3d ed. Phildelphia: Lippincott Williams and Wilkins 2006:847850. 25. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain 1997; 120:193209. 26. Morales-Asin F, Mauri JA, Iniguez C, Espada F, Mostacero E. The hypnic headache syndrome: report of three new cases. Cephalalgia 1998; 18:157158. 27. Grossberg BM, Lipton RB, Solomon S, Ballaban-Gill K. Hypnic headache in childhood?. Headache 2004; 44:497. 28. Gould JD, Silberstein SD. Unilateral hypnic headache: a case study. Neurology 1997; 49:17491751. 29. Gould JD, Silberstein SD. Unilateral hypnic headache: a case study. Cephalalgia 1997; 17:310. 30. Ivanez V, Soler R, Barreiro. Hypnic headache syndrome: a case with good response to indomethacin. Cephalalgia 1998; 18:225226. 31. Peateld RC, Mendoza ND. Posterior fossa meningioma presenting as hypnic headache. Headache 2003; 43:10071008. 32. Freeman WD, Brazis PW, Capobianco DJ, Lamer T. Hypnic headache and intracranial hypotension. Headache 2004; 44:498. 33. Evers S, Goadsby PJ. Hypnic headache: clinical features, pathophysiology, and treatment. Neurology 2003; 60(6):905909. 34. Dodick DW, Jones JM, Capobianco DJ. Hypnic headache: another indomethacinresponsive headache syndrome?. Headache 2000; 40:830835. 35. Jones JM, Dodick DW. Hypnic headache: another indomethacin responsive headache syndrome?. Headache 2000; 40:412. 36. Fischer CM. Painful states: a neurological commentary. Clin Neurosurg 1984; 31:3253. 37. Day JW, Raskin NH. Thunderclap headache: symptom of unruptured cerebral aneurysm. Lancet 1986; 2:12471248. 38. Dodick DW. Thunderclap headache. Current Pain Headache Rep 2002; 6:226232. 39. Slivka A, Philbrook B. Clinical and angiographic features of thunderclap headache. Headache 1995; 35:16. 40. Dodick DW, Brown RD, Britton JW, Huston J. Nonaneurysmal thunderclap headache with diffuse, multifocal, segmental, and reversible vasospasm. Cephalalgia 1999; 19:16. 41. Harling DW, Peateld RC, Van Hille PT, Abbott RJ. Thunderclap headache: is it migraine?. Cephalalgia 1989; 9:8790. 42. Wijdicks EF, Kerkhoff H, van Gigjn J. Long-term follow-up of 71 patients with thunderclap headache mimicking subarachnoid haemorrage. Lancet 1988; 2:6870. 43. Takeuchi T, Kasahara E, Iwasaki M, Kojima S. Necessity for searching for cerebral aneurysm in thunderclap headache patients who show no evidence of subarachnoid hemorrhage: investigation of m8 minor lead cases on operation [Japanese]. No Shinkei Geka 1996; 24:437441. 44. Strum JS, Macdonell RA. Recurrent thunderclap headache associated with reversible intracerebral vasospasm causing stroke. Cephalalgia 2000; 20:132135. 45. Nowak DA, Rodiek SO, Henneken S, et al. Reversible segmental cerebral vasoconstriction (Call-Fleming syndrome): are calcium channel inhibitors a potential treatment option? Cephalalgia 2003; 23:218222. 46. Lu SR, Liao YC, Fuh JL, Lirng JF, Wang SJ. Nimodipine for treatment of primary thunderclap headache. Neurology 2004; 62(8):14141416.

Other Primary Headaches

507

47. Sjaastad O, Spierings ELH. Hemicrania continua: another headache absolutely responsive to indomethacin. Cephalalgia 1980; 4:6570. 48. Peres MFP, Silberstein SD, Nahmias S, et al. Hemicrania continua is not that rare. Neurology 2001; 57:948951. 49. Newman LC, Goadsby P, Lipton RB. Cluster and related headaches. In: Mathew NT, ed. Headache. Medical Clinics of North America. Philadelphia: WB Saunders, 2001:9971016. 50. Newman LC, Lipton RB, Russell M, Solomon S. Hemicrania continua: attacks may alternate sides. Headache 1992; 32:237238. 51. Marano E, Giampiero V, Gennaro DR, et al. Hemicrania continua: a possible case with alternating sides. Cephalalgia 1994; 14:307308. 52. Newman LC, Spears RC, Lay CL. Hemicrania continua: a third case in which attacks alternate sides. Headache 2004; 44(8):821823. 53. Pasquier F, Leys D, Petit H. Hemicrania continua: the rst bilateral case. Cephalalgia 1987; 7:169170. 54. Iordanidis T, Sjaastad O. Hemicrania continua: a case report. Cephalalgia 1989; 9: 301303. 55. Trucco M, Antonaci F, Sandrini G. Hemicrania continua: a case responsive to piroxicam-beta-cyclodextrin. Headache 1992; 32:3940. 56. Newman LC, Lipton RB, Solomon S. Hemicrania continua: ten new cases and a review of the literature. Neurology 1994; 44:21112114. 57. Sjaastad O, Antonaci F. Chronic paroxysmal hemicrania (CPH) and hemicrania continua: transition from one stage to another. Headache 1993; 22:551554. 58. Pareja JA. Hemicrania continua: remitting stage evolved from the chronic form. Headache 1995; 35:161162. 59. Young WB, Silberstein SD. Hemicrania continua and symptomatic medication overuse headache. Headache 1993; 33:485487. 60. Peres MF, Zuckerman E. Hemicrania continua responsive to rofecoxib. Cephalalgia 2000; 20:130131. 61. Peres MF, Silberstein SD. Hemicrania continua responds to cyclooxygenase-2 inhibitors. Headache 2002; 42:530531. 62. Kuritzky A. Indomethacin-resistant hemicrania continua. Cephalalgia 1992; 12:5759. 63. Vanast WJ. New daily persistent headaches denition of a benign syndrome. Headache 1986; 26:318. 64. Silberstein SD, Lipton RB, Solomon S, Mathew NT. Classication of daily and neardaily headaches: proposed revisions to the IHS criteria. Headache 1994; 34:17. 65. Rozen TD. New daily persistent headache. Curr Pain Headache Rep 2003; 7:218223. 66. Li D, Rozen TF. The clinical characteristics of new daily persistent headache. Cephalalgia 2002; 22:6669. 67. Takase Y, Nakano M, Tatsumi C, Matsuyama. Clinical features, effectiveness of drugbased treatment, and prognosis of new daily persistent headache (NDPH): 30 cases in Japan. Cephalalgia 2004; 24:955959. 68. Gladstein J, Holden EW. Chronic daily headache in children and adolescents: a 2-year prospective study. Headache 1996; 36:349351. 69. Bigal ME, Lipton RB, Tepper SJ, Rapoport AM. Primary chronic daily headache and its subtypes in adolescents and adults. Neurology 2004; 63:843847. 70. Diaz-Mitoma R, Vanast WJ, Tyrell DL. Increased frequency of Epstein-Barr virus excretion in patients with new daily persistent headaches. Lancet 1987; 1:411415. 71. Evans RW. New daily persistent headache. Curr Pain Headache Rep 2003; 7:303307. 72. Goadsby PJ, Boes C. New daily persistent headache. J Neurol Neurosurg Psychiat 2002; 72(suppl II):ii6ii9. 73. Santoni JR, Santoni-Williams CH. Headache and painful lymphadenopathy in extracranial or systemic infection: etiology of new daily persistent headaches. Intern Med 1993; 32:530533.

32
When the Treatment of Headache Fails
Richard B. Lipton
Departments of Neurology, Epidemiology and Population Health, Albert Einstein College of Medicine, and The Monteore Headache Center, New York, New York, U.S.A.

Marcelo E. Bigal
Department of Neurology, Albert Einstein College of Medicine, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut, U.S.A.

INTRODUCTION Headache disorders are a leading reason for neurologic consultation in the United States; they account for about one in ve outpatient visits (1,2). Managing the headache patient, particularly the patient with chronic daily headaches, is difcult (3,4). When a patient fails to respond as expected to an appropriate therapy or announces at the rst consultation that he or she has already tried everything and nothing works, it is important to identify the reason(s) for failure of that treatment. In this chapter, we summarize the common as well as uncommon reasons for headache treatment failure. We have grouped these treatment failures into ve broad categories (Table 1). We nd it helpful to consider these categories when confronting treatment-refractory patients. The discussion that follows is organized around these categories of treatment failure with an emphasis on opportunities to improve patient outcomes. REASON 1: THE DIAGNOSIS IS INCOMPLETE OR INCORRECT Perhaps the most common reason for treatment failure is that the diagnosis is inaccurate or incomplete. This issue takes three major forms: a secondary headache disorder goes undiagnosed, a primary headache disorder is misdiagnosed, or two or more headache disorders are present and at least one goes unrecognized. We will consider these three forms of diagnostic error one at a time. Secondary Disorders Go Undiagnosed Patients with intractable headache often live with both the hope and the fear that the doctor missed something. This is also a concern for clinicians who care for
509

510 Table 1 Possible Reasons Leading to Treatment Failure The diagnosis is incomplete or incorrect A secondary headache disorder goes undiagnosed A primary headache disorder present is misdiagnosed The number of headache disorders is not clear Important exacerbating factors have been missed Acute headache medication or caffeine overuse Hormonal triggers Dietary or lifestyle triggers Psychosocial factors Other medications Pharmacotherapy has been inadequate Ineffective drug Excessive initial doses Inadequate nal doses Inadequate duration of treatment Combination therapy required Poor absorption Noncompliance Nonpharmacologic treatment has been inadequate Physical medicine Cognitive behavioral therapy Other factors Unrealistic expectations Comorbid and concomitant conditions Inpatient treatment required

Lipton and Bigal

patients with difcult-to-manage headaches. Acute medication overuse with rebound headache is probably the most common secondary disorder that causes intractability (36). Other less common secondary causes of intractable headaches are summarized in Table 2. Detection of many of these disorders requires a systematic approach to the headache history and physical examination as well as a high index of suspicion. We will highlight some of these critical issues. Temporal Prole of Headache Onset The temporal prole of the headache, as well as its nature and the circumstances of its onset, is crucial for diagnosis. The temporal prole of a headache can provide important clues to its etiology. A few examples are listed below:  A rapid-onset headache may suggest a subarachnoid hemorrhage (7), pituitary apoplexy (8), or other intracranial catastrophes (9). These disorders rarely cause chronic headaches, but can result in the intractability of an ongoing headache attack. They are of particular concern in patients presenting to the emergency department. Rapid-onset headache also can be acute-onset migraine.  Sphenoid sinusitis may cause a subacute intractable headache and may be missed radiologically unless appropriate studies are performed (10).  Headaches that start after age 55 suggest an organic disorder such as a mass lesion or giant cell arteritis (11). Giant cell arteritis is often underdiagnosed and is an important cause of preventable blindness in the elderly.

When the Treatment of Headache Fails Table 2 Secondary Headaches That Mimic Chronic Benign Headache Syndromes

511

Headache associated with vascular disorders Cerebrovascular disease including carotid artery dissection and arteriovenous malformation Arteritis including giant cell arteritis Headache associated with nonvascular intracranial disorders Low CSF pressure syndrome (spontaneous or posttraumatic CSF leak) High CSF pressure without papilledema Intracranial: Lyme disease, human immunodeciency virus, encephalitis, fungal meningitis, etc. Headache associated with substances or their withdrawal Overuse of acute headache medications (rebound or toxic drug overuse syndromes) Headache associated with cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures Otolaryngologic disease, including chronic sphenoid sinusitis (or other sinus disease) Nasopharyngeal disorders, including carcinoma Disorders of the trigeminal nerve, including dental and oral disease, jaw pathology Subacute angle closure glaucoma, optic neuritis and other ocular disorders Occipitocervical disease, including Arnold-Chiari Malformation Type I; upper cervical joint, root, or nerve (neuralgic) syndromes Headache associated with noncephalic infection, metabolic or systemic disturbances Hepatitis, renal disease, B12 deciency, anemia, exposure to carbon monoxide and other toxins Hormonal disturbances/endocrinologic disease (estrogen, thyroid disease, hyperprolactinemia, etc.) Vasculitis/rheumatic/connective tissue disorders Miscelanias Mediastinal and thoracic processes including angina, mass lesions, superior vena cava syndrome
Abbreviation: CSF, cerebrospinal uid.

Concurrent Events or Provoking Activity Concurrent events and headache triggers may give clues to diagnosis, and some of them are listed and commented upon below:  Headaches that occur in the peripartum period may be due to dural sinus thrombosis (12).  Fever suggests an infectious etiology.  Orthostatic headache suggests headache attributed to low cerebrospinal uid (CSF) pressure (from a spontaneous CSF leak, a previous lumbar puncture, or an epidural block) (13).  Headache triggered by straining, coughing, or sneezing suggests a hindbrain malformation, occipitocervical junction disorder, or increased intracranial pressure (14).  When headache is worse in the morning, it may suggest raised intracranial pressure.  In contrast, when headache is better in the morning and worse at night, it may suggest low CSF volume headache (13).  Similarly, headaches that are worse on awakening sometimes occur with obstructive sleep apnea (13).

512

Lipton and Bigal

 Increasing pain while upright, neck pain, and headache provoked by exion or extension of the neck might suggest an occipitocervical junction disorder or a systemic medical illness (15).  Headaches associated with exercise may be an anginal equivalent, a rare disorder sometimes termed cardiac cephalalgia (16).  A skin rash suggests Lyme disease, herpes zoster, or sarcoidosis (17). Other dermatologic disorders might suggest the presence of a systemic or localized disease such as antiphospholipid syndrome, Sneddons syndrome, etc. (17).  Search for opportunistic infections, including toxoplasmosis and cryptococcal meningitis, in patients who may have HIV infection or HIV risk factors (18).  A previous mild to moderate head or neck injury is frequently overlooked in the standard history, despite the fact that it can render an individual refractory to standard headache treatments (19). A diagnosis of posttraumatic headache may lead to additional treatment including trigger point injections and facet joint and cervical nerve blocks.  Postictal headaches might be of special importance especially considering that migraine and epilepsy are comorbid (20).  The history often neglects recent dental procedures. Root canals, tooth extractions, or bite disturbances may provoke or be associated with the development of intractable headache due to brain abscess (21).  Consider ocular disturbances such as subacute angle closure glaucoma, or infection if the pain is periorbital (22).  Nasal blockage, drainage, pus, or pressure may suggest sinus disease (23). Nasopharyngeal carcinoma can produce chronic head and face pain and can be identied by detailed, expert examination of the nasopharynx or neuroimaging (24). Physical Examination. The physical examination should focus on the organs that are important in headache provocation, such as eyes, ears, neck, and others with trigeminal innervation. Occipitocervical pain on palpation and movement, submandibular pain (indicating styloid process factors, lymph nodes, carotid artery tenderness masses), disc margin clarity, visual function, eye movement, oral cavity health, and pain and discomfort in the temporomandibular joint area may provide diagnostic clues (25). Diagnostic Testing. Many patients with intractable headache have had multiple neuroimaging procedures. The strategies for investigation of secondary headaches are described in detail in Chapter 10. In brief, if prior studies are negative, consider studies targeted to suspected sites of pathology, including the occipitocervical junction, sella tursica, sphenoid sinus, and nasopharyngeal regions (2628). For truly intractable patients who fail many therapies, including intravenous dihydroergotamine, a lumbar puncture is important to identify inammatory or infectious changes that could indicate aseptic or chronic meningitis (including seronegative Lyme disease) (29), as well as idiopathic intracranial hypertension (IIH) (without papilledema) (30). Neuroimaging does not obviate the utility of lumbar puncture in these circumstances (31). Cisternography or computed tomography (CT) myelography is indicated when low CSF pressure is the most likely diagnosis. In such cases, lumbar puncture should be avoided because it can worsen intracranial hypotension. Obesity and pulsatile tinnitus are risk factors for idiopathic intracranial hypertension (IIH) (31).

When the Treatment of Headache Fails

513

Misdiagnosed Primary Headache Misdiagnosed primary headache disorders constitute a rare but important reason for intractability. Herein, we will review some primary headache disorders often missed in neurologic practices. All these disorders are described in detail in previous chapters. Hemicrania continua (32,33) with its chronic, unilateral pain is commonly mistaken for transformed migraine (34,35). Both disorders are characterized by chronic unilateral pain with superimposed painful exacerbations. In hemicrania continua, the painful exacerbations are often associated with ipsilateral autonomic features such as conjunctival injection, lacrimation, and ptosis (32,33,36). In transformed migraine, exacerbations are more typically accompanied by nausea, photophobia, and phonophobia (34,35). In addition, patients with hemicrania continua usually do not have antecedent history of episodic migraine. In chronic migraine, attacks increase in frequency over time. If the headaches are longstanding, the patient may not remember how they began. Although pain uctuates in hemicrania continua, it does not usually have the morning and end-of-dosing-interval pattern of exacerbations typical of chronic migraine. It is advisable to offer patients with unilateral chronic daily headache a therapeutic trial with indomethacin prior to other intervention (doses of up to 225 mg/day for three to four days). Paroxysmal Hemicrania. Paroxysmal hemicrania (PH) is occasionally mistaken for cluster headache. Both disorders are characterized by short-lived, unilateral attacks of pain with ipsilateral autonomic features (37,38). In contrast to cluster headache, the PHs show a female preponderance, a shorter attack duration (typically 230 minutes), and a greater attack frequency (often ve or more attacks per day) (37,38). Like cluster headache, the PHs may be either episodic or chronic (39). In typical patients, a prompt response to indomethacin conrms the diagnosis (39). In atypical patients, a trial of indomethacin may be warranted when conventional treatment for cluster headaches or trigeminal neuralgia fails (40). When headache is controlled, the dose can generally be lowered and headache control is maintained. Responses to indomethacin are usually very clear and easy to evaluate in PH, but may take up to two weeks to develop fully. Hypnic Headache. The hypnic headache syndrome is a primary headache disorder of the elderly, usually occurring in individuals over the age of 60 (41,42). Like cluster headache, it is characterized by short-lived attacks (typically 30 minutes) of nocturnal head pain that awakens the patient at a consistent time each night, sometimes from rapid eye movement sleep. Unlike cluster headache, hypnic headache pain is usually bilateral, throbbing, or diffuse and lacks the intense, unilateral orbital and periorbital knife-like quality of cluster headaches, and also does not have the autonomic features. Unilateral headache does not exclude the diagnosis. The hypnic headache syndrome responds promptly to an evening dose of lithium carbonate 300 mg or to slow-release lithium. If lithium is unsuccessful, melatonin, caffeine, or 120 mg of verapamil at night can be useful. A recent case series suggests that unilateral hypnic headache is more common than previously believed (43). Two or More Headache Disorders Diagnosis is complicated when two or more headache disorders coexist or when patients classify their headache experience differently than the doctor. One example is the well-recognized association described as the cluster-tic syndrome; patients have both cluster headache and trigeminal neuralgia and need treatment for both disorders.

514

Lipton and Bigal

Diagnosis may be difcult if two or more disorders are present simultaneously (44). The patient may not be able to clearly report the onset or characteristics of the two disorders. The patient with migraine commencing after head injury may have components of the post-traumatic headache disorder. When a new headache type emerges in a patient with an established headache disorder, caution is advisable. It may be difcult to distinguish an intracranial catastrophe from an unusually severe migraine. A superimposed infectious or metabolic process may not be recognized. Intractable bouts of headache in established migraine sufferers, similar to but worse than their preexisting headache, may be due to aseptic meningitis and intracerebral and subarachnoid hemorrhage.

REASON 2: IMPORTANT EXACERBATING FACTORS MAY HAVE BEEN MISSED Medication overuse (prescription or over-the-counter analgesics, butalbital, ergotamine, and triptans), caffeine overuse, dietary or lifestyle triggers, hormonal triggers, psychosocial factors, or the use of other medications that trigger headaches such as nitroglycerine may lead to intractability. In the search for exacerbating factors, we begin by asking about factors the patient may have identied and then probe for common and uncommon exacerbating factors, especially those that are subject to modication or intervention. In headache subspecialty practices, medication overuse and withdrawal is by far the most common cause of intractability (45,46). It is, therefore, important to specically establish the patients pattern of medication use, including both prescription and over-the-counter medication. Many patients do not consider over-the-counter medications as real drugs and will not report them unless specically asked. Patients are often embarrassed about medication misuse and fear that the physician will make harsh judgments. Excessive use of agents that contain caffeine, opioids, barbiturates, ergots, and triptans produce increased headache frequency and signicantly attenuate the effectiveness of both acute and preventive treatments. Caffeine overuse (including the dietary intake) can be an important cause of intractability (3,4,46). The treatment of medication overuse is described in detail in Chapter 27. Hormonal factors may trigger headaches and contribute to intractability (47). Estrogen withdrawal and uctuation leads to headache exacerbation during menses and during the perimenopausal period. Hormonal contraceptives and hormone replacement therapy have effects that vary widely from individual to individual. Historical clues should be sought to determine the inuence of hormones on patients who are taking them. If historical evidence suggests that exogenous hormones contributed to intractability, they should probably be modied or even eliminated. However, we can often control headaches despite hormone therapy. Sometimes hormonal therapy improves headache control. Dietary or lifestyle factors may play a signicant role in headache (17). Explore the patients marital and family status, education, occupation, outside interests, and friendships. Stressful life events such as divorce, widowhood, separation, and problems with children are more likely to be associated with refractory headaches, when compared with controls (48). Alcohol use, especially red wine, may trigger headaches (49). A history of multiple partners should prompt a search for a potential infectious cause of the headache. Sleep apnea is common in middle-aged obese men

When the Treatment of Headache Fails Table 3 Selected Medications Reported to Cause Headaches Amantadine Calcium-channel blockers Caffeine Corticosteroids Cyclophosphamide Dipyridamole Estrogens Ethanol Hydralazine Indomethacin L-Dopa Monoamine oxidase inhibitors Nonsteroidal anti-inammatory agents Nitrates Nicotinic acid Phenothiazines Ranitidine Sympathomimetic agents Tamoxifen Theophyllines (thioxanthines) Tetracyclines Trimethoprim

515

and may cause morning headache (50). Depression or anxiety may present with difculty in falling asleep or staying asleep, or with early morning awakening. Careful questioning about possible stressors may uncover a source of conict or a psychological component to the headache, which can lead to intractability in some patients, especially in those with very frequent headaches. Some dietary factors, including aspartame, may trigger headache (51,52). Vitamin A and D overuse may cause IIH (53). Occupational and environmental factors may cause or aggravate the headache. Environmental exposures to carbon monoxide, solvents, or other environmental contaminants may trigger headaches (54). Workers in munitions factories may develop nitroglycerine induced headaches (55). Taking certain medications may contribute to headache. Table 3 summarizes some of the medications that may cause headache.

REASON 3: PHARMACOTHERAPY MAY BE INADEQUATE Inadequate pharmacotherapy may occur if inappropriate treatments are selected, excessive initial doses are used, nal doses are inadequate, the duration of treatment is too short, combination treatment is required, the patient fails to absorb the drug, or the patient is noncompliant. Medications appropriate for the patients diagnosis or diagnoses should be carefully reviewed. It is important to determine the dosage and duration of treatment with prior therapies. Several common issues may lead to treatment failure in the acute management of migraine. One important issue is the failure to use stratied care in selecting the initial therapy. A randomized trial supports the U.S. Headache Consortium Guidelines in their recommendation for stratied care (56,57). That strategy is based on the selection of initial therapy based on patient characteristics at the time of presentation, including headache-related disability. When patients report that acute treatment is unsuccessful, it is important to understand what they mean: (i) Was there no response or was there an incomplete response to treatment? (ii) Did treatment response take too long? (iii) Did the headache respond well initially but then recur? (iv) Did the treatment cause too many side effects? By understanding the type of treatment failure, corrective strategies can be developed. One strategy is to treat early during the attack (58). Recent evidence demonstrates that acute migraine treatment works best if given early in the course

516

Lipton and Bigal

of the headache, while pain is still mild. Aspirin plus metoclopramide, ergotamine, and several triptans produce higher pain-free rates when given while pain is mild (58,59). Once central sensitization develops, treatment is much less likely to work (24). For that reason, early treatment is an important approach to making acute treatment more successful. Caution is required to avoid the development of medication overuse. Another option is to change the route of administration. Migraine-related gastric paresis may delay or prevent the absorption of oral medication. Nasal sprays and injections, therefore, provide important, underutilized treatment alternatives. It is sometimes helpful to escalate the dose or to switch drugs. When switching drugs, it is helpful to consider the difculty the patient had with the original drug. For example, if tolerability or headache recurrence are the problems, almotriptan, naratripan, and frovatriptan are important options. If efcacy or speed of onset is the issue among the oral agents, rizatriptan or eletriptan may be helpful; nonoral therapy may also be needed (60). Combining triptans with metoclopramide or nonsteroidal anti-inammatory agents is sometimes helpful (61). There are also common reasons for preventive treatment failure. Unsuccessful treatment is often the result of incorrect dosing strategies. Short-acting propranolol given once a day may be ineffective. Treatment is often discontinued prematurely, if one or two breakthrough headaches occur before an effective dose is established. Preventive treatment is often ineffective if taken when the patient is overusing acute medications (rebounding). Preventive medications must be given at an adequate dose for an adequate duration. It is best to start preventive agents at a low dose, and then gradually increase the dose until therapeutic effects, treatment limiting side effects, or the ceiling dose for the agent in question is reached. At least several weeks are required to evaluate the success or failure of a treatment. Further increases beyond the ceiling dose may be necessary if there is a partial response at the ceiling dose without side effects but the headaches remain disabling. Some patients may take appropriate doses of a drug but not achieve the necessary blood levels for response due to difculty with absorption. Rational Polytherapy. Although monotherapy is usually recommended, rational combination therapy is sometimes necessary, especially in the setting of comorbid illness. For the depressed or anxious migraine sufferer, antidepressants are usually a rational choice, but the addition of an antiepileptic medication (divalproex sodium), a beta-blocker, or a calcium channel blocker may be useful. For the patient with truly refractory headache and refractory depression, a monoamine oxidase inhibitor is sometimes the only effective treatment option. Methysergide, alone or in combination with a calcium channel blocker, may help control refractory headache, particularly refractory chronic cluster headache. Selection of preventive medications has been reviewed elsewhere (62). Noncompliance with Treatment. Noncompliance with prescribed preventive medication or misuse of acute treatment is common. Because migraine attacks are episodic, the patients motivation to treat may diminish between the attacks. Patients may not understand that sustained treatment is necessary to achieve therapeutic success (63). Unanticipated side effects may lead patients to discontinue the treatment. Compliance may improve if the patient understands the need for long-term treatment and anticipates the process of dose adjustment (64). Compliance is improved if the patient can see that the degree of disability caused by the headache outweighs the disadvantages of prophylactic drugs. Ideally after an explanation of the options,

When the Treatment of Headache Fails

517

the patient should suggest or opt for a prophylactic rather than have the decision imposed by the doctor. Side effects may be better tolerated if the patient knows that they may ameliorate over time (65). If rebound headache was present during previous therapeutic trials, it may be necessary to retry unsuccessful but incorrectly used treatments. When treatment trials are repeated, it is well worth explaining the reasons for returning to a previously used drug. Noncompliance with nonpharmacologic treatment can render treatment unsuccessful. Patients may not avoid known provoking factors, leading to poor headache control (65).

REASON 4: NONPHARMACOLOGIC TREATMENT MAY BE INADEQUATE Patients who are tense sometimes need physical medicine or behavioral interventions. Patients with occipital tenderness and trigger points often do not get relief of their headache disorder until they have a nerve block or trigger point injection (66). Patients with intractable headache disorder sometimes are relieved by the use of trigger point injections into tender areas using a combination of a local anesthetic and a depocorticosteroid. Occasional occipital nerve and facet joint blocks are useful, generally when there are concomitant physical signs such as a sensory abnormality over the C2 distribution on the back of the head. Physical therapy is often a useful adjunct for these patients. Patients who are tense and anxious and have trouble coping with their daily existence can have trouble getting their headaches under control. Cognitive training helps them decrease the stress they impose on themselves and may improve their headaches (64,65). In intractable headache patients, it is useful to separate pain and ability to function. If pain does not improve, behavioral strategies should focus on optimizing function.

REASON 5: OTHER REASONS FOR TREATMENT FAILURE Treatment may fail if the patient has unrealistic expectations, comorbid conditions that complicate therapy, or when inpatient treatment is required but not offered. As patients improve, their expectations may escalate and they may forget how bad they were. The patient who has a chronic daily headache may complain a year later that he is no better because he is having two attacks per month that respond promptly to acute treatment. Headache diaries can be used to remind patients about their previous headache pattern. Modulating expectations can be difcult. Patients should not tolerate pain and disability needlessly. But it may not be realistic to expect a treatment regimen to give perfect headache control with no side effects. Patients with comorbid or concomitant medical or neurologic illness are often more difcult to treat. Comorbid diseases occur in migraineurs with a greater frequency than would be expected by chance. Migraine is comorbid with depression, anxiety, affective disorders, stroke, and epilepsy (20,6769). These disorders can impose therapeutic challenges and limit treatment options. Concomitant diseases occur together with chance frequency; common concomitant diseases that limit options in migraine treatment include asthma (beta blockers), ulcers and gastritis (nonsteroidal anti-inammatory drugs), vascular disease, and uncontrolled hypertension (triptans and ergot alkaloids). Concomitant obesity may limit the utilization of many prophylactic drugs. A restricted therapeutic armamentarium can severely

518

Lipton and Bigal

compromise treatment. Patients with major comorbid psychiatric disorders may require ongoing care with a mental health professional appropriate to the disorder. Psychiatric problems often abate as headache comes under control. Inpatient care. When outpatient treatment fails and patients have continuing and severe pain and disability, more aggressive treatment interventions may be required (70). Inpatient level treatment should be reserved for people who require the intense interventions and around-the-clock monitoring that can only be provided in an inpatient setting. Aggressive parenteral treatment to break the headache cycle and/or maintain the patient in reasonable comfort during detoxication (if necessary) represents the initial step. Rehydration and careful monitoring are often required. Attendant medical and psychological issues must be addressed, and pharmacologic and nonpharmacologic maintenance treatment can be started. CONCLUSIONS In this chapter, we have presented the ve most common categories of treatment failure in the patients who consult in headache subspecialty centers based on the authors experience. We believe that the vast majority of refractory headache patients have a biologically determined problem that has been either misdiagnosed or mistreated, or is simply very difcult to treat. Persistence in treating these patients can be very rewarding. U.S. headache subspecialty centers use a team approach to patient management, which can help reduce the burden of caring for difcult patients. Nurses, fellows, physicians assistants, and psychologists can help support and educate the patient, answer questions, and manage patients. Available inpatient programs provide an important option for carefully selected patients. REFERENCES
1. Linet MS, Celentano DD, Stewart WF. Headache characteristics associated with physician consultation: a population-based survey. Am J Prev Med 1991; 7:4046. 2. Pascual J, Combarros O, Leno C, Polo JM, Rebollo M, Berciano J. Distribution of headache by diagnosis as the reason for neurologic consultation. Med Clin 1995; 104:161164. 3. Mathew NT. Chronic daily headache: clinical features and natural history. In: Nappi G, Bono G, Sandrini G, eds. Headache and Depression: Serotonin Pathways as a Common Clue. New York: Raven Press, 1991:4959. 4. Mathew NT, Stubits E, Nigam MP. Transformation of episodic migraine into daily headache: analysis of factors. Headache 1982; 22:6668. 5. Saper JR. Ergotamine dependencya review. Headache 1987; 27:435438. 6. Saper JR. Chronic headache syndromes. Neurol Clin 1989; 7:387412. 7. Linn FH, Rinkel GJ, Algra A, et al. Headache characteristics in subarachnoid hemorrhage and benign thunderclap headache. J Neurol Neurosurg Psychiatry 1998; 65: 791793. 8. Dodick DW, Wijdicks EF. Pituitary apoplexy presenting as a thunderclap headache. Neurology 1998; 50:510511. 9. Forsyth PA, Posner JB. Headaches in patients with brain tumours: a study of 111 patients. Neurology 1993; 43:16781683. 10. Lawson W, Reino AJ. Isolated sphenoid sinus disease: an analysis of 132 cases. Laryngoscope 1997; 107:15901595. 11. Edmeads J. Headaches in older people. How are they different in this age-group? Postgrad Med 1997; 101:9194.

When the Treatment of Headache Fails

519

12. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin 1992; 10:87111. 13. Lay CL, Campbell JK, Mokri B. Low cerebrospinal uid pressure headache. In: Goadsby P, Silberstein SD, eds. Blue Books of Practical Neurology: Headache. Boston: Butterworth-Heinemann, 1997:355368. 14. Sands GH, Newman LC, Lipton RB. Cough, exertion and other miscellaneous headaches. Med Clin North Am 1991; 75:733748. 15. Edmeads JG. Disorders of the neck: cervicogenic headache. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache and Other Head Pain. New York: Oxford University Press, 2001:447458. 16. Lipton RB, Lowenkopf T, Bajwa ZH, et al. Cardiac cephalgia: a treatable form of exertional headache. Neurology 1997; 49:813816. 17. Marks DR, Rapoport AM. Practical evaluation and diagnosis of headache. Semin Neurol 1997; 7:307312. 18. Evers S, Wibbeke B, Reichelt D, et al. The impact of HIV infection on primary headache. Unexpected ndings from retrospective, cross-sectional, and prospective analyses. Pain 2000; 85:191200. 19. Solomon S. Posttraumatic headache. Med Clin North Am 2001; 85:987996. 20. Andermann E, Andermann FA. Migraine-epilepsy relationships: epidemiological and genetic aspects. In: Andermann FA, Lugaresi E, eds. Migraine and Epilepsy. Boston: Butterworths, 1987:281291. 21. Graff-Radford S. Disorders of the mouth and teeth. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache and Other Head Pain. New York: Oxford University Press, 2001:475493. 22. Martin TJ, Soyka D. Ocular causes of headache. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven Press, 1993:748. 23. Cady RK, Schreiber CP. Sinus headache or migraine? Considerations in making a differential diagnosis. Neurology 2002; 58(suppl 6):1014. 24. Wenig BM. Nasopharyngeal carcinoma. Ann Diagn Pathol 1999; 3:374385. 25. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000; 123:17031709. 26. Evans RW. Diagnostic testing for the evaluation of headaches. Neurol Clin 1996; 14:126. 27. Frishberg BM. The utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations. Neurology 1994; 44:11911197. 28. Mokri B, Sundt T, Houser W. Spontaneous internal carotid dissection, hemicrania, and Horners Syndrome. Arch Neurol 1979; 36:677680. 29. Scelsa SN, Lipton RB, Sander H, Herskovitz S. Headache characteristics in hospitalized patients with Lyme disease. Headache 1995; 35:125130. 30. Silberstein S, Marcelis J. Pseudotumor cerebri without papilledema. Headache 1990; 30:304305. 31. Wang SJ, Silberstein SD, Patterson S, Young WB. Idiopathic intracranial hypertension without papilledema: a case-control study in a headache center. Neurology 1998; 51:245249. 32. Sjastaad O, Spierings EHL. Hemicrania Continua. Another headache absolutely responsive to indomethacin. Cephalalgia 1984; 4:6570. 33. Newman LC, Lipton RB, Solomon S. Hemicrania continua: 10 new cases and a literature review. Neurology 1994; 44:21112114. 34. Silberstein SD, Lipton RB, Solomon S, Mathew NT. Classication of daily and neardaily headaches: proposed revisions to the IHS criteria. Headache 1994; 34:17. 35. Silberstein SD, Lipton RB. Chronic daily headache, including transformed migraine, chronic tension-type headache, and medication overuse. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache and Other Head Pain. New York: Oxford University Press, 2001:247282. 36. Peres MFP, Silberstein SD, Nahmias S, et al. Hemicrania continua is not that rare. Neurology 2001; 57:948951.

520

Lipton and Bigal

37. Headache Classication Committee of the International Headache Society. Classication and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):196. 38. Sjastaad O, Dale I. A new (?) clinical headache entity chronic paroxysmal hemicrania 2. Acta Neurol Scand 1976; 54:140159. 39. Price RW, Posner JB. Chronic paroxysmal hemicrania: a disabling headache syndrome responding to indomethacin. Ann Neurol 1978; 3:183184. 40. Newman LC, Lipton RB. Paroxysmal hemicranias. In: Goadsby PJ, Silberstein SD, eds. Headache. London: Butterworth-Heinemann, 1997:243254. 41. Newman LC, Lipton RB, Solomon S. The hypnic headache syndrome. Headache 1990; 40:19041905. 42. Dodick DW, Mosek AC, Campbell JK. The hypnic (alarm clock) headache syndrome. Cephalalgia 1998; 18:5256. 43. Gould JD, Silberstein SD. Unilateral hypnic headache: a case study. Neurology 1997; 49:17491751. 44. Rasmussen BK, Jensen R, Schroll M, Olesen J. Interrelations between migraine and tension-type headache in the general population. Arch Neurol 1992; 49:914918. 45. Saper JR, Jones JM. Ergotamine tartrate dependency: features and possible mechanisms. Clin Neuropharmacol 1986; 9:244256. 46. Rapoport A, Stang P, Gutterman DL, Cady R, Markley H, et al. Analgesic rebound headache in clinical practice: data from a physician survey. Headache 1996; 36:1419. 47. Silberstein SD. Headache and female hormones: what you need to know. Curr Opin Neurol 2001; 14:323333. 48. Stewart WF, Scher AI, Lipton RB. Stressful life events and risk of chronic daily headache: results from the frequent headache epidemiology study [abstract]. Cephalalgia 2001; 21:279. 49. Nicolodi M, Sicuteri F. Wine and migraine: compatibility or incompatibility? Drugs Exp Clin Res 1999; 25:147153. 50. Poceta JS, Dalessio DJ. Identication and treatment of sleep apnea in patients with chronic headache. Headache 1995; 35:586589. 51. Newman LC, Lipton RB. Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches. Headache 2001; 41:899901. 52. Blumenthal HJ, Vance DA. Chewing gum headaches. Headache 1997; 37:665666. 53. Jacobson DM, Berg R, Wall M, et al. Serum vitamin A concentration is elevated in idiopathic intracranial hypertension. Neurology 1999; 53:11141118. 54. Hampson NB, Hampson LA. Characteristics of headache associated with acute carbon monoxide poisoning. Headache 2002; 42:220223. 55. Van Gelderen EM, Saxena PR. Nitroglycerin-induced headache. Cephalalgia 1996; 16:405. 56. Silberstein SD, Rosenberg J. Multispecialty consensus on diagnosis and treatment of headache. Neurology 2000; 54:1553. 57. Lipton RB, Silberstein SD. The role of headache-related disability in migraine management: implications for headache treatment guidelines. Neurology 2001; 56(suppl 1): 3542. 58. Cady RK, Lipton RB, Hall C, Stewart WF, OQuinn S, Gutterman D. Treatment of mild headache in disabled migraine sufferers: results of the Spectrum Study. Headache 2000; 40:792797. 59. Cady RK, Sheftell R, Lipton RB, et al. Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials. Clin Ther 2000; 22:10351048. 60. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001; 358:16681675.

When the Treatment of Headache Fails

521

61. Diener HC, Limmroth V. Advances in pharmacological treatment of migraine. Exp Opin Invest Drugs 2001; 10:18311845. 62. Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalalgia 2002; 42: 491512. 63. Holroyd KA. Learning from our treatment failures. Appl Psychophysiol Biofeedback 2001; 26:319323. 64. Weeks R. The difcult headache patient calls for a multifaceted approach. Neurol Rev 1995; 3:1516. 65. Holroyd KA, Penzien DB, Lipchik GL. Behavioral management of headache. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolffs Headache and Other Head Pain. New York: Oxford University Press, 2001:562598. 66. Davidoff RA. Trigger points and myofascial pain: toward understanding how they affect headaches. Cephalalgia 1998; 8:436448. 67. Breslau N, Davis GC, Schultz LR, Peterson EL. Joint 1994 Wolff Award Presentation. Migraine and major depression: a longitudinal study. Headache 1994; 34:387393. 68. Lipton RB, Ottman R, Ehrenberg BL, Hauser WA. Comorbidity of migraine: the connection between migraine and epilepsy. Neurology 1994; 44(suppl 7):2832. 69. Tzourio C, Tehindrazanarivelo A, Iglesias S, et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ 1995; 310:830833. 70. Lake AE, Saper JR, Madden SF, Kreeger C. Comprehensive inpatient treatment for intractable migraine: a prospective long-term outcome study. Headache 1993; 33:5562.

Index

Abdominal pain, 204 Acephalgic migraine, 227 Acetaminophen, 275, 416 Acetylsalicylic acid (ASA), 274 Acute migraine therapy, 447 Adenosine receptors, 318, 450 Age headache prevalence and, 138, 157 Agency for Healthcare Policy and Research (AHCPR), 315, 321, 324, 338,340, 343 Allodynia, 99, 182 effect of, 106107 in migraine, 104108 Almotriptan, 299 a-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), 451 Alpha antagonists, 340 Alternating hemiplegia of childhood (AHC), 119 American Migraine Study-1 (AMS-1), 29 Amitriptyline, 320 Amnesia, transient global, 196 Analgesics, 163 Analysis of covariance (ANCOVA), 332 Aneurysm, unruptured, 503 Angiotensin-converting enzyme inhibitors, 340341 Antagonists calcium-channel, 322 serotonin, 337340 Anticonvulsants, 325, 383385 antiepileptic drugs (AEDs), 331 Antidepressants, 385 clinical trials, 319 mechanism of action, 317319 tricyclic, 320 Antiemetics, 381 Antiepileptic drugs (AEDs), 227, 331 Antihistamines, 386

APAP. See Aspirin, acetaminophen Aphasic aura, 196 Arteriovenous malformation (AVM), 133. See also Migraine, mimicking Aspirin, 274, 341 Ataxia, cerebellar, 198 ATP1A2 gene, clinical spectrum of, 118120 Atrial natriuretic peptide (ANP) gene expression, 75 Aura diagnosis, 7 meaning of, 189 pathophysiology of, 6973 prolonged, 227 subtypes, 7 symptoms, 476 visual, 193 Aura-like symptoms, 199

Balance disorders, 208 Basilar-type migraine, 198199 BBB. See Bloodbrain barrier BDNF. See Brain-derived neurotrophic factor Benign familial infantile convulsions (BFIC), 119 Benign paroxysmal torticollis (BPT), 204 Benign paroxysmal vertigo, 8 b-Adrenergic blockers clinical use of, 316317 mechanism of action, 315316 Beta-blockers, 386387 Biofeedback training, 262 Bipolar disorder, 5253 Black box warning, 420 Blind spots, 194 Blindness, preventable, 512 Bloodbrain barrier (BBB), 75, 295, 481 Botox1, 341342, 405 523

524 Botulinum toxin, 467 type A, 341342, 405408 use of, 408 See also Botox1 BPT. See Benign paroxysmal torticollis BPV of childhood, 207 Brain abscess, 514 imaging, 88 Brain-derived neurotrophic factor (BDNF), 318319 Butterbur (Petasites hybridus), 344, 369

Index Chronic paroxysmal hemicrania (CPH), 7, 475 Chronic tension-type headache (CTTH), 123, 431, 460 Cluster headache (CH), 1, 7, 107, 123, 139, 504 acute (symptomatic) therapy of, 478 classication, 11 clinical features of, 475 differential diagnosis of, 477 effective drugs for, 483 refractory, 483484 treatment for, 478 Clusterin, 75 Coenzyme Q, 344345, 366367 Comorbid pain, 4142 Compliance/noncompliance to treatment, 518 Contingent negative variation (CNV), 89, 316 Continuum theory, 465 Convergence hypothesis, 181 Cortical spreading depression (CSD), 6970, 182, 228, 313314 Corticosteroids, 421, 480 Cough headache, 12, 498 Cranial neuralgias, 16 Cranial or cervical vascular disorders, 1415. See also Headache: secondary CSD. See Cortical spreading depression Cutaneous allodynia, 100, 104 Cyclic adenosine monophosphate (cAMP), 318 Cyclic guanosine monophosphate (cGMP), 75 Cyclic vomiting syndrome (CVS), 123 Cyclical vomiting (CV), 204 Cyclooxygenase (COX), 101, 277 Cyproheptadine, 339, 386, 398

CACNA1A gene mutations, clinical spectrum of, 114117 Caffeine consumption of, 40 overuse, 516 as treatment agent, 502 Caffeine-withdrawal headache, 421 Calcitonin generelated peptide (CGRP), 8485, 102, 313, 448449, 475 receptor antagonists, 452 Calcium channel blockers, 220, 323, 325, 387, 481, 501 mechanism of action, 324 pharmacology of, 322 types of, 322 Capsaicin, 483 Car (motion) sickness, 209 Carbamazepine, 326 Cardiac cephalalgia, 514 CDH. See Chronic daily headaches Cerebral ischemia, transient, 139 Cerebral thrombosis, symptomatic, 234 Cerebral venous thrombosis (CVT), 141 C-bers, 451 CGRP. See Calcitonin generelated peptide CH. See Cluster headache Chiari malformation, 499 Childhood, hemiplegia of, 209 Chlorpromazine, 279, 420 Chronic daily headache (CDH), 1618, 400401, 431, 460 classication, 3738 demographic factors associated with, 3840 epidemiology of, 432 history of, 38 risk factors, 439 treatment of, 405 Chronic migraine (CM), 5, 416, 431 early stage of TM, 434

Depression, effect on sleep, 516 Diclofenac, 276 Dihydroergocryptine (DEK), 324 Dihydroergotamine (DHE), 85, 289, 380381, 400, 454, 479 Dihydropyridines, 323 Diltiazem, 501 Dipyrone, 275276 Disability assessment, 160, 249 Strategies of Care (DISC) study, 281 Distal internal carotid artery dissection, 135. See also Migraine, mimicking Divalproex sodium, 330, 383, 482

Index Dopamine receptor antagonists/ phenothiazines, 419420 Dorsal horn, sensitization of, 100102 Dosing strategies, 518 Droperidol, 420 Dysarthria, 194 Dyskinesia, paroxysmal, 208 Dysphasia. See Aura EA-2. See Episodic ataxia type 2 Electroencephalogram (EEG), 227, 231232 Eletriptan, 298299 Epilepsy, manifestation of, 205 Episodic ataxia type 2 (EA-2), 114, 116 Episodic migraine (EM), 104 Episodic paroxysmal hemicrania (EPH), 486 Ergot alkaloids, 379381 Ergotamine, 289290, 388, 419 vs. oral triptans, 290292 Ergotamine tartrate (ET), 380, 480 Ethmoid pressure, 67 Exclusion, diagnosis of, 8 Exertional headache, 1213, 499 Facial pain, causes of, 16 Familial hemiplegic migraine (FHM), 1, 8, 7677, 8283, 113114, 189, 197 Fatigue, trigger factor for BPV, 208 Feverfew (Tanacetum parthenium), 342344, 367369 FHM. See Familial hemiplegic migraine First-line migraine therapy, 421 Fluid-attenuated inversion recovery sequence, 137 Flunarizine, 324, 387 Frovatriptan, 299300 Gabapentin, 326, 483 Galanin, 75 Gamma-aminobutyric acid (GABA), 70 Gamma-knife radiosurgery, 485 Gender bias, retinal migraine and, 216 Generalized tonic/clonic (GTC), 228 Giant cell arteritis, 512 Glutamate receptors, 451 Glyceryl trinitrate (GTN), 453 Greater occipital nerve (GON), 107, 480 HC. See Hemicrania continua Head and/or neck trauma, 14. See also Headache: secondary Head pain, anatomy of, 6163

525 Head tilt, 208 Headache anatomy of, 83 calendars, 176, 252253 causes of, 13, 414 classication by frequency and duration, 148 common location of, 138 diagnosis algorithm, 146, 151, 242244 diaries, 519 disorders, and reasons for treatment failure, 253 genetic studies on, 113 ICHD-2 classication, 24 inpatient, treatment, 393, 395 intensity of, 196 medication-overuse, 303, 399 prevention of, 261262 primary, 1, 4, 5, 1214 progression, 444 secondary, 12, 1416 temporal prole of, 512 treatment plan, 253 triggers, 513514 types of, 460 visual loss and, 215 Headache impact test (HIT-6), 249 Headache physiology central connections, 86 peripheral connections, 8486 Health Maintenance Organization (HMO), 266267 Hemianopsia, 193, 218 Hemicrania continua (HC), 7, 13, 147, 431, 473, 487, 515 Hemiplegia, of childhood, 209 Hepatotoxicity, valproate, 330 HMO. See Health Maintenance Organization Homeostasis, disorders of, 15. See also Headache: secondary Hormonal therapy, 516 Horner syndrome, 476 5-HT1F receptor, 449450 5-Hydroxytryptamine (5-HT1), 376 Hyperalgesia, 99 Hyperammonemia, 383 Hyperandrogenism, 330 Hyperemia, 74 Hypertension, 4647 Hypertensive encephalopathy, 226 Hypertensive headaches, 416 Hypnic headache (HH), 13, 150, 477, 501, 515

526 Hyporcretin neurons, role in, 123 Hypotension, spontaneous intracranial, 141 Ibuprofen, 276 ICHD. See International Headache Society Classication ICHD-2. See International Classication of Headache Disorders, Second Edition Idiopathic intracranial hypertension (IIH), 514 Indomethacin, 148, 486, 499, 505 Inpatient headache treatment, 393395, 403404 Intent-to-treat (ITT) population, 332 International Classication of Headache Disorders (ICHD), 1, 431, 459 International Classication of Headache Disorders, Second Edition (ICHD)-2, 174, 189

Index MIDAS questionnaire, 160 Middle cerebral artery (MCA), 63, 65 Migraine, 59, 448 acute confusional, 205 aura, 57, 83, 192, 199, 313 basilar-type, 8 chronication, 434 clinical phases of, 178180 comorbidity, evidence, 46, 313 complications of, 9 diagnosis of, 177 epidemiology of, 23 epilepsy and, association of, 230 family and twin studies in, 120121 genetic epidemiology, 82, 121123 ICHD-2 classication of, 5 incidence of, 24 pain, origin, 100 precursors of, 204 prevalence of, 25, 29, 31 preventive therapy, principles, 313314 retinal, 89 sensitization in, 106 stroke, 232236 tiggers, 220, 250 treatment of, 164, 262266, 376, 405, 448 Migraine-abortive therapy, 413 Migraine-associated stroke (MAS), 227 Migraine-preventive agents, 315 Migraine-triggered seizure, denition, 230 Migrainous infarction, 235 Migralepsy, 228232 Minocycline, 102 Mitral valve prolapse (MVP), 234 MMP. See Matrix metalloproteinases Monoamine oxidase inhibitors (MAOIs), 295, 321322, 396 Monoamine-reuptake inhibitors, 321 Monocular visual loss (MVL), 215 Monocular visual scintillations, 135 Mood disorders, 207 Motor weakness, 189, 198 MRM. See Menstrually related migraine Mydriasis, 336 Naratriptan, 295 Nasal congestion, 486 Nausea, medications for treatment of, 277278 NDPH. See New daily-persistent headache Neck pain, 174 Nervous system function, episodic disruption of, 173 sensory processing by, 100

Kainate (KA), 451 Ketorolac, 420 Lamotrigine, 336337 Lanepitant (substance P antagonist), 342 Leukotriene receptor antagonist (montelukast), 342 Lithium carbonate, 481, 515 L-type calcium channels, 481 Lumbar puncture, 137, 499 Lymphocytic pleocytosis, 114 Lysine clonixinate, 277

Magnesium, 370 Maintenance prophylaxis, 481 Matrix metalloproteinases (MMP), 75 MCA. See Middle cerebral artery MCP. See Metoclopramide Medications classes of, 417422 headache causing, 517 overuse, 147, 439 Medication overuse headache (MOH), 399, 460 Melatonin, 483, 498 Meninges, 66 Meningismus, 499 Menstrually related migraine (MRM), 182, 224, 275 Methysergide, 338339, 481 Metoclopramide (MCP), 274, 278, 420

Index Neuroimaging, use of, 219, 499 Neuroleptics, 278279 Neuromuscular junction (NMJ), 114, 117 Neurotrophins, 318 New daily-persistent headache (NDPH), 1314, 17, 431, 505 New-onset headache, acute severe, 135 Nitric oxide synthase (NOS), 450, 452453 NMDA. See N-methyl-D-aspartate receptor N-methyl-D-aspartate receptor (NMDA), 6970, 101 NMJ. See Neuromuscular junction Nociceptin/orphanin FQ (N/OFQ), 450 Nonsteroidal anti-inammatory drugs (NSAIDs), 273, 276, 301302, 341, 387388, 467 efcacy of, 277 and triptans, combinations of, 278 Nonvascular intracranial disorders, 15. See also Headache: secondary Nortriptyline, secondary amines, 321 NOS. See also Nitric oxide synthase NSAIDs. See Nonsteroidal antiinammatory drugs Numbers needed to harm (NNH), 292293 Numbers needed to treat (NNT), 292293 Obesity, 39 Occipital cortex excitability, 76 Occipital nerve stimulation, 486 OCP. See Oral contraceptive Octreotide, 479 Oligohidrosis, 336 Opioid receptorlike (ORL)-1 receptor, 450 Opioids, 279280, 376 Optic nerve ischemia, 216 Oral contraceptive (OCP), 234235 Orgasmic headaches, 500 Over-the-counter (OTC) users, 419 Oxygen inhalation, 478 P/Q calciumchannel, 453, 454 Pain abdominal, 204 chronic unilateral, 515 facial, 179, 183 location of, 173 migrating limb, 209 Papilledema, 138 Paralysis, accid, 197 Paraphasia, 196 Paresis, gastric, 518 Paresthesias, 192

527 Paresthesias. See Monocular visual scintillations Paroxysmal dyskinesia, 208 Paroxysmal hemicrania (PH), 1112, 150, 486, 515 Patent foramen ovale (PFO), 234235 Patient health questionnaire (PHQ), 163 Periaqueductal gray (PAG) matter, 88, 438 Periodic lateralized epileptiform discharges (PLED), 232 Periodic syndromes (PS), denition of, 203 Petadolex1, 344 Petasites, 344 PH. See Paroxysmal hemicrania Phenobarbital taper, 399 Pituitary apoplexy, 512 Pizotifen, 339 Plasma protein extravasation, 8485 Positive predictive value (PPV), 158 Prednisone, 480. See also Corticosteroids Pregnancy and lactation, general care during, 250251 Preventive prescription drugs, 312 Primary stabbing headache (PSH), 489 Probable migraine (PM), 9, 23 Prochlorperazine, 279, 420 Prodrome. See Symptoms, premonitory Prophylactic therapy, 479480 Propranolol, 316 Prostaglandin E2 (PGE2), 101 Prostaglandins, 74 Protein extravasation (PPE), 72 PS. See Periodic syndromes Pseudomigraine, 114 Pseudotumor cerebri (PTC), 141 Psychiatric disorders, 16, 5052. See also Headache: secondary Pyrrolizidines alkaloids (PA), 370

Queckenstedts maneuver, 66 Rapid eye movement (REM) sleep, 476 Raskin IV protocol, 425 Red ag features, 414 Regional cerebral blood ow (rCBF), 69, 405 Relaxation training, 466 Retinal migraine, 89, 216217 IHS criteria for diagnosis of, 214 Retinal neurons, spreading depression of, 218 Retrochiasmatic lesions, 218 Reyes syndrome, 376 Riboavin, 344, 364366 Rizatriptan (maxalt), 278279, 297298, 379

528 Rofecoxib, 277 Rostral ventral medulla (RVM), 101

Index [Tension-type headache (TTH)] sex and age distribution of, 461 treatment of, 466467 types of, 10 TG. See Trigeminal ganglion Therapy cognitive-behavior, 262 preventive, 381382 Thioctic acid (a-lipoic acid), 367 Thrombotic or thromboembolic stroke, 235 Thunderclap headache (TCH), 13, 502 Timed-released dihydroergotamine (TR-DHE), 319 TM. See Transformed migraine TNC. See Trigeminal nucleus caudalis Todd phenomenon, 199 Tonabersat, 83 Topiramate, 330336, 383, 482483 Toxoplasmosis, 514 Transformed migraine (TM), 17, 104, 147, 431, 432434, 439 treatment of, 440441 Transitional prophylaxis, 480 Treatments, nonspecic vs. specic, 280281 Tricyclic antidepressants (TCAs), 317318 pharmacology of, 320 principles of, 320 Trigeminal autonomic cephalalgias (TACs), 1, 149, 504 pathophysiology of, 473475 Trigeminal ganglion (TG), 451452 Trigeminal neuralgia, ICHD-2 classication of, 16 Trigeminal nucleus caudalis (TNC) neurons, 61, 71, 99, 451 Trigeminal pain, 88 Trigeminal receptor targets, 448 Trigemino vascular system, 231 Trigger point injections, 519 Triggers, headache, 513514 Triptans, 102, 295, 302, 376, 417 medications, 293 meta-analysis, 300301 and NSAIDS, combinations of, 278 oral, 179, 183 treatment, 103 use of, 302303 Triptan-nonresponder, 302 TTH. See Tension-type headache Tunnel vision, 216

SAH. See Subarachnoid hemorrhage SCA. See Spinocerebellar ataxia type 6 Scotoma, 135, 193, 216 Seizures, 139, 199 Selective serotonin reuptake inhibitors (SSRIs), 317, 321, 385, 396 Sensory aura, 194 Sensory modulation, 88 Serotonergic axon, 318 Serotonin (5-HT) receptor, 448449 Serotoninergic syndrome, risk of, 396 Sexual activity associated primary headaches, 500-501 Shared gene hypothesis, 231 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome, 12, 149, 473, 475, 488489 Silberstein and Lipton (S-L) criteria, 431 Single-ber electromyography (SFEMG), 117 Single-nucleotide polymorphisms (SNPs), 116 Sinus headaches, 181 Sinusitis, acute, diagnosis of, 174 Sleep apnea, obstructive, 513 Speech disturbances, 196 Spinocerebellar ataxia type 6 (SCA6), 114, 116 Sporadic hemiplegic migraine, 120 Status migrainosus, 223226, 425 Subarachnoid hemorrhage (SAH), 133, 499, 512 Sumatriptan, 290, 292295, 377, 478 Superior sagittal sinus (SSS), 84, 331 Syndrome, post-feverfew, 343

TCAs. See Tricyclic antidepressants Testretest reliability, 159 Tension-type headache (TTH), 1, 123, 146, 196, 413, 459 characteristics of, 462463 clinical presentation of, 462 epidemiological of, 460 episodic, 459 history of, 461 ICHD-2 classication of, 10 psychological aspects of, 465 severity of, 463

Valproate, 326330, 421 hepatotoxicity, 330

Index Valproic acid, 326330 Valsalva maneuver, 148, 498 Vanilloid type 1 (VR1) receptors, 451 Vasoactive intestinal polypeptide (VIP), 85, 475 Vasoconstrictive properties, medications with, 220 Vasopasm, diffuse, 503 Ventroposteromedial (VPM), 87 Verapamil, 324325, 481

529 Vertigo, 198, 204 Visual aura, 83, 193 Visual loss and headache, relationship, 215

Xanthochromia, 137

Zolmitriptan (zomig), 295297, 379, 478 nasal spray, 479

About the Editors

RICHARD B. LIPTON is Professor and Vice Chair of Neurology and Professor of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York; and Director of The Monteore Headache Center, New York, New York. Dr. Lipton is past president of the American Headache Society and has published over 400 original articles and reviews in the elds of headache, neuroepidemiology, and health services research. He is an Associate Editor of the journals Cephalalgia and Headache, and serves on the editorial board of Neurology, among other journals. He completed a neurology residency and clinical neurophysiology fellowship at the Albert Einstein College of Medicine, New York, New York, as well as an additional fellowship in neuroepidemiology at the Sergievsky Center of Columbia University College of Physicians and Surgeons, New York, New York. MARCELO E. BIGAL is Assistant Professor of Neurology, Albert Einstein College of Medicine, New York, New York, and Director of Research, The Monteore Headache Center, New York, New York, and The New England Center for Headache, Stamford, Connecticut. Dr. Bigal is currently on the Scientic and Education Committees of the American Headache Society, as well as in the Scientic Committee of the International Headache Society. Dr. Bigal has published over 100 original articles and reviews in indexed medical journals. He is an Associate Editor of the Journal of Headache and Pain, Contributing Editor of the journal Headache Currents, and Abstract Editor of the journal Headache.