Escourolle & Poirier's Manual of Basic Neuropathology - 5E (2014) (PDF) (UnitedVRG)

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Escourolle & Poirier’s
Manual of Basic Neuropathology
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Escourolle & Poirier’s
MANUAL OF BASIC
NEUROPATHOLOGYR
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F I F T H EDITION
FRANÇ O IS E G RAY, MD, PHD
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PROFE S S OR OF PATHOL O G Y
UNIVE R S I TY PAR I S V I I N E U R O PAT H O L O G IS T A P H P L A RI B O I SI È RE H O SPI TA L
PARIS, FR ANC E
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CH A R L ES D U YCKAERTS, MD, PHD
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UNIVE R S I TY PAR I S V I N E U R O PAT H O L O G IS T A P H P, G H P I T I É - SA L PÊ T RI È RE
PARIS, FR ANC E
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UM B ER TO D E GI ROLAMI, MD
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HARVA R D M EDI C AL S C H O O L N E U R O PAT H O L O G IS T B R IG H A M A N D W O M E N ’S H O SPI TA L
BOSTO N, M A
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Library of Congress Cataloging-in-Publication Data
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Escourolle & Poirier’s manual of basic neuropathology / [edited by] Françoise Gray, Charles Duyckaerts, Umberto De Girolami ; foreword by
Martin A. Samuels. – 5th ed.
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p. ; cm.
Escourolle and Poirier’s manual of basic neuropathology
Manual of basic neuropathology
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Rev. ed. of: Escourolle & Poirier’s manual of basic neuropathology / Françoise Gray, Umberto De Girolami, Jacques Poirier. c2004.
Includes bibliographical references and index.
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ISBN 978–0–19–992905–4 (alk. paper)—ISBN 978–0–19–933048–5 (alk. paper)—ISBN 978–0–19–933049–2 (alk. paper)
I. Gray, Françoise. II. Duyckaerts, C. III. De Girolami, Umberto. IV. Escourolle, Raymond, 1924– V. Gray, Françoise. Escourolle
& Poirier’s manual of basic neuropathology. VI. Title: Escourolle and Poirier’s manual of basic neuropathology. VII. Title: Manual of
basic neuropathology.
[DNLM: 1. Central Nervous System Diseases—pathology. WL 301]
RC347
616.8′047—dc23
2013010266
The science of medicine is a rapidly changing field. As new research and clinical experience broaden our knowledge, changes in treatment
and drug therapy occur. The author and publisher of this work have checked with sources believed to be reliable in their efforts to provide
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possibility of human error or changes in the practice of medicine, neither the author, nor the publisher, nor any other party who has been
involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete.
Readers are encouraged to confirm the information contained herein with other reliable sources, and are strongly advised to check the product
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Printed in the United States of America
on acid-free paper
Contents
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Foreword vii
- 5. Infections of the Central Nervous
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Martin A. Samuels System 114
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Preface to the Fifth Edition ix Françoise Gray, Kum Thong Wong,
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Contributors xi Francesco Scaravilli, and Leroy R. Sharer
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1. Basic Pathology of the Central
Nervous System 1
6. Human Prion Diseases 149
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James W. Ironside, Matthew P. Frosch, and
Danielle Seilhean, Umberto De Girolami, and Bernardino Ghetti
Françoise Gray
7. Multiple Sclerosis and Related
2. Tumors of the Central Nervous System 20 Inflammatory Demyelinating
Diseases 161
Keith L. Ligon, Karima Mokhtari, and
Thomas W. Smith Hans Lassmann, Raymond A. Sobel, and
Danielle Seilhean
3. Central Nervous System Trauma 59
8. Pathology of Degenerative Diseases of
Colin Smith the Nervous System 173
Charles Duyckaerts, James Lowe, and
4. Neuropathology of Vascular Disease 76 Matthew Frosch
Jean-Jacques Hauw, Umberto De Girolami, and
Harry V. Vinters
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9. Acquired Metabolic Disorders 205 12. Pathology of Skeletal Muscle 278
Leila Chimelli and Françoise Gray Hart G. W. Lidov, Umberto De Girolami,
Anthony A. Amato, and Romain Gherardi
10. Hereditary Metabolic Diseases 227 13. Pathology of Peripheral Nerve 313
Frédéric Sedel, Hans H. Goebel, and Jean-Michel Vallat, Douglas C. Anthony, and
Douglas C. Anthony Umberto De Girolami
14. Diseases of the Pituitary Gland 343

11. Congenital Malformations and Vânia Nosé and E. Tessa Hedley-Whyte
Perinatal Diseases 257
Féréchté Encha-Razavi, Rebecca Folkerth,
Appendix: Brief Survey of Neuropathological
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Brian N. Harding, Harry V. Vinters, and
Techniques 365
Jeffrey A. Golden
Homa Adle-Biassette and Jacqueline Mikol
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Index 379
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vi • CONTENTS
Foreword
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It has been a decade since the previous edition of brain could react to disease. My roadmap in this new
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the Manual of Basic Neuropathology was published terrain was the then-new little blue book, Escourolle
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in 2003. In 1971, Raymond Escourolle and his and Poirier’s Manual of Basic Neuropathology. My
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student, Jacques Poirier, published a book on the heavily worn copy remains on my bookshelf.
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basic aspects of neuropathology, the English ver- A second edition appeared in 1977 and a third in
sion of which was translated by Lucien Rubinstein 1989, with Françoise Gray succeeding Raymond
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and published in 1973. I was in the midst of my Escourolle, who had died in 1984. Then, after a lon-
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neurology residency at the time and on July 1, ger interval, Umberto De Girolami joined Françoise
1973, I was embarking with trepidation on a year of Gray and Jacques Poirier for the fourth edition, pub-
neuropathology, a requirement of my training pro- lished in 2003. In the foreword to the fourth edition
gram in that era. Knowing only the pathology that I noted how dependent I was on the original manual
I had learned in medical school and having virtu- and bemoaned the loss of intense neuropathology
ally no concept of neuropathology, I found myself training in the making of modern neurologists.
immersed in an alien world. Little did I know that In the past decade, neuroimaging and molecu-
this was to be one of the most influential years in my lar medicine have become even greater parts of
career. The ritual of removing the brains, obtaining the routine life of the clinician. At our daily morn-
the appropriate sections for microscopic analysis, ing report conferences, it is difficult to prevent
and wading through the slides converted me from our residents from showing the images first, skip-
an internist into a neurologist. Neuropathology was ping the history and the neurological examination
the basic science of clinical neurology. I learned how entirely. Some have even argued that listening
to correlate clinical symptoms and signs with find- to the patient, performing a careful neurological
ings in the brain and the various ways in which the examination, and trying to localize the lesion have
• vii
become quaint fossils of times past. This has led For the fifth edition of the Manual, the distin-
to a new problem, the “incidentaloma,” a finding guished neuropathologist Charles Duyckaerts,
on imaging or other testing that is unrelated to the himself an expert in neurodegenerative diseases, par-
patient’s actual problem. The only way to put “inci- ticularly Alzheimer’s disease, joins Drs. Gray and De
dentalomas” in perspective and to prevent harm Girolami as the editors. Over 30 additional experts
to patients is to fully understand what is actually have written authoritative but characteristically brief
possible in the nervous system; in other words, and clear chapters on the full array of major topics in
neuropathology. the field. The organization of the book remains reas-
Other powerful societal forces aimed at saving suringly unchanged. The first chapter reviews the
time and money have put pressure on the effort basic pathology of the nervous system, followed by
it takes to think through complex patient prob- chapters on tumors, trauma, vascular diseases, and
lems carefully and to correlate them rigorously infections. A separate chapter deals with the increas-
with the real pathology found in the nervous sys- ingly important prion diseases, followed by chap-
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tem. Fortunately for us, Umberto De Girolami has ters on multiple sclerosis, degenerative disorders,
championed the continuing need to use modern- acquired metabolic diseases, hereditary metabolic
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ized neuropathology as a powerful tool for better diseases and congenital malformations, and peri-
patient care and for progress in understanding the natal diseases. Separate chapters follow on skeletal
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causes of diseases of the nervous system. His suc- muscle, peripheral nerve, and the pituitary gland.
cessor as Chief of Neuropathology at the Brigham, The book ends with a modernized survey of neuro-
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Rebecca Folkerth (a co-author of the chapter on pathology techniques.
congenital malformations and perinatal diseases, This newly updated version of a truly venerated
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in the Manual), has continued this tradition. Each book will be valued by students, trainees, and practi-
week at our neuropathology conference we are tioners in all of the fields related to the nervous sys-
impressed with how much is learned from the neu- tem, including neurology, neurosurgery, psychiatry,
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ropathological analysis of patients, whether that be neuroradiology, neuroendocrinology, neuropathol-
autopsy or biopsy material. With the prudent appli- ogy, and neuroscience. The new edition will have
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cation of modern techniques, including molecular an honored place on my bookshelf, right next to the
and genetic analysis, we repeatedly learn that we little blue book that got me started over 40 years ago.
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often did not have a full grasp of clinical problems,
even with the most skilled application of modern Martin A. Samuels, MD, DSc (hon),
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technology. FAAN, MACP, FACP
My own clinical practice and education is contin- Chairman, Department of Neurology,
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uously in flux based largely on the reflection on our Brigham and Women’s Hospital
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clinical analysis using the powerful tools of modern Professor of Neurology, Harvard Medical School
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neuropathology. Boston, Massachusetts, USA
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viii • FOREWORD
Preface to the Fifth Edition
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The first two French editions of the Manuel
- This fifth edition of the Manual attempts to delib-
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Elémentaire de Neuropathologie, published in 1971 erately maintain the general intention of the first
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and 1977, were conceived, written, and edited by and subsequent editions of Professors Escourolle
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Raymond Escourolle and Jacques Poirier. After and Poirier’s monograph—that is, to provide a basic
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the death of R. Escourolle in 1984, Françoise Gray description of the lesions underlying the diseases of
joined Jacques Poirier for the third edition; in addi- the nervous system and to limit pathophysiological
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tion, Jean-Jacques Hauw and Romain Gherardi considerations to essential principles. Historical,
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contributed to selected chapters. The first three edi- clinical, neurological, and radiologic imaging data,
tions reached the English-speaking public thanks once again, are specifically excluded, as well as refer-
to the friendship and translating ability of the ence listings, while recognizing this to be essential
now-deceased Lucien Rubinstein. For the fourth information for the erudite and informed practice
edition, Umberto De Girolami joined as co-editor of neuropathology. Our premise, however, has been
and the scope of the monograph was expanded that it would be presumptuous for us to do justice to
with the collaborative efforts of multiple experts this vast body of information, well beyond the scope
throughout the world to write the English-language of a basic overview of neuropathology. We also have
text. Jacques Poirier is now retired, and we are made the assumption that the reader has some
delighted that Charles Duyckaerts has agreed to join familiarity with general concepts of neuroanatomy,
the editorial team for the fifth edition. There have neurohistology, and the principles of anatomical
also been some changes in the authorship of several pathology as well as clinical neurology.
chapters in response to the changing status of senior With these guidelines in mind, our aim has been
authors and the need to recruit active investigators to produce a text that mainly presents those aspects
to replace them. of neuropathology that are morphologic, and to
• ix
demonstrate these with accurate descriptions and degenerative and metabolic disorders, develop-
good illustrations, all within the scope of a concise mental disorders, and neuromuscular diseases.
and inexpensive “manual.” Morphologic neuropathological data, obtained
For several reasons, we think that the time is now at biopsy or at postmortem examination, there-
right for a new edition since the last one in 2003. fore need to be integrated with this new knowl-
Over the past decade, specialty training in neu- edge for the reinterpretation and reclassification
rology, neurosurgery, and pathology has changed of many diseases. For example, neuropathologi-
throughout much of the world, such that in these cal information obtained at biopsy, combined
disciplines less time is being devoted to neuro- with molecular biology and genetic data, is now
pathology. This has been due in large part to the required for the diagnosis, prognosis, and guid-
tremendous expansion of knowledge in allied sub- ance of the choice of treatment modalities for
specialty areas, requiring that more time be devoted cerebral tumors.
to them. As a result, the trainee is now very much in • Lastly, an urgent responsibility to present an
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need of a concise introductory text. updated synopsis of neuropathology is that this
In addition, several other important changes in knowledge is important to allied disciplines, as
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medicine and society have had an impact on the there is a constant need for surveillance of newly
field of neuropathology and need to be addressed in recognized diseases, including iatrogenic ones.
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this text.
We need to thank first of all Susan Pioli, who
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• For a variety of social and scientific reasons, although now retired from the publishing business
autopsy studies are currently being performed was instrumental in the prior edition and led us to
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much less frequently than in years past. This Craig Panner with Oxford University Press, who has
change has been brought about in part because given fundamental support. Secondly, we thank the
the progress in radiological imaging, both struc- contributing authors and their staff for the text and
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tural and functional, has decreased the need to illustrations provided in this new edition.
draw on clinical–anatomical correlations derived In the Introduction to the First Edition,
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from autopsy data to guide medical practice. Professors Escourolle and Poirier offered an apology
Oddly enough, conversely, autopsy-derived to the reader that is still valid 40 years later:
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knowledge of the anatomical distribution and the
neuropathological basis of lesions continues to The compilation of a basic work designed to famil-
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be a valuable body of information for the inter- iarize physicians-in-training with such a highly
pretation of imaging data. To this aim we have specialized discipline as Neuropathology entails
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made ample use of macroscopic illustrations and two opposing risks: in attempting to compress
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whole-brain celloidin-/paraffin-embedded sec- the maximum amount of information within the
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tions from our archives. minimum space, the text is liable to become unin-
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• Progress in molecular biology and genetics has telligible to beginners; if on the contrary, one tries to
revolutionized the laboratory diagnosis of many maintain too elementary a level, the danger is that
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groups of neurological diseases. Neuropathology only the obvious will be stated. In presenting to the
stands at the vanguard of the development and non-initiated reader neuropathological informa-
implementation of these diagnostic studies. tion that some may find too simple, we have pre-
In the past decade, progress in immunohisto- ferred the hazard of the second pitfall.
chemistry methods for in situ identification of
abnormal proteins, and the enormous advances Françoise Gray
in molecular biology to uncover specific gene Charles Duyckaerts
mutations, have led to greater understanding of Umberto De Girolami
many hereditary neurological diseases, including
x • P R E FA C E TO T H E F I F T H E D I T I O N
Contributors
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Homa Adle-Biassette, M.D., Ph.D.
- Umberto De Girolami, MD
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Maitre de Conférence en Anatomie Pathologique, Professor of Pathology
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University of Paris VII Harvard Medical School
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Neuropathologiste, Practicien Hospitalier, APHP, Neuropathologist, Brigham and Women’s Hospital;
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Hopital Lariboisière, Paris, France Consultant Neuropathologist
Boston Childrens’ Hospital,
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Anthony A. Amato, MD
Boston, MA
Professor of Neurology
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Harvard Medical School Charles Duyckaerts, MD, PhD
Vice-chairman, Department of Neurology; Professor of Pathological Anatomy,
Chief, Neuromuscular Division University of Paris VII
Brigham and Women’s Hospital, Director, Neuropathology Laboratory, Pitié-
Boston, MA Salpêtrière Hospital,
Paris, France
Douglas C. Anthony, M.D., PhD.
Professor, Alpert Medical School of Brown University Féréchté Encha-Razavi, MD
Pathologist-in-Chief, Lifespan Academic Medical Fetal Pathology, Necker Hospital
Center, Paris, France
Providence, RI
Leila Chimelli, MD, PhD
Professor of Pathology
Federal University of Rio de Janeiro
Neuropathologist, National Cancer Institute,
Rio de Janeiro, Brazil
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Rebecca Folkerth, MD Brian N. Harding, MD PhD
Associate Professor of Pathology Professor of Pathology & Laboratory Medicine,
Harvard Medical School University of Pennsylvania
Director, Neuropathology Service, Brigham and Neuropathologist, Department of Pathology and
Women’s Hospital; Laboratory Medicine
Consultant Neuropathologist, Boston Childrens’ Children’s Hospital of Philadelphia
Hospital, Philadelphia, PA
Boston, MA
Jean-Jacques Hauw, MD
Matthew P. Frosch, MD, PhD Emeritus Professeur d’Anatomie Pathologique,
Lawrence J. Henderson Associate Professor of University of Paris VI
Pathology and Health Sciences & Technology Paris, France
(HST); Associate Director, HST
E. Tessa Hedley-Whyte
Harvard Medical School
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Professor of Pathology
Director, Neuropathology Service
C.S. Kubik Laboratory for Neuropathology
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Neuropathologist, C.S. Kubik Laboratory for
Massachusetts General Hospital,
Neuropathology
Boston, MA
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Massachusetts General Hospital,
Bernardino Ghetti, MD Boston, MA
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Distinguished Professor and Director of
James W. Ironside, FRCPath
Neuropathology
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Professor of Clinical Neuropathology
Department of Pathology and Laboratory Medicine
School of Clinical Sciences
Indiana University School of Medicine
University of Edinburgh, UK
Indianapolis, Indiana
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Honorary Consultant Neuropathologist
Romain K. Gherardi, MD Lothian University Hospitals Division and Tayside
Professor of Histology University Hospitals
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Reference Center, INSERM U955 Scotland, UK
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Henri Mondor University Hospital
Hans Lassmann, MD
Paris-Est University, F-94010 Créteil, France
Professor of Neuroimmunology
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Hans H. Goebel, MD Center for Brain Research
Professor of Neuropathology Medical University of Vienna
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Department of Neuropathology Vienna, Austria
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University Medical Center of the Johannes
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Hart G. W. Lidov, MD, PhD
Gutenberg University
Associate Professor of Pathology
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Mainz, Germany
Harvard medical School
Jeffrey A. Golden, MD Director of Neuropathology
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Harvard Medical School Department of Pathology ;
Chair, Boston Children’s Hospital
Brigham and Women’s Hospital Neuropathologist Brigham and Women’ Hospital
Boston, MA Boston, MA
Françoise Gray, MD, PhD Keith L. Ligon, MD, PhD
Professeur d’Anatomie Pathologique, Assistant Professor of Pathology
University of Paris VII Harvard Medical School
Praticien Hospitalier, AP,HP, Hôpital Lariboisière, Investigator, Dana-Farber Cancer Institute Center
Paris, France for Molecular Oncologic Pathology
Neuropathologist, Brigham and Women’s Hospital,
Boston Children’s Hospital
Boston, MA
xii • CO N T R I BU TO R S
James Lowe, DM, FRCPath Colin Smith, MD, FRCPath
Professor of Neuropathology Reader in Pathology
University of Nottingham Medical School University of Edinburgh
Hon Consultant in Neuropathology, Nottingham Honorary Consultant in Neuropathology
University Hospitals NHS Trust, Nottingham NHS Lothian
UK Edinburgh, UK
Karima Mokhtari, MD Thomas W. Smith, MD
Neuropathologist, Pitié-Salpêtrière Hospital, Professor of Pathology and Neurology
Paris, France University of Massachusetts Medical School
Director of Neuropathology and Diagnostic
Jacqueline Mikol, MD
Electron Microscopy,
Emeritus Professeur d’Anatomie Pathologique,
UMass Memorial Medical Center
University of Paris VII
Worcester, MA
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Praticien Hospitalier, AP, HP, Hôpital Lariboisière,
Paris, France Raymond A. Sobel, MD
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Professor of Pathology (Neuropathology)
Vânia Nosé, MD, PhD
Stanford University School of Medicine
Associate Professor of Pathology
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Neuropathologist, Veterans Affairs Health Care
System
Director of Anatomic and Molecular Pathology
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Palo Alto, CA
Massachusetts General Hospital
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Boston, MA Jean-Michel Vallat, MD, PhD
Francesco Scaravilli, MD, PhD, FRCPath, DSc
University of Limoges
Emeritus Professor of Neuropathology
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Department of Neurology
Institute of Neurology, UCL, London, UK
University Hospital Dupuytren
Frédéric Sedel, MD, PhD Limoges, France
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Harry V. Vinters, MD, FRCPC, FCAP
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Fédération des Maladies du Système Nerveux
Distinguished Professor of Pathology & Laboratory
APHP, Pitié-Salpêtrière Hospital
Medicine, and Neurology,
University Paris of VI
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David Geffen School of Medicine at University of
Danielle Seilhean, MD, PhD California Los Angeles (UCLA),
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Professor of Pathological Anatomy, University of Chief, Section of Neuropathology, Ronald Reagan-
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Paris VI UCLA Medical Center
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Neuropathologist, Pitié-Salpêtrière Hospital, Member, Brain Research Institute, UCLA
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Paris, France Los Angeles, CA
Leroy R. Sharer, MD Kum Thong Wong, MBBS, MPath,
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Professor of Pathology FRCPath, MD
New Jersey Medical School Dept of Pathology, Faculty of Medicine,
Neuropathologist, University Hospital, University of Malaya,
Newark, NJ Kuala Lumpur, Malaysia
Contributors • xiii
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1
Basic Pathology of the Central
Nervous System
D A NI ELLE S E I LHE AN , U MB ER TO D E G I R O L A MI , A ND FRA NÇO ISE G RAY
AUTOPSY DIAGNOSIS in neuropathology is characterized morphologically by the co-expression of

based on the macroscopic and microscopic study multiple reactions to injury that may not be diagnos-
of the brain, brainstem, cerebellum, and spinal cord. tic in themselves. These reactions affect the cellular
Increasingly, the ability to reach greater diagnostic elements of the nervous system (neurons, astrocytes,
precision is buttressed by the new laboratory tech- oligodendrocytes, and microglia) and/or the support-
niques of molecular biology and genetics. Three ing structures (meninges, connective tissue, or blood
consecutive steps are involved in reaching a diagno- vessels). Basic cellular reactions are demonstrable only
sis and these are, in fact, closely interrelated: (1) a on microscopic examination, whereas tissue lesions
morphologic/laboratory analysis of the lesions; that can be associated with more extensive destructive
(2) a topographic analysis of the lesions; and (3) a or atrophic changes are recognized macroscopically or
critical integration of these findings and their subse- with the help of a magnifying lens.
quent correlation with the clinical data and the gen- Although, for didactic purposes, the reactions
eral autopsy findings, thus permitting an etiological to injury seen in the neurons, glia, connective tis-
diagnosis to be made in most instances. sue, and vascular structures will be described sepa-
rately in the text below, it is essential to emphasize
that there is a close functional interdependence of
1. MORPHOLOGIC ANALYSIS the various cellular elements of the nervous system.
OF CENTRAL NERVOUS This is particularly important in the case of nerve
cell alterations where, except for very acute injury,
SYSTEM LESIONS the possibility of artifactual change should be enter-
With the exception of tumors and malformations, most tained whenever the reaction is not accompanied by
disorders of the central nervous system (CNS) are a glial cell response.
• 1
1.1. BASIC cellular reactions to sclerosis). It is also seen in anterograde and retro-
CNS injury grade transsynaptic degeneration, as may occur in
the lateral geniculate body following a lesion of the
1. 1. 1. NE UR ONAL LES I O NS optic nerve.
Neuronal injury may sufficiently severe to result in Programmed cell death (apoptosis) is an active,
irreversible damage (cell death) or may be transient genetically controlled, energy-consuming process
or minimal and cause reversible functional dam- frequent in neurodegeneration and involving pri-
age. Destruction of neurons may be focal, or extend marily the nucleus of the cell. Neurons undergoing
diffusely, involving many populations of neurons simple neuronal atrophy or apoptosis have similar
throughout the nervous system. In acute neuro- morphologic features and may show positive in situ
nal injury, when the tissue is examined with H&E end labeling of internucleosomal DNA fragmen-
preparations at a time shortly after a lethal insult to tation (Fig.1.1)or be demonstrable by activated
the cell, one observes eosinophilia of the cytoplasm, caspase-3 immunostaining.
shrinkage and hyperchromasia of the nucleus, and Nerve cell atrophy should not be mistaken for
disappearance of the nucleolus; subsequent to the what is referred to as “dark neurons.” This phenom-
disintegration of the cell, neuronophagia by scav- enon is now recognized to be an artifactual change
enger cells ensues. In chronic diseases, evidence of of the neuron cell body, seen particularly in brain
cell death is recognized morphologically as neuro- biopsies fixed in formalin by immersion, and charac-
nal “cell loss” or, alternately, as “atrophy” when the terized by shrunken cytoplasm and deeply-stained
irreversible injury has occurred relatively slowly and and irregularly-shaped nucleus without other cellular
has progressively involved ever greater numbers of alterations.
cells. In some degenerative diseases of the nervous
system in which there is progressive loss of neurons 1.1.1.2. Acute Neuronal Necrosis (Anoxic/
over variable time periods, the affected cells have Ischemic Neuronal Change) This type of cell death
distinctive morphologic hallmarks (e.g., neurofibril- occurs in a variety of acute injuries, including anoxia
lary degeneration, neuronal storage of metabolic and ischemia, but may also be seen in many other
products, disorders associated with intracellular acute pathological processes (e.g., hypoglycemia or
inclusion bodies).
The end stage of all irreversible lesions that
affect the nerve cells is neuronal loss, evidenced
by an appreciable reduction in the number of cell
bodies in a particular area, as compared to normal.
This assessment can be difficult to estimate in the
absence of rigorous morphometric analysis, when
it involves less than 30% of the normal cell popula-
tion. This estimate depends on the thickness of the
section and on the normal cytoarchitectonics of the
region examined.
1.1.1.1. Nerve cell “atrophy” Neuronal “atro-

phy” is the descriptive term that is given to a wide
range of irreversible neuronal injuries that give
rise to a relatively slowly-evolving death of the FIGURE 1.1 Two neurons undergoing apopto-
cell. Neuronal “atrophy” is characterized morpho- sis are positively stained by in situ end labeling to
logically by retraction of the cell body with dif- demonstrate internucleosomal DNA fragmentation.
fuse basophilia of the cytoplasm and pyknosis and In one neuron, on the left, only the nucleus is stained,
hyperchromasia of the nucleus of the neuron, in whereas in the other, which is at a later stage of the
the absence of an inflammatory reaction. Neuronal programmed cell death process, the entire cell body is
“atrophy” is thought to occur in many degenera- stained. Compared to a normal neuron, on the right,
tive disorders that involve several interconnected both apoptotic neurons have similar morphologic
neuronal systems (i.e., multiple system atrophy, in features and show pyknotic nucleus and shrunken
Friedreich ataxia, and even in amyotrophic lateral cytoplasm.
2 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y
FIGURE 1.2 Acute ischemic nerve cell change FIGURE 1.3 Ferrugination (mineralization)
(H&E). Eosinophilic, shrunken cytoplasm and hyper- of the neurons at the edge of an old hemorrhagic
chromatic nucleus. infarct (H&E).
exposure to excessive amounts of excitotoxic neu- degeneration or axonal reaction). Subsequent recov-
rotransmitters). Unlike apoptosis, the predominant ery of normal cell morphology or, conversely, further
cellular changes in acute neuronal necrosis involve progression to nerve cell degeneration depends on the
the cytoplasmic organelles and the cell membrane, reversibility of the axonal lesion (Fig. 1.5). Central
which ruptures, leading to cell death. chromatolysis may also be seen in upper motor neu-
In experimental animal studies and in carefully rons, but the phenomenon is rare and difficult to
preserved human tissue at postmortem, by light interpret. Axonal lesions of neurons whose axons do
and electron microscopy, the following sequence of not leave the confines of the CNS apparently either
changes is noted over the course of 12 to 24hours after do not produce changes in perikaryal cell body mor-
the insult: (a) cytoplasmic microvacuolation due to phology or result in “simple” type of atrophy. Oddly
swelling of mitochondria and endoplasmic reticulum; enough, some metabolic disorders that do not a priori
(b) shrinkage of cell body with retraction of the cel- involve axons (e.g., Wernicke encephalopathy, pellagra
lular outlines, and disappearance of Nissl bodies with encephalopathy, porphyria) may be accompanied by
eosinophilic condensation of the cytoplasm (“red central chromatolysis in cortical neurons.
neuron”); (c) condensation of nuclear chromatin and A confident diagnosis of central chromatolysis
nuclear pyknosis (Fig. 1.2); (d) late disappearance of requires comparison with the normal morphology
the nuclear chromatin, resulting in increased acido-
philia of the nucleus, which appears to merge into the
surrounding cytoplasm (karyorrhexis).
Occasionally, dead neurons, especially those
adjacent to old, mostly hemorrhagic, infarcts, or to
traumatic scars, become encrusted with basophilic
mineral deposits, chiefly iron and calcium salts. This
condition is referred to as mineralization or ferrugi-
nation of neurons (Fig.1.3).
1.1.1.3. Central chromatolysis Central chroma-

tolysis is characterized morphologically by swelling
of the cell body, disappearance of Nissl bodies begin-
ning centrally and extending outward, and flatten-
ing and eccentric displacement of the nucleus to the
periphery (Fig. 1.4). It is seen usually in lower motor FIGURE 1.4 Central chromatolysis (Nissl stain).
neurons (anterior horns of the spinal cord, cranial Note the cellular swelling, the eccentric displace-
nerve nuclei), where it represents a reparative reac- ment of the nucleus, and the margination of the Nissl
tion of the cell body to a lesion of the axon (retrograde bodies.
Chapter 1 Basic Pathology of the Central Nervous System • 3

Complete
central
chromatolysis
Normal
neuron
Recovery
Cell death
FIGURE 1.7 Fenestrated neuron in a case of olivary
Stages of hypertrophy (Nissl stain).
hyperchromasia
FIGURE 1.5 Nerve cell changes in central
chromatolysis. 1.1.1.5. Binucleated neurons These lesions are
seen rather infrequently, sometimes under normal
of the affected gray matter structure because the circumstances, at the edge of old focal destructive
nerve cell-body in some nuclei (e.g., the mesen- lesions, as a dysplastic/malformation phenomenon
cephalic nucleus of the fifth cranial nerve, Clarke’s (e.g., tuberous sclerosis), or in certain neoplasms
column) normally contains rounded neurons with (e.g., ganglion-cell tumors).
marginated Nissl bodies.
1.1.1.6. Neuronal storage In some hereditary
1.1.1.4. Vacuolated neurons and neuropil metabolic diseases related to enzymatic defects
Vacuolated neurons and neuropil are observed involving synthetic or degradative pathways for lip-
in Creutzfeldt-Jakob disease (Fig. 1.6). In rare ids or carbohydrates, interruption of the pathway
instances, swelling with vacuolization of the nerve leads to cytoplasmic accumulation of intermediate
cell is thought to result from transsynaptic degen- substrates or their byproducts, resulting in swelling
eration—for example, in the neurons of the inferior and distention of the cell body of nerve cells, with
olive in olivary hypertrophy, secondary to a lesion of eccentric displacement of the nucleus (Fig. 1.8). In
the ipsilateral central tegmental tract, or of the con- several neuronal storage disorders, the stored mate-
tralateral dentate nucleus—so-called “fenestrated rial has distinctive histochemical and ultrastruc-
neurons”(Fig. 1.7). tural features that may help characterize clinically
FIGURE 1.8 Distended nerve cell bodies in a case

FIGURE 1.6 Vacuolated neuron in a case of of neuro-lipidosis (combined Luxol fast blue and
Creutzfeldt-Jakob disease (H&E). Bodian silver impregnation).
suspected cases. Biochemical tests on blood, leu- cells (Fig.1.10B, C). Compact globose perikaryal
kocytes, and other body fluids are now particularly NFTs are mainly seen in small cortical neurons
useful to more precisely diagnose many of these (Fig.1.10D). Large globose NFTs reminiscent of
disorders. a ball of string are more common in neurons of
Lipofuscin accumulation within the perikaryon the nucleus basalis of Meynert and in the brain-
of neurons and other cells in the nervous system stem (Fig.1.10E). In the final stages of the disease,
is a characteristic aging change. Lipofuscin accu- the cell outline disappears and only the distorted
mulates in neurons diffusely throughout the brain fibrils remain as “ghost NFT” (Fig.1.10F).The pre-
in ceroid-lipofuscinosis, a neuronal storage disor- dominant biochemical component of NFTs is the
der. Lipofuscin is identified on H&E preparations microtubule-associated protein tau, which accumu-
as refractile yellow-brown pigment aggregates lates in an abnormally highly phosphorylated form.
(Fig. 1.9). It is autofluorescent and rich in acid Tangles are particularly well demonstrated by tau
phosphatase. The pigment is PAS-positive and can immunocytochemistry, which is now used routinely
be stained by Luxol fast blue. It has distinctive ultra- in diagnostic work. Some NFTs can also be immu-
structural features (see Chapter 10). noreactive for ubiquitin. On electron microscopic
examination most NFTs consist of paired helical fil-
1.1.1.7. Alzheimer neurofibrillary degenera- aments measuring around 20 nm across, with a regu-
tion and granulovacuolar degeneration Alzheimer lar constriction to 10nm occurring every 80nm. In
neurofibrillary degeneration is characteristically seen Alzheimer disease, they may also be associated with
in the brains of aged individuals and in patients with straight filaments. In progressive supranuclear palsy,
senile dementia of Alzheimer type but has also been NFTs have been found to consist mainly of straight
described in a variety of other cerebral disorders. filaments measuring 15 nm in diameter.
This degenerative change is manifest by the forma- Granulovacuolar degeneration is a neuronal altera-
tion of neurofibrillary tangles (NFTs), structures tion found in pyramidal cells of Ammon’s horn; this
that are well demonstrated by silver impregnation abnormality is seen in normal aging as well as in
and by immunohistochemical techniques and con- Alzheimer disease and Pick disease. It consists of an
sists of thickened and tortuous skeins within the accumulation of small clear vacuoles measuring 4 to
neuronal perinuclear cytoplasm. The configuration 5μm in diameter, containing an argyrophilic granule
of the tangle may vary according to the anatomical that is also well stained by hematoxylin (Fig. 1.11).
site, the type of neuron affected, and the stage of its Some of the granules are immunoreactive for phos-
development (Fig.1.10). A band-shaped perikaryal phorylated neurofilaments tubulin, tau, and ubiq-
NFT can be seen both in large and small pyrami- uitin, suggesting that the vacuoles are autophagic
dal cells and is perhaps an early stage of NFT for- lysosomal structures in which cytoskeletal compo-
mation (Fig.1.10A). A triangular flame-shaped nents are being degraded.
perikaryal NFT is seen mainly in large pyramidal
1.1.1.8. Intraneuronal inclusion bodies
Intracytoplasmic or intranuclear inclusion bodies
are important indicators of neuronal injury. They
occur in degenerative, metabolic, and viral diseases
and often have diagnostic immunocytochemical
and ultrastructural features.
Pick bodies are round homogenous intracytoplas-
mic neuronal inclusions (Fig. 1.12), characteristic of
Pick disease, where they may be seen in pyramidal
neurons and dentate granule cells of the hippocam-
pus, as in affected regions of the neocortex. They are
intensely argyrophilic and are immunoreactive for
ubiquitin, tau, and tubulin. Ultrastructurally, they
consist of poorly circumscribed masses of interme-
diate filaments, 15-nm straight filaments, and some
FIGURE 1.9 Lipofuscin in neuronal cell paired helical filaments, as well as entrapped vesicu-
body (H&E). lar structures.

A B
C D
E F
FIGURE 1.10 Different types of NFTs (Bodian silver impregnation combined with Luxol fast blue).
(A) Band-shaped perikaryal NFT. (B, C) Triangular, flame-shaped perikaryal NFT. (D) Small, compact, globose
perikaryal NFT. (E) Large globose NFT. (F) “Ghost NFT.”
Lewy bodies are neuronal cytoplasmic inclu- (Fig.1.13A, B). They may also be oval or elongated
sions; their appearance varies depending whether structures, especially when they occur in axonal
they are found in the perikaryon or in the nerve cell processes or in sympathetic ganglia (Fig.1.13C, D).
processes, in the cortex, brainstem, or sympathetic Cortical Lewy bodies are less clearly circumscribed
ganglia (Fig. 1.13). Typical (brainstem) Lewy bod- and consist of a homogenous zone of hypereosino-
ies are roughly spherical with an eosinophilic core philia that usually lacks the characteristic surrounding
surrounded by a paler “halo.” One or more inclusions “halo”(Fig.1.13E, F). Lewy bodies are immunoreac-
may be present in the cytoplasm of a single neuron tive for ubiquitin, αB-crystallin, and α-synuclein.
for cystatin-C. Ultrastructurally they appear as
electron-dense membrane-bound bodies.
Skein-like inclusions are abnormal ubiquitinated
structures occurring in anterior horn cells in motor
neuron diseases. They are linear, thread-like struc-
tures; some are present singly and others form
networks of threads. Occasionally, the threads are
aggregated to form larger and dense inclusions
(Fig.1.15). They contain TDP-43, ordinarily a
nuclear protein, and accumulate within the cyto-
plasm of motor neurons in amyotrophic lateral scle-
rosis. Ultrastructurally, they consist of bundles of
filaments of 15 to 25 nm in diameter, with a tubular
FIGURE 1.11 Granulovacuolar degeneration profile on cross section.
(Bodian silver impregnation). Marinesco bodies are small eosinophilic intranu-
clear inclusions located chiefly in melanin-containing
By electron microscopy, they consist of an amor- brainstem neurons (Fig. 1.16A). They are strongly
phous electron-dense core surrounded by a corona ubiquitin positive.
of radiating filaments. Their presence defines several When ubiquitinated intranuclear inclusions
conditions termed “Lewy body disorders”; the most occur in other regions of the brain they suggest
common disorder in this group is Parkinson disease. various other disorders. Small round eosinophilic
Hirano bodies are brightly eosinophilic inclusions (about the same size of the nucleo-
rod-shaped or elliptical cytoplasmic inclusions that lus) are found in neurons of CAG-repeat dis-
appear to overlap the cell border of a neuron cell eases (including SCA, Huntington, and DRPLA)
body. They are mostly found in the CA1 field of (Fig. 1.16B). Larger, eosinophilic, ubiquitinated
the hippocampus and are particularly numerous in inclusions are found in association with CGG
Alzheimer disease, Pick disease, and in patients with repeats (fragile X) and NIID (neuronal intranu-
the Guam parkinsonism-dementia complex. They clear inclusion disease). Similar large intranuclear
are immunoreactive for actin and actin-associated inclusions are found in INIBD (intranuclear inclu-
proteins. Ultrastructurally, they consist of parallel sion body disease).
filaments 60 to 100 nm in length, which alternate Lafora bodies are rounded structures composed
with a longer sheet-like material. of polyglucosan (polymers of sulfated polysac-
Bunina bodies are eosinophilic, nonviral intra- charides) and are similar to corpora amylacea (see
cytoplasmic inclusions found in motor neurons further on) in composition and staining character-
in cases of familial or sporadic amyotrophic lateral istics. They are found in large number in myoclonic
sclerosis (Fig.1.14A , B). They are immunoreactive epilepsy both in the CNS (chiefly in the dentate
nucleus) and in tissues outside the nervous system,
such as sweat glands, liver, and skeletal muscle. They
usually have a dense, intense periodic-acid-Schiff
(PAS)-positive core surrounded by filamentous,
fainter PAS-positive structures (Fig.1.17).
Viral inclusions. Eosinophilic intranuclear
inclusions that occupy a variable volume of the
nucleus and be surrounded by a clear halo are
associated with some viral infections of the CNS
(cf. Chapter 5). They are seen in herpes virus
infections, particularly in necrotizing encephalitis
caused by herpes simplex virus, and in subacute
sclerosing panencephalitis. In rabies, the viral
inclusions are intracytoplasmic and are referred
FIGURE 1.12 Neuronal argyrophilic inclusion in to as Negri bodies. In some instances (e.g., cyto-
Pick disease (Bodian silver impregnation). megalovirus infection) both intranuclear and

A B
C D
E F
FIGURE 1.13 Lewy bodies (H&E). Single (A) and multiple (B) Lewy bodies in the perikaryon of pigmented
neurons of the substantia nigra in a case of Parkinson disease. Lewy bodies in axonal processes (C, D), in the
dorsal nucleus of the Xth cranial nerve, in a case of Parkinson s disease. Cortical Lewy bodies (E, F) in the peri-
karyon of a cortical neuron, in a case of Lewy body disease.
intracytoplasmic inclusion bodies may be seen. 1.1.1.9. Axonal alterations Following focal
Viral inclusion bodies are immunoreactive with axonal lesions that disrupt the integrity and con-
appropriate antivirus antibodies, allowing for a tinuity of the nerve fiber, the distal part of the cell
specific diagnosis. Electron microscopy may also process undergoes Wallerian degeneration, which
be used to identify virions; however, it is now used will be described further on (see basic lesions of the
less often in diagnostic work. peripheral nervous system; Chapter 13).
A B
FIGURE 1.14 Bunina bodies in anterior horn cells of the spinal cord, in a case of motor neuron disease
(H&E) (A). Immunocytochemistry for ubiquitin (B).
In conditions associated with nerve cell “atro-

phy” as described above, the destruction of the cell
body of the neuron results in degeneration of all of
its processes, including the dendrites and the axon,
which become swollen, then fragmented, and even-
tually undergo disintegration. This phenomenon,
if widespread, as occurs in system degenerations,
results in rarefaction of the white matter demonstra-
ble with myelin and axon stains. In these diseases,
the phenomenon probably begins at the most distal
portions of the longest axons.
Axonal swellings or spheroids are localized eosino-
philic enlargements of the axon. At these sites along
FIGURE 1.15 Skein-like inclusion in an anterior the axon there is a condensation of neurofilaments,
horn cell, in a case of motor neuron disease (immuno- organelles, and other materials that are normally
cytochemistry for ubiquitin). conveyed along the axon by an anterograde trans-
port system, but accumulate focally when the trans-
port system is interrupted. Spheroids are a feature
A B
FIGURE 1.16 Intranuclear inclusions. (A) Marinesco bodies: small intranuclear inclusion in a pigmented

neuron of the substantia nigra (H&E). (B)Ubiquitin-positive intranuclear inclusion in a case of spinocerebellar
degeneration with CAG repeat expansion (courtesy of Professor Francesco Scaravilli).

amyloid protein (beta APP) (Fig. 1.18C). The latter
is transported by axonal flow and accumulates when
this process is disrupted. The term torpedo is applied
to Purkinje cell axonal swellings and is a feature of
a many metabolic and degenerative cerebellar dis-
eases. Torpedoes are well demonstrated by silver
impregnation and by the immunohistochemical
methods. They are most notable in the initial por-
tion of the axis cylinder before the origin of the col-
lateral branches (Fig. 1.18C).
The axonal swellings that develop when axonal
transport is disrupted by neuronal metabolic dys-
function are usually termed dystrophic. This occurs
FIGURE 1.17 Lafora body in a case of myoclonic in some acquired (e.g., vitamin E deficiency) or
epilepsy (PAS). inherited metabolic diseases. Extensive formation
of axonal swellings is characteristic of neuroaxonal
of axonal damage by diverse extrinsic insults and dystrophy and of some leukodystrophies.
are seen especially in trauma and ischemia. They The term dystrophic neurite is used to describe
are well demonstrated by either silver impregnation neuronal cytoplasmic processes distended by tau
(Fig. 1.18A) or by immunostaining with ubiqui- protein or other abnormal ubiquinated material.
tin (Fig. 1.18B) and with the precursor of the beta These occur in several neurodegenerative diseases.
A B
FIGURE 1.18 Axonal swellings in the white matter identified on silver impregnation (A) (Bodian stain)
and on ubiquitin immunostain (B). Torpedo (axonal swelling) on a Purkinje cell axon identified by β-APP
immunostaining (C).
1.1.2. ASTROCYTIC LESIONS nucleus, which is often hyperchromatic and eccentri-
cally placed in the perikaryon. As mentioned above,
1.1.2.1. Gliosis (astrogliosis) The presence of
the cytoplasm around the nucleus and cell processes
gliosis (alternate term astrogliosis) is the most cer-
becomes more extended than normal and contains
tain indication that a microscopic finding is of patho-
glycogen(Fig. 1.19A). Characteristically, at this
logical significance and not artifactual. This reactive
stage, in H&E preparations, the cytoplasm is homog-
process accompanies almost any type of subacute or
enized and eosinophilic: these reactive astrocytes are
chronic injury of the CNS. The process of gliosis is
referred to as gemistocytic astrocytes(Fig. 1.19B, C).
in essence the response of astrocytes to CNS tissue
Over time, in chronic disease states and
injury. The associated morphologic changes include
slowly-evolving degenerative processes, astrocyte
an increase in the number of astrocyte nuclei per
nuclei return to their resting size and shape, although
unit area, eosinophilia of the cytoplasm around the
their cytoplasmic network of cell processes is more
nucleus, and expansion and distortion of the astro-
extensive and can best be appreciated with immu-
cytic cytoplasmic arborization. For reasons that are
nostaining for glial fibrillary acidic protein (GFAP).
not understood, mitotic figures are only rarely iden-
An older term, isomorphorphic fibrillary gliosis,
tified in gliotic tissue, and techniques that bring out
refers to the alignment of reactive astrocyte pro-
dividing cells (Mib-1/Ki 67) also confirm the slow
cesses conforming to a degenerating fiber tract.
turnover.
The morphologic aspects of the process of gliosis
will vary depending on the location, stage of evolu- 1.1.2.2. Alzheimer type II glia Alzheimer type
tion, and nature of the pathological process. The II glia is seen particularly in hyperammonemic
early stages are characterized by hypertrophy of the states such as occur in Wilson disease and in liver
A B
FIGURE 1.19 Gliosis. Fibrillary gliosis, (A) hypertrophy of nucleus as of cytoplasm and processes that are
well seen on GFAP stain. Gemistocytic astrocytes with large homogenized and eosinophilic cytoplasm (H&E)
(B), (GFAP) (C).

pilocytic astrocytomas, particularly of the cerebel-
lum) (cf. Chapter 2), and of Alexander disease (cf.
Chapter 10).
Eosinophilic granular bodies are rounded hyaline
droplets that occupy the cytoplasm of astrocytes and
are seen in pilocytic astrocytomas and ganglion-cell
tumors.
1.1.2.4. Inclusions and storage material

Accumulation of lipofuscin occurs in astrocytes as
part of aging as it does in neurons. Similarly, in lipid
storage diseases, glial lipid storage may accompany
neuronal storage.
FIGURE 1.20 Alzheimer type II glial cells (H&E). Tau protein, which is the main component of
NFTs, can also accumulate in astrocytes, particu-
failure from acquired or hereditary metabolic dis- larly in progressive supranuclear palsy (PSP) and cor-
ease, but it can also be found in other systemic ticobasal degeneration (cf. Chapter 8).
metabolic disorders (e.g., renal failure). This reac- Tufted astrocytes are considered to be highly char-
tion of astrocytes is characterized by enlargement acteristic of PSP (see Fig. 8.5A). The whole length
of the nucleus, reaching 15 to 20 μm in diameter, of their processes contains tau protein and they are
which appears irregular in shape and pale and often binucleated. They may be demonstrated by
empty-looking because of the disappearance of Gallyas stain or tau immunocytochemistry. Thorn
chromatin granules (Fig. 1.20). One or two dense astrocytes have an argyrophilic cytoplasm with a
rounded PAS-positive bodies resembling nucle- few short processes (see Fig. 8.5B) and often a small
oli are often seen next to the nuclear membrane, eccentric nucleus. They are commonly seen in PSP
which is always sharply outlined. The cell body is but are not specific to this disease and may be seen
not usually visible on conventional preparations in other neurodegenerative conditions.
and stains poorly with GFAP. Alzheimer II glia In corticobasal degeneration, the accumulation
(unrelated to Alzheimer disease) occur in the gray of tau protein in astroglial cells results in distinctive
matter, involving particularly deep gray nuclei, structures in gray matter which are termed astrocytic
especially the pallidum and the dentate nuclei and plaques. In these plaques, tau protein accumulates at
also the cerebral cortex. Alzheimer type II glia are the end of the astrocytic processes, while the center
metabolically active cells engaged in the detoxifi- of the plaque is devoid of tau immunoreactivity (see
cation of ammonia; on ultrastructural study, they Fig. 8.11).
are shown to contain numerous mitochondria. Viral inclusion bodies may also be found in
astrocytes, particularly in subacute sclerosing pan-
1.1.2.3. Rosenthal fibers By light microscopy, encephalitis and cytomegalovirus (CMV) infection
Rosenthal fibers are rounded, oval, or elongated, (cf. Chapter 5).
beaded structures, measuring 10 to 40μm, which Corpora amylacea are spherical, basophilic,
appear homogenous, and brightly eosinophilic. On PAS-positive inclusions, 10 to 50 μm in diameter,
electron microscopy, they consist of swollen astro- that are predominantly found in astrocytic pro-
cytic processes that are filled with electron-dense cesses, although they occasionally occur within
amorphous granular material and glial filaments. axons. Ultrastructurally, they consist of densely
With immunohistochemical methods peripheral packed 6- to 7-nm filaments that may be admixed
labeling for GFAP, ubiquitin, and ΑBcrystallin can with amorphous granular material and are not
be demonstrated. Rosenthal fibers are seen in vari- membrane bound. Corpora amylacea increase in
ous pathological conditions that have in common number with aging, particularly in the subpial and
intense fibrillary gliosis of long standing, as seen subependymal regions, around small blood vessels
throughout the brain in multiple sclerosis plaques, and in the posterior columns of the spinal cord.
in the spinal cord in syringomyelia, and in the Adult polyglucosan body disease (cf. Chapter 10)
hypothalamus around craniopharyngiomas. They is characterized by diffuse accumulation of corpora
are also characteristic of certain neoplasms (e.g., amylacea, involving the cortex and white matter,
and associated with diffuse and/or focal myelin In normal brain, microglia has been subdivided
damage. into (a) resident microglia, with little turnover and
present throughout the CNS parenchyma and
(b) perivascular microglia, found within the perivas-
1.1.3. LESIONS OF OLIGODENDROCYTES
cular basal lamina and showing characteristic turn-
Like neurons and astrocytes, oligodendrocytes over as with hematogenous monocytes. Microglial
may be infected by virus and show intranuclear or activation occurs in inflammatory conditions of the
intracytoplasmic inclusions (e.g., progressive mul- CNS and involves (a) increased entry of hematog-
tifocal leukoencephalopathy) (cf. Chapter 5) or be enous monocytes into the CNS; (b) proliferation of
affected with excess storage of lipid or glycogen in resident microglia; and (c) expression or secretion
genetically-determined enzymopathies (e.g., meta- of a wide range of proteins, most of which are con-
chromatic leukodystrophy). cerned with antigen presentation and inflammation.
Cytoplasmic inclusions involving mainly oligo- Microglial basic reactions to injury are typically
dendrocytes have been shown to be a characteristic seen in three situations:
feature of multiple system atrophy (cf. Chapter 8).
These inclusions are usually flame- or sickle-shaped • Macrophage proliferation and phagocytosis (the
and can be demonstrated by silver impregnation and cells are also known as compound granular cor-
are immunoreactive for ubiquitin, αB-crystallin, puscles, foam cells, lipid phagocytes, or gitter
and α-synuclein. cells). This is a frequent finding in many brain
The accumulation of tau protein in oligodendro- lesions, particularly those associated with demy-
cytes, known as “coiled body,” may be found in PSP, elinating processes or with traumatic or ischemic
corticobasal degeneration, and argyrophilic grain tissue destruction. After a destructive or demy-
disease (cf. Chapter8). These are fibrillary structures elinating insult, macrophages invade the dam-
“coiling” around the nucleus. aged region within 48 hours of injury. These are
rounded cells with distinct cytoplasmic borders
and measure 20 to 30 μm in diameter. They have
a small, darkly-staining and sometimes eccentric
1.1.4. MICROGLIAL LESIONS
nucleus, and a clear, granular cytoplasm that can
Microglial cells are of monocyte lineage and have contain lipids, hemosiderin pigment, or any other
important phagocytic functions. They can be dem- phagocytized material (Fig. 1.21A , B). The num-
onstrated by silver impregnation, lectin-binding ber of these scavenger cells increases over a period
techniques, and immunohistochemical techniques of days and weeks, and they may still be present in
using antibodies that react with monocyte/macro- injured tissue many months after the injury. Most
phages (e.g., CD68) (Fig. 1.21B). derive from blood monocytes.
A B
FIGURE 1.21 Perivascular lipid-laden macrophages (compound granular corpuscles, foam cells, or gitter
cells) in a demyelinating lesion (Luxol fast blue combined with Bodian silver impregnation) (A) and with CD68
immunostaining (B).

specific pathological processes (i.e., vascular, infec-
tious, inflammatory, demyelinating, metabolic,
degenerative). As will be described in the forthcom-
ing chapters, these may accompany one or more of
the specific pathological processes visible under the
microscope that are described above or may result
in more extensive changes that can be visible to the
naked eye.
1 .2 . 1. CEREBRAL ATROPHY
Cerebral atrophy is the end-stage of a num-
ber of neurological diseases. The brain weight
FIGURE 1.22 Rod-shaped microglia in a case of is lighter than a normal age-matched control.
general paresis of the insane (Nissl stain). Macroscopically, there is narrowing of the gyri and
widening of sulci. On section, the cortical ribbon
• Rod cell proliferation(Fig. 1.22 and 5.25) is a form is thinned, and ventricular dilatation is often pres-
of microglial response to subacute parenchymal ent. The histological substratum consists of a vari-
injury in which necrosis is minimal or absent. Rod able loss of neurons often associated with gliosis,
cells are elongated, spindle-shaped cells that can depending on the underlying illness, and a variety
be recognized on H&E preparations by the pres- of neuronal alterations, which will be discussed in
ence of a cigar-shaped nucleus. The best descrip- turn in subsequent chapters.
tions of this glial change are found in reports of
cases of general paresis in the older literature (cf.
Chapter 5). Rod cells are also seen in cases of sub- 1 .2 . 2. CEREBRAL EDEM A
acute encephalitis and evolving ischemic lesions. Cerebral edema is defined as an increase in brain
• Microglial nodules consist of discrete clusters of volume due to an increase in water and sodium con-
microglial cells that are typically found in subacute tent. Depending on its pathogenesis, brain edema
viral encephalitis, in and around sites of neuronal has been classified as vasogenic, cytotoxic, or inter-
destruction—neuronophagic nodules (cf. Chapter 5). stitial (hydrocephalic). Combination of these proto-
types of edema is frequent.
1. 1. 5. E PE NDYMAL C EL L S
• Vasogenic edema, probably the most common type
Ependyma have a limited range of reactions to
of brain edema, complicates head injury, abscess,
injury. Along with neurons and other glial cells,
tumors, and hemorrhages. Both vasogenic edema
ependymal cells may be infected in viral diseases. In
and cytotoxic edema occur with ischemia. Vasogenic
the adult CNS, ependymal cells do not proliferate
edema results from blood–brain barrier injury lead-
in response to injury and cell loss. Their destruction
ing to increased permeability of the microcircula-
leaves bare stretches of the ventricular lining; this
tion to macromolecules, particularly to proteins.
is accompanied by proliferation of subependymal
By radiological imaging, sites of vasogenic edema
astrocytes that form small hillocks along the ventric-
are marked by contrast enhancement, because the
ular surface—ependymal granulations. Occasionally,
injected contrast medium leaks across the perme-
surviving ependymal cells may be overgrown by the
able vascular lining. Biochemically, the edema fluid
astrocytic reaction and appear as clusters of tubules
resembles a plasma filtrate. It is located chiefly in the
buried within the ependymal granulations.
extracellular spaces of the white matter.
• In cytotoxic edema, excessive amounts of water
enter one or more of the intracellular compart-
1.2. General Tissue Reactions ments of the CNS (neurons, glia, endothelial cells,
of the CNS to Injury and Herniations or myelin sheaths) because the cellular concen-
A set of general tissue reactions are known to occur tration of osmotically active solutes is increased.
in the CNS that stand apart from the reactions to This usually results from an injury impairing the
capacity of the cell to maintain ionic homeosta-
sis. It is also seen in association with systemic
disturbances in fluid and electrolyte metabolism.
Cytotoxic edema complicates hypoxia and isch-
emia because of failure of the ATP-dependent
sodium pump in the affected cells. It also occurs
in osmotic-disequilibrium syndromes associated
with hemodialysis or diabetic ketoacidosis and in
acute plasma hypo-osmolality states such as water
intoxication and inappropriate secretion of antidi-
uretic hormone. In contrast to vasogenic edema,
because the blood-brain macromolecular barrier
remains intact, disease processes that give rise to
cytotoxic edema are not associated with radio- FIGURE 1.23 Cerebral edema of the left cerebral
hemisphere with swelling of the parenchyma that
logical enhancement after injection of contrast
appears paler, flattening of the gyri, narrowing of the
medium.
sulci and left lateral ventricle.
• Interstitial or hydrocephalic edema is the accu-
mulation of cerebrospinal fluid (CSF) in the
extracellular spaces of the periventricular white and reabsorption. Rarely, it results from increased
matter resulting from obstructive hydrocephalus. production of CSF (e.g., choroid plexus papilloma).
As fluid collects within the obstructed ventricles, More commonly, it is the consequence of altered
pressure increases and the CSF is forced across flow and absorption of the CSF as a result of obstruc-
the ependymal lining into the adjacent extracel- tion of CSF pathways within the ventricular system
lular spaces. (noncommunicating hydrocephalus) or in the sub-
arachnoid space (communicating hydrocephalus).
Obstruction at “bottleneck” areas such as the foram-
Macroscopically, the edematous areas of brain
ina of Monro, the aqueduct of Sylvius, and the exit
are swollen and soft (Fig. 1.23). The swelling
foramina of the fourth ventricle (lateral foramina
increases the volume of the intracranial contents,
of Luschka and midline foramen of Magendie) can
with consequent increased intracranial pressure (see
occur when there is extension of blood or tumor
below). When the brain is cut, the slice surfaces may
into the ventricular system. Subarachnoid pathways
be wet and shiny. If the edema is diffuse, the ventri-
most often become blocked over the cerebral con-
cles are compressed; in severe cases they are reduced
vexities and around the rostral brainstem (incisural
to slit-like cavities.
block) as a result of inflammation or hemorrhage.
Under light microscopy, myelin stains demon-
In the acute phases, the blood clot or inflammatory
strate pallor of the white matter. The cerebral tissue
exudate forms a barrier to flow. Subsequently, orga-
has a loose appearance and is split by vacuoles of
nization of the clot or exudate leads to fibrous oblit-
variable size. Glial cells are swollen, and perivascular
eration of the subarachnoid space.
spaces are dilated.
Hydrocephalus is often associated with increased
These macroscopic and microscopic features cor-
intracranial pressure. In children, in the absence of
respond to ultrastructural features that vary accord-
appropriate shunting procedures, the head can
ing to the etiological and pathogenetic mechanism.
become enlarged when hydrocephalus develops
They include dilatation of the perivascular and extra-
before the cranial sutures close. When the progres-
cellular spaces, swelling of astrocytic cell processes,
sive obstructive lesion causing the hydrocephalus
and splitting of the myelin lamellae (Fig. 1.24).
is not severe, the hydrocephalic process may stabi-
lize and the CSF pressure returns to normal limits
(“normal-pressure hydrocephalus”).
1.2.3. HYDROCEPHALUS
Several alterations in the brain are common to
Hydrocephalus is an abnormal increase in the intra- all forms of hydrocephalus. These include dilation
cranial volume of CSF associated with dilatation of of the ventricular system, interstitial edema, reduc-
all or some portion of the ventricular system. It is section of the volume of the white matter, accentuation
ondary to a dysequilibrium between CSF formation of the primary, secondary, and tertiary cerebral sulci

A B
Ast.
A A A
L
Ast. G
Ast. E.C. G
B.M. A
E.C.S
Ast. A
G G
N.
A
V
M
V V
M V
A A
FIGURE 1.24 Cerebral edema: principal ultrastructural forms.
(producing a prominent gyral pattern), and perfora- flow and blood volume, or the development of
tion of the septum pellucidum. Disruption and loss of space-occupying lesions such as tumors, abscesses,
the ependymal lining, with localized subependymal hematomas, or large, recent infarcts accompanied
astrocytic proliferations protruding into the ventricu- by edema. The effects of space-occupying lesions
lar cavities—ependymal granulations—is frequent on intracranial pressure are the result not only of
(see above). Proliferation of the subependymal glia the mass of the lesion, but also of the accompany-
may bring about stenosis of the aqueduct, which is a ing edema and obstruction of venous or CSF path-
cause of obstructive hydrocephalus in childhood. ways. In children with still-open cranial sutures,
an increase in volume of intracranial contents
will lead to splaying of the sutures, resulting in
1.2.4. INCREASED INTRACRANIAL an increase in the size of the skull and in digital
convolutional markings. In older children and in
PRESSURE AND BRAIN HERNIATION
adults when the bony skull can no longer expand,
After closure of the sutures, the volume of the cranial intracranial hypertension leads to compression
cavity is fixed by rigid bony walls and compartmen- of the brain surfaces against the inner table of the
talized by partitions of bone and dura. The normal skull, with consequent flattening of cerebral gyri,
contents of the cranial cavity (blood, brain, and narrowing of intervening sulci, and accentuation
CSF) are relatively incompressible. Under these of foraminal and tentorial markings on the infe-
circumstances, an increase in the volume of the rior cerebellar and medial temporal surfaces. The
cranial contents will result in increased intracranial expanding cerebral mass will also insinuate itself
pressure. into the anatomical openings that can accom-
The intracranial contents may expand because modate it. These compensatory displacements
of diff use brain edema, increased cerebral blood of brain from one intracranial compartment to
A Skull B C 5
Falx 1
Tentorium 2
cerebelli
Tentorial 4
3
notch
Foramen
magnum
D E F
6 6
3 4 4
3
7 7
FIGURE 1.25 Principal types of cerebral herniation.
another, caused by an increase in the volume of a hemiparesis contralateral to the lesion may
intracranial contents, are referred to as cerebral ensue; when the contralateral peduncle is dis-
herniations. The site of herniation differs depend- placed and compressed against the free edge of
ing on whether the space-occupying lesion is the tentorium (Kernohan’s notch), an ipsilateral
supratentorial or infratentorial (Fig. 1.25). hemiparesis may follow; if the adjacent posterior
cerebral artery is compressed, there can be sec-
1.2.4.1. Cerebral herniations in supratentorial ondary infarction anywhere along its territory of
lesions A unilateral lesion (Fig. 1.26)that increases distribution.
the hemispheric volume is likely to cause a hernia- • Compression due to temporal herniation and the
tion of the cerebral hemisphere through openings downward thrust of central diencephalic hernia-
limited by the inferior border of the falx and by the tion may result in stretching of the blood vessels,
free edge of cerebellar tentorium on the ipsilateral especially the veins, that supply the midbrain and
side of the lesion. Depending on the size and the site pons, which may be torn and cause potentially
of the expanding lesion within the hemisphere, one lethal brainstem hemorrhages; these are called
of several forms of herniation will occur, sometimes Duret hemorrhages.
in combination: • External cerebral herniation through surgi-
cal or traumatic defects in the calvarium may
also occur.
• Herniation of the cingulate gyrus under the falx
(subfalcine herniation) with lateral displacement
of the anterior cerebral arteries Bilateral cerebral lesions or circumstances
• Lateral displacement of the midline structures that result in a global increase of the volume
(i.e., the third ventricle, pineal gland, vein of both hemispheres will ordinarily result in
of Galen) central diencephalic herniation and/or bilateral
• Downward herniation of the diencephalon temporal lobe herniation. A midline, expanding
through the tentorial notch with downward dis- lesion will likely result in central diencephalic
placement of the floor of the hypothalamus and herniation.
of the mammillary bodies (central, diencephalic
herniation) 1.2.4.2 Cerebellar herniations in infratentorial
• Herniation of the hippocampal gyrus in the lesions
tentorial notch between the brainstem and the Two types of herniations exist:
free edge of the tentorium cerebelli. The herni-
ated temporal lobe can compress and stretch the • Upward herniation of the mesencephalon and cere-
third and sixth cranial nerves. When the ipsilat- bellum through the tentorial notch. Direct mesence-
eral cerebral peduncle is compressed directly, phalic lesions may result from this complication,

A B
FIGURE 1.26 Cerebral herniations. (A) Inferior aspect of the cerebral hemispheres; note the herniated rim
of the right hippocampal gyrus compressing the oculomotor nerve and displacing the brainstem. (B) Cerebral
metastases causing temporal herniation; note displacement of the midline structures and cingulate herniation.
(C) Midbrain; note hemorrhagic lesion in the crus of the peduncle contralateral to the temporal herniation
(Kernohan’s notch). (D,E) Midbrain and pontine hemorrhages involving mostly the tegmentum, secondary to
temporal herniation.
as well as secondary lesions due to vascular 2. TOPOGRAPHIC ANALYSIS

compression.
• Cerebellar tonsillar herniation through the foramen
OF CNS LESIONS
magnum is the most frequent and most danger- Topographic analysis of the lesions observed is just as
ous complication of an infratentorial expanding important as the study of their morphologic aspects.
process, regardless of the nature of the insult or, It constitutes a crucial step in the attempt to arrive at
in case of a neoplasm, the degree of malignancy. an etiological diagnosis and necessitates a rigorous and
The result of increased intracranial pressure in the systematic examination of all the neural structures.
posterior fossa is the herniation of the cerebellar Systematic sampling of multiple anatomical levels is
tonsils downward through the foramen magnum necessary and, wherever possible, techniques that allow
(Fig. 1.27), culminating in medullary compres- for whole-brain sections provide invaluable material
sion with compromise of vital cardiorespiratory that permits the synchronous study of various areas of
centers. the CNS under the dissecting and the light microscope.
A B
FIGURE 1.27 Cerebellar tonsillar herniation. (A) Posterior view. (B) Anterior view.
2.1. Diffuse Distribution systems—for example, involvement of upper and

lower motor neurons in amyotrophic lateral sclero-
Lesions that are diffusely distributed thought the sis, spinocerebellar involvement in Friedreich ataxia.
brain may be seen in systemic diseases such as meta-
bolic or circulatory disorders or also can be the
result of blood-borne, infective processes. Some of 3. SYNTHETIC INTEGRATION
the degenerative diseases may likewise cause diffuse
lesions of the CNS. Nevertheless, it is important to The findings in the two components of the neuro-
emphasize that, despite the diffuse character of these pathological examination, artificially set apart as
changes, lesions often show regional predominance. morphologic and topographic analyses, need to be
integrated. Furthermore and most importantly,
correlation of these findings with the clinical data,
2.2. Focal Distribution laboratory and radiological data, general autopsy
findings, and all other available diagnostic data must
Lesions may be localized to an anatomically
occur to arrive at an accurate etiological diagnosis.
well-defined area (lobe of the cerebral hemisphere,
Thus, for example, a thorough neuropathologic
basal ganglia, brainstem), and certain preferential
understanding of cerebral infarcts is possible only
sites of involvement are linked to specific etiologi-
after careful and complete postmortem examination
cal entities (e.g., some cerebral tumors preferentially
of the vascular tree, heart, and lungs and after com-
occur in certain locations of the brain). Lesions may
paring the anatomical findings with information
also be localized to a vascular territory.
provided by the clinical picture, the chronology of
the functional disturbances, and data from cerebral
2.3. Disseminated Distribution and vascular imaging.
Likewise, the study of the lipidoses cannot be
This is seen essentially in multifocal processes, of based solely on neuropathological findings. It neces-
which multiple sclerosis is the most characteristic sitates detailed correlation with data from the gen-
example. eral postmortem examination and neurochemical/
genetic analysis.
As a further example, the interpretation of mor-
2.4. Systematized Distribution phologic findings in hereditary disorders of the CNS
A number of nervous system disorders, espe- or peripheral nervous system and of diseases of skel-
cially degenerative diseases, cause changes that etal muscles requires correlation with molecular and
involve certain functionally related morphologic genetic data.

2
Tumors of the Central Nervous System
K E I T H L . LIGON, KAR I M A M O KH TA RI , A N D T H O M A S W . S MIT H
1. CLASSIFICATION when alterations occur in growth regulatory genes,

such as oncogenes and tumor suppressor genes. Thus
The basis of classification of nervous system tumors it is paramount that any classification scheme be flex-
remains the histological appearance of a particular ible enough to allow for the inclusion of new diagnostic
neoplasm by light microscopic examination (sup- categories as well as the modification and even removal
plemented by immunohistochemical and electron of prior categories on the basis of information derived
microscopic observations where appropriate). It is from newer methodologies. The classification scheme
becoming clear, however, that information derived used in this book is based on the current (2007) World
from cytogenetics and molecular genetics will play Health Organization (WHO) classification of nervous
an increasingly important role in tumor classification, system tumors.
particularly with respect to providing more precise CNS tumors can be grouped into two major
diagnostic and prognostic information about a par- categories: primary tumors and secondary tumors.
ticular tumor. Underlying most histology-based clas- Primary tumors arise from cells that are intrinsic to
sification approaches has been an implicit assumption the CNS or its coverings, including the calvarium,
that the phenotypic appearance of a particular tumor and include tumors of neuroepithelial origin and
accurately reflects its cellular origins (e.g., low-grade non-neuroepithelial origin. Secondary tumors arise
astrocytomas are derived from mature astrocytes, from sites elsewhere in the body and involve brain or
etc.). Recent evidence, however, suggests that at least spinal cord mainly by hematogenous dissemination
some CNS tumors, such as glioblastoma and medul- (metastases) or less often by contiguous extension.
loblastoma, might be derived from neural progenitor CNS tumors can also be grouped according to
cells that persist throughout adult life. It is also clear location and their corresponding incidence by age.
that, as with other human cancers, CNS tumors arise In adults, approximately 70% of all brain tumors
20 •
occur supratentorially (i.e., within the cerebral hemi- above features), this has proved to be such a rare and
spheres or coverings); these include, in order of possibly controversial entity that the WHO scheme
frequency, metastases followed by gliomas, menin- uses modifications of the Sainte Anne/Mayo crite-
giomas, and schwannomas. By contrast, in children, ria for only the three higher grades of diffuse astro-
approximately 70% of brain tumors are infratento- cytoma (Table 2.1). The WHO grade I category is
rial in location (e.g., cerebellum, brainstem) and are reserved for circumscribed astrocytomas, including
neuroepithelial in origin, the most common being the pilocytic astrocytoma and subependymal giant
pilocytic astrocytoma, medulloblastoma, and epen- cell astrocytoma (SEGA).
dymoma in decreasing order of frequency. Spinal
cord tumors constitute about 15% of all primary 2.1.1.1.1. Diffuse Astrocytoma (WHO Grade II).
CNS tumors and include schwannomas, meningio- These tumors constitute about 10 to 15% of all
mas, and gliomas (ependymoma, astrocytoma) in astrocytic neoplasms. They can affect all age groups
decreasing order of frequency. but are mainly tumors of adults, with 25% occurring
between the ages of 30 and 40. They most commonly
occur in the cerebral hemispheres (especially frontal
2. PRIMARY NEOPLASMS and temporal lobes), followed by brainstem and spi-
nal cord, and are rarely seen in the cerebellum. The
2.1. Tumors of Neuroepithelial Tissue clinical features reflect the location of the tumor,
with seizures being a frequent presenting symptom.
2.1.1. ASTROCYTIC TUMORS
Imaging studies usually show an ill-defined, homo-
2.1.1.1. Diffusely Infiltrating Astrocytomas. geneous, non–contrast-enhancing lesion; the pres-
As a group these astrocytomas share the following ence of focal contrast enhancement may suggest
features: widespread occurrence throughout the progression toward anaplasia and a higher grade.
CNS, clinical presentation in adults, diffuse infiltra- Macroscopically, these tumors enlarge and dis-
tion of adjacent and often distant brain structures, tort involved brain structures, often with blurring of
and tendency for progression to anaplasia over time. normal anatomical landmarks (Fig. 2.1A). Cysts of
A number of histological grading schemes have varying sizes and focal calcifications may be present.
been used for diffusely infiltrating astrocytomas; Microscopically, diffuse astrocytomas are low to
however, the Sainte Anne/Mayo grading system and moderately cellular tumors composed of well-differ-
its adaptation to the current WHO classification has entiated astrocytes (Fig. 2.1B). Some degree of nuclear
proved to be the most reproducible and predictive atypia is almost always present, which should help dis-
of tumor behavior. The Sainte Anne/Mayo criteria tinguish the neoplastic cells from reactive astrocytes.
are based on the presence or absence of four easily Mitoses are extremely rare or absent. Microvascular
recognizable histological features: nuclear pleomor- proliferation and necrosis are never present. The back-
phism, mitoses, microvascular proliferation, and necro- ground matrix may be loose, vacuolated, or even micro-
sis. While the Sainte Anne/Mayo system recognizes cystic. The Ki-67/MIB-1 labeling index (a measure of
a grade I diffuse astrocytoma (lacking all of the cellular proliferation) is usually less than a few percent.
Table 2.1. Grading of Diffuse Astrocytoma
WHO GR ADE D E S I G N AT I O N H I S T O L O G I C A L C R I T E R I A ( S T E . A N N E / M AY O )
I (Pilocytic astrocytoma; SEGA) (Not applicable)
II Diffuse astrocytoma One criterion—usually nuclear pleomorphism
III Anaplastic astrocytoma Two criteria—usually nuclear pleomorphism and
mitoses*
IV Glioblastoma Three OR four criteria—nuclear pleomorphism,
mitoses, microvascular proliferation, AND/OR
necrosis **
* The presence of a single mitosis in a diffuse astrocytoma that only exhibits nuclear pleomorphism is not usually sufficient to reclassify it as a
WHO grade III tumor (except in the case of very small samples).
** Necrosis is not required for the diagnosis of glioblastoma as long as microvascular (endothelial) proliferation is present.
Chapter 2 Tumors of the Central Nervous System • 21

A B
C D
FIGURE 2.1 Diffuse astrocytoma. (A) Thalamic astrocytoma (gross). Microscopic features: (B) Low-grade fibril-
lary astrocytoma (H&E). (C) Gemistocytic astrocytoma (H&E). (D) Anaplastic astrocytoma (H&E).
Three histological variants of diffuse astrocytoma have also be focally seen in other tumors (e.g., oligodendro-
been recognized, although in practice most have a mix- glioma, dysembryoplastic neuroepithelial tumor). For
ture of cell types. By far the most common variant is this reason the inclusion of protoplasmic astrocytoma as
the fibrillary astrocytoma, which is composed of neo- a distinct variant of astrocytoma has been challenged.
plastic cells with scant perikaryal cytoplasm within a Characteristic molecular changes in grade II
loose but consistently GFAP-positive fibrillary matrix. astrocytomas include polysomy of chromosome 7
Gemistocytic astrocytoma is defined as a tumor in which PMID: 21343879 (~76% of cases), mutations of
at least 20% of the neoplastic cells resemble gemisto- isocitrate dehydrogenase genes 1 or 2 (IDH1/2) in
cytic astrocytes (i.e., have abundant eosinophilic cyto- more than 70% of tumors, mutations in the TP53
plasm and peripherally-displaced nuclei)(Fig. 2.1C). tumor suppressor gene in about 50% of cases, over-
These tumor cells strongly express GFAP. Although expression of the platelet-derived growth factor and
gemistocytic astrocytomas are highly associated with its receptor, and loss of portions of chromosome
progression to anaplastic astrocytoma and glioblas- 22. Most adult diffuse low-grade astrocytomas will
toma, they should not automatically be assigned a progress to a higher-grade tumor such as anaplastic
higher grade unless the appropriate histological cri- astrocytoma WHO grade III. The average interval to
teria are fulfilled. The protoplasmic astrocytoma is the malignant change is about 4 to 5 years, but this may
least common (and most controversial) variant. It is vary considerably.
an astrocytic tumor composed mainly of small round
cells with scant, minimally GFAP-reactive processes 2.1.1.1.2. Anaplastic Astrocytoma (WHO Grade
in a prominent mucoid or microcystic background III) These tumors often arise in the setting of a
matrix. This pattern bears a striking resemblance to the preexisting low-grade diffuse astrocytoma but can
loose/spongy tissue of pilocytic astrocytomas and may also present de novo without clear evidence of a
less malignant precursor. The average age of pre- CNS; however, the cerebral hemispheres, in par-
sentation is about 10 years higher than low-grade ticular the frontal and temporal lobes, basal ganglia,
diffuse astrocytoma; the location, clinical presenta- and commissural pathways are recognized sites of
tion, macroscopic appearance, and imaging features predilection. The radiological features of GBM typi-
are otherwise similar, except that some contrast cally include the presence of an irregular mass with
enhancement may be present within the tumor a central hypodense region of necrosis surrounded
(but not the typical “ring” enhancement seen in by a contrast-enhancing “ring,” which represents
glioblastoma). the more cellular and vascularized portions of the
Microscopically, this tumor has the appearance tumor. A classic radiological (and macroscopic) pre-
of a diffusely infiltrating astrocytoma but shows sentation is the “butterfly” pattern due to spread of
increased cellularity, nuclear atypia, and mitotic the tumor across the corpus callosum into the oppo-
activity in comparison to its low-grade counterpart, site hemisphere. The tumor may be surrounded by
but microvascular proliferation and necrosis are considerable vasogenic edema manifested as hyper-
absent (Fig. 2.1D). Many but not all tumor cells may intensity on a T2-weighted MRI scan.
express GFAP and OLIG2. Ki-67/MIB-1 labeling Macroscopically, GBMs often appear as rela-
indices are generally increased (usually 5% to10%) tively well-defined mass lesions, although there is
but can overlap with both low-grade diffuse astro- almost always significant microscopic infiltration
cytoma and glioblastoma. These tumors are aggres- of tumor into the surrounding parenchyma. They
sive, with typical survivals of only 2 to 3 years from typically have a “variegated” appearance with solid
diagnosis. gray-pink tissue at the periphery and yellow zones
At a molecular level, anaplastic astrocytomas of central necrosis (Fig. 2.2A). Some have old and
share the molecular features of diffuse astrocytoma recent hemorrhage. In common with other diffuse
grade II lesions including chromosome 7 polysomy, astrocytomas, GBMs may widely infiltrate adjacent
IDH1/2 mutation, and TP53 mutations. However, tissue and extend for long distances within fiber
in addition they also acquire events critical to malig- tracts. They may sometimes form additional masses
nant progression, such as inactivation of cell cycle at distant sites, creating the impression of a multifo-
control pathway genes CDKN2A/p16/ARF and RB, cal or “multicentric” glioma on neuroimaging stud-
amplification of CDK4/6, losses on chromosome ies (see below discussion of gliomatosis cerebri). True
10, as well as loss of parts of the long arm of chromo- multifocal gliomas probably do occur, although their
some 19. Given that these mutations are also seen exact frequency has been difficult to establish and
in glioblastoma, no alterations specific to anaplastic may actually be much lower than their previously
astrocytoma have yet been proposed. Conversely, estimated range (2.4% to 7.5% of all gliomas). These
it is generally felt that the glioblastoma-associated tumors would by definition be polyclonal and, at
molecular alterations of EGFR amplification and present, can only be proved by the use of molecular
EGFRvIII should be present only rarely in WHO markers. Some GBMs extend into the subarachnoid
grade III tumors. space or ventricles with the potential for cerebro-
spinal fluid (CSF) dissemination, although this
2.1.1.1.3. Glioblastoma (WHO grade IV) appears to be a relatively infrequent phenomenon.
Glioblastoma (also known as glioblastoma multi- Extracranial extension and hematogenous dissemi-
forme and still abbreviated as GBM) is a malignant, nation are very rare in patients who have not had
rapidly progressive, and fatal astrocytic neoplasm. It prior surgery. GBMs are among the most malig-
is the most common primary brain tumor, account- nant tumors, having a mean survival ranging from
ing for approximately 10% to 15% of all intracranial less than 1 year to 18 months, with less than 2% of
tumors and 40% to 50% of all glial tumors. They patients surviving longer than 3 years.
most commonly arise de novo in the absence of a All GBMs share in common the histological
preexisting astrocytic tumor (“primary GBM”, more features of high cellularity, marked nuclear atypia,
than 90% of tumors) but may also develop from a mitoses, microvascular proliferation, and necro-
less-malignant diffuse astrocytoma typically associ- sis. However, their microscopic appearance can be
ated with IDH1/2 mutation (“secondary GBM”). highly variable, with considerable regional heteroge-
GBMs occur in all age groups, but most arise in neity. In some GBMs the tumor cells may show con-
adults, with a peak incidence between the ages of siderable nuclear and cytoplasmic pleomorphism
45 and 70 years. They may arise in any region of the with multinucleated giant cells (Fig. 2.2B), whereas

A
D
C
FIGURE 2.2 Glioblastoma. (A) Glioblastoma (gross). Microscopic features: (B) Cellular anaplasia, mitoses
(H&E). (C) Necrosis with pseudopalisading (H&E). (D) Microvascular proliferation with glomeruloid struc-
tures (H&E).
others may consist mainly of small “undifferentiated” small undifferentiated cells. Necrosis is a character-
cells with scant cytoplasm and often poor GFAP istic feature of GBM and can consist of either large
expression (see small cell GBM below). While many confluent foci of coagulative necrosis and/or small
GBMs contain zones having better-differentiated band-like or serpiginous “geographic” necrotic foci
fibrillary and gemistocytic astrocytes, all astrocy- surrounded by a rim of densely packed tumor cells
tomas, including GBM, have significant oligoden- imparting the characteristic and highly diagnostic
droglial cell populations in almost all cases and are pseudopalisading pattern (Fig. 2.2C). Microvascular
positive for OLIG2 like other diffuse gliomas. Other proliferation is defined as the presence of abnormal
cell types that may be infrequently present in GBM vessels with walls composed of two or more lay-
include cells with glandular or epithelioid features, ers of mitotically active endothelial (and/or other
PAS-positive granular cells, and heavily lipidized vascular wall) cells, often forming glomeruloid
cells. Proliferative activity is prominent in GBM and structures (Fig. 2.2D). Microvascular proliferation
both typical and atypical mitoses are found. Ki-67/ has also been referred to as “capillary endothelial
MIB-1 labeling indices are likewise high, commonly proliferation,” although it is likely that other vas-
averaging 15% to 20%. Proliferative activity is usu- cular components besides the endothelial cells
ally greatest in tumors composed predominantly of undergo proliferation. Microvascular proliferation
is frequently associated with thrombosis of the mutations. Pediatric GBMs (most of which arise de
affected vessels. Occasional GBMs may show con- novo) also differ genetically from adult GBMs in
siderable connective tissue reaction, which may be that they frequently harbor mutations in H3F3A
due to meningeal invasion by tumor or organiza- and ATRX, which are presumed to affect the epi-
tion of zones of necrosis, or as a response to marked genetic state of tumor cells. Pediatric GBMs also
microvascular proliferation. frequently exhibit mutations in the core pathways
The pathogenesis and molecular genetics of involved in adult GBMs such as TP53 gene muta-
GBM have been an area of intense investigation in tions, PDGFRA amplification, and loss of chromo-
recent years. The origin of GBM remains controver- some 17p, particularly in children older than 4 years
sial: the “traditional” explanation is that they arise of age and in childhood brainstem GBMs.
from differentiated adult astrocytes or astrocyte pre- The prognostic evaluation of GBM patients is a
cursors. However, based on recent human and ani- frequent clinical problem, and genetic testing has
mal studies, it is now suggested that they arise from emerged as a reliable means for predicting patient
neuroepithelial progenitor cells, including oligoden- outcomes. Studies have consistently identified
droglial progenitor cells, that are present throughout that increased methylation of the promoter of the
adult life, MGMT gene is associated with increased progres-
GBM represents one of the best-characterized sion-free survival in adult GBM. Subsequent stud-
cancers at the molecular level in all of oncology and ies have expanded on this finding to determine that
was one of the first cancers to be studied in large- such tests likely identify patients with an increased
scale integrative genomic approaches. Collectively, methylation state, not just at the MGMT locus but
these molecular studies have consistently identified throughout the tumor genome, consistent with a
three core signaling pathways that are disrupted in “methylator phenotype” (G-CIMP), which is asso-
GBM: increased activation of receptor tyrosine ciated with or may result from mutations in IDH1/2.
kinase/RAS/PI3K signaling, loss of function in Detection of IDH1/2 mutations by immunohisto-
TP53 signaling, and reduced signaling of the RB chemistry or sequencing has therefore emerged as
pathway, The activation of RTK/RAS/PI3K signal- the most effective means of identifying patients with
ing is evident in 88% of GBMs and most character- a more favorable prognosis.
istically occurs due to amplification of the EGFR
gene, along with rearrangements and overexpres- 2.1.1.1.4. Glioblastoma variants Giant cell glio-
sion of mutant EGFRvIII and extracellular domain blastoma (WHO grade IV) This is a rare tumor,
mutants. Additional activation of these pathways accounting for less than 5% of all GBMs. They usually
can occur through amplification of PDGRA, MET, arise de novo without evidence of a preexisting astrocy-
AKT, or PIK3CA and aberrations that lead to loss toma and are otherwise similar in clinical presentation
of function for the PTEN tumor suppressor gene. to typical GBMs. Radiologically and macroscopically
Studies of the TP53 gene have shown that rates they tend to be better circumscribed than ordinary
of mutation and inactivation of this pathway are GBMs. They are characterized histologically by the
higher than once previously thought in adult GBM, presence of giant and multinucleated cells that may
and TP53 is now known to be the most frequently show variable expression of GFAP. Many examples
mutated gene in GBM, occurring in at least 42% of have an abundant stromal reticulin network. They have
adult tumors. The RB pathway is targeted through other histological features typical of GBM, includ-
a number of different means, including genomic ing mitoses, necrosis, and microvascular proliferation,
losses and mutation of RB1, along with genomic which distinguishes them from the morphologically
losses targeting the CDKN2A family of genes or similar pleomorphic xanthoastrocytoma (see below).
amplification of the negative regulators of the RB Genetically this tumor has a high frequency of TP53
pathway, such as CDK4. mutations. Giant cell GBMs generally have a poor
Molecular studies have shown that primary and prognosis, although some reports have suggested a
secondary GBMs often have different sets of genetic somewhat better clinical outcome, possibly due to their
alterations: primary GBMs are commonly charac- greater resectability and less infiltrative behavior.
terized by EGFR gene amplification/overexpression
while secondary GBMs arising from lower-grade Gliosarcoma (WHO grade IV) Gliosarcomas
precursors have a sequential series of genetic altera- are tumors having a biphasic pattern of both neo-
tions, including concurrent IDH1/2 and TP53 gene plastic glial and mesenchymal tissue. They represent

approximately 2% of all GBMs. They are usually nodules of “small blue cells” resembling medullo-
found in the cerebral hemispheres, with a predilec- blastoma (see below). These PNET-like foci immu-
tion for the temporal lobes. Their clinical presenta- nohistochemically express neuronal markers (e.g.,
tion is similar to ordinary GBM. The radiographic synaptophysin), diffuse p53 reactivity, and a very
appearance can be identical to typical GBM or, if the high Ki-67/MIB-1 labeling index (often greater than
sarcomatous component predominates, can present 80%). Homer Wright rosettes or large-cell/anaplas-
as a hyperdense, circumscribed, uniformly contrast- tic histology may be present in these areas. This vari-
enhancing mass mimicking a meningioma. The his- ant may be more likely to show CSF dissemination.
tological diagnosis rests on establishing the presence
of unequivocally malignant glial and mesenchymal 2.1.1.1.5. Gliomatosis cerebri (GC) GC is defined
elements. The sarcomatous regions usually consist of as a diffusely infiltrating glioma that involves more
malignant spindle cells arranged in a fascicular, her- than two lobes of the brain. It is frequently bilateral
ringbone, or sometimes “storiform” pattern and rarely and may extend into posterior fossa structures and
show other types of mesenchymal differentiation, rarely the spinal cord. Until recently the diagnosis of
including cartilage, bone, and skeletal and smooth GC was only made at postmortem examination, but
muscle. Rare examples have shown cytokeratin-pos- it may be suggested clinically on the basis of MRI
itive epithelial and adenoid structures. GFAP immu- findings and a biopsy showing an infiltrating glioma.
nohistochemistry is very helpful in distinguishing Molecular biological data suggest that GC most
between the glial and mesenchymal components; likely represents a clonal diffuse astrocytic tumor
likewise, a reticulin stain will show abundant reticu- with unusually infiltrative behavior. Some cases of
lin fibrils in the sarcomatous but not the glial compo- GC may originate from a small, often inapparent
nent. The origin of the sarcomatous component has focus of GBM; however, GC may also occur as a de
been traditionally ascribed to malignant transforma- novo phenomenon. Some patients with GC may sec-
tion of the proliferating blood vessels in GBM, but ondarily develop multiple small foci of GBM. This
there is now convincing cytogenetic and molecular feature may account for many instances of so-called
evidence for a monoclonal origin of both the glial “multicentric” GBM. The microscopic appearance
and mesenchymal components of the tumor (i.e., the of GC can be quite variable, with some neoplastic
mesenchymal component probably represents a form cells resembling astrocytes and others having more
of metaplasia analogous to carcinosarcoma of epithe- indeterminate features (often resembling microglia)
lial tumors). The overall prognosis of gliosarcoma is or rarely oligodendroglial histology. GFAP immu-
essentially the same as ordinary GBM. nostaining can likewise be variable. Tumor nuclei
usually show enough atypia to facilitate their iden-
Small Cell GBM (WHO grade IV) This tumor tification as neoplastic, although mitoses may be
is a variant of GBM composed predominantly, or minimal or even absent. Microvascular proliferation
exclusively, of small cells with scant, minimally and necrosis are usually absent. For these reasons,
GFAP-positive cytoplasm and oval to round nuclei it has often been difficult to assign a specific WHO
exhibiting mild to moderate atypia. Mitoses may grade to GC: although a small biopsy may show his-
be numerous, and the Ki-67/MIB-1 labeling index tological features compatible with a grade II or III
is typically very high. Since the histological appear- glioma, the overall biological and clinical behavior
ance of this tumor may closely resemble anaplastic of GC often reflects a more aggressive tumor.
oligodendroglioma or GBM with an oligodendrog-
lial component (see below), ancillary immunohis- 2.1.1.2. Circumscribed astrocytomas
tochemical and molecular studies may be helpful in 2.1.1.2.1. Pilocytic astrocytoma (WHO grade I)
distinguishing these entities. Small cell GBM almost This tumor is a well-circumscribed, slow-growing,
always presents as a de novo or “primary” GBM, and often cystic glioma that predominantly occurs in
molecular studies have shown that greater than 70% children and young adults (Fig. 2.3A). They are
will have amplification of EGFR. the most common glioma in children but are much
less frequent in adults and are rare after age 50. The
GBM (or malignant glioma) with PNET-like most common sites are the cerebellum followed
foci (WHO grade IV) This tumor is a recently by hypothalamus/third ventricular region, optic
described variant of high-grade glioma (usually nerves, brainstem, cerebral hemispheres, and spinal
GBM or gliosarcoma) that focally contains discrete cord. The clinical presentation is largely dependent
A B
FIGURE 2.3 Pilocytic astrocytoma. (A) Optic glioma (gross). Microscopic features: (B) Rosenthal fibers
(H&E). (C) Microcystic change (H&E).
on tumor location, with an evolution in keeping of pilocytic astrocytoma. Pilocytic astrocytomas

with the slow rate of growth. Imaging studies show may also contain histological features that could be
a circumscribed, cystic or (less often) solid mass mistaken for evidence of anaplasia; these include
with contrast enhancement. In the cystic examples, microvascular proliferation (including glomeruloid
contrast enhancement may be localized to a mural vessels), nuclear atypia, extension into the subarach-
nodule. noid space, and occasionally bland (infarct-like)
The histological features of pilocytic astrocy- areas of necrosis. Mitoses are rare and most exam-
toma are highly distinctive and classically consist of ples have a very low Ki-67/MIB-1 labeling index
a biphasic pattern of compact and loose (“spongy”) (usually less than 1%).
tissue (Fig. 2.3B, C). The compact zones consist of The vast majority of pilocytic astrocytomas are
dense aggregates of elongated bipolar astrocytes indolent and treated primarily by surgical excision
with variable numbers of strongly eosinophilic irreg- with excellent long-term survivals; however, hypo-
ular Rosenthal fibers, whereas the loose or spongy thalamic and brainstem tumors can be difficult to
areas consist of small round multipolar astrocytes in manage and often recur, with adverse consequences.
association with microcysts and eosinophilic granu- True malignant transformation of a pilocytic
lar bodies. The proportion of these two classic his- astrocytoma is very rare, and most examples have
tological patterns may vary within a given tumor, occurred following radiotherapy. Histologically they
and some tumors (especially in small biopsies) show significantly increased proliferative activity
may show a predominance of one pattern. Adding (e.g., mitoses, Ki-67 labeling), focally high cellular-
to the diagnostic difficulty is the presence of other ity, and/or pseudopalisading necrosis.
tissue patterns (e.g., foci of oligodendrocyte-like The most common molecular alteration identified
cells) that can form part of the histological spectrum in pilocytic astrocytoma is a tandem duplication/

fusion event involving the genes KIAA1549 and histological features include the presence of a con-
the serine/threonine kinase BRAF. This alteration spicuous reticulin network (possibly reflecting a
leads to creation of loss of a negative regulatory putative origin from subpial astrocytes), lympho-
domain in the BRAF fusion protein and constitu- cytic infiltrates, and eosinophilic granular bodies
tive activation of the MAPK/ERK signaling path- similar to those found in pilocytic astrocytomas
way. Such alterations can be identified in more than and ganglion cell tumors. The prognosis of this
90% of cerebellar pilocytic astrocytomas but are tumor is excellent with surgical excision alone,
found to a lesser degree in gliomas with piloid fea- with recurrence-free 10-year survivals of greater
tures in the supratentorial regions (~50%). Recent than 60%. Recurrences may show the same histol-
studies suggest that the presence of KIAA1549- ogy as the original tumor or evidence of anapla-
BRAF aberrations may also indicate a more favor- sia, including significantly increased proliferative
able prognosis. activity, necrosis, and microvascular proliferation.
PXAs are highly associated with BRAFV600E
2.1.1.2.2. Pilomyxoid astrocytoma (WHO grade point mutations at a similar rate to that seen in gan-
II). Pilomyxoid astrocytoma is a recently described gliogliomas (more than 50%); however, this muta-
variant of pilocytic astrocytoma that most often tion is also detected in several other CNS tumor
presents in the hypothalamic region as a solid, types.
well-circumscribed contrast-enhancing mass.
Histologically it consists of a monomorphous pop- 2.1.1.2.4. Subependymal giant cell astrocytoma
ulation of bipolar cells with fibrillary GFAP-positive (SEGA) (WHO grade I). SEGA is a benign, slow-
processes within a loose myxoid background that growing intraventricular tumor that is characteris-
often have an angiocentric arrangement. Mitoses tically associated with tuberous sclerosis. In some
may be present. Histological features character- cases SEGA may be the presenting feature of this
istic of typical pilocytic astrocytoma, such as a disease; however, it is unresolved whether SEGAs
biphasic pattern and Rosenthal fibers, are absent. occur in the absence of tuberous sclerosis. Most
Pilomyxoid astrocytomas have been reported to SEGAs arise during the first two decades of life
have a more aggressive clinical course and are con- and present with worsening of a seizure disorder
sidered WHO grade II tumors. or symptoms of increased intracranial pressure.
They typically occupy the wall of one of the lateral
2.1.1.2.3. Pleomorphic xanthoastrocytoma (WHO ventricles and can cause blockage of the foramen
grade II). Pleomorphic xanthoastrocytoma (PXA) of Monro. Rare examples have undergone massive
is a low-grade, slow-growing cortical astrocytoma hemorrhage. SEGAs have a characteristic histo-
that occurs primarily in children and young adults, logical appearance, being composed of relatively
often presenting with a chronic seizure disorder. large cells resembling gemistocytic astrocytes
PXAs characteristically involve the superficial cor- but often having “ganglioid” nuclei with promi-
tex with extensive involvement of the leptomenin- nent nucleoli (Fig. 2.4). Spindle-shaped cells with
ges and may be solid or cystic; the latter may have elongated fibrillar processes may also be encoun-
a mural nodule. Almost all are supratentorial in tered. Some tumor cells may show considerable
location and have a predilection for the temporal nuclear pleomorphism and occasional mitoses
lobes. Microscopically PXAs have a varied mix of may be present; however, these features do not
cell types, including more typical astrocytic cells indicate anaplastic change. Calcifications may be
with fibrillary processes as well as often strikingly present. Immunohistochemically the tumor cells
bizarre giant cells with single or multiple pleomor- may express either or both glial and neuronal-
phic nuclei and variable xanthomatous change in associated antigens, which may reflect their puta-
the cytoplasm. Mitoses are usually rare or absent, tive origin from dysplastic bipotential cells in the
as are necrosis and microvascular proliferation. subependymal region. Most genetic alterations in
The Ki-67/MIB-1 proliferative index is usually less SEGAs relate to the two genes implicated in tuber-
than 3%. Immunohistochemically the tumor cells ous sclerosis: the TSC1 gene on chromosome 9q
show consistent but often variably intense GFAP that encodes the hamartin protein and the TSC2
immunoreactivity. Some examples also express gene on 16p that encodes the tuberin protein.
“neuronal” markers, including synaptophysin SEGAs are treated by surgical excision alone and
and neurofilament protein. Other characteristic rarely recur.
from previously frozen material. These tumors also
characteristically contain a network of thin-walled
branching capillaries, often described as a “chicken-
wire” or “wishbone” vascular pattern (Fig. 2.5B).
The presence of occasional mitoses and nuclear
atypia (which may be marked in some cases) is still
compatible with a WHO grade II neoplasm; how-
ever, the presence of significant mitotic activity,
microvascular proliferation, or necrosis indicates
anaplastic transformation (WHO grade III). Most
WHO grade II oligodendrogliomas have a Ki-67/
MIB-1 labeling index less than 5% (an index of 5%
or greater has been associated with more aggres-
FIGURE 2.4 Microscopic appearance of subependy- sive clinical behavior). Some oligodendrogliomas
mal giant cell astrocytoma (H&E). may contain nodules of increased cellularity; careful
attention to these areas may reveal other anaplastic
features within these nodules. Small calcifications
2.1.2. OLIGODENDROGLIAL TUMORS
(calcospherites) are a characteristic histological fea-
2.1.2.1. Oligodendroglioma (WHO grade II). ture (Fig. 2.5A) but are only seen in 20% of cases
Oligodendrogliomas are diffusely infiltrating glio- and are not specific for oligodendroglioma. Another
mas composed of cells morphologically resembling characteristic and diagnostically useful feature is the
mature oligodendrocytes. They account for approxi- presence of perineuronal, perivascular, or subpial
mately 5% of all intracranial gliomas, and most occur tumor aggregates (so-called “secondary structures”)
in adults, with a peak incidence between the ages when the tumor infiltrates the cortex. It is not
of 30 to 60. They are most often found in the cere- uncommon to find well-differentiated astrocytes
bral hemispheres but have been reported in the with visible cytoplasm admixed with the oligo-
cerebellum, brainstem, and spinal cord and even dendrocytes. In most cases, their morphology and
in the leptomeninges as a primary site. Because of uniform distribution suggest that they are reactive
the relatively benign, slow-growing nature of the rather than neoplastic.
tumor, patients may often present with a long his- Oligodendrogliomas can be immunohistochem-
tory of neurological symptoms, most often chronic ically identified using antibodies specific for the
seizures. Imaging studies usually show a well-demar- IDH1(R132H) mutant protein, which also serves
cated mass, often with calcification and occasionally as a tumor-specific antigen(Fig. 2.5C). In addition,
intratumoral hemorrhage, but peritumoral edema the oligodendroglial lineage-restricted transcription
and contrast enhancement are not common except factor OLIG2 is expressed in all oligodendrogliomas
in the more anaplastic examples. and in more than 90% of the tumor cells. While these
Macroscopically, oligodendrogliomas are usu- markers are not specific to oligodendrogliomas, oli-
ally well circumscribed and grayish-pink and godendrogliomas can often be distinguished from
often include areas of mucoid change, which may IDH mutant anaplastic astrocytomas, which more
result in a gelatinous consistency as well as zones frequently have TP53 staining and exhibit more het-
of cystic degeneration, focal hemorrhage, and erogeneous staining for OLIG2, with typically fewer
calcification. than 90% of tumor cells expressing the protein. In
Oligodendrogliomas have an easily recognizable, some cases, oligodendrogliomas may express GFAP,
highly uniform histological appearance. In paraf- and when present such cells often resemble small
fin sections, the tumor cells are closely packed and gemistocytic astrocytes and are referred to as micro-
appear swollen, consisting of a small round nucleus gemistocytes. These cells have no specific prog-
(usually slightly larger than a normal oligodendro- nostic significance but are often seen in anaplastic
cyte) surrounded by a clear halo (Fig. 2.5A). This oligodendrogliomas and oligoastrocytoma. They
imparts a very characteristic “honeycomb” or “fried are thought to be either a transitional form between
egg” appearance to the tumor; however, this pattern oligodendrocytes and astrocytes or a phenotypic
is not apparent in smear preparations or frozen sec- recapitulation of the premyelination stage of normal
tions and is often absent in paraffin sections made immature oligodendrocytes.

A B
C D
FIGURE 2.5 Microscopic appearance of oligodendroglioma. (A) Oligodendroglioma with microcalcifica-

tions (H&E). (B)“Chicken-wire” vascular pattern (H&E). (C) IDH1 R132 immunoreactivity in tumoral cells.
Anaplastic oligodendroglioma (D) Microvascular proliferation (H&E). (E) Nuclear atypia, mini-gemistocytes
(H&E).
Cytogenetic evaluation of the 1p and 19q chro- with the oligodendroglial phenotype; thus, the find-
mosome arms (usually tested by fluorescence in situ ing of co-deleted 1p/19q within in a glial tumor
hybridization [FISH]) is now commonly done as with equivocal oligodendroglial histology may
part of the workup of oligodendroglial tumors or provide additional support for the diagnosis of oli-
mixed gliomas. Concurrent whole-arm co-deletion godendroglioma (or oligodendroglial component
of 1p and 19q, resulting from a translocation involv- of a mixed glioma). Mutations in the transcription
ing these chromosomes, has been strongly associated factor, CIC, appear to be more specifically associated
with oligodendrogliomas, and concurrent identifi- astrocytomas such as glioblastoma: most com-
cation of IDH mutations could help to specifically monly CDKN2A/p16/ARF deletions. Such tumors
distinguish oligodendroglioma and oligoastrocy- often have a poorer prognosis, with less favorable
toma from other CNS tumors with similar histo- response to chemotherapy and median survivals of
logical features (e.g., clear cell ependymoma, central less than 2 years.
neurocytoma).
Oligodendrogliomas with 1p/19q co-deletion
2.1.3 . MIXED GL IOMAS
and IDH mutation generally have a highly favorable
outcome, with a median postoperative survival of 3 2.1.3.1. Oligoastrocytoma (WHO grade II).
to 5 years. Some patients have extensive postopera- These are tumors which are felt to prominently
tive recurrences with progression to frank anaplasia. contain a population of tumor cells with astrocytic
Metastases through the cerebrospinal pathways may morphology as well as distinct populations of tumor
also occur. cells with oligodendroglial morphology. Their exact
incidence has been difficult to determine due to
2.1.2.2. Anaplastic oligodendroglioma (WHO lack of uniformity of the histological criteria used
grade III). The exact incidence of anaplastic oligo- to define this tumor as distinct from other diffuse
dendroglioma has been difficult to determine for astrocytic class tumors (grades II to IV) that also
various reasons, including the lack of clear-cut his- biologically have been revealed to always contain a
topathological criteria in prior studies. Age of onset, mixture of oligodendroglial and astrocytic lineage
location, and clinical features are generally similar cells. Their reported incidence varies between 2%
to those of oligodendroglioma. Imaging studies and 10% of all gliomas. The age and sex distribu-
usually show some degree of contrast enhance- tion, location, clinical presentation, and imaging
ment. The macroscopic appearance is similar to oli- features are all similar to those of WHO grade II
godendroglioma except that areas of necrosis may oligodendroglioma.
be present. Two histological variants have been recog-
Microscopically these tumors have the general nized: a “compact” or biphasic variant and a “dif-
histological appearance of an oligodendroglioma fuse” or intermingled variant. Neither component
but in addition demonstrate focal or diffuse fea- should have anaplastic histology. The diagnosis
tures of overt malignancy, including increased cel- of oligoastrocytoma is usually much easier and
lularity, cytological atypia, frequent mitoses, and less controversial in the biphasic variant, which
usually microvascular proliferation and/or necrosis shows distinct areas of oligodendroglial and astro-
with or without pseudopalisading (Fig. 2.5D, E). cytic differentiation. The diagnosis of the inter-
GFAP-positive “microgemistocytes” are often pres- mingled variant is much more difficult because
ent but have no prognostic significance. Although of the occurrence of reactive astrocytes within
the presence of a clear-cut oligodendroglial pattern the tumor and GFAP-positive oligodendrocytes
is a prerequisite for the histological diagnosis of this (i.e., microgemistocyte or gliofibrillary oligoden-
tumor, it is acknowledged that some examples may drocytes) and the inability to reliably distinguish
be difficult to distinguish from GBM (see below such tumors from diff use astrocytomas. However,
discussion of “glioblastoma with oligodendroglial the presence of GFAP-positive oligodendrocytes
component”). should prompt a search for more definitive areas
Many (but not all) anaplastic oligodendroglio- of astrocytoma.
mas share in common with low-grade oligoden- Molecularly, mixed gliomas have mutations most
drogliomas the characteristic loss of chromosome in common with diffuse astrocytomas WHO grade
arms 1p and 19q, mutation of IDH genes, and CIC II, including frequent mutations in IDH (>70% of
mutations. Tumors with this genetic signature have tumors) and TP53. The presence of 1p/19q whole-
been reported to show a more favorable response, arm co-deletions is rare in most studies of mixed
at least initially, to chemotherapy (previously com- gliomas. No mutations or combination of markers
bined procarbazine, CCNU, and vincristine [PVC], has been found to be specific for oligoastrocytomas.
and more recently temozolomide) and may have Oligoastrocytomas are generally considered to be
longer median survivals of over 10 years. However, monoclonal tumors in which the oligodendroglial
other anaplastic oligodendrogliomas can share and astrocytic components share the same genetic
some of the genetic alterations found in high-grade alterations.

2.1.3.2. Anaplastic oligoastrocytoma (WHO tumors. Some ependymomas, especially those aris-
grade III). These tumors consist of both neoplastic ing infratentorially, may spread widely throughout
oligodendrocytes and astrocytes in which one or the CSF and rarely outside the CNS.
both components show clearly anaplastic histology. Ependymomas have a characteristic and easily
The most challenging aspect of the diagnosis is dis- recognizable microscopic appearance, although cel-
tinguishing this tumor from a GBM due to a great lular density and cytoarchitecture may vary among
degree of histological and biological overlap. As pre- cases and within the same case. The typical tumor is
viously mentioned, anaplastic oligodendrogliomas moderately cellular and composed of polygonal cells
may have features in common with glioblastoma, having uniform nuclei. Two diagnostically impor-
including the presence of GFAP-positive cells, often tant but often inconstant features include the pres-
in transition with microgemistocytes. Since the ence of perivascular pseudorosettes (Fig. 2.6B) and
presence of necrosis within an anaplastic oligoastro- true ependymal rosettes or tubules (canals)(Fig. 2.6C).
cytoma has now been shown to be prognostically Perivascular pseudorosettes are by far the more
significant and associated with shorter patient sur- common pattern and consist of tumor cells arranged
vival, the WHO consensus recommends classifying radially around a central vessel with a “clear” region
this tumor as a GBM with an oligodendroglial compo- composed of slender GFAP-positive cytoplasmic
nent. Regardless, the presence of mutations in IDH processes oriented perpendicular to the vessel wall.
genes in these tumors is associated with favorable The ependymal rosettes (tubules) are composed of
prognosis relative to GBMs with absence of IDH ependymal cells lining central lumens that recapitu-
mutations. late the appearance of a normal ventricle. In general
the tumor cells show minimal atypia and mitoses are
rare or absent; however, some WHO grade II epen-
2. 1. 4. E P E NDY MAL TU M O R S
dymomas may have foci of necrosis without pseu-
2.1.4.1. Ependymoma (WHO grade II). Epen- dopalisading. Occasional examples show myxoid
dymomas account for approximately 6% of intracra- degeneration, focal hemorrhage, and occasionally
nial gliomas. Although they are encountered at any bone and cartilage formation. GFAP immunoreac-
age, they are definitely more frequent in childhood tivity is almost always present in the cytoplasmic
and adolescence. They occur at any level of the ven- process surrounding the perivascular pseudoro-
tricular system, but supratentorial tumors (approxi- settes but is more variable elsewhere; the tumor cells
mately 40%) are less common than infratentorial in ependymal canals may express epithelial mem-
ones (approximately 60%). In the spinal cord, epen- brane antigen (EMA) in the luminal surface of
dymomas are the most common neuroepithelial ependymal rosettes or as dot-like signal (Fig. 2.6D).
tumor, accounting for approximately 60% of the Ependymomas generally lack significant expression
spinal gliomas; they are most often found in the of the diffuse glioma marker OLIG2, which can be
lumbosacral segments and region of the filum ter- a very useful negative feature. Ultrastructurally the
minale/cauda equina. The clinical symptoms vary tumor cells show features of ependymal differen-
with location of the tumor and include local effects tiation, including cilia, basal bodies blepharoplasts,
as well as hydrocephalus and symptoms of increased surface microvilli, and sometimes microrosettes.
intracranial pressure. Imaging studies show a rela- Several histological variants are recognized:
tively well-circumscribed mass with varying degrees
of contrast enhancement, with tumor infiltration Cellular ependymomas show high cellularity with-
and edema being infrequent. Hydrocephalus or out increased mitotic rate or other anaplastic
displacement of the ventricles or brainstem can be features; perivascular rosettes and ependymal
observed. Some spinal ependymomas are associated tubules are uncommon.
with syringomyelia. Papillary ependymomas have well-formed papillary
Macroscopically, ependymomas are gray-red, structures and are distinguished from choroid
lobulated, and usually well-demarcated tumors plexus papillomas by the presence of GFAP-
that often have a relationship to a ventricular cavity positive processes abutting central vessels.
(Fig. 2.6A). Some infratentorial tumors may extend Clear cell ependymomas have tumor cells with promi-
into the cerebellopontine angle or within the cisterna nent clear perinuclear halos; immunohistochem-
magna along the medulla. In the spinal cord they istry or electron microscopy may be needed to
usually present as circumscribed intramedullary distinguish this variant from oligodendroglioma
A B
C D
E F
FIGURE 2.6 Ependymoma. (A) Ependymoma of fourth ventricle (gross). Microscopic features: (B) Perivascular
pseudorosettes (H&E). (C) Ependymal tubules (H&E). (D)Dot-like EMA positivities. (E)Anaplastic ependy-
moma with increased cellularity and brisk mitotic activity (H&E). (F)Myxopapillary ependymoma (H&E).
or central neurocytoma. The clear cell variant is Ependymomas are generally considered to be
frequently associated with anaplastic histology slow-growing “benign” tumors; however, it has been
(see below) and more aggressive biological behav- difficult to precisely correlate tumor histology with
ior, and would be considered a grade III tumor. prognosis, partly due to the prior inability to define
Tanycytic ependymomas have tumor cells arranged reliable indicators of anaplasia (see below). As a gen-
in fascicles with ill-defined perivascular pseudo- eral rule, ependymomas in the pediatric age group
rosettes and rare ependymal tubules; they most tend to fare worse than in adults, primarily due to
often occur in the spinal cord and may appear a higher incidence of anaplastic histology and their
similar to astrocytomas or schwannomas. location in the posterior fossa, making surgical

resection more challenging, and leading to a greater not present. This tumor is slow growing and has an
likelihood of CSF dissemination, which by itself is overall favorable survival, although some patients
associated with a poorer prognosis. experience local recurrence after surgical resection.
Neurofibromatosis type 2 (NF2) is associated An exception is the sacrococcygeal variant of myxo-
with the occurrence of spinal cord ependymo- papillary ependymoma, which is associated with a
mas, indicating a role for the NF2 tumor suppres- greater rate of regrowth and potential for metastatic
sor gene (located on chromosome 22q12) in this dissemination.
tumor. In sporadic tumors, spinal ependymomas
more frequently have alterations of the NF2 gene. 2.1.4.4. Subependymoma (WHO grade I).
Ependymomas have been the focus of several Subependymomas are well-demarcated, slow-grow-
genomic studies, which have revealed a complex ing benign tumors composed of cells resembling
landscape of mutations and copy number aberra- subependymal glia. They are typically attached
tions, the clinical significance of which is currently to the ventricular wall and project into the lumen.
being evaluated. They may occur at any site but are most often
encountered in the fourth ventricle. Most subepen-
2.1.4.2. Anaplastic ependymoma (WHO dymomas are clinically silent, but some are symp-
grade III). As noted above, histology and clinical tomatic due to ventricular obstruction, increased
outcome in ependymomas have not always shown intracranial pressure, or rarely spontaneous hemor-
a good correlation. However, recent studies have rhage. Microscopically they consist of small nests
identified more rigorous criteria for identifying of glial cell nuclei embedded in a hypocellular
anaplasia and more aggressive clinical behavior GFAP-positive fibrillary matrix. Mitoses are rare or
in these tumors. The diagnosis of WHO grade III absent. Additional histological features include the
(anaplastic) ependymoma can be made if the tumor presence of microcysts, calcifications, focal hemor-
has two or more of these histological features: ele- rhage, and abnormal vasculature. Mixed tumors with
vated mitotic index, hypercellularity with nuclear features of both subependymoma and ependymoma
hyperchromasia and/or pleomorphism, microvas- have been described; their overall behavior is more
cular proliferation, and pseudopalisading necrosis aligned with ependymomas and they are considered
(Fig. 2.6E). An elevated Ki-67/MIB-1 labeling index WHO grade II neoplasms.
also correlates well with anaplastic histology.
2 .1 . 5. CHOROID PLEXUS TUM ORS
2.1.4.3. Myxopapillary ependymoma (WHO
grade I). This is a distinct subtype of ependy- Choroid plexus tumors (papilloma and carcinoma)
moma that almost exclusively occurs in the conus account for 0.5% of all brain tumors and for 2% of
medullaris/cauda equina region of the spinal cord, the tumors of the glioma group. They are encoun-
where they are thought to arise from ependymal tered most frequently in the first decade, with 10%
cells in the filum terminale. They have rarely been to 20% presenting in the first year of life. The ratio of
described in other locations in the brain and spi- choroid plexus papilloma to carcinoma is approxi-
nal cord. Subcutaneous sacrococcygeal or presa- mately 5:1; however, 80% of the carcinomas arise in
cral myxopapillary ependymomas arising from children. These neoplasms occupy the sites of the
ectopic ependymal remnants are a recognized vari- ventricular system where choroid plexus is normally
ant. They occur primarily in young adults, usually found. They occur, in order of decreasing frequency,
presenting clinically with back pain. On imaging within the fourth ventricle, the lateral ventricles
studies, they appear as well-circumscribed lesions (more so on the left), and the third ventricle. Most
with strong contrast enhancement and sometimes lateral ventricle tumors occur in individuals less
cystic change and hemorrhage. Myxopapillary than 20 years old, whereas those in the fourth ven-
ependymomas have a characteristic histological tricle are more evenly age-distributed. Patients
appearance, consisting of GFAP-positive cuboidal present clinically with signs of hydrocephalus and
tumor cells arranged around vascularized stromal increased intracranial pressure. Only rarely do they
cores, which exhibit variable amounts of mucoid produce excessive amounts of CSF. Imaging studies
material or fibrous tissue (Fig. 2.6F). The tumor show them to be hyperintense, contrast-enhancing
may also contain microcystic areas. Mitoses are very intraventricular tumors. Choroid plexus tumors are
rare or absent and other features of anaplasia are treated primarily by surgical excision. The prognosis
is excellent for choroid plexus papilloma (nearly is most confidently made in children, whereas in
100% 5-year survival) but much less favorable adults the major differential diagnosis is that of met-
(40%) for carcinoma. astatic carcinoma, which would be distinctly more
common in this age group. Immunohistochemistry
2.1.5.1. Choroid plexus papilloma (WHO may be helpful, especially if the tumor expresses
grade I) and atypical choroid plexus papilloma markers that are considered more characteristic
(WHO grade II). Choroid plexus papilloma (CPP) of choroid plexus. However some of these mark-
is a histologically benign tumor whose structure ers (e.g., transthyretin) are not always expressed in
recapitulates that of normal choroid plexus except choroid plexus carcinoma, or conversely may also
for having slightly more crowded and elongated be expressed by some metastatic carcinomas. Some
papillae (Fig.2.7A , B). The papillae consist of vascu- CPCs may have prominent rhabdoid histology,
lar connective tissue cores (cf. gliovascular cores of which can lead to confusion with atypical teratoid/
papillary ependymoma) lined by a simple columnar rhabdoid tumors; however, unlike the latter, CPCs
or cuboidal epithelium. Prominent mitotic activity, will show normal nuclear immunoreactivity for
necrosis, and brain invasion are absent. The major- INI-1. As for their carcinoma counterparts outside
ity of CPPs are immunoreactive for transthyretin the brain, the molecular alterations of CPC can be
as well as for vimentin, pancytokeratin, and S-100 complex, although mutations in TP53 have been
protein but not epithelial membrane antigen. Focal found to be present in a subset of these tumors,
staining for GFAP may also be present (25% yo 55% including familial variants.
of cases). Atypical CPPs (WHO grade II) are distin-
guished from CPPs (WHO grade I) primarily by the
2.1.6 . GL IAL TUMORS OF UNCERTAIN
presence of elevated mitotic activity (defined as 2 or
ORI GIN
more mitoses per high-power field) and clinically
may show an increased risk of recurrence. Some 2.1.6.1. Angiocentric glioma (WHO grade I).
atypical CPPs also have more complex architecture This is a rare tumor that most often occurs in chil-
and other histological features that may overlap with dren and young adults and presents as a slow-grow-
choroid plexus carcinoma (CPC) but do not exhibit ing mass in the cerebral hemispheres; it is most often
the frankly anaplastic morphology characteristic of associated with a history of treatment-refractory sei-
the latter. zures. On imaging studies, the tumor is mainly local-
ized to the cortex with minimal mass effect and no
2.1.5.2. Choroid plexus carcinoma (WHO contrast enhancement. Histologically it consists of
grade III). CPCs show clear histological features elongated GFAP-positive bipolar glial cells arranged
of malignancy, including frequent mitoses, nuclear either radially or perpendicularly around blood
and cytoplasmic atypia, more solid growth pattern vessels. Tumor cells also infiltrate the surrounding
with at least some loss of papillary architecture, and brain parenchyma, although the angiocentric pat-
often diffuse brain invasion. The diagnosis of CPC tern is clearly the predominant morphologic feature.
A B
FIGURE 2.7 Choroid plexus papilloma. (A) Surgical specimen (gross). (B) Microscopic features (H&E).

Mitoses are absent or very rare, and other histologi- neurofilament protein, synaptophysin). Tumors
cal features of anaplasia are absent. Electron micro- with neuronal elements tend to occur more often
scopic studies suggest a possible ependymal origin in children and young adults and are often located
for the tumor cells. within or adjacent to foci of cortical dysplasia
(defined as cortex having disorganized, nonlami-
2.1.6.2. Astroblastoma. This is a rare glial neo- nar architecture and bizarre cytological features,
plasm of uncertain histogenesis. It is characterized such as binucleation).
histologically by perivascular pseudorosettes com-
posed of GFAP-positive tumor cells with processes 2.1.7.1. Gangliocytoma and ganglioglioma.
radiating to a central blood vessel, which often has Gangliocytomas and gangliogliomas occur most
a thickened hyalinized wall. The tumor cell pro- commonly in the temporal lobe where they are
cesses are usually shorter, thicker, and less vari- often associated with seizures; however, they
able in diameter and lack the fibrillar characteristic can arise in almost all regions of the neuraxis,
of ependymomas. Most astroblastomas occur in including the spinal cord. They most often appear
young adults, but some have also been reported in as circumscribed, homogeneous masses hav-
children and infants. Although both low- and high- ing an even, granular cut surface, although small
grade examples have been described, this tumor cysts or calcifications can be encountered. They
has not been assigned a WHO grade due its vari- may present as a cyst with a mural nodule (simi-
able biological behavior and the lack of adequate lar to pilocytic astrocytoma and pleomorphic
clinical correlative data. Pure astroblastoma should xanthoastrocytoma).
be distinguished from conventional astrocytomas
and glioblastomas that may have focal “astroblas- 2.1.7.1.1. Gangliocytoma (WHO grade I).
toma-like” histology. Gangliocytomas consist entirely of mature, readily
recognized ganglion cells, some of which may be
2.1.6.3. Chordoid glioma of the third ventri- binucleated or bizarre (Fig. 2.8A). A fine reticu-
cle (WHO grade II). This rare glioma exclusively lin network may be identified around individual
occurs within the rostral third ventricle and hypo- cells, particularly in those occupying a very super-
thalamus. It consists of nests and cords of strongly ficial cortical location. Mitoses and necrosis are
GFAP-positive cells within a mucinous stroma, absent, and, while conspicuous in number, vessels
often containing lymphoplasmacytic infiltrates. do not have multilayered walls. A variant is seen
The tumor has little or no mitotic activity and a rarely in a sellar or suprasellar location, with con-
very low Ki-67/MIB-1 labeling index. They are current pituitary adenomas in some instances. By
relatively circumscribed, slow-growing tumors but definition a neoplastic glial component should be
are difficult to treat surgically because of their loca- absent.
tion. A putative origin from specialized ependymal
cells has been proposed on the basis of ultrastruc- 2.1.7.1.2. Ganglioglioma (WHO grade I or III)
tural studies. Gangliogliomas have a neoplastic glial compo-
nent, which is usually astrocytic, although oli-
godendroglial differentiation has been reported
2. 1. 7. NE URONAL A N D
(Fig. 2.8B). In some cases, the neuronal com-
G L I O N E UR ONALT UM O R S
ponent may be overshadowed by the glial com-
These tumors are less common than pure glial ponent and requires immunostaining for neural
tumors and are made up either entirely or partially markers for confirmation. Care must be taken that
by cells having neuronal features. These cells may “entrapped” neurons, for example in a segment of
be evident at the light-microscopic level and may cortex infiltrated by astrocytoma, are not mistak-
range from small “blue” cells reminiscent of neuro- enly identified as neoplastic. The presence of binu-
blasts to differentiated neurons or “ganglion cells” cleated or bizarre forms, as well as disorganized
with vesicular chromatin, prominent nucleoli, and cytoarchitecture, serves to distinguish neoplastic
even cytoplasmic Nissl substance. It is not unusual, from entrapped ganglion cells. Immunostains for
however, for neuronal features to be appreciated CD 34 can be helpful with a positivity in the neu-
only on ultrastructure or after immunostain- ronal component or in the peritumoral area. The
ing for neuronal epitopes (e.g., phosphorylated glial component often shares histological features
A B
FIGURE 2.8 Neuronal-glial tumors (microscopic appearance). (A) Gangliocytoma (H&E). (B) Ganglioglioma

(H&E). (C) Desmoplastic infantile ganglioglioma (H&E).
in common with pilocytic astrocytoma, includ- 2.1.7.1.3. Dysplastic gangliocytoma of the cerebel-
ing fibrillary or piloid cytoarchitecture, granu- lum (Lhermitte-Duclos disease) This is a distinctive
lar eosinophilic bodies, and Rosenthal fibers. lesion that is characterized by grossly visible expan-
Gangliogliomas may also have prominent lym- sion of the cerebellar folia, usually in only one hemi-
phoid infiltrates and stromal fibrosis. sphere. The centers of the affected folia contain large,
The behavior of gangliogliomas is determined bizarre ganglion cells, with morphologic and focal
by the degree of anaplasia of the glial component, immunohistochemical resemblance to Purkinje cells,
so documentation of necrosis, mitotic activity, and and some small granular neurons, while the surface
vascular proliferation must be made. Most ganglio- is covered by aberrant white matter bundles, a con-
gliomas are WHO grade I and are indolent tumors figuration sometimes referred to as “inverted cerebel-
best treated by excision. Gangliogliomas that show lar cortex.” In the WHO classification, this lesion is
anaplasia of the glial component would be desig- considered a grade I tumor, but biologically it tends
nated as anaplastic ganglioglioma (WHO grade III). to behave more like a hamartoma than a true neo-
A high percentage of gangliogliomas of all grades plasm. Local recurrences after surgical resection are
have BRAFV600E point mutations, which are not uncommon. About half of all cases of Lhermitte-
thought to be activating the RAS/MAPK signaling Duclos disease are associated with Cowden syndrome
pathway in these tumors and may represent a thera- which is a constellation of multiple verrucous skin
peutic target in these cancers, given the success of lesions, facial trichilemmomas, fibromas of the oral
targeted therapeutics in BRAF mutant melanoma mucosa, and hamartomatous polyps of the gastro-
and other cancers. intestinal tract, as well as thyroid and breast tumors

(both benign and malignant). Cowden syndrome histology, including microvascular proliferation,
arises from mutations in the PTEN gene on chromo- focal necrosis, and elevated mitotic activity. These
some 10q, and it is therefore likely that alterations tumors, referred to as atypical central neurocytomas,
of PTEN function are related to Lhermitte-Duclos have not been assigned a higher WHO grade; how-
pathogenesis. This association is supported by a ever, they may be associated with more aggressive
recent mouse model of disrupted PTEN activity, growth and a greater tendency toward recurrence,
which develops lesions that are histologically similar especially if accompanied by a Ki-67/MIB-1 prolif-
to those seen in Lhermitte-Duclos disease. eration index of greater than 2%.
2.1.7.1.4. Desmoplastic infantile ganglioglioma/ 2.1.7.2.2. Cerebellar liponeurocytoma (WHO grade

astrocytoma (WHO grade I) These are rare tumors II) This is a variant tumor composed of neurocy-
that occur up to the age of 2 years and most often toma-like cells admixed with lipidized neuroepi-
involve the superficial aspect of the frontal and thelial cells (not true adipocytes) that arises in the
parietal lobes, often with an accompanying cyst. cerebellum of adults. “Atypical” histological features
Histologically the tumor may have both astrocytic are usually absent. Although the clinical behavior of
and neuronal components (Fig. 2.8C) or, in some this tumor is generally favorable following surgical
cases, only an astrocytic component. Additional excision, recent reports have documented a rela-
characteristic histological features include the pres- tively high rate of recurrence.
ence of abundant connective tissue (desmoplasia)
and a tendency to adhere to overlying meninges. 2.1.7.3. Other glioneuronal tumors
Both are slow-growing and treatable by surgery. 2.1.7.3.1. Dysembryoplastic neuroepithelial tumor
(WHO grade I) The dysembryoplastic neuroepi-
2.1.7.2. Neurocytic tumors thelial tumor (DNT) is a low-grade tumor con-
2.1.7.2.1. Central Neurocytoma (WHO grade II) taining oligodendroglial-like and neurocytic areas
Central neurocytoma is a low-grade tumor that usu- but with a nodular (or multinodular) architecture
ally arises in the third or lateral cerebral ventricle in and intracortical location. The tumor occurs in
the region of the foramen of Monro, most commonly children, although adult examples have been rec-
in older children and young adults. It is composed ognized. It is often heralded by medically intrac-
of small, well-differentiated neurons with uniform table seizures. A histological hallmark of DNT is
round nuclei, fine chromatin, and occasional nucle- the “specific glioneuronal element,” which is the
oli, in a loose neuropil-like background (Fig. 2.9A). micro-architectural association of round oligoden-
An artifact of fixation results in perinuclear clearing, droglial- or neurocytic-like cells with axon bundles
which results in a histological appearance similar bounding microcystic spaces in which larger gan-
to oligodendroglioma. These tumors were initially glion cells lie (“floating neurons”) (Fig. 2.9B, C).
thought to be unusual intraventricular oligoden- The cortex adjacent to the tumor nodules is often
drogliomas or ependymomas until their neuronal dysplastic, suggesting a developmental (or ham-
character was established by electron microscopy. artomatous) nature. Calcifications and cysts are
Immunostaining for NeuN (generally weak but frequent accompaniments. Mitoses are usually
diffuse) is the most specific means of their identi- absent or rare. Microvascular proliferation or focal
fication, while strong diffuse staining for synapto- necrosis very rarely occur and does not appear to
physin can also confirm the neuronal nature of the have a negative prognostic effect. Surgical excision
lesion. Tumors having a morphologic appearance is considered curative. The existence of anaplastic
similar to central neurocytoma may occasionally versions has been suggested but is not universally
occur in other regions of the CNS (extraventricu- accepted.
lar neurocytoma). In the latter situation, distinction
from similar-appearing tumors such as oligodendro- 2.1.7.3.2. Papillary glioneuronal tumor (WHO
glioma can be aided by immunohistochemistry for grade I) This is a recently described low-grade glio-
OLIG2, which is rarely expressed in neurocytomas, neuronal tumor that most often arises in the cere-
and IDH-1 or FISH for 1p/19q co-deletions, both bral hemispheres (usually temporal lobe) of young
of which are negative in neurocytoma. Most cen- adults. Grossly they present as contrast-enhancing
tral neurocytomas are low-grade tumors (WHO circumscribed solid or cystic masses. Histologically
grade II); however, some may show more aggressive these tumors are characterized by pseudo-papillary
A B
FIGURE 2.9 Neuronal-glial tumors (microscopic appearance). (A)Central neurocytoma (H&E).

(B) Dysembryoplastic neuroepithelial tumor (DNT) (H&E). (C) DNT (immunostain for synaptophysin).
structures consisting of a central hyalinized blood 2.1.7.3.4. Paraganglioma Tumors of extra-

vessel surrounded by spindle-shaped to cuboidal adrenal chromaffin tissue, analogous to pheochro-
GFAP-positive glial cells with an intervening syn- mocytomas of the adrenal gland, can arise within
aptophysin-positive neuronal component. Based the cranial vault and spinal canal. Most often these
on their indolent behavior following surgical resec- are circumscribed nodules in the filum terminale,
tion, they are currently regarded as WHO grade although cranial and spinal nerve root masses
I tumors. extending into skull or vertebral foramina have been
noted. Those arising in the middle ear, often extend-
2.1.7.3.3. Rosette-forming glioneuronal tumor of ing into the posterior fossa at the cerebellopontine
the fourth ventricle (WHO grade I) This is a rare angle, are also known as “glomus jugulare” tumors.
low-grade glioneuronal tumor exclusively aris- Regardless of where they are seated within the neur-
ing in the midline posterior fossa region (usually axis, these neoplasms are identical histologically to
fourth ventricle) of adults. Grossly they are cir- paragangliomas elsewhere in the body, being made
cumscribed solid masses that show no or hetero- up of nests or “Zellballen” of plump neuroendo-
geneous contrast enhancement. Histologically crine cells separated by fine fibrovascular septa.
they demonstrate a biphasic neurocytic and glial Tumor cells are chromogranin- and synaptophysin-
architecture, the former characterized by the pres- positive, while interspersed sustentacular cells are
ence of neurocytic rosettes and perivascular pseu- S100positive. Focal ganglion cell differentiation
dorosettes. The glial component closely resembles may occur in some examples. They only rarely pro-
a pilocytic astrocytoma. The tumor is generally duce catecholamines, instead causing symptoms as
considered clinically benign and is treated by sur- a result of local compression. The biological behav-
gical excision. ior of these neoplasms is determined more by their

anatomical extent at the time of presentation than transcription factor, CRX, has been identified as a
by histological features. useful diagnostic immunohistochemical marker for
these tumors. Ultrastructurally, synaptic vesicles and
2.1.7.3.5. Olfactory neuroblastoma The olfac- microtubules confirm neural differentiation; cyto-
tory neuroblastoma (or esthesioneuroblastoma) plasmic annulate lamellae are further reminiscent
is a neuroblastic small “blue” cell tumor localized of retinal differentiation. The molecular genetics of
to the olfactory epithelium in the upper nasal cav- pineal tumors appears to be complex and is not yet
ity. It occurs in late childhood through adulthood, incorporated into clinicopathological management.
with presenting symptoms of sinus obstruction
or headache. Destruction of the cribriform plate 2.1.8.1. Pineocytoma (WHO grade I) The
may allow growth of tumor into the anterior cra- pineocytoma occurs in young to middle-aged adults
nial fossa, meninges, and frontal lobes of the brain. and represents about 45% of all pineal parenchy-
It has a characteristic broad, nodular growth pat- mal tumors. The component cells are uniform, with
tern. The neoplastic cells have a neural immuno- round to oval nuclei and occasional fine nucleoli,
phenotype and ultrastructure. Homer Wright-type and have fibrillary or club-shaped eosinophilic pro-
rosettes (with central neurofibrillary processes) or cesses, which may converge in the center of pineo-
occasionally Flexner-Wintersteiner rosettes (with cyte rosettes. The tumor has a lobular architecture
central lumina) may be seen. Olfactory neuroblas- recalling the normal structure of the pineal gland;
tomas may be either low-grade (Hyams grade I and however, the lobules are separated by delicate fibro-
II) or high-grade (Hyams grade III and IV). The lat- vascular septa (Fig. 2.10A , B). Variable amounts of
ter are characteristic by loss of differentiation, a high neuropil may be present in the background. The
mitotic rate, nuclear pleomorphism, and necrosis tumor is histologically low grade and lacks mitotic
and generally portend more aggressive biological activity or pleomorphism. It is well-circumscribed
behavior. Some high-grade olfactory neuroblasto- and slow-growing but not easily resectable because
mas may express epithelial markers and thus overlap of its central location. Nonetheless, 5-year survivals
with small-cell neuroendocrine carcinoma. of up to 90% may be expected.
2.1.8.2 Pineal parenchymal tumor of inter-

2. 1. 8. P I NE AL PARE N C H Y M A L TU M O R S
mediate differentiation (WHO grade II or III)
Pineal region tumors are rare and represent less than These tumors occur in both children and adults but
1% of all CNS tumors. They are grouped into three are relatively rare. Histologically they are either dif-
major categories: germ cell tumors (most common), fuse (neurocytoma-like) or slightly lobulated and
pineal parenchymal tumors, and gliomas. Other non- have somewhat more atypical cytology compared
glial tumors (e.g., meningioma) may rarely occur in to pineocytoma, with moderately high cellularity,
this region. This section will only discuss the pineal mild to moderate nuclear pleomorphism, and low
parenchymal tumors, which are derived from pineo- to moderate mitotic activity. They do not have the
cytes (or their precursors). Pineocytes have pheno- overt small-cell malignant phenotype of the pineo-
typic characteristics of both neuroendocrine cells blastoma. Well-validated histological grading cri-
and retinal photoreceptors, with which they share teria for this variant have not yet been established
a common embryonic lineage. Pineal parenchy- although it has provisionally been assigned grade II
mal tumors may be well-differentiated and difficult or III in the WHO classification. Biological behavior
to distinguish on biopsy from normal pineal gland and clinical survival are intermediate between those
(pineocytoma) or they may be poorly differentiated, of the aggressive pineoblastoma and the more indo-
small “blue” cell tumors (pineoblastoma). Tumors lent pineocytoma.
with histological features that fall between these
two extremes are currently designated as pineal 2.1.8.3. Pineoblastoma (WHO grade IV)
parenchymal tumors of intermediate differentiation. The pineoblastoma arises in children and young
All demonstrate neural characteristics on immu- adults as a rapidly growing mass, with heterogene-
nohistochemistry (synaptophysin, neuron-specific ity on neuroimaging reflecting its tendency toward
enolase, neurofilament protein) and may addition- hemorrhage, necrosis, and cystic degeneration.
ally show retinal S-antigen and rhodopsin, as well as Histologically, it is a densely cellular “small blue
melatonin. More recently, the retinal/pineal specific cell” tumor made up of oval, hyperchromatic nuclei
A B
FIGURE 2.10 Pineal parenchymal tumors. (A) Pineocytoma (H&E). (B) Pineocytoma (immunostain for
synaptophysin). (C) Pineoblastoma with Homer Wright rosettes (H&E).
with little visible cytoplasm, resulting in molding of of its gross similarity to pineocytoma. This tumor
nuclear contours. Some cells may have recognizable presents as a relatively large, well-circumscribed,
eosinophilic processes or form rosettes of Homer and occasionally cystic mass that on MR imaging
Wright or Flexner-Wintersteiner type (Fig. 2.10C). exhibits low T1 signal, increased T2, and contrast
Single-cell invasion of adjacent brain structures, enhancement. Histologically this tumor has epithe-
high mitotic activity, and necrosis are evidence of lial features and papillary architecture with occa-
malignancy. Like other small blue cell tumors of sional ependymal-like differentiation. The tumor
the CNS, pineoblastomas are “seeding” tumors that shows immunoreactivity for cytokeratins and
can invade parenchyma, gain access to the CSF, and focally GFAP; it is negative for neurofilament pro-
spread within the ventricles and subarachnoid space tein but may be weakly positive for synaptophysin
to other sites in the neuraxis. Such malignancies are and chromogranin. Proliferative activity (mitotic
often treated prophylactically with craniospinal irra- index, Ki-67/MIB-1 labeling) has been described
diation and systemic chemotherapy in anticipation as moderate. Necrosis may be present but micro-
of such a route of spread, which carries a very high vascular proliferation is usually absent. Because of
mortality. its immunohistochemical and ultrastructural fea-
tures suggestive of ependymal, secretory, and neu-
2.1.8.4 Papillary tumor of the pineal region roendocrine differentiation, a possible origin from
(WHO II or III) This is a rare neuroepithelial specialized ependymal cells of the subcommissural
tumor that primarily occurs in the pineal region of organ has been proposed. The biological behavior
both children and adults. Although it is not consid- of this tumor is variable and may correspond to
ered a true pineal parenchymal tumor derived from either WHO grades II or III; however, more precise
pineocytes, it is included in this section because histological grading criteria remain to be defined.

2. 1. 9. E MBRY ONAL TU M O R S 3. Anaplastic medulloblastoma, which shows
marked nuclear pleomorphism and molding,
This category comprises neoplasms of immature
cell–cell “wrapping,” and high mitotic activity,
cells resembling the primitive neuroepithelium,
often with atypical forms; these features must be
the origin of the precursor cells of the nervous sys-
the predominant pattern within the tumor.
tem. Tumors made up of these cells may retain the
4. Large cell medulloblastoma, which closely resem-
capability to differentiate along both neural and
bles typical medulloblastoma but has larger
glial lines, as detected by immunohistochemical or
vesicular nuclei containing prominent nucleoli
ultrastructural means. As a group they tend to pres-
and may show unusually intense immunohisto-
ent as large, bulky tumors that grow rapidly and have
chemical staining for synaptophysin. This tumor
a marked tendency to spread (“seed”) along CSF
often overlaps cytologically with the anaplastic
pathways. Metastatic dissemination to extraneural
variant and for this reason has sometimes been
sites such as bone, lymph nodes, and rarely other
termed large cell/anaplastic medulloblastoma.
organs has been described, often as a late complica-
5. Medulloblastoma with myogenic differentiation,
tion following treatment or recurrence.
which includes “strap” cells representing imma-
ture rhabdomyoblasts.
2.1.9.1. Medulloblastoma (WHO grade IV)
6. Medulloblastoma with melanotic differentiation,
Medulloblastoma is the most common and “proto-
which has scattered tubular clusters of pig-
typical” embryonal tumor of the CNS, representing
mented, melanosome-laden tumor cells. The
a significant proportion of primary brain tumors
latter two variants are extremely rare.
in children. A second peak age incidence occurs in
early adulthood. This tumor by definition arises in
the cerebellum, usually the vermis, and may cause All medulloblastomas are considered malignant
ataxia, headache, and vomiting due to acute obstruc- (WHO grade IV) biologically aggressive tumors;
tion of the fourth ventricle with hydrocephalus however, advances in current treatment, including
(Fig. 2.11A). aggressive surgical excision, craniospinal radiation,
Neuroimaging studies reveal an enhancing, lobu- and adjuvant chemotherapy, have resulted in 5-year
lated mass, and as many as one third of patients will survivals in the range of up to 60% to 70%.
have leptomeningeal enhancement representing A great deal of progress has been made in char-
CSF seeding at presentation. Histologically, classic acterization of medulloblastoma at the molecular
medulloblastoma is a densely cellular “small blue- level. Several clinically relevant subclasses of medul-
cell” tumor that may contain Homer Wright rosettes loblastoma have been defined using RNA expres-
with central neurofibrillary processes (only seen in sion and genetic copy number aberrations. The
about 40% of cases)(Fig. 2.11B). Necrosis occurs most common subclass is characterized as having a
both as single cells (apoptosis) as well as in conflu- “classic” histology and frequently exhibits isochro-
ent fields. Mitotic activity is conspicuous. mosome 17q. The association of medulloblastoma
The major histological variants of medulloblas- with Gorlin syndrome (basal cell nevus syndrome,
toma include: from mutation of the PTCH gene on chromosome
9q) and other recent studies has implicated the
1. Desmoplastic/nodular medulloblastoma, which is SHH-PTCH-SMO signaling pathway in desmo-
characterized by broad nodules of tumor cells plastic and non-desmoplastic tumors. A rarer but
separated by collagenous septa. The periphery clinically more favorable subclass is characterized by
of the nodules is occupied by densely-arranged alterations in the WNT-ß-catenin pathway, includ-
tumor cells, while the centers are neuropil-rich ing tumors arising in association with Turcot syn-
“pale islands.” drome (colon and brain tumors, due to mutation
2. Medulloblastoma with extensive nodularity (“cer- of the APC gene on chromosome 5q or defects in
ebellar neuroblastoma”) (Fig. 2.11C), which mismatch repair genes) and those with chromo-
differs from the desmoplastic subtype by less some 6 monosomy. Tumors not associated with
conspicuous collagenous stroma and greater these classes generally are more heterogeneous and
evidence of neural differentiation in the form of include those with large cell/anaplastic histology
neurocytoma-like areas and rarely mature gan- and are considered to have a less favorable progno-
glion cells (following radio/chemotherapy). sis, with frequent amplification of MYC/NMYC.
A B
FIGURE 2.11 Medulloblastoma. (A) Medulloblastoma of cerebellar vermis with ependymal and leptomen-
ingeal spread (H&E whole mount). Microscopic features: (B) Homer Wright rosettes (H&E). (C) Nodular
architecture (H&E).
2.1.9.2. CNS primitive neuroectodermal glial, neuronal, sometimes mesenchymal) by ultra-

tumors (PNETs) (WHO grade IV) These con- structural or immunohistochemical methods.
stitute a heterogeneous group of tumors that arise CNS PNETs exhibiting only neuroblastic differ-
mainly in children and adolescents and can occur entiation have been termed cerebral neuroblastoma,
almost anywhere along the neuraxis. They are bio- or cerebral ganglioneuroblastoma if more mature
logically aggressive tumors. Histologically they neurons (ganglion cells) and neuroblastic cells are
share in common a population of relatively undif- both present. Molecular studies have shown that
ferentiated neuroepithelial cells (“small blue cell” supratentorial PNETs are genetically distinct from
component) variably admixed with more differen- medulloblastomas.
tiated neuroepithelial cells of neuronal and/or glial
phenotype. The specific subtypes of CNS PNET are 2.1.9.2.2. Medulloepithelioma The medulloepi-
described below. thelioma is a very rare tumor that arises in infants
and young children and has a distinctive papillary,
2.1.9.2.1. CNS/supratentorial PNET This trabecular, or tubular growth pattern of primitive,
tumor histologically resembles medulloblastoma small “blue” cells recapitulating the appearance
and primarily occurs in the cerebral hemispheres of the embryonic neural tube. They may be found
(supratentorial PNET). Other sites of occur- throughout the CNS but most often occur in the
rence in the CNS, including the suprasellar region, cerebral hemispheres in a periventricular location.
brainstem, and spinal cord, have been described. On neuroimaging, the tumor has a heterogeneous
Histologically these tumors consist largely of small, appearance corresponding to areas of necrosis, hem-
poorly differentiated neuroepithelial cells but can orrhage, cysts, and calcification. In addition to the
demonstrate multiple lines of differentiation (e.g., primitive neural tube-like histology, multiple lines

of differentiation, which may include neuronal, glial, of one copy of chromosome 22 and mutation in
and sometimes mesenchymal elements, may be INI1/SNF5 (a putative tumor suppressor gene)
found in the tumor. It is mitotically active and clini- on the remaining copy of 22q. The diagnosis of
cally aggressive. AT/RT and its distinction from other histologi-
cally similar tumors has been facilitated by immu-
2.1.9.2.3. Ependymoblastoma This rare, highly nohistochemical staining for the INI1protein,
aggressive CNS embryonal tumor occurs primarily which is normally expressed within the nucleus of
in the cerebral hemispheres of infants and young chil- normal cells and other CNS tumors but is absent
dren and is histologically characterized by the pres- in AT/RTs. Molecular testing (e.g., FISH) may be
ence of distinctive ependymoblastic rosettes. These helpful in the evaluation of AT/RTs with equivo-
are multilayered rosettes with true lumina bounded cal INI1 immunohistochemistry or in establishing
by ciliated neuroepithelial cells, which are distinct the presence of a germline mutation.
from the single-layered ependymal tubules present
in ependymomas. Ultrastructurally the tumor cells
lining the rosettes may contain basal bodies (bleph- 2.2. Peripheral Nerve Sheath Tumors
aroplasts) and “abortive” cilia. Ependymoblastic These are defined as tumors that clearly arise from
rosettes may be widely scattered or form back-to- an identifiable peripheral nerve or whose compo-
back arrangements amid a population of small, nent cells show evidence (by immunohistochemis-
undifferentiated cells or more differentiated cells try and/or electromicroscopy) of nerve sheath cell
with glial and/or neuronal characteristics within an differentiation (i.e., Schwann or perineurial cells).
abundant neuropil. The existence of ependymoblas- Only the four major categories of nerve sheath
toma as a distinct pathological entity has recently tumor will be considered here: schwannoma, neu-
been challenged, largely due to uncertainty regard- rofibroma, perineurioma, and malignant peripheral
ing the precise histological criteria required for diag- nerve sheath tumor.
nosis since ependymoblastic rosettes can also occur
in other well-characterized embryonal tumors such
2 .2 . 1. SCHWAN N OM A (W HO GRADE I)
medulloblastoma, supratentorial PNETs, and atypi-
cal teratoid/rhabdoid tumor. Although ependymo- Schwannomas are benign encapsulated tumors
blastoma may appear histologically similar to some that are composed entirely of Schwann cells. They
examples of anaplastic ependymoma (see above), it may occur at all ages, with a peak of incidence in
lacks the perivascular pseudorosettes that character- the fourth to sixth decades, and are rare in the
ize the latter. pediatric age group. As they originate wherever
Schwann cells are present, they may be found
2.1.9.3. Atypical teratoid/rhabdoid tumor on cranial nerves, spinal nerve roots, peripheral
(WHO grade IV) Atypical teratoid/rhabdoid nerve trunks, and even at nerve endings, leading
tumor (AT/RT) is a highly malignant embryonal to cutaneous, subcutaneous or, less often, visceral
tumor that primarily occurs in infants within the tumors. Intracranial schwannomas most often
supra- and infratentorial compartments. It is histo- involve the vestibular branch of the eighth cra-
logically characterized by the presence of distinc- nial nerve, where they are referred to as vestibular
tive rhabdoid cells, which have an eccentric nucleus schwannomas (Fig. 2.12A). Most are situated in
with a prominent nucleolus and “inclusion-like” the cerebellopontine angle and, when reaching a
pink cytoplasm. These cells often exhibit positive critical size, can cause clinical symptoms due to
immunostaining for vimentin, epithelial mem- changes on neighboring structures, which include
brane antigen, and sometimes desmin or cytoker- enlargement and erosion of the internal auditory
atin. The rhabdoid cell component is frequently meatus, stretching of neighboring cranial nerves,
admixed with undifferentiated small “blue” cells and cerebellar and brainstem compression.
resembling medulloblastoma or PNET; the lat- Schwannomas of the fifth, ninth, and tenth cra-
ter may be the predominant histological pattern, nial nerves are much less common. Motor cranial
which can lead to diagnostic confusion. Some AT/ nerves are involved only rarely. Spinal schwanno-
RTs may express widely divergent differentiation mas are situated most frequently on dorsal sensory
along neuronal, glial, and mesenchymal lines. AT/ nerve roots, but some have also been described
RTs are nearly always associated with allelic loss on the ventral motor nerve roots. The thoracic
A
C D
FIGURE 2.12 Schwannoma. (A) Vestibular schwannoma (gross). Microscopic features: (B) Antoni A tissue
with nuclear palisading (Verocay bodies) (H&E). (C) Antoni B tissue (H&E). (D) Pleomorphic nuclei (H&E).
segments are most often implicated, but cervical erosion is sometimes evident on imaging studies.
and lumbar schwannomas are not rare. They may As a general rule schwannomas are solitary tumors;
also be situated in the cauda equina. The tumor is however, in neurofibromatosis (NF) type 2, mul-
usually restricted to the subdural space but may tiple schwannomas, especially bilateral vestibu-
sometimes extend through the intervertebral lar schwannomas (which are pathognomonic for
foramen, resulting in an hourglass appearance. NF2), may be found. Multiple schwannomas in the
Intraparenchymatous (intracerebral or intraspi- absence of other features of NF2 are seen in schwan-
nal) or intraosseous schwannomas have been nomatosis. The clinical evolution of schwannomas
exceptionally reported. is slow, and they remain histologically benign but
Macroscopically schwannomas are firm, well- may recur. More than half of schwannomas have a
circumscribed, encapsulated tumors of variable size. deletion of the long arm of chromosome 22 and a
Small tumors are spherical and white or slightly mutation or a deletion of NF2 gene on the remain-
translucent and have an elastic consistency. Larger ing allele. Total inactivation of NF2 gene, with sub-
examples are irregularly lobulated and may be cys- sequent loss of merlin (schwannomin) expression
tic. On section, some may show hemorrhages and demonstrated by immunocytochemistry or Western
yellowish foci. These tumors displace rather than blotting, seems to be a crucial step in the tumorigen-
invade the nerves from which they originate. Bone esis of schwannomas.

Microscopically, schwannomas consist of two cases. However, cellular schwannomas always have a
characteristic tissue types, which are often inter- benign course and show a high degree of schwann-
mingled within the same tumor: (1)dense fibril- ian differentiation by electron microscopy and
lary (Antoni A) tissue, which consists of elongated immunohistochemistry.
bipolar cells having scant cytoplasm and cylindrical
nuclei arranged in elongated drifts, whorls, or char- 2.2.1.3. Melanotic Schwannomas These
acteristic palisades (Verocay bodies) (Fig.2.12B), relatively rare, grossly pigmented tumors consist
and (2) loose reticulated (Antoni B) tissue, which is of Schwann cells with melanosomes and exhibit
less densely cellular and consists of small round immunoreactivity for melanocytic markers such as
nuclei randomly arranged in a matrix containing HMB-45 and MART-1. They are divided into non-
microcysts and vacuolated cells, imparting a finely psammomatous and psammomatous forms, the for-
honeycombed appearance (Fig. 2.12C). Reticulin mer having a predilection for posterior spinal nerves
fibers are present in both tissue types. Antoni B and ganglia and the latter frequently involving
tissue usually predominates in intracranial schwan- autonomic ganglia and viscera as part of the Carney
nomas. Although a moderate degree of nuclear pleo- complex (a multi-endocrine autosomal dominant
morphism may be seen (Fig. 2.12D), mitotic figures disorder). Melanotic schwannomas generally have
are absent. Many examples show hyaline thickening a benign course, although about 10% to 25% may
of vessel walls and sometimes thrombosis and evi- have more aggressive or frankly malignant behavior,
dence of prior hemorrhage. Unlike neurofibromas, including metastases.
nerve fibers are usually not present within a schwan-
noma but are displaced and incorporated within
2 .2 . 2. N EUROFIBROM A (W HO GRADE I)
the surrounding fibrous capsule. Ultrastructurally
schwannomas are composed solely of Schwann cells Neurofibromas constitute a spectrum of benign nerve
ensheathed by a continuous basal lamina in associa- sheath tumors that include (1) localized or diffuse
tion with a variable proliferation of collagen fibers. cutaneous lesions; (2) solitary or plexiform intra-
Virtually all schwannomas show strong immunore- neural lesions, and (3) massive soft tissue tumors.
activity for S100 protein; some examples may also Multiple and plexiform neurofibromas (involving
show variable GFAP expression. multiple nerve fascicles) are a hallmark of NF1. All
ages and both sexes may be affected. Histologically
2.2.1.1. Plexiform Schwannomas These neurofibromas contain a variable mixture of Schwann
are most often dermal or subcutaneous in loca- cells, perineurial-like cells, fibroblasts, and cells with
tion and occur on the trunk or upper extremities. intermediate features. They often have a more cellular
Histologically they consist of multiple nodules of central zone that contains fibroblasts and Schwann
varying sizes embedded in fibrous connective tis- cells, as well as dense collagen bundles and myelin-
sue. Occasional examples may be locally aggressive ated/unmyelinated nerve fibers (Fig. 2.13) and usu-
and recur but are not considered overtly malignant. ally a less-dense peripheral zone devoid of nerve
Plexiform schwannomas may be associated with fibers. The Schwann cells and fibroblasts are embed-
NF2; they must be distinguished from plexiform ded in a clear, often myxoid-appearing matrix. Some
neurofibromas, which are almost always associated neurofibromas may contain numerous atypical nuclei
with NF1. (atypical neurofibromas) or show increased cellularity
(cellular neurofibromas), but mitoses are typically rare
2.2.1.2. Cellular Schwannomas These are or absent. Large diffuse neurofibromas may contain
composed exclusively or predominantly of an tactile-like structures (“pseudo-Meissnerian” cor-
Antoni A pattern of spindle-shaped Schwann cells puscles) and occasionally melanotic cells. Malignant
without Verocay bodies. The tumor is characteristi- change in a neurofibroma may occur, with produc-
cally located near the vertebral column in the medi- tion of a malignant peripheral nerve sheath tumor (see
astinum or retroperitoneum. Occasionally, bone below). Such an evolution is frequently associated
destruction and neurological symptoms develop. with NF1 and affects particularly plexiform neurofi-
Their clinical appearance, together with the high bromas and neurofibromas of major nerves.
cellularity, fascicular pattern, moderate nuclear Although there has been some controversy
pleomorphism, and mitotic activity, has led to the about the clonal nature of neurofibromas, they are
erroneous diagnosis of a soft tissue sarcoma in some most likely derived from Schwann cells since allelic
are not specifically related to NF1 or NF2, altera-
tions of the long arm of chromosome 22 have been
documented in these tumors and probably involve
the NF2 gene. Some authors believe that intraneural
perineuriomas may represent a relatively organized
hyperplastic process that selectively involves peri-
neurial cells, perhaps as a reaction to minor trauma
to the perineurial sheath. A closely related, but histo-
logically distinct, tumor also composed of perineu-
rial cells is the soft tissue perineurioma, which is very
rarely associated with a nerve.
FIGURE 2.13 Microscopic appearance of neurofi- 2.2.4 . MAL IGNANT PERIPHERAL NERVE

broma (H&E). SHE ATH TUMOR (MPNST) (WHO GRADES
II, III OR IV)
loss can be demonstrated at the NF1 locus in the MPNST is defined as a malignant tumor that either
Schwann cells of neurofibromas. The genetic basis arises from or within a peripheral nerve or occurs
of neurofibroma formation is unclear, but the NF1 in soft tissues unassociated with a nerve but shows
gene on the long arm of chromosome 17 is clearly histological evidence of nerve sheath differentiation.
involved in the early stages of tumorigenesis. Studies Several terms (e.g., malignant schwannoma, neuro-
in mouse models of the disease have interestingly genic sarcoma, and neurofibrosarcoma), which are
suggested that the genetic aberrations in stromal more or less synonymous with MPNST, are mislead-
cells may also modify or contribute to disease ing and should be avoided. Tumors derived from
progression. epineurial elements or blood vessels are excluded.
MPNSTs primarily occur in adults and represent
about 5% of soft tissue sarcomas. They can occur de
2.2.3. INTRANEURAL PERINEURIOMA
novo, although most arise from a preexisting tumor,
( WHO GRADE I)
usually a neurofibroma. MPNSTs are very closely
This rare neoplasm most often presents in adoles- associated with NF1: 25% to 65% occur during the
cence or early adulthood and shows no sex predi- course of NF1, and approximately 4% of patients
lection. It mainly affects peripheral nerves of the with NF1 will develop a MPNST. The most com-
extremities and presents as a localized segmental or mon locations are along the main nerve trunks of
tubular enlargement of the nerve. Multiple fascicles limbs (sciatic nerve, brachial plexus, sacral plexus),
may be involved, although the lesion does not have on the trunk, and in the head and neck. MPNSTs of
a “plexiform” growth pattern. Microscopically, the cranial nerves are rare. Most MPNSTs have a poor
tumor is characterized by proliferations of perineu- prognosis, with a 10-year survival rate of about 23%.
rial cells in the form of concentric layers (“pseudo- Histologically MPNSTs are highly cellular malig-
onion bulbs”) around nerve fibers within the nant spindle cell tumors that exhibit nuclear atypia,
endoneurium. Although the histology of intraneural numerous mitoses, and frequent geographical necro-
perineurioma may closely resemble the onion-bulb sis. Invasion through the perineurium and epineu-
formations seen in the various forms of hypertrophic rium into adjacent soft tissues may occur. MPNSTs
neuropathy (e.g., Charcot-Marie-Tooth disease), can be further subdivided into low-grade (WHO
the tumor lacks the multiplicity of nerve involve- grade II) and high-grade (WHO grade III or IV)
ment or genetic background of those conditions. tumors, which are distinguished from the former by
Electron microscopy and immunohistochemistry high mitotic activity and necrosis. The majority of
of the cells forming the pseudo-onion bulbs support MPNSTs have a high Ki-67/MIB-1 labeling index.
their perineurial nature: they are immunopositive Various forms of divergent differentiation may be
for EMA and negative for S100 protein. They are observed in some MPNSTs, which may include
benign tumors with no tendency toward recurrence elements of osteosarcoma, chondrosarcoma, lipo-
or metastasis. Although intraneural perineuriomas sarcoma, angiosarcoma, or rhabdomyosarcoma

(malignant Triton tumor). Epithelial components (tentorium, foramen magnum) and intraventricu-
(epithelioid, epidermoid, or glandular), mela- lar meningiomas are considerably less common
nocytes (melanotic malignant schwannoma), or (approximately 10%); spinal meningiomas are most
perineurial cells may also be encountered in some frequently situated in the thoracic segments and are
MPNSTs. Immunohistochemistry can be an invalu- usually located in the lateral compartment of the
able aid in the diagnosis of MPNSTs and in particu- subdural space.
lar distinguishing them from other different spindle Macroscopically the typical meningioma is a
cell tumors with a similar histological appearance. spherical or lobulated, well-circumscribed tumor
However, in keeping with the overall poor differen- that is firmly attached to the inner surface of the dura
tiation of MPNSTs, only 50% to 70% will show S100 (Fig. 2.14A, B) and displaces the underlying brain
protein immunoreactivity for schwannian differen- parenchyma without invading it. Meningiomas en
tiation. For the same reasons, electron microscopy plaque spread along the deeper surface of the dura
has generally limited diagnostic utility. and tend to invade the overlying bone, which often
Sporadic and NF1-associated MPNSTs have results in hyperostosis. Meningiomas are usually
complex numerical and/or structural karyotypic single, but multiple tumors may occur either as spo-
abnormalities. More common ones include trip- radic cases or in patients with NF2.
loidy, loss of the NF1 locus (17q11), and loss of The light-microscopic appearance of meningio-
the band containing the tumor suppressor gene mas can be variable and sometimes quite challeng-
TP53 (17p13). The genetic evolution of MPNSTs ing. However, with the possible exception of some
appears to be a multistep process initiated by poorly differentiated anaplastic tumors, virtually
mutations in one or both copies of the NF1 gene, all meningiomas will demonstrate morphologic
leading to subsequent loss or mutation of the features consistent with their arachnoid origin,
TP53 tumor suppressor gene. MPNSTs also show either ultrastructurally (e.g., abundant intermedi-
alterations in other genes involved in cell cycle ate filaments, complex interdigitating cell processes,
regulation. desmosomes) or by immunohistochemistry (e.g.,
reactivity for epithelial membrane antigen). The
current WHO classification groups meningiomas
2.3. Tumors of the Meninges into three histological grades which are described
in further detail below. The WHO grade, which is
2. 3. 1. T UMORS OF M ENI N G O TH EL I A L
currently based primarily on histological appear-
C EL LS: ME NI NGI OM A S
ance, correlates relatively well with the overall bio-
Meningiomas are tumors originating from arachnoi- logical and clinical behavior of a given tumor; this
dal cells and attached to the inner surface of the dura can often be enhanced by additional data provided
mater. They are very commonly encountered neo- by the Ki-67/MIB-1 proliferative index. Grade
plasms, accounting for 13% to 25% of primary intra- I meningiomas are considered clinically benign and
cranial tumors and approximately 25% of intraspinal have a low risk of recurrence or aggressive growth,
tumors. Most meningiomas occur in adults between whereas grade II and III tumors are associated with
the ages of 20 and 60, with a peak incidence around a greater probability of recurrence and/or aggressive
45. They are predominantly found in females (male behavior.
to female ratio between 2:3 and 1:2), except for
atypical and anaplastic meningiomas, whose inci- 2.3.1.1. WHO grade I meningiomas WHO
dence is higher in males. Many small meningiomas grade I meningiomas are benign tumors that
are incidental findings due to the wide clinical use of (1) have a mitotic index of less than 4 mitoses per
CT and MRI imaging. 10 high-power (40×) fields, (2) have fewer than
Meningiomas arise wherever arachnoidal cells three (or none) of the “atypical” histological features
are present but have a predilection for the follow- associated with grade II or III tumors (see below),
ing sites: convexity meningiomas (parasagittal, falx, (3) do not belong to one of the defined grade II or
lateral convexity) are the most frequent (approxi- III subtypes, and (4) do not show evidence of true
mately 50%); basal meningiomas (olfactory groove, brain invasion. They have a low Ki-67/MIB-1 prolif-
intraorbital, lesser wing of the sphenoid, pterion, eration index (usually less than 4% to 5%). The fol-
parasellar or suprasellar) are next in frequency lowing well-recognized meningioma subtypes are
(approximately 40%); posterior fossa meningiomas almost always classified as WHO grade I.
A B
FIGURE 2.14 Meningioma. (A) Convexity meningioma (gross). (B) Meningioma of skull base (gross).
Microscopic features: (C) Cellular whorls (H&E). (D) Whorls and psammoma body (H&E).
2.3.1.1.1. Meningothelial meningioma This is 2.3.1.1.2. Fibrous (fibroblastic) meningioma This

composed of polygonal epithelial-like cells, with is composed of elongated fusiform cells, arranged in
ill-defined cell borders, pale cytoplasm, and a rela- wavy interlacing fascicles. A well-developed network
tively voluminous spherical nucleus containing a of collagen and reticulin fibers is found between the
conspicuous nucleolus and occasionally showing individual cells. Whorls and occasionally psam-
a pseudo-inclusion in the shape of a clear, well- moma bodies may be present.
defined intranuclear vacuole. The distribution
of the cells is fairly uniform, being diffuse and 2.3.1.1.3. Transitional (mixed) meningioma This
arranged in elongated sheets or in islands sepa- is a frequent subtype with intermediate features
rated by scant vascular connective tissue trabecu- between those of meningothelial and fibroblastic
lae. In some cases the tumor cell borders may be meningioma. Whorls and sometimes psammoma
difficult to visualize, imparting a “syncytial” pat- bodies are often numerous.
tern to the tumor. A characteristic and diagnostic
pattern, which is almost always present to a greater 2.3.1.1.4. Psammomatous meningiomaThis vari-
or lesser extent, is the formation of cellular whorls ant has exceptionally numerous psammoma bodies,
(Fig. 2.14C) in which the tumor cells are closely which may become confluent. They are most com-
wrapped around one another. The whorls show a monly encountered in the spinal region.
hyalinized and calcified center and are then termed
psammoma bodies(Fig. 2.14D). However, the fre- 2.3.1.1.5. Angiomatous meningioma This shows
quency of psammoma bodies in a given tumor is a very rich degree of vascularization. The vessels,
variable, and some meningothelial meningiomas most often of small diameter, have frequently
may have very few. hyalinized walls. The histological features of this

variant often overlap with those of microcystic (4) uninterrupted patternless or sheet-like growth,
meningioma. and (5) foci of spontaneous or “geographic” necro-
sis. Necrosis (infarction) that clearly results from
2.3.1.1.6. Microcystic meningioma This vari- therapeutic embolization must be excluded. The
ant has tumor cells with elongated processes that presence of “cytologic atypia” (enlarged or bizarre-
circumscribe multiple small “cystic” spaces with a appearing hyperchromatic nuclei) is neither a
variable mucinous content. Pleomorphic cells and required nor a defining histological feature used to
nuclei may be prominent, as well as many vessels classify a tumor as an atypical meningioma. These
with thickened hyalinized walls. nuclei are usually considered a form of degenerative
change and may be seen in otherwise typical WHO
2.3.1.1.7. Secretory meningioma This variant is grade I tumors. The Ki-67/MIB-1 labeling indices
characterized by the presence of small eosinophilic of WHO grade II meningiomas are moderately high
PAS-positive globular inclusions within cells that (usually less than 10%) but can be variable, with
are immunoreactive for carcinoembryonic antigen some cases overlapping with grade I tumors and
and cytokeratin (in addition to EMA). These inclu- others approaching the range of anaplastic menin-
sions should not be confused with calcified psam- gioma. The additional presence of true brain inva-
moma bodies. sion may be prognostically significant but by itself is
not sufficient to reclassify an atypical meningioma
2.3.1.1.8. Lymphoplasmacyte-rich meningioma as anaplastic (grade III).
This demonstrates a conspicuous plasma cell-lym-
phocytic component and should be distinguished 2.3.1.2.2. Chordoid meningioma In this rare
from other intracranial masses that are rich in lym- variant, some regions of the tumor histologically
phocytes and/or plasma cells and resemble menin- resemble chordoma with trabeculae of vacuolated
giomas on imaging studies or at surgery. cells in a myxoid matrix. Inflammatory cell infil-
trates may be conspicuous. They frequently show a
2.3.1.1.9. Metaplastic meningiomas This variant high rate of recurrence following subtotal surgical
include tumors that show (1) xanthomatous change resection.
with the presence of lipid-filled cells, (2) myxoma-
tous change characterized by an abundant homo- 2.3.1.2.3. Clear cell meningioma This rare vari-
geneous stroma separating the individual cells, ant is characterized by a patternless proliferation of
(3) cartilage or bone within the tumor, and (4) mela- polygonal cells with clear PAS-positive glycogen-
nin pigment within the connective tissue trabeculae rich cytoplasm. They generally lack other histo-
(pigmented meningiomas). logical features typical of meningioma. They have
a predilection for the spinal cord and posterior
2.3.1.2. WHO grade II meningiomas A menin- fossa and tend to occur more often in children and
gioma is classified as WHO grade II if it belongs to young adults. They can be biologically aggressive,
one of these three categories: (1) atypical menin- with frequent recurrence and occasional seeding of
gioma based on the specific histological criteria the CSF.
outlined below, (2) chordoid or clear cell subtype,
or (3) a meningioma whose histological appear- 2.3.1.3. WHO grade III meningiomas A
ance resembles a benign (WHO grade I) tumor but meningioma is classified as WHO grade III if it
shows true brain invasion. The latter are classified as belongs to one of these two categories: (1) ana-
WHO grade II due to their more aggressive clinical plastic meningioma based on the histological cri-
behavior. teria outlined below or (2) papillary or rhabdoid
subtype.
2.3.1.2.1. Atypical meningioma This is defined as
a tumor that has increased mitotic activity (4 or more 2.3.1.3.1. Anaplastic meningioma This is defined
mitoses per 10 high-power fields) and/or the presence as a meningioma having either histological features
of three or more of the following histological features: that are clearly malignant (i.e., resembles a carci-
(1) increased cellularity, (2) small cells with a high noma, sarcoma, or melanoma) and/or has 20 or
nuclear–cytoplasmic ratio, (3) prominent nucleoli, more mitoses per 10 high-power fields. The histological
distinction between atypical and anaplastic menin- commonly in females and can express progesterone
gioma is usually fairly clear-cut, but there are bor- (common) and estrogen (infrequent) receptors, the
derline cases that remain difficult to classify. Tumors functional significance of these hormone receptors
that show diffusely anaplastic histology can be diag- is uncertain. There is a clear connection between the
nostically challenging and may require documenta- occurrence of meningiomas (especially multiple)
tion of evolution from a lower-grade meningioma at and NF2; however, other families with an increased
the same site or convincing immunohistochemical susceptibility to meningiomas but without NF2
and/or ultrastructural evidence of meningothelial have been described, indicating the likely presence
differentiation (which may itself be challenging due of other genetic predisposition loci.
to poor differentiation of the tumor). Anaplastic The cytogenetic alterations found in meningio-
meningiomas typically have Ki-67/MIB-1 labeling mas most commonly consist of loss of chromosome
indices greater than 15% to 20%. They are clinically 22q and mutations of the NF2 gene. As meningio-
and biologically aggressive tumors, with a median mas increase in histological grade, additional genetic
survival of about 2 years. Invasion of the brain events often occur, including loss of the short arm of
parenchyma, although frequent in anaplastic menin- chromosome 1 and the long arms of chromosomes
giomas, is not by itself sufficient for the diagnosis 10 and 14 and 9p21 deletions.
of anaplastic meningioma since brain invasion may
also be observed in atypical or even histologically
2.3.2 . NONMENINGOTHEL IAL TUMORS
benign meningiomas. Rare anaplastic meningiomas
may metastasize within the CNS along CSF path- 2.3.2.1 Meningeal Hemangiopericytoma
ways or systemically. (WHO grade II or III) Meningeal hemangio-
pericytomas (HPC) are much less frequent than
2.3.1.3.2. Papillary meningioma This rare sub- meningiomas. Despite its name, the histogenesis of
type is characterized by the presence of a perivas- hemangiopericytoma is uncertain: convincing evi-
cular papillary or pseudo-papillary pattern. These dence of a pericytic origin has been lacking, and many
tumors are highly aggressive and are often invasive, surgical pathologists regard HPCs as a fibroblastic
recurrent, and even metastatic. tumor that is part of the spectrum of solitary fibrous
tumor (see below). Macroscopically HPCs are solid,
2.3.1.3.3. Rhabdoid meningioma This uncom- rather firm tumors, attached to the dura mater, and
mon and clinically aggressive tumor contains disco- well-delineated from the adjacent CNS parenchyma
hesive aggregates or sheets of cells resembling classic (i.e., resembling a meningioma). Microscopically
rhabdoid cells, which are characterized by plump they consist of a highly cellular, homogeneous pro-
eccentric nuclei with prominent nucleoli and pink liferation of elongated cells individually embedded
inclusion-like cytoplasm. Although these tumor in a dense network of reticulin fibers. They are highly
cells resemble those found in rhabdoid tumors in vascular and often display prominent slit-like, branch-
other sites, they show normal nuclear immunoreac- ing channels (“staghorn sinusoids”). The distinction
tivity for INI1 protein. Other histological features of between WHO grade II and III HPC is based mainly
anaplasia are also usually present. The diagnosis of on the degree of cellular anaplasia and mitotic activ-
rhabdoid meningioma should be restricted to cases ity. Grade III tumors should have 5 or more mitoses
where greater than 50% of the tumor has rhabdoid per 10 high-power fields and/or necrosis and at least
architecture. Tumors having both rhabdoid and two of these features: hemorrhage, moderate to high
papillary architecture may occur. nuclear atypia, and cellularity. The tumor cells are
The etiology of most meningiomas remains consistently immunoreactive for vimentin and more
unknown. However, there is a well-established variably for CD34 (in contrast to diffuse staining in
association between the occurrence of a menin- solitary fibrous tumor) and are negative for EMA and
gioma and prior radiation therapy, which usu- S100 protein. The Ki-67/MIB-1 labeling indices may
ally precedes tumor presentation by many years. range from 5% to 10%, the latter approaching the level
Radiation-induced meningiomas are more com- of anaplastic meningiomas. Meningeal HPCs are con-
monly multiple, often have atypical or anaplastic sidered to be tumors of variable malignant potential,
histology, and occur at younger ages. A possible role similar to their soft-tissue counterparts, and have the
of sex hormones in the causation of meningiomas same tendency to recur and metastasize. Brain inva-
is less certain. Although meningiomas occur more sion may also occur.

Solitary fibrous tumor is a rare benign tumor Angiolipomas are rare benign mesenchymal
that involves the cranial or spinal meninges or lat- tumors composed of mature adipose tissue and
eral ventricles of adults and mimics a meningioma. blood vessels that are either normal or may mimic a
Elongated fibroblasts, disposed in fascicles between capillary angioma, cavernous angioma, or arteriove-
conspicuous bands of collagen fibers, display strong nous malformation. It may be difficult to distinguish
and uniform immunoreactivity for both vimentin them from hemangiomas, which are often accompa-
and CD34 but not EMA. As noted above, solitary nied by adipose tissue. They are usually found in the
fibrous tumors may have a histological pattern that epidural space at the thoracic level. Invasion of sur-
is very difficult to distinguish from HPC, and many rounding tissues and especially vertebral bodies has
pathologists now consider solitary fibrous tumor been noticed in rare cases so that total removal is not
and HPC to be part of the same morphologic and always possible. The exceptional angiomyolipomas
histogenetic spectrum. contain a more or less conspicuous smooth muscle
component intermingled with blood vascular chan-
2.3.2.2. Other mesenchymal non-menin- nels and mature adipose tissue. Spinal angiolipomas
gothelial tumors Various benign and malignant and angiomyolipomas are to be distinguished from
tumors of mesenchymal origin may arise within spinal epidural lipomatosis associated with Cushing
the CNS; their histological appearance is essen- syndrome or induced by long-term corticosteroid
tially identical to their extra-CNS counterparts therapy.
arising from soft tissue and bone. They are rela-
tively rare, accounting (in aggregate) for less than 2.3.2.2.2. Fibrous tumors Solitary fibrous tumor
0.5% of all intracranial tumors, and may occur at is described above (see Meningeal Hemangio-
any age. Many of these tumors are localized to pericytoma).
the skull, vertebral column, or meninges but can Fibromatosis is an infiltrative but benign lesion
also occur within the brain or spinal cord itself composed of elongated fibroblasts within a dense
(e.g., lipomas). Their etiology is largely unknown, collagenous stroma. Their occurrence within the
although some malignant examples (sarcomas) CNS is extremely rare. From a histological stand-
have been related to prior cranial radiation, and point, this process must be distinguished from sim-
more recently Epstein-Barr virus (EBV) has been ilar-appearing but likewise uncommon entities such
implicated in the pathogenesis of cranial and spinal as childhood cranial fasciitis, cranial infantile myo-
smooth muscle tumors in immunocompromised fibromatosis, myofibroblastoma, and hypertrophic
patients. intracranial pachymeningitis.
Intracranial fibrosarcomas are very rare neo-
2.3.2.2.1. Tumors of adipose tissue Lipomas are plasms that account for less than 1% of all intra-
rare benign growths. In the cranial cavity, they cranial tumors. They are derived from fibroblasts,
favor midline sites: corpus callosum (often asso- which may be situated in the dura, leptomeninges,
ciated with partial or complete agenesis of that perivascular spaces, tela choroidea, or stroma of the
structure), quadrigeminal plate, and cerebellopon- choroid plexus. Fibrosarcomas are most frequently
tine angle. Most intraspinal lipomas are discov- attached to the meninges but may sometimes be
ered in childhood and are congenital lumbosacral entirely parenchymatous. Macroscopically they are
lipomas associated with spinal dysraphism (spina well circumscribed but nonencapsulated, they are
bifida occulta) or “tethered cord” (abnormally low- firm in consistency, and they have fairly homoge-
lying conus tethered by the lipomatous mass). In neous gray cut surfaces. In some cases, the tumor
adults intraspinal intradural lipomas are isolated is not a well-defined mass but consists of a diffuse
tumors, composed of normal-appearing adipose infiltration of the meninges (meningeal sarcoma-
tissue and most frequently located at the thoracic tosis). Their microscopic appearance is identical
level; they represent less than 1% of all spinal cord with that of fibrosarcomas arising elsewhere in the
tumors. Rare complex lipomas containing bundles body and presents the same range of cellular dif-
of nerve fibers associated with muscle fibers have ferentiation. The better-differentiated examples are
been described. They have been referred to as neu- characterized by interlacing bundles of elongated
romuscular hamartomas, suggesting a possible fibroblastic cells of which only the nuclei are clearly
relationship with peripheral nerve fibrolipomatous visualized, separated by a rich network of reticulin
hamartomas. fibers. Nuclear abnormalities are usually rare, but
mitoses are common. Foci of necrosis are frequent. Osteosarcomas of the skull or spinal bones may be
They may invade the neural parenchyma. encountered in Paget disease.
Fibrohistiocytic tumors are rare tumors com-
posed of a mixture of spindle-shaped fibroblast-like 2.3.2.2.5. Blood vessel tumors Hemangiomas
and round histiocyte-like cells that may be benign of either the capillary or cavernous type (cav-
(benign fibrous histiocytoma) or malignant with ernomas) are not true tumors but vascular
numerous mitoses and foci of necrosis (malignant malformations.
fibrous histiocytoma). Some authors believe that Epithelioid hemangioendothelioma is an endothe-
exhaustive study of such tumors by immunohisto- lial cell tumor rarely encountered in the region of
chemistry or electron microscopy will usually allow the skull base and exceptionally in the brain paren-
more definitive classification as a neural or myo- chyma. Histological examination reveals typical
genic sarcoma. epithelioid cell cords or nests in a myxoid stroma.
Mitoses and necrosis may be present. Tumor cells
2.3.2.2.3. Muscle tumors Leiomyosarcoma is a express endothelial-specific antigens such as factor
very exceptional tumor, corresponding microscopi- VIII or CD31.
cally to its well-known soft-tissue counterpart. It Angiosarcoma may rarely occur as a primary CNS
is positive for desmin and smooth muscle actin by malignancy, often requiring immunohistochemical
immunohistochemistry. Rare examples have been and ultrastructural studies for a definitive diagnosis.
described in HIV-positive immunocompromised Cerebral involvement by Kaposi sarcoma is meta-
individuals; the tumor cells in these cases often static, probably from primary foci in the lungs.
express the EBV genome.
Rhabdomyosarcoma may arise within the menin- 2.3.2.3 Primary melanocytic lesions These
ges or CNS parenchyma, and virtually all are histo- are relatively rare tumors that originate from mela-
logically of the embryonal type, consisting primarily nocytes located within the leptomeninges. They
of small cells that show little or no myogenic dif- can present either as circumscribed or diffuse
ferentiation on H&E staining. Thus immunohis- tumors and may be benign or malignant. Three
tochemistry (tumor cells reactive for myoglobin, major categories are recognized: (1) diffuse mela-
desmin, and muscle-specific actin) and/or elec- nosis and melanomatosis, (2) melanocytoma, and (3)
tron microscopy (demonstration of myofilaments malignant melanoma. The first category is associated
arranged in sarcomeres) is usually required for diag- with a rare childhood phakomatosis known as neu-
nosis. Primary CNS rhabdomyosarcoma should be rocutaneous melanosis, which in addition to the CNS
distinguished from other tumors that may occasion- lesion is characterized by numerous large congeni-
ally show skeletal muscle differentiation, such as tal cutaneous nevi. The histological diagnosis of all
medulloblastoma with myogenic differentiation. of these lesions rests on confirmation of their mela-
nocytic nature, which is most easily achieved by
2.3.2.2.4. Osteocartilaginous tumors Chondroma, demonstrating immunohistochemical reactivity for
osteoma, and osteochondroma are benign osteocartilagi- S100 protein and one of the melanocytic markers,
nous tumors, commonly arising from the bones of the HMB45 and/or MART-1. The differential diagno-
skull base or spine. Their histology is similar to that of sis of a primary CNS melanocytic lesion must also
their more frequent systemic counterparts. include (1) metastatic melanoma from another pri-
Chondrosarcomas are preferentially located in mary site (which may be occult) and (2) occasional
the petrosal, occipital, or sphenoid bone. They are primary CNS tumors (e.g., schwannoma, menin-
histologically classified in four subtypes of increas- gioma, medulloblastoma) that may show melano-
ing malignancy: grade I, grade II, mesenchymal, cytic differentiation.
and myxoid. Examples located at the skull base
must be distinguished from chordomas (especially 2.3.2.4 Hemangioblastoma (WHO grade I)
so-called chondroid chordomas); thus immuno- Hemangioblastomas account for approximately 1%
histochemistry is of paramount importance. S100 to 2.5% of all intracranial tumors. They are encoun-
protein is expressed in both tumors, but chordomas tered at any age but are seen most frequently in
are vimentin-negative and EMA and cytokeratin- young and middle-aged persons. They are most
positive, whereas chondrosarcomas are vimentin- often situated in the cerebellum; indeed, they rep-
positive and EMA and cytokeratin-negative. resent approximately 7% of the primary tumors

originating in the posterior fossa. In addition, they that have been emptied of their lipid contents as a
may be found within the parenchyma of the spinal result of the embedding procedure. Mitoses are rare.
cord, in the medulla oblongata, and, exceptionally, A fine network of reticulin fibers surrounds the cap-
in the supratentorial compartment. illary blood vessels and individual stromal cells. The
Although hemangioblastomas are often demon- endothelial cells express factor VIII, CD31, CD34,
strably or apparently solitary, in approximately 25% and VEGF receptor. The stromal cells do not express
of cases they are multiple and, in that setting, they endothelial cell markers, GFAP, EMA, or cytokera-
permit the diagnosis of von Hippel-Lindau (VHL) tin, but they do express vimentin and VEGF. In
disease. This inherited autosomal dominant con- some cases, these immunohistochemical charac-
dition is caused by mutations of the VHL tumor teristics may be helpful in distinguishing between
suppressor gene located on chromosome 3p. The hemangioblastoma and metastatic clear cell renal
diagnosis of VHL disease is based on the presence carcinoma. Approximately 10% of hemangioblasto-
of a CNS or retinal hemangioblastoma, associated mas will have foci of extramedullary hematopoiesis,
with a known family history, or with a pheochro- most likely due to erythropoietin production by the
mocytoma, clear cell renal carcinoma, pancreatic stromal cells.
tumor, or endolymphatic sac tumor of the inner ear. The histogenesis of hemangioblastoma remains
Macroscopically hemangioblastomas are well unresolved, primarily due to uncertainty about the
circumscribed and very often cystic; they some- nature of the neoplastic stromal cell component
times consist solely of a small mural nodule attached of the tumor. Although these cells had long been
to the wall of a considerably larger cyst. The fairly regarded as being derived from capillary endothe-
characteristic yellow color is due to its abundant lial cells, this has never been proved. More recently
lipid content. In addition, the tumor is usually vas- the stromal cells have been found to express pro-
cularized and drained by well-developed vascular teins characteristic of embryonic progenitor cells
pedicles, which in some cases may erroneously sug- associated with hemangioblastic differentiation.
gest an associated arteriovenous malformation. This From the molecular standpoint, inactivation of the
rich vascularization accounts for the frequency of VHL tumor suppressor gene and subsequent loss
bleeding within the tumor. of function of VHL and VHL elongin BC results in
The histological picture of hemangioblastoma is abnormal ubiquitination of hypoxia inducible fac-
highly characteristic, consisting of numerous capil- tor (HIF), which in turn leads to overexpression of
lary blood vessels of different sizes separated by tra- several hypoxia-inducible genes, including VEGF,
beculae or sheets of clear cells (stromal cells) with erythropoietin and PDGF, which have been related
round or elongated nuclei(Fig. 2.15). These stromal to the development of various angiogenic tumors.
cells, which are considered the neoplastic compo- Hemangioblastomas are histologically benign
nent of the tumor, often have a spongy appearance tumors (WHO grade I) and have a low Ki-67 pro-
due to an abundance of intracytoplasmic vacuoles liferation index (less than 2%), but postoperative
recurrences occur if incompletely resected. The
prognosis in patients with VHL is somewhat less
favorable due to the occurrence of multiple tumors.
3. LYMPHOMAS AND
HEMATOPOIETIC NEOPLASMS
3.1. Lymphomas
3 .1 . 1. PRIM ARY CN S LYM PHOM AS
Primary CNS lymphomas (PCNSLs) are by defini-
tion confined to the brain, spinal cord, eyes, or lep-
tomeninges without evidence of lymphoma outside
the CNS. They occur in two distinct clinical popu-
FIGURE 2.15 Hemangioblastoma. Microscopic lations: immunocompetent and immunosuppressed
appearance (H&E). patients. In immunocompetent patients, PCNSL
is uncommon, accounting for approximately 4% to immunophenotyping of the diffuse large B-cell vari-
5% of all primary CNS tumors and 1% to 2% of all ant of PCNSL has shown that the majority stain
non-Hodgkin lymphomas. In this group, they tend for bcl6, MUM1/IRF4 (a marker of late germinal
to occur in older adults, with a slight male prepon- center/post-germinal center stage of differentia-
derance. In immunodeficient patients, most cases tion), and SHP1 (a non-germinal center marker).
of PCNSL occur in the setting of HIV infection, but PCNSLs are negative for CD138 (a plasma cell
they can also occur in immunosuppressed transplant marker). Ki-67/MIB-1 proliferation indices may
recipients, patients with autoimmune disorders, vary from 20% to more than 90%. Almost all cases
and patients with congenital immunodeficiency of PCNSL in immunocompromised patients show
syndromes. Recently the occurrence of PCNSL expression of the EBV genome in tumor cells.
in HIV-infected individuals has been diminishing The origin of PCNSL remains uncertain.
due to the effects of highly effective antiretroviral Lymphoid cells are normally quite sparse in the
therapy. For unexplained reasons, the incidence of CNS, and it is unclear whether neoplastic trans-
PCNSL in older immunocompetent patients has formation of these cells occurs within the CNS or
been increasing. before they enter the CNS. It has been suggested
PCNSLs may occur as either single or mul- that the CNS, as a relatively immune-privileged
tiple masses (the latter more common in immuno- organ, could provide a “safe haven” for circulating
suppressed patients) and can rarely infiltrate the neoplastic lymphoid cells, or alternatively lymphoid
cerebral parenchyma in a diffuse manner (lympho- cells existing within the CNS as part of a chronic
matosis cerebri). PCNSLs can occur almost any- inflammatory reaction could become neoplasti-
where in the CNS, including the spinal cord (very cally transformed. Likewise, the specific type of B
rare) and leptomeninges, but their most frequent cell that gives rise to the diffuse large B-cell variant
site is supratentorially in the deep periventricular of PCNSL is undetermined: immunophenotyping
region (Fig. 2.16A).PCNSLs contiguous with the suggests that the majority of these tumors corre-
subarachnoid space or ventricles can lead to CSF spond to a post-germinal center stage of differen-
dissemination. tiation and are activated B-cell-type lymphomas by
PCNSLs are classified on the basis of their his- gene expression profiling.
tological appearance and immuno- and molecular Patients who present with a CNS lymphoma
phenotype. The vast majority (nearly 95%) are dif- must be staged to exclude systemic lymphoma
fuse large B-cell lymphomas, with the remaining 5% with secondary CNS involvement, and this should
being T-cell lymphomas, low-grade B-cell lympho- include ophthalmologic examination due to the
mas, and Burkitt lymphomas (rare). The CNS is high frequency of concurrent ocular involvement
involved in about one third of cases of intravascular in PCNSL and spinal fluid examination for possible
lymphoma, most of which are large B-cell lympho- CSF dissemination of lymphoma. The management
mas. Histologically the diffuse large B-cell variant of PCNSL currently emphasizes limiting surgery to
of PCNSL consists of dense aggregates of relatively biopsy only rather than removal of the tumor, with
large atypical lymphoid cells (mainly centroblasts treatment primarily being radiation and chemother-
with variable numbers of immunoblasts), which apy (especially methotrexate); this approach has
are frequently centered around blood vessels and extended median survivals of PCNSL to the 2.5- to
associated with prominent perivascular reticulin 5-year range.
hoops (Fig. 2.16B, C). Disseminated small infarcts
are commonly present, and the parenchyma adja-
3.1.2 . SECONDARY CNS INVOLVEMENT
cent to the main tumor may show variable num-
BY SYSTEMIC LYMPHOMAS AND
bers of reactive T cells, macrophages, and gliosis.
LEUKEMIAS
Immunohistochemical and molecular phenotypic
analysis is now routinely used to further character- Secondary involvement of the CNS by systemic non-
ize the biological behavior, prognosis. and response Hodgkin lymphoma is more common than PCNSL,
to therapy of PCNSL. Most CNS diffuse large B-cell with an incidence ranging from 2% up to 27% (usu-
lymphomas typically express the leukocyte com- ally around 5%). Leukemias (especially acute lym-
mon antigen (CD45), pan-B cell antigens (e.g., phoblastic leukemia/lymphoma) also involve the
CD20), and monotypic immunoglobulin (almost CNS relatively frequently. The propensity for CNS
all PCNSLs are IgM positive). More detailed involvement by these hematopoietic neoplasms is

A B
FIGURE 2.16 Primary CNS lymphoma. (A) Tumor in periventricular white matter (gross). Microscopic fea-
tures: (B) Perivascular localization of tumor cells (H&E). (C) Immunoreactivity of neoplastic lymphoid cells for
B-cell marker (CD20).
most often a function of the specific tumor type and the CNS most often occur in children and are rare,
stage of the disease. Diffuse large B-cell lymphomas with a 0.5% incidence of involvement by LCH; the
are the most likely lymphoma subtype (greater than other types are distinctly rarer. The etiology of these
80%) to secondarily involve the CNS. They usually tumors is unknown and in most patients there may
manifest as dural or leptomeningeal disease with occa- be only mild or no known abnormality of immune
sional superficial cortical involvement, in contrast to function. Regardless, it is likely that abnormal T-cell/
PCNSLs, which more often present as deep periven- macrophage interaction or other immune-regulation
tricular lesions. Hodgkin lymphoma rarely involves abnormalities underlie these disorders. Viral infec-
the CNS and most often occurs in the setting of a tion, especially by EBV, is associated with some forms
relapse with widespread concurrent systemic disease. of hemophagocytic lymphohistiocytosis.
3.2. Histiocytic Tumors 3 .2 . 1. LAN GERHAN S CELL

H I STIOCYTOSIS
The common histological feature of this relatively het-
erogeneous group of tumors is the presence of histio- LCH involving the CNS occurs most often in chil-
cytes, which occurs primarily as dendritic Langerhans dren and may present in several ways: bone involve-
cells (Langerhans cell histiocytosis [LCH]) or as ment (skull base, craniofacial bones); intracranial
conventional macrophages in the non-LCH vari- extra-axial involvement of pituitary-hypothalamus,
ants. The histopathological features of these tumors meninges, or choroid plexus; and intracranial
in the CNS generally mimic those of their systemic intra-axial involvement of the brain. Histologically
counterparts. As a group histiocytic tumors involving the LCH lesions consist of variable numbers of
eosinophils, macrophages, lymphocytes, plasma 3.2.2 . NON- L ANGERHANS CEL L
cells, Langerhans cell histiocytes, and sometimes HISTIOCYTOSES
Touton giant cells. Abundant collagen may be pres-
This somewhat diverse group of diseases arising
ent. The diagnosis of LCH requires identification of
from mononuclear phagocytes includes intracra-
the characteristic Langerhans cells by immunohis-
nial Rosai-Dorfman syndrome, Erdheim-Chester
tochemistry (reactivity for S100 protein and CD1a)
disease, hemophagocytic lymphohistiocytosis,
and/or electron microscopy (intracytoplasmic
juvenile xanthogranuloma, and xanthoma dissemi-
Birbeck granules). Recent molecular studies have
natum, and also the usually asymptomatic cases of
identified a mutation in the serine/threonine kinase,
choroid plexus xanthoma and xanthogranuloma.
BRAF (V600E), in LCH tumors at multiple sites,
CNS involvement by malignant histiocytic tumors
which may be causative for these tumors.
FIGURE 2.17 Metastatic tumors. (A) Multiple hemorrhagic metastases from melanoma (gross). (B) Lung
carcinoma metastatic to cerebrum (gross). (C) Meningeal carcinomatosis involving cauda equina (gross).
(D) Metastatic adenocarcinoma (lung) involving parenchyma and leptomeninges (H&E).

(e.g., histiocytic sarcoma, follicular dendritic cell well-circumscribed masses, either firm or soft, and
sarcoma) is extremely rare. may have hemorrhage, necrosis, or cystic degenera-
tion within the tumor. Hemorrhagic metastases are
4. SECONDARY (METASTATIC) especially frequent in choriocarcinoma, melanoma,
and renal cell carcinoma. Meningeal involvement
NEOPLASMS (carcinomatosis) may cause diffuse meningeal
This category includes any tumor that originates out- opacification or present as discrete nodules, which
side the CNS and spreads secondarily to the CNS can conspicuously involve the spinal nerve roots of
either via the hematogenous route (metastasis) or the cauda equina. Dural involvement can manifest as
by direct spread from adjacent tissues. Metastatic diffuse plaque-like lesions or discrete nodules.
tumors are the most common intracranial and intra- In most cases the histopathological appearance
spinal tumors, occurring in about 25% of patients and immunophenotype of the metastatic tumor
who die of cancer. Their incidence increases with resembles that of the primary source. However,
age. They may occur in virtually any region of the determination of a primary site of origin can be chal-
cranial cavity or spinal canal, including the central lenging in poorly-differentiated or undifferentiated
neuraxis (cerebral hemispheres, cerebellum, brain- tumors or in cases with scant tissue, hemorrhage,
stem, or, less often, spinal cord), spinal or cranial or extensive necrosis. Immunohistochemistry can
nerve roots, choroid plexus, or meningeal cover- prove especially useful in these situations, even in
ings (e.g., meningeal carcinomatosis, spinal epidural what may appear to be significantly “suboptimal”
metastases, dural metastases at skull base or convex- specimens. Published algorithms for the immuno-
ity)(Fig. 2.17A–D). In adults the most common pri- histochemical evaluation of CNS metastatic tumors
mary sources of brain metastases are lung (especially may also be helpful. Even when the primary site is
adenocarcinoma and small-cell carcinoma), breast well-established, immunohistochemical testing of a
cancer, melanoma, renal cancer, and colon cancer. cerebral metastatic tumor for important treatment/
In children, the most common sources are leukemia, prognosis-associated markers (e.g., estrogen and
lymphoma, osteogenic sarcoma, rhabdomyosar- progesterone receptors and HER2/neu in meta-
coma, and Ewing sarcoma. Prostate, breast, and lung static breast carcinoma) may be indicated. Electron
cancer are the most common sources of spinal epi- microscopy may occasionally be helpful in defining
dural metastases. Direct extension of a tumor to the the nature of a metastatic (or primary) CNS tumor
CNS is relatively uncommon by contrast, and most but has largely been supplanted by immunohisto-
are head and neck tumors such as squamous cell car- chemistry. While not yet routine, as whole-genome
cinoma and olfactory neuroblastoma. and multiplexed molecular testing methods have
Macroscopically, CNS metastases may be soli- emerged (e.g., array CGH, expression profiling),
tary but are most often multiple. Their size ranges such tests are showing promise for diagnostically
from less than a millimeter to over several centi- aiding determination of the site of origin for meta-
meters. In the brain parenchyma they are generally static tumors.
3
Central Nervous System Trauma
COLIN SMITH
The various pathological processes that result response. In general, patients with mild head injury
from head injury are now collectively referred to as have a score 13 to 15, moderate head injury a score 9 to
traumatic brain injury (TBI). 12, and severe head injury a score of 8 or less.
Based on clinical and neuroradiological data,
1. CLASSIFICATION OF TBI can be categorized as either focal or diffuse
(multifocal). In individuals with focal damage
TRAUMATIC BRAIN INJURY lesions are detectable by scans and these patients
No single classification of TBI encompasses all the are often responsive to treatment. In unconscious
clinical, pathological, and cellular/molecular fea- individuals with diffuse damage there is wide-
tures of the complex series of process that occur in spread pathology, but not always demonstrable
these cases. In practice, the various classification sys- neuroradiologically.
tems employed have been clinical, pathological, or The neuropathological classification of TBI is
mechanistic or have combined various components based on information derived from postmortem
of these. studies in patients who have had clinical evidence of
The clinical classification of TBI in adults includes neurological disability of varying severity after the
the widely used Glasgow Coma Scale (GCS). The injury. In fatal cases, the extent of clinical impair-
scale is less useful in the assessment of children and is ment ranges from persistent coma from the moment
also not effective in assessing the extent of mild head of injury until death, to normal initial examination
injury. The GCS summarizes the numerical evalua- immediately after injury but subsequent progressive
tion of three clinical parameters (eye response, verbal deterioration and death as a result of complications.
response, and motor response) and results in a score Pathological classifications can be anatomi-
between 3 and 15, 3 being the worst and 15 the best cal, describing injuries as focal or diffuse, or
• 59
Table 3.1. Mechanisms of TBI
MECHANISM M A I N PAT H O L O G Y
Impact Vascular (hemorrhages)
Traumatic axonal injury
Inertial loading Traumatic axonal injury
Penetrating Local tissue necrosis
Blast Brain swelling
pathophysiological, based on primary (occurring caused by the pressure cavities produced by the
at the moment of injury) and/or secondary (occur- projectile passing through brain tissue.
ring in an already mechanically injured brain) • Blast injuries are less well described and are seen
injuries. Secondary damage is often due to com- particularly in military or terrorist situations;
plications that are not unique to trauma but that here, the shock waves from an explosive device
are also seen in association with other intracranial can result in injuries to the brain parenchyma.
diseases.
Mechanistic classifications describe impact, iner- The description of the neuropathology of trau-
tial loading (acceleration–deceleration), penetrat- matic brain injury that is presented in this chapter
ing, and blast injuries (Table 3.1). will consider traditional subdivisions (i.e., focal
and diffuse injuries) (Table 3.2); it will also discuss
• Impact injuries are invariably associated with penetrating and blast injuries, as well as specific
situations where the head makes contact with an pediatric issues and long-term problems associated
object; here the forces of impact are transmitted with TBI.
to the brain,
• Acceleration–deceleration brain injury results from
unrestricted movement of the head, leading to 2. FOCAL INJURY
shear and compressive strains.
While the focal lesions associated with impact are 2.1. Scalp and Skull Lesions
likely to be sustained from a fall or an assault, and
2 .1 . 1. SCALP LESION S
diffuse lesions are more commonly seen in trauma
cases after vehicular accidents, in any given The scalp and skull may be injured by contact injury.
patient, the distribution of lesions is the product The presence of scalp bruising is indicative of con-
of many associated factors; therefore, the inter- tact injury and in some situations may provide clues
pretation of the physical circumstances leading to to the possible intracranial lesions; occipital bruising
the brain damage may be complex and difficult to is typically associated with a backward fall and indi-
interpret. rect “contrecoup” contusions (see below) involving
• Penetrating injuries produce brain damage when the frontal and temporal tips. Incised wounds are
an object passes through the skull and extends usually insignificant and easily managed in the emer-
directly into the underlying brain, causing paren- gency room, but some patients with these types of
chymal damage; in the case of fire arm injuries lesions may have had significant blood loss and
there is an additional element of tissue damage hypotension with consequent brain injury.
Table 3.2. Classification of TBI
FOCAL DIF F USE

Scalp lacerations Global ischemic injury
Skull fractures Traumatic axonal injury/diffuse vascular injury
Contusions/lacerations Brain swelling
Intracranial hemorrhage
Focal lesions secondary to raised intracranial pressure
Table 3.3. Types of Skull Fracture
T YPE DESCRIP TION

Linear Break in bone extending through both the outer and the inner tables of the skull.
No bone displacement.
Depressed Fragments of the inner table of the skull are displaced inwards.
Compound A depressed skull fracture with associated scalp laceration. Complex, or
penetrating, fractures are associated with additional dural tearing.
Hinge (basilar) Fracture extends across the base of the skull.
Diastatic Seen in infants and young children, with a fracture line extending across skull bone
sutures causing widening of the suture.
Growing In infancy, meninges extend through fracture, preventing fracture healing.
2.1.2. SKULL LESIO NS forces more arachnoid through the dural defect,
adhesions form, and what is essentially an enlarg-
The prevalence of skull fractures is directly related
ing, CSF-filled leptomeningeal cyst continues
to the severity of the head injury. In one autopsy
to erode bone, preventing healing. The result is
study, skull fracture was found in 80% of subjects
that the fracture widens as the child gets older
with fatal head injury. Clinical series indicate that
(Fig. 3.1A , B).
skull fractures occur in 3% of patients with mild
head injury at the time of presentation in the emer-
No direct correlation can be drawn between the
gency room and in 65% of patients requiring neuro-
presence or absence of a skull fracture and likelihood
surgical attention.
of an underlying parenchymal brain injury, unless
A description and classification of skull fractures,
the fracture is depressed and the broken bone makes
including linear, depressed, and basilar fractures, is
direct contact with the underlying brain tissue. This
given in Table 3.3.
is particularly true in pediatric practice, where the
pliable skull may not actually fracture, but the dis-
• Fractures of the cranial vault are usually linear and
torted bone may allow for considerable underlying
situated between the bony ridges of the skull.
traumatic brain damage. On the other hand, there
• Fractures of the skull base also include fractures
does seem to be a direct correlation between the
of the vault where the fracture lines radiate toward
presence of a skull fracture and the development of
the base involving the anterior fossa, the middle
intracranial hemorrhages (see further on).
fossa, or the posterior fossa. The impact neces-
sary to cause the fracture is much greater than
that required for other fractures. In these cases,
there may be severe brain damage in addition to 2.2. Contusions and Lacerations
the bone injury. Furthermore, the cranial nerves Contusion is a hallmark of brain damage in head
and blood vessels are also particularly vulnerable injury; it consists of a bruise on the surface of the
in cases of fracture involving the floor of the skull. brain. By definition the overlying pia mater is intact
Finally, patients who survive these injuries may in contusions but torn in lacerations.
develop complications such as ascending infec- Two prototypical types of contusions are recog-
tion or pneumocephalus. nized: “coup contusions” and “contrecoup contu-
• Infants who incur skull fracture may develop sions”. In coup contusions the damaged brain tissue
a characteristic though less common lesion occurs beneath the point of impact; for example,
that has been termed “growing” fracture. The when scalp bruising is over the forehead, the brain
pathogenesis of this lesion is believed to evolve contusions involve frontal and temporal lobes. In
from an initial tear in the dura at the time of the contrecoup contusions, on the other hand, the iden-
injury, through which a small piece of arachnoid tical structural damage to the surface of the brain
becomes extruded and interposed between the occurs in a region diametrically opposite the point
fractured bone edges. Over ensuing months and of external impact—e.g., bruising in the occipital
years, pulsation of the cerebrospinal fluid (CSF) scalp after a forehead blow (Fig. 3.2).
Chapter 3 Central Nervous System Trauma • 61

A hemorrhage (DTICH) usually becomes apparent
within 48 hours after the head injury. The precise
mechanism of this form of injury is uncertain but is
thought to reflect increased blood flow or pressure
through a vascular capillary network that is focally
damaged, possibly compounded by posttraumatic
coagulopathy.
Topography: Contusions typically involve the
frontal poles, the inferior frontal lobe including
the gyrus rectus and medial and lateral orbital gyri,
the temporal poles and lateral and inferior aspects
of the temporal lobes, and the cortex above and
below the Sylvian fissure. Fracture contusions may
be seen at atypical sites in direct relationship to a
B skull fracture. Contusions typically involve the
crests of gyri and are often superficial, involving the
gray matter only. However, the lesion may be found
to extend into underlying white matter and develop
into a hematoma. In severe cases, extensive lacera-
tion injury with underlying parenchymal hemor-
rhage may be associated with subdural hemorrhage,
forming a so-called burst lobe. This type of injury
involves most often the temporal lobes.
On neuropathological examination, the smallest
contusions are merely collections of minute peri-
vascular hemorrhages in the cortex, often only a
few millimeters in diameter, without any edema
(Fig. 3.3A , B). Larger contusions contain areas of
tissue destruction as well as hemorrhage and are
often associated with focal swelling. In the weeks
after an injury, on macroscopic examination the
affected brain appears abnormally pigmented and
is shrunken (Fig. 3.4). Over time, the hemorrhage
FIGURE 3.1 An arrested growing fracture found in and the dead tissue are removed by macrophages
a woman of 38. When asked about childhood injuries, and there are foci of gliosis, often with associated
she remembered having been told she fell out of her hemosiderin deposition. Old contusions are not
carriage as a very young child. (A) Plain skull x-ray. infrequent incidental autopsy findings, particularly
(B) The excised portion of bone. in at-risk groups, such as patients with chronic alco-
holism. The lesion can usually be distinguished from
an old infarct because the topographic distribution
Coup lesions may follow a fall forwards, contre- is typically on the ventral surface of the frontal and
coup lesions a backwards fall, or underlying frac- temporal lobes and can overlap multiple vascular
tures. Contusions involving the occipital lobes and territories. In addition, the lesion is characteristi-
cerebellum are rare, perhaps in part because the cally wedge-shaped, with the base on the crest of the
adjoining smooth inner surface of the posterior cortical gyri and apex in white matter, and there is
fossa of the skull offers less attrition as compared often evidence of previous hemorrhage.
with the irregular bony ridges of the anterior and
middle fossae. These lesions are usually associated
with an adjacent skull fracture.
The size of a contusion may increase over
2.3. Intracranial Hemorrhage
time, some hours after the initial head injury. This Intracranial hemorrhages are classified according to
phenomenon of delayed traumatic intracerebral the anatomical compartment in which they develop.
A B
C D
FIGURE 3.2 Typical patterns of distribution of contusion injury, showing contusions related to the site of
impact (“coup”) and contusions away from the impact (“contrecoup”). (From Courville CB. Pathology of the
Central Nervous System. 1937.)
2.3.1. EXTRADURAL (EPIDURAL) to the underlying middle meningeal artery or vein.

HEMORRHAGE Subsequent to the fracture, the dura (periosteum) is
stripped from the inner table of the skull to form a
An extradural hemorrhage (EDH) is an extravasa- circumscribed ovoid mass, producing an extradural
tion of blood between the inner table of the skull space that is then filled by blood (Fig. 3.5). Other
and the dura. It is composed of a dense blood clot sites of involvement include the anterior cranial
that tends to adhere early and firmly to the dura. fossa (damage to the anterior meningeal artery),
EDHs are limited in size; the bleeding remains parasagittal region (superior sagittal sinus), and
localized to this space. EDH most commonly occipital lobe and posterior fossa (damage to the
(approximately 50%) results from fracture of the occipital meningeal artery or transverse or sigmoid
squamous temporal bone causing contact damage sinuses). EDH has also been described in relation to
A B
FIGURE 3.3 Small intracortical contusions in typical sites at the base of frontal (A) and temporal lobes (B).

FIGURE 3.5 Gross appearance of a classical
extradural hematoma situated in the parietotemporal
region.
and outer layer of the arachnoidal layer (arachnoid

FIGURE 3.4 Old contusions on the base of the cap cell layer). This is a potential space, not an ana-
frontal lobes. (Reproduced with the permission tomical space; during life the two layers are apposed.
of Springer-Verlag, from Geddes JF, Whitwell HL. Bleeding that occurs underneath the dura results in
Head injury in routine and forensic pathological the physical separation of the inner surface of the
practice. In Love S (ed). Current Topics in Pathology: dura from the outer surface of the arachnoid. .
Neuropathology. Vol. 95. Berlin: Springer-Verlag, After blunt force head injury, acute SDH may
2001:101–24.) be due to rupture of a bridging vein (cortical vein
passing from the cortical surface to a dural sinus)
the internal carotid artery before it enters the intra- or, probably more commonly, secondary to contu-
cranial dura. Spontaneous EDH has been described sions with damage to cortical veins or arteries and
in association with vascular malformation, infec- the overlying leptomeninges. In this latter situa-
tions, and rarely as a complication of malignancy tion there may be an associated intracerebral hem-
and anticoagulation therapy. orrhage and the term “burst lobe” is applied (cf.
In up to 30% of cases, EDH may be associated supra). Occasionally, the subdural bleeding results
with a “lucid interval”. In patients with this clini- from the rupture of a cortical artery rather than a
cal phenomenon, there may be a period of vari- vein. Previous head injury with subdural adhesions,
able duration after the head injury with normal which tend to limit displacement of the brain within
neurologic function, prior to the development of the cranial cavity, may predispose to this type of
an often-rapid clinical decline. This syndrome has injury.
been presumed to be the consequence of the rapid Experimental studies in nonhuman primates
volumetric expansion of the EDH. Indeed, in the have demonstrated that, biomechanically, acute
absence of surgical evacuation of the hematoma, SDHs secondary to torn bridging veins occur in a
extension of the EDH results in a “space-occupying” setting of rapid acceleration–deceleration injuries.
lesion with concave deformation of the underly- This is consistent with the recognized association
ing brain, midline shift and axial displacement; between SDH and falls or assaults in human beings,
increased intracranial pressure and brain herniation both situations in which there is a rapid acceleration
can be the terminal event. or deceleration of the head on impact. Patients with
SDH may also develop the clinical phenomenon of
a lucid interval as defined above. Rarely, a SDH may
occur in the setting of a ruptured cerebral saccular
2. 3. 2. S UBDUR AL H EM O R R H A G E
aneurysm with extension into the subdural space.
Subdural hemorrhages (SDH) develop within the SDH may follow an episode of relatively trivial
subdural space, which is located between the dural head injury, and in 25% to 50% of cases there is no
history of trauma. This is particularly the case in Secondly, multiple episodes of rebleeding within a
patients with brain atrophy, in whom the bridging subdural hematoma are known to occur not infre-
veins are presumably stretched out and therefore quently, making problematic definitive judgment of
potentially more vulnerable to tearing. Medical the age of the lesion. The process of resolution of a
conditions associated with SDH include anticoagu- SDH starts with proliferation of arachnoidal cells
lation therapy, intracranial shunting procedures, epi- over the surface of the hematoma, which eventually
lepsy, alcohol abuse, and, rarely, intracranial tumors. becomes encapsulated in a fibrous membrane. In the
Pathologically, SDH can be separated into acute early stages, numerous thin-walled capillaries grow
(Fig. 3.6A , B), subacute (Fig. 3.6C), and chronic into the edges of the clot. Rebleeding from these
(Fig. 3.7) forms. Notwithstanding this empiric sub- blood vessels may cause a resolving hematoma to
division, it is often most difficult to be absolutely enlarge and produce symptoms. The usual end stage
certain of the exact age of a hematoma using radio- of the involution of SDH is a collapsed, pigmented,
logical, intraoperative, and/or histological criteria. membranous sac adherent to the undersurface of
The reasons for this predicament are multiple and the dura.
complex. In the first place, although it may be pos- At postmortem, the subdural blood extends
sible to give the time of onset of an episode of acute within the subdural space; the dura is tense and
SDH, radiological imaging studies have demon- blood can be seen underneath the dura. This fresh
strated that in many patients, acute SDHs involute blood spills out when the dura is incised at surgery or
spontaneously and do not become chronic lesions. autopsy (Fig. 3.6A , B). In subacute lesions the blood
A B
FIGURE 3.6 Acute and subacute subdural hematomas. Acute subdural hematoma: gross appearance before
(A) and after (B) incision of the dura. (C) Subacute subdural hematoma: gross appearance.

clot shows at least focal attachment to the dura, and such a patient, who may be predisposed to develop
there may be early golden-brown color change due subdural bleeding because of cerebral atrophy, there
to hemosiderin (Fig. 3.6C). Chronic subdural hemor- may be no history of preceding trauma, and the clin-
rhage refers to a clot that is encapsulated in fibrous ical signs develop slowly because there is a relatively
membranes. Magnetic resonance imaging (MRI) large subdural space to accommodate the blood.
is the most sensitive method of demonstrating the With time, the fibrous tissue encapsulating the
heterogeneous nature of such lesions (Fig. 3.7A), hematoma becomes very thick (Fig. 3.7B, C). By the
and MRI scans suggest that chronic subdurals may time the patient comes to medical attention, there
be either old hemorrhages undergoing resolution may be considerable distortion and compression of
or chronic lesions into which acute rebleeding has the underlying cerebral hemisphere (Fig. 3.7D).
occurred.
A unilateral—or sometimes bilateral—SDH is
2 .3 . 3. SUBDURAL HYGROM A
not uncommonly found in the radiological evalu-
ation of an elderly person being investigated for A subdural hygroma is a collection of CSF within the
fluctuating confusion or subtle cognitive decline. In subdural space. The lesion may be associated with
A B
C D
FIGURE 3.7 Chronic subdural hematomas. (A) MRI showing a unilateral chronic subdural hematoma, not
causing midline shift, but flattening the left hemisphere) Old organized subdural hematoma, gross appearance
after removal of the dura. (C) The brain of a 6-year-old child with cerebral palsy: bilateral chronic subdurals,
encapsulated by a thick collagenous membrane resembling dura. (D) After removal of the hematomas, both
hemispheres are seen to be markedly flattened.
trauma, chronic SDH in adults, or infection in infants contusion may develop some time after the initial
or may be seen after ventricular shunting. In the major- traumatic insult, and this phenomenon may be wit-
ity of these cases, the lesion is not clinically signifi- nessed clinically when a patient is observed to dete-
cant; however, some patients with subdural hygroma riorate several hours after the initial head injury.
develop acute neurological deficits after a traumatic Deep-seated ICH in the region of the basal gan-
injury that may mimic acute SDH. The two types of glia may be seen in a high-velocity blunt force head
lesions can be distinguished by MRI. At surgery or injury, such as is seen in road traffic accidents. If
autopsy, subdural hygroma fluid is clear or xantho- extensive, it can be difficult to distinguish them from
chromic and not associated with a fibrous membrane. a primary hypertensive hemorrhage. However, in
motor vehicle accidents, the more typical lesions are
the small parenchymal hemorrhages in the region
2.3.4. SUBARACHNOID HEMORRHAGE of the diencephalic structures. These are considered
Within the setting of blunt force head injury, sub- to be part of the spectrum of lesions associated with
arachnoid bleeding is commonly observed and rotational damage (Fig. 3.8A), including diffuse trau-
typically associated with damage to cortical veins matic axonal injury and diffuse vascular injury. In
located in the subarachnoid space, or related to sites themselves, these hemorrhagic lesions do not pro-
of contusions. The autopsy finding of basal sub- duce a significant mass effect but rather are an indica-
arachnoid hemorrhage (SAH) is most often second- tion that severe parenchymal damage has occurred.
ary to intraventricular bleeding (see further on). Parasagittal white matter lesions, also known
In general, the development of subarachnoid as gliding contusions, are hemorrhagic lesions seen
bleeding, in itself, is not necessarily of adverse clini- predominantly in frontal parasagittal white mat-
cal/prognostic significance in traumatic injury. ter (Fig. 3.8B). As deep-seated hemorrhages,
Occasionally, traumatic damage to an artery at they are secondary to rotational forces and severe
the base of the brain or at the craniocervical junc- head injury. These lesions are often symmetrical,
tion may produce abundant arterial subarachnoid and when the interval of time between the initial
bleeding. Such extensive basal hemorrhage can injury and postmortem examination is prolonged,
mimic a ruptured berry aneurysm and should be they evolve into a gliotic scar with surrounding
excluded by angiography or at postmortem by care- hemosiderin-containing macrophages (Fig. 3.8C).
ful examination. It is typically seen in the setting
of vertebral artery trauma. The bleeding originates
2.3.6 . INTRAVENTRICUL AR
from the extracranial vertebral arteries. This is well
HEM ORRHAGE
described following a blow to the under-aspect of
the jaw resulting in tearing of the vertebral artery. Intraventricular hemorrhage is relatively uncom-
The clinical picture is one of sudden collapse and mon in blunt force head injury, but when present,
coma, usually with a short survival period. At post- it carries the risk of acute hydrocephalus. Blood
mortem examination, the site of origin of the mas- within the ventricular system may be a consequence
sive bleeding may be difficult to identify. However, of direct extension of a parenchymal hemorrhage
when the vertebral arteries are carefully dissected into the ventricular system or of retrograde flow of
from the point at which they enter the foramina subarachnoid hemorrhage. In rare cases, there is
transversaria at the low cervical vertebrae and fol- isolated intraventricular hemorrhage with no obvi-
lowed up to the point where they leave the vertebrae ous source of primary bleeding. In these cases the
and enter the base of the skull, the site of traumatic hemorrhage is considered to be from subependymal
rupture, or the identification of a pseudo-or dissect- veins, choroid plexus, or damage to the septum pel-
ing aneurysm, will be found in most cases. lucidum and forniceal vessels.
2.3.5. INTRACEREBRAL HEMORRHAGE

2.4. Other Focal Lesions
Intracerebral hemorrhage (ICH) may be found at
2.4.1 . VASCUL AR
autopsy in association with contusions and may
attain sufficient size to cause mass effect with asso- Large blood vessels may be damaged as a conse-
ciated shift of midline structures. As discussed quence of blunt force head injury. Posttraumatic
above, in some cases, hemorrhagic expansion of a pseudo-aneurysms may involve both the external

A B
FIGURE 3.8 Severe head injury. (A) and (B) show gliding contusions in the parasagittal white matter, on
the left, and small hemorrhages in the corpus callosum. There are also small parenchymal hemorrhages in the
diencephalic structures (A). In a patient unconscious after head injury, such lesions are the hallmark of severe
DAI. Chronic lesions may form scars with surrounding hemosiderin-containing macrophages (C); note that the
lesions are often symmetrical.
and internal carotid arteries and are thought to be hemorrhages) or are part of diffuse traumatic axonal
a consequence of stretching of the blood vessel after injury with a dorsolateral localization.
neck injury. Vessel wall dissection is described after
trauma involving most large arteries, and symptoms
develop over several hours as a consequence of 3. DIFFUSE BRAIN INJURY
thrombus formation (Fig. 3.9).
Diffuse lesions in TBI include diffuse ischemia,
diffuse traumatic axonal injury (TAI), and diffuse
2. 4. 2. BRAI NS T E M L ES I O NS brain swelling. In the absence of a demonstrable
mass lesion, persistent coma after head injury can be
A number of brainstem lesions are described in the
assumed to be a consequence or either TAI or dif-
setting of blunt force head injury. At the most severe
fuse ischemia, or a combination of both.
end, there is pontomedullary rent, a lesion incompat-
ible with life. A tear is seen at the junction between
the lower pons and medulla, and histologically tis-
sue damage can be identified. Such lesions are rare
3.1. Ischemia
and are associated with high-velocity lesions causing Ischemic brain injury may be focal or diffuse. Either
extreme hyperflexion- or hyperextension-type inju- form of injury is a common finding in fatal traumatic
ries, such as falls from a height or motorcycle acci- brain injury and was found to be present in 91%
dents with primary head impact. of brains studied in one autopsy study. Ischemia
Hemorrhages within the brainstem are second- remains an important factor in determining clini-
ary to axial displacement causing large midline cal outcome after head injury. Early stabilization of
hemorrhages in the midbrain and pons (Duret patients reduces the incidence of focal hypotensive
vegetative state in survivors of head injury. In cases
of diffuse TAI there is always a period of uncon-
sciousness; this period may be short, or one of
prolonged coma.
Experimental studies have shown that TAI is pri-
marily a non-impact phenomenon, resulting from
angular or rotational acceleration. This is in keep-
ing with the circumstances in which TAI primar-
ily occurs in human injuries—namely, road traffic
accidents and falls from a height. In such situations,
TAI is primarily the result of inertial phenomena,
and there is a lower incidence of impact lesions and
skull fractures. TAI is also found occasionally in fatal
cases following accelerated falls from standing, nota-
FIGURE 3.9 A man of 31 developed a large right
bly assaults, but in these cases, impact phenomena
middle cerebral artery territory infarct after an assault play an important role, and a skull fracture is much
and died 2 days later of raised intracranial pressure. more usual.
The cause of the infarct was traumatic dissection of the
right middle cerebral artery with occlusive thrombus
(arrow). 3.2.1 . MACROSCOPIC ASPECTS OF TAI
In the most severe cases of TAI, hemorrhagic
lesions are seen in the lateral aspects of the corpus
brain injury but not of diffuse ischemic injury. There callosum and dorsolateral quadrant of the brain-
are a number of causes of ischemia after head injury stem. Three grades of TAI have been described. In
(Table 3.4), and many types of lesions may be seen, Grade 1 lesions, there are only microscopic changes
including neuronal injury within selectively vulnera- in the white matter of the cerebral cortex, corpus
ble areas documented on microscopic examination, callosum, brainstem, and cerebellum. In Grade 2
and infarcts, involving watershed areas or within lesions, macroscopically visible focal lesions are
major arterial territories. present in the corpus callosum only (Fig. 3.10A). In
Grade 3 lesions, additional focal lesions are seen in
the dorsolateral quadrants of the rostral brainstem
3.2. Diffuse Traumatic Axonal Injury (Fig. 3.10B).
The term diffuse axonal injury (DAI) was introduced
to apply to the structural lesions of axons found at
autopsy examination that follow severe traumatic 3.2.2 . MICROSCOPIC ASPECTS OF TAI
injury. By definition, the phenomenon occurs in the A recommended protocol for microscopic assess-
absence of focal lesions. It may be seen in fatal cases ment of TAI is presented in Table 3.5.
of progressively severe coma or in patients surviv-
ing head injury who manifest severe disability,
eventually evolving into vegetative state. Nowadays, Table 3.4. Patterns and Causes of
the term DAI is used primarily in clinical practice Ischemic Brain Damage After TBI
to apply to the clinical syndrome and supporting
neuroradiological data. The term currently used to PAT T E R N CAUSE
apply to the neuropathological substrate of DAI is
traumatic axonal injury (TAI). TAI contributes to Diffuse Cardiorespiratory arrest
at least 35% of the mortality and morbidity of TBI Focal Raised intracranial pressure
cases that do not have associated space-occupying Vasospasm
lesions and also contributes to the mortality and Hypotension
morbidity in focal brain injuries. In addition, along Embolism
with diffuse ischemic injury, TAI is considered
Penetrating injuries
to be an important cause of severe disability and

A Originally, trauma-induced axonal injury was
thought to be the result of axonal disconnection at
the time of the impact (primary axotomy), lead-
ing to axonal retraction and axoplasmic pooling.
However, current opinion, based on experimental
studies, offers an alternative view. The applied forces
affect axons focally, resulting in mechanoporation
(i.e., mechanically-induced membrane pores) with
calcium influx. Calcium influx results ultimately in
the activation of calcium-dependent proteases and
B caspases. There is modification of neurofilament
subunits, particularly in relation to the phosphoryla-
tion of side arms, resulting in microtubule compac-
tion causing local axonal transport impairment and
axonal swelling. Over time this is followed by rup-
ture of the axon.
On routine histological preparations (e.g.,
stained with H&E), the damaged axons can be
seen as eosinophilic swellings (Fig. 3.11A). Several
special histological techniques have been used
to demonstrate them to better advantage. The
abnormal axons can be detected by silver stains
and, in affected long white matter tracts, using the
appropriate stain techniques for demonstration of
myelin breakdown products. The relative disadvan-
tage of these techniques is that the abnormal axons
can only be demonstrated after a survival period
of at least 12 to 18 hours. Immunostaining for
beta-amyloid precursor protein (ß-APP), which is
able to detect axonal flow disruption, is the most
sensitive and widely used method (Fig. 3.11B).
ß-APP, a membrane-spanning glycoprotein and a
normal component of neuronal cells, is transported
along axons by fast transport mechanisms. When
there is axonal transport interruption, ß-APP has
been shown to accumulate, indicative of dysfunc-
tion or possibly rupture of the axon. ß-APP accu-
mulation has been demonstrated in subjects who
have survived for a period as short as 35 minutes
from the time of injury.
ß-APP accumulation is well known to occur in
many other conditions that cause axonal damage
(e.g., ischemia). In the context of TBI, the topo-
graphic pattern of axonal injury is rather distinctive.
Because of the anatomical orientation of certain
FIGURE 3.10 Macroscopic aspects of traumatic white matter bundles (namely the corpus callosum,
axonal injury. Hemorrhagic lesions in the lateral internal capsule, cerebellar peduncles, and descend-
aspects of the corpus callosum (A) and in the upper ing long tracts in the brainstem), these tracts are
brainstem (B). Note that the lesions in the dorsolat- particularly vulnerable in TBI (Fig. 3.11A , B). In
eral quadrant of the brainstem are very different from ischemia, axonal injury and ß-APP accumulation
the brainstem hemorrhages seen as a result of raised does not follow this pattern of white matter damage;
intracranial pressure and brain shift. rather, it involves all fiber tracts within the ischemic
Table 3.5. Histology in Cases Where Diffuse Brain Injury Is Suspected
R E C O M M E N D E D M I N I M U M S A M P L E F O R A D I A G N O S I S O F TA I +
Corpus callosum with adjacent parasagittal cortex and white matter
Deep gray matter including posterior limb of internal capsule
Temporal lobe including hippocampus
Genu (anterior sections) of corpus callosum
Cerebellar hemisphere including the dentate nucleus
Midbrain at the level of the decussation of the superior cerebellar peduncles
Pons at the level of the middle cerebellar peduncles
Medulla
R E C O M M E N D E D S TA I N S * *
Survival < 12 hours H&E, β-APP
Survival > 12 hours H&E, β-APP, silver preparation, CD68¶
Survival > 1 week H&E, β-APP, silver preparation, CD68
Survival > 6 weeks H&E, CD68
O T H E R U S E F U L S TA I N I N G M E T H O D S
Method Demonstrates
Perls hemosiderin
Reticulin stain, hematoxylin van Gieson organization of a subdural hematoma
Cresyl-fast violet microglial “clusters” or “stars”

Modified PTAH‡, Marchi method secondary long tract degeneration
+
Blocks to beas large as possible; if only small blocks are taken, bilateral samples are recommended
** Survival times given as an approximate guide
¶
CD68 in short-survival cases may show (i) evidence of a previous TAI; (ii) selective cortical or hippocampal damage from an
episode of global hypoxia
‡
A modification of the routine PTAH stain that eliminates myelin staining (Manlow A, Munoz DG. A non-toxic method for the
demonstration of gliosis. J Neuropathol Exp Neurol 1992;51:298–302)
regions. Often a zigzag pattern can be seen in isch- 3.2.3 . AXONAL INJURY IN MIL D
emic injury. In some cases the degree of ischemic HEA D INJURY
axonal injury may be so severe that it is not possible
After mild head injury, axonal pathology has been
to comment on the presence or absence of TAI.
detected in patients who have died from unrelated
There is a sequence of cellular responses that
causes relatively soon after the insult. In these cases, the
evolves over time following TAI injury. In general, at
axonal injury was seen in the corpus callosum and for-
5 to 10 days’ survival after injury, microglial activa-
nices; it has been suggested that the forniceal pathology
tion is first noted and followed by the formation of
may be particularly relevant to posttraumatic amnesia.
microglial “clusters” or “stars” around degenerating
axons. There is nevertheless some variability from
case to case as axonal degeneration is a continu-
3.2.4 . F OCAL AXONAL INJURY
ing process. Eventually, the swellings are no longer
detectable by any technique; the microglial nod- Focal axonal injury (AI) is characterized by scattered
ules remain as the only sign of damage. In some foci of damaged axons scattered in various parts of
long-term survivors after widespread TAI, long tract the neuraxis; in the context of TBI, its significance
degeneration can be detected by the traditional is currently uncertain. Focal AI within the brainstem
method of Marchi (Fig. 3.12A) or immunohisto- occurs in the hyperflexion–hyperextension type of
chemically using a macrophage marker (e.g., CD68) injuries. In adults, this abnormality may be seen in
(Fig. 3.12B). With time, glial scarring occurs in the fatal falls or in motorcycle accidents, and in children,
central white matter and long tracts. it is described in abusive head trauma (AHT). Focal

A B
FIGURE 3.11 Microscopic aspects of traumatic axonal injury. (A) Two days’ survival after injury: damaged
axons are easily seen on routine stains. (B) Short survival after head injury: immunohistochemistry for β-APP
delineates damaged axons and reveals early axonal swelling.
AI has been described within the corpus callosum diffuse within one cerebral hemisphere, or diffuse
in the absence of any diffuse process, and its sig- involving both cerebral hemispheres.
nificance is currently uncertain. It is associated with The swelling may be congestive, secondary to
concussive syndromes. an increase in the cerebral blood volume, or due to
edema. The majority of edema in trauma is cytotoxic,
3.3. Diffuse Vascular Injury with only a small component of swelling due to vaso-
genic edema, mostly in focal swelling adjacent to
Diffuse vascular injury is a severe form of rotational contusions. Adjacent to contusions, there is physical
injury seen in fatal head injury with only a short disruption of the tissues, including the blood–brain
survival. Hemorrhagic lesions are seen throughout barrier, and loss of the normal autoregulation within
the brain with a distribution similar to TAI; lesions the local vasculature. Focal brain swelling may be
occur in the frontal parasagittal white matter, basal seen in mild TBI, but diffuse brain swelling is ordi-
ganglia, and brainstem (Fig. 3.13). narily only associated with severe head injury.
3.4. Brain Swelling 4. PENETRATING INJURIES

Brain swelling is a common finding in fatal TBI. The Penetrating injuries are injuries in which an object
swelling may be localized, in relation to contusions, enters the cranial cavity; in strict terms a penetrating
A B
FIGURE 3.12 In sections from a patient with DAI who survived 6 months after injury, secondary long tract
degeneration may be demonstrated by two methods. (A) The Marchi method reveals myelin breakdown prod-
ucts (black) in the long tracts and in the cerebellar peduncles. (B) Immunohistochemistry for CD68 demon-
strates the numbers of foamy macrophages in the corticospinal tracts in a more rostral section of the pons.
A
FIGURE 3.14 Perforating injury by a bullet produc-

ing a hemorrhagic tract through the two cerebral
hemispheres into which the missile extended.
B
extends (Fig. 3.14). High-velocity missiles, such as
bullets, cause considerably more damage, the extent
of the damage being related to the velocity of the
missile. High-velocity military weapons will pro-
duce greater tissue damage than small firearms. As
the missile travels through the parenchyma it will
produce pressure cavities, which can lead to tissue
damage.
5. BLAST INJURIES
Traditionally the study of blast injuries has focused
on the damage caused by blast waves to air-filled
viscera, such as the lungs in the thoracic cavity.
However, increasingly attention has now focused
on the possibility of injury to solid viscera as well,
particularly the brain. The abrupt pressure changes
associated with a blast can lead to a mild head injury,
FIGURE 3.13 Diffuse vascular injury. Widespread in particular to concussion. Long-term clinical
small hemorrhages in the hemispheres (A) and brain- behavioral sequelae (e.g., impaired concentration,
stem (B) of a road traffic accident victim who died of memory difficulties) have been found with a greater
a head injury almost immediately after the accident. frequency in these individuals in particular when
Such widespread damage is believed to be incompat- compared with others exposed to non-blast TBI.
ible with survival. The cellular events that occur in this type of
injury are poorly defined; microscopic examination
injury is one in which the missile enters the cra- of brain tissue has shown microglial and astrocytic
nial cavity but does not exit, whereas a perforating activation.
injury is one where the missile also exits. While
infection is an important complication of almost all 6. CHRONIC TRAUMATIC
penetrating injuries, the actual damage to the brain
is extremely variable and depends on the nature of
ENCEPHALOPATHY
the missile. Sharp objects, such as knives, long nails, For many years, an association has been known
or metal poles, may pierce the skull and extend into between repetitive head injury and the develop-
the underlying brain parenchyma, causing local ment of late neurological sequelae, including severe
damage. They produce a hemorrhagic tract through impairment of cognitive function. Although rare,
the regions of parenchyma into which the missile dementia pugilistica, the neurological syndrome

7. SPINAL CORD INJURIES
Acute spinal cord injury is most commonly seen
in road traffic accidents and in contact sports, or in
the specific setting of rheumatoid arthritis with cer-
vical spine instability, with the risk of atlanto-axial
subluxation. The most usual mechanism of acute
spinal cord injury is vertebral fracture–dislocation,
or a ruptured intervertebral disc. Vertebral body dis-
location may impinge directly on the cord, causing
contusion injury (Fig. 3.16) or, in the most severe
injuries, cord transection.
FIGURE 3.15 Chronic brain damage in a

23-year-old boxer dying from the effects of an acute
subdural hematoma. Immunohistochemistry for tau
protein reveals neurofibrillary tangles and neuropil
threads around a small vessel in the neocortex.
recognized in elderly boxers, is one of the earli-

est described manifestations of chronic traumatic
encephalopathy. Neurodegenerative disorders that
occur more commonly following repetitive head
injury include cerebellar and parkinsonian syn-
dromes. In these patients, neuropathological stud-
ies have demonstrated septum pellucidum damage
(and cavum septum), substantia nigra pallor, and
cerebellar cortical degeneration. Neocortical early
neurofibrillary tangles (often in a perivascular dis-
tribution deep within sulci) (Fig. 3.15), neuro-
pil threads, and diffuse amyloid plaques have all
been described, but not the neuritic plaques seen
in Alzheimer disease. The term chronic traumatic
encephalopathy (CTE) has been used in recent
literature to describe this condition, which has
now been linked to contact sports, such as soc-
cer, American football, and ice hockey, in selected
cases, in some studies.
The association between a single head injury and
subsequent cognitive decline is less well established.
However, epidemiological studies suggest the asso-
ciation is more common in males and is related to
the severity of the head injury. There is likely to be FIGURE 3.16 Trauma at the craniocervical
a genetic influence, and some neuropathological junction—the patient died following transoral exci-
studies of long- term survivors have described an sion of fragments of a fractured odontoid. The lower
increased incidence of Alzheimer-type pathology. medulla and upper cervical segments are compressed.
is central cavitation with the development of a post-
traumatic syrinx.
It is now recognized that some patients with
traumatic spinal cord injury may have no demon-
strable evidence of a radiological or structural
lesion (spinal cord injury without radiographic
abnormality[SCIWORA]); the hypothesis in these
instances is that the patient’s symptoms reflect a
type of spinal cord “concussion”.
8. PEDIATRIC HEAD INJURY
FIGURE 3.17 Subdural bleeding in an infant
with a head injury, believed to have been inflicted. Fatal head injury is not common in young chil-
As in this case, severe brain swelling is the usual dren. Pediatric head injury after the age of 9 to
immediate cause of death. (Reproduced with the 12 months very much reflects adult patterns of
permission of Springer-Verlag, from Geddes JF, head injury; that is, focal and diffuse injuries deter-
Whitwell HL. Head injury in routine and foren- mined by the force and direction of the impact.
sic pathological practice. In Love S (ed). Current Most injuries in this age group are due to falls or
Topics in Pathology:Neuropathology. Vol. 95. road traffic accidents.
Berlin: Springer-Verlag, 2001:101–24.) In the infant population, inflicted (“nonacciden-
tal”) injury, also called abusive head trauma (AHT),
is an important cause of TBI. AHT may occur after
Traumatic damage to the spinal column may the age of 9 to 12 months but it is more common
cause acute or chronic cord compression with local- in younger infants, and in this group, head injury is
ized axonal damage at the level of the injury and rather different, presumably because of the anatomi-
secondary changes in ascending and descending cal and physiological immaturity of the infant’s ner-
fiber tracts. Hyperflexion–hyperextension injuries vous system. Infants younger than 9 months believed
to the neck in the absence of craniocervical fracture to have been shaken show a much higher incidence
or subluxation may cause damage to the long tracts of global brain ischemia and focal pontomedul-
in the lower brainstem or upper cervical segments. lary axonal injury. A thin film of subdural bleeding
Spinal nerve roots may be damaged in cases of non- or a small subdural hematoma, often midline, and
accidental head injury in infants, possibly caused by retinal hemorrhages accompany the brain swell-
a similar mechanism of excessive movement at the ing (Fig. 3.17), and this “triad” is often considered
craniocervical junction, resulting in stretch to the “diagnostic” of abusive injury. However, the triad is
spinal cord and nerve roots. not in itself pathognomonic of AHT. It has been sug-
The neuropathology of acute spinal cord trauma gested that this unique type of SDH may sometimes
is similar to that of head injury, and comparable have a “congestive” and/or hypoxic rather than a
findings indicating the progression of damage traumatic etiology, and that retinal hemorrhages
after injury are seen on microscopic examination. may result from the rapid rises in intracranial pres-
However, because of the peculiar anatomical posi- sure aggravated by hypoxia. There is also evidence
tion of the cord within the confines of the bony that low-level accidental falls in children may on
spinal canal and the distinctive blood supply of occasion prove fatal. DAI frequently found in chil-
the cord, the patterns of injury and the likelihood dren, are not specific of trauma and may, at least in
of clinical recovery following even relatively minor part, result from ischemia (see supra). It is therefore
trauma (e.g., after small parenchymal contusions or important to develop as high a degree of certainty
hemorrhages) are quite different than in the brain. as possible from objective criteria before ascribing a
One possible late outcome of a traumatic cord lesion brain injury in a child to nonaccidental causes.

4
Neuropathology of Vascular Disease
J E AN-JACQUES HAU W, U M B E RT O D E G I RO LA M I , A N D H A R R Y V. V IN T E R S
FOR CONVENIENCE of presentation we will 1. INTRACEREBRAL

divide the discussion of the neuropathology of cere-
brovascular disease in this chapter into three broad
AND SUBARACHNOID
categories: hemorrhage, infarction, and other dis- HEMORRHAGE: PRINCIPAL
orders. Within these subdivisions it is also possible PATHOPHYSIOLOGICAL
to consider these entities under the general concept MECHANISMS
of disorders that involve large vessels and those that
primarily involve arterioles or various components An extravasation of blood within the brain and/or
of the microcirculation. The term “cerebral micro- the leptomeninges, whatever its cause, constitutes
circulation” has been used in various settings; in an intracerebral and/or meningeal hemorrhage.
its broadest sense, the microcirculation includes Intracranial hemorrhage due to trauma (includ-
brain parenchymal and leptomeningeal arterioles, ing subdural or epidural hematoma) is described
venules, and capillaries—capillary endothelium is in Chapter 3. Also excluded from present con-
the site of the blood–brain barrier, the important siderations are the topics of hemorrhagic infarct
regulator of brain metabolism. Many pathologists (cf. 2.1.2), hemorrhage within neoplasms, and
include arteries and veins with external diameters brainstem hemorrhage secondary to herniation
of 350 to 400 um or less as components of the (cf. Chapter 1).
microcirculation. Within the limits delineated above, the two main
types of intracranial and/or cerebral hemorrhage to
76 •
be discussed here are subarachnoid hemorrhage and compartments provides a practical anatomical
intraparenchymal hemorrhage. approach to assess different pathophysiological
mechanisms (Figs. 4.1 and 4.2), these subdivi-
• In subarachnoid hemorrhage (SAH), bleeding pri- sions are somewhat arbitrary. Causative agents and
marily takes place in the leptomeningeal spaces, risk factors that lead to SAH, for example, are also
potentially extending diffusely throughout the important in intracerebral hemorrhage.
subarachnoid space (SAS), or rarely it is localized
in the form of a subarachnoid hematoma. Under
certain circumstances, the causative factors that Subarachnoid Hemorrhage
give rise to an SAH may be such that the bleed- Hemorrhage into the subarachnoid space is an
ing bursts into the brain parenchyma and even important cause of morbidity and mortality in
extends into the ventricles, either directly from people of all age groups. A major cause of primary
brain parenchyma or by extension from the SAS. SAH is the rupture of an arterial aneurysm, usually
• In intracerebral hemorrhage, or intraparenchy- within the circle of Willis or one of its main branches
mal hemorrhage (IPH), bleeding occurs first and most often at a major bifurcation point. Less
within the brain parenchyma. The hemorrhage often, SAH may complicate a vascular malformation
may remain entirely within the brain substance, within brain parenchyma and, if in close proximity
or may extend into the ventricular cavities and to the surface of the brain, associated with extension
thence the SAS. Extensive outpouring of blood of bleeding to the subarachnoid space. SAH may
into the ventricles eventually makes its way to the also be seen in a number of other settings, including
subarachnoid space via the foramina of Luschka systemic hemorrhagic diatheses (e.g., severe throm-
and Magendie. Less often, in cases of intracerebral bocytopenia) or vasculitides (see below).
hemorrhages that involve the superficial portions
of the hemispheres, there may be direct extension
of the bleed into the subarachnoid space (cerebro-
meningeal hemorrhage). 1.1.1 . BERRY/SACCUL AR ANEURYSMS
An aneurysm is a localized pathological dilatation
Notwithstanding the considerations delineated of the cardiac ventricular wall or of a blood vessel;
above, although hemorrhage into various intracranial this phenomenon is the result of an abnormality of
TRAUMATIC
Cerebral and/or meningeal hemorrhage in the usual sense
From Hypertensive
ARTERIOLAR CHANGE Amyloid angiopathy
Intracranial arterial aneurysms

From rupture of
Arteriovenous malformations
Cerebral and/or VASCULAR MALFORMATION
Capillary telangiectases and
meningeal hemorrhage
cavernous angiomas (cavernomas)
Leukemias
Thrombocytopenic purpura
Hemophilia
From Hypothrombinemia
BLOOD DYSCRASIAS (especially anticoagulant therapy)
NONTRAUMATIC Sickle cell anemia
(“spontaneous”)
Polycythemia
Afibrinogenemia
Waldenström’s macroglobulinemia
Brainstem hemorrhage secondary

to herniation
Secondary to Hemorrhage within a tumor
VARIOUS CAUSES Hemorrhagic infarcts
Other causes
FIGURE 4.1 The principal causes of cerebral and/or meningeal hemorrhages.
Chapter 4 Neuropathology of Vascular Disease • 77

4 5
3 6
2
8
1 9
Cerebral parenchyma
Cerebral ventricles Subarachnoid space
Subdural space
Dura
Extradural space
Skull
1. Pure cerebral hemorrhage (or cerebral hematoma)
2. Cerebral hemorrhage with ventricular rupture Cerebral hemorrhages
3. Cerebromeningeal hemorrhage
4. Cerebromeningeal hemorrhage with ventricular ruputre
5. Meningocerebral hemorrhage with ventricular rupture
6. Meningocerebral hemorrhage
Meningeal hemorrhages
7. Pure meningeal (subarachnoid) hemorrhage
8. Subdural hematoma
9. Extradural (epidural) hematoma
FIGURE 4.2 Distribution of the blood in the various forms of intracranial hemorrhages.
the components of the wall of the involved structure 1.5 to 2 times more common in women than men;
such that it eventually gives way under pressure. Berry 10% to 30% of patients have multiple aneurysms,
aneurysms are localized sac-like dilatations of intra- and familial cases are rare. Though referred to as
cranial arteries. The aneurysmal outpouching is usu- “congenital”, clinically significant berry/saccular
ally connected to the artery by a narrow segment, or aneurysms are almost never encountered in infants
“neck”; its wall is formed by thin fibrous tissue with or children. As in all aneurysms, berry aneurysms
patchy interruption and attenuation of the elastic develop as the result of degenerative changes within
laminae and is associated with thinning of the media
(Fig. 4.3). Berry aneurysms usually occur at major
bifurcation points on the circle of Willis (Figs. 4.4
and 4.5). Most are found in the carotid anterior cir-
culation and involve the following sites: junction of
internal carotid (ICA) and posterior communicat-
ing artery, the origin of the anterior choroidal artery,
middle cerebral artery (MCA) bi/trifurcation in the
Sylvian fissure, and anterior cerebral artery (ACA)
and anterior communicating artery junction. Ten
percent of all aneurysms are found in the vertebro-
basilar territory, mainly at the tip of the basilar artery
in the interpeduncular cistern.
Most patients with symptomatic berry aneu-
rysms come to medical attention between the ages of FIGURE 4.3 Berry aneurysm, microscopic
40 and 70 years. Berry aneurysms are approximately appearance.
A B 30%
INTERNAL
CAROTID
(terminal bifurcation and angle with
AC posterior communicating artery)
A
MCA I C I C
APPROXIMATELY 90% OF ANEURYSMS ANTERIOR MIDDLE CEREBRAL

COMMUNICATING (especially at origin
30% (and anterior 30%
BA of first main branches)
cerebrals)
10% Vertebrobasilar system
FIGURE 4.4 Distribution and frequency of arterial aneurysms. ACA, anterior communicating artery; IC,
internal carotid artery; MCA, middle cerebral artery; BA, basilar artery.
cerebral blood vessel walls, possibly secondary to (subarachnoid hematoma). In a number of cases,
abnormal smooth muscle and connective tissues. the bleeding penetrates into the adjacent cere-
There is an increased incidence of intracerebral bral parenchyma (meningocerebral hemorrhage)
aneurysms in polycystic kidney disease, Marfan and (Figs. 4.8 and 4.9). Bleeding of a ruptured aneurysm
Ehlers-Danlos syndromes, pseudoxanthoma elasti- may also occur directly into brain parenchyma and
cum, fibromuscular dysplasia, sickle cell disease, and not extend into the SAH immediately, especially if
coarctation of the aorta. the site of rupture on the dome of the aneurysm is
The clinical course of patients with berry aneu- embedded within brain substance. In these patients,
rysms depends on whether the lesion goes on to intraventricular rupture and life-threatening intra-
rupture (Fig. 4.6). Rupture of a berry aneurysm cranial hypertension may ensue.
usually produces life-threatening SAH (Fig. 4.7).
Bleeding within the subarachnoid spaces spreads • Cerebral infarcts associated with aneurysmal rup-
rapidly through the cerebrospinal fluid (CSF), caus- ture are frequent. Although their pathogenesis is
ing multiple neurological manifestations, including uncertain, possible causes include one or more of
sudden onset of headache, neck stiffness, and evi- the following: vascular compression from a sub-
dence of irritation of cranial nerves. Some patients arachnoid hematoma, thrombosis of the affected
experience smaller “leaks” from an aneurysm vessel, embolization arising from thrombus within
(before a large life-threatening hemorrhage), some- the aneurysmal sac, and arterial spasm.
times described as “sentinel leaks or bleeds”. Blood • Compression of structures adjacent to the aneu-
products elicit vasospasm in subarachnoid arteries, rysmal sac, particularly cranial nerves, may occur,
which may cause multifocal infarcts or extensive especially in relation to large aneurysms.
anoxic-ischemic change. Very extensive SAH may • Survivors of a SAH may have significant late
also result in rapidly increasing intracranial pres- postbleed morbidity, often associated with the
sure, leading to death; alternately, the hemorrhage development of hydrocephalus (secondary to
may stop spontaneously or in response to thera- fibrosis of the meninges resulting from accumula-
peutic intervention. The blood in the CSF under- tion of blood products within the leptomeninges).
goes resorption within a period of approximately 3 A rare sequela of repeated episodes of smoldering
weeks. Rebleeding may occur within 1 or 2 weeks SAH is subpial cerebral siderosis. This phenom-
after the initial event. In some patients, the spread enon is the result of seepage of breakdown prod-
of hemorrhage in the SAH may be contained by the ucts of red blood cells, including iron pigment,
development of a localized pool of clotted blood from the SAS into the adjacent molecular layer,

A B
C D
FIGURE 4.5 Different types of berry aneurysms. (A) Vestigial aneurysm at the termination of the internal
carotid artery, obliterated by a clip. (B) Massive aneurysm at the termination of the internal carotid artery.
(C) Bilateral berry aneurysms at the termination of the internal carotid arteries. (D) Middle cerebral artery
aneurysm. (E) Aneurysm of the anterior communicating artery. (F) Aneurysm of the bifurcation of the basilar
artery.
Inf ct
Extr
H
S,A.H
Compression Rupture
Intrasaccular thrombosis
FIGURE 4.7 Diffuse subarachnoid hemorrhage,

FIGURE 4.6 Representation of the main complica-
gross appearance.
tions resulting from arterial intracranial aneurysms.
Infct, infarction; Extr., ventricular extravasation;
H, intracerebral hematoma; S.A.H., subarachnoid infective/mycotic aneurysms usually occur in distal
hematoma. branches of the arterial tree. Rupture may result in
subarachnoid or intraparenchymal bleeding. In the
course of pathological examination of an intracere-
with secondary toxic injury of the crests of the
bral blood clot, the presence of an infective/mycotic
cerebellar folia.
aneurysm, friable and weakened because of polymor-
• In the general population, unruptured aneurysms
phonuclear leukocytes in the vessel wall, should be
are a relatively common “incidental” finding at
an important diagnostic consideration and diligently
autopsy, or detected on imaging studies under-
sought within the specimen. Stainable microorgan-
taken in the workup of patients with neurological
isms may be demonstrable among inflammatory
manifestations for other reasons.
cells on sections of infective aneurysms.
Infective/mycotic aneurysms due to endocardi-
Though neurosurgical “clipping” of a ruptured
tis result from a septic embolus that lodges within a
aneurysm is still standard therapy; “noninvasive”
branch of a cerebral artery, with subsequent exten-
endovascular treatments (e.g., “coiling” to induce
sion of microorganisms from the embolus into the
thrombosis of the aneurysm, or wrapping) are
adjacent vessel wall. Septic emboli in individuals
increasingly being used in various parts of the world.
with infective endocarditis may also lead to an isch-
emic (bland) infarct that may undergo hemorrhagic
1.1.2. INFLAMMATORY/INFECTIVE transformation, or result in a pyogenic arteritis,
ANEURYSMS (“MYCOTIC” ANEURYSMS) causing an intracerebral hematoma.
These lesions, which account for 3% to 6% of all intra-
cranial aneurysms, are usually associated with sub-
1.1.3 . DISSECTING ANEURYSMS
acute or acute infective endocarditis. They are seen
(ARTERIAL DISSECTIONS)
less often with spread of infection from a contiguous
site (e.g., osteomyelitis, meningitis) into the vessel These are almost always encountered in young and
wall. The microorganisms causing the endocarditis middle-aged patients (25 to 45 years) and may be
are multiple and frequently of low virulence; both associated with infarcts and SAH. Dissection may
bacteria and fungi can be responsible (particularly occur in extracranial and/or intracranial branches
in immunocompromised subjects and persons who of the carotid or vertebrobasilar system. When intra-
use intravenous drugs). Unlike berry aneurysms, cranial dissection occurs in the anterior circulation,

A B
C D
FIGURE 4.8 The sites of hematomas secondary to rupture of an arterial aneurysm. (A) Aneurysm of the ante-
rior communicating artery (and of the anterior cerebral artery). (B) Aneurysm of the posterior communicating
artery. (C) Aneurysm of the middle cerebral artery. (D) Aneurysm of the bifurcation of the internal carotid artery.
the site of dissection is usually between the internal to the neck (often perceived as rather minimal), cer-
elastic lamina and the media, often with resultant vical manipulation, exercise, administration of hepa-
intravascular thrombosis. When dissection occurs rin, or in the context of fibromuscular dysplasia, but
in the posterior circulation, transmural dissection in most cases, the pathological substrate remains
can result in SAH. undefined.
Specific vasculopathies associated with dissec-
tion include fibromuscular dysplasia and connective
1 .1 . 4. FUSIFORM AN EURYSM S
tissue disorders, including Marfan syndrome and
Ehlers-Danlos syndrome (type IV). Arterial dissec- These lesions result from enlargement and widen-
tion of cervical arteries may occur following trauma ing of an arterial segment along its length (arterial
A B
FIGURE 4.9 Hematomas resulting from the rupture of an arterial aneurysm. (A) Bifrontal hematoma
with ventricular rupture, following rupture of an aneurysm of the anterior communicating cerebral artery.
(B) Hematoma of the Sylvian fissure, following rupture of an aneurysm of the middle cerebral artery.
A B
FIGURE 4.10 Giant atherosclerotic aneurysm (A) of the anterior cerebral artery and (B) of the basilar artery.
dolichoectasia). They are unusual lesions, more cavernous hemangiomas) and aneurysms, and “rec-
frequently recognized in the geriatric population. reational” drug use.
Although not believed to be directly caused by ath-
erosclerosis, they are often associated with it. On
1.2.1 . HYPERTENSION AND
microscopic examination of the involved portion of
HYP ERTENSIVE CEREBROVASCUL AR
the arterial wall, there is interruption of the smooth
DISEASE
muscle layers and fraying of the internal elastic lam-
ina. A pathogenic theory recently advanced is that Arterial hypertension has long been consid-
fusiform aneurysms may be related to internal elastic ered the major cause of IPH; however, given the
lamina injury and dysfunction of matrix metallopro- increasingly effective pharmacological treatment
teinases. Fusiform aneurysms are defined as widen- of hypertension, the incidence of “hypertensive
ing of the artery to a diameter larger than 2.5 cm, but hemorrhage” has markedly declined in many parts
they may reach giant proportions (Fig. 4.10A). They of the world.
most often involve the basilar artery (Fig. 4.10B),
causing brainstem displacement and compression, 1.2.1.1. Mechanisms IPH resulting from hyper-
resulting in cranial nerve deficits, among other focal tension is largely attributed to hypertensive cerebral
neurological manifestations. vascular disease, i.e., due to arteriosclerosis, arteriolo-
When examined in cross-section, the aneu- sclerosis (AS) and to lipohyalinosis (a term now less
rysm often contains laminated thrombi within the commonly used). The molecular pathogenesis of AS
expanded lumen, the result of severe, complicated is poorly understood. Its evolution has been firmly
atherosclerosis. As a result, platelet-fibrin or athero- associated with a documented history of hyperten-
matous emboli may travel distally in the circulation sion; however, despite effective prophylactic treat-
to produce transient ischemic attacks or infarcts ment of severe and moderate hypertension in many
in branches of the vertebrobasilar circulation. The countries, arteriosclerotic microvascular disease is
aneurysm rarely ruptures or produces SAH. still seen commonly in autopsy brain specimens,
especially in the elderly. In such individuals, other
accompaniments of chronic hypertension (e.g., car-
1.2. Intraparenchymal Hemorrhage diomegaly, left ventricular hypertrophy, and nephro-
The site and mechanisms of IPH vary according sclerosis) may be absent.
to etiology. The most common causes of IPH are Histopathological features of AS include hya-
hypertension inducing small artery diseases, coag- line thickening (sometimes with degeneration of
ulopathies (including hemorrhagic diatheses and the internal elastic lamina), intimal fibromuscular
iatrogenic causes in the setting of anticoagulation), hyperplasia, variable degrees of luminal narrowing,
cerebral amyloid (congophilic) angiopathy (CAA), thinning of the media, concentric “onion-skin”-type
vasculitis, primary or secondary brain neoplasms, smooth muscle cell proliferation or hyperplasia, and
arteriovenous malformations (AVMs) (less often the presence of foamy macrophages in the arterial

commonly encountered in association with other
microangiopathies, especially CAA (see below).
1.2.1.2. Evolution The appearance of the hema-

toma varies depending on the duration between
the clinical ictus and the time of neuropathological
examination.
Initially, the intraparenchymatous bleeding gives
rise to an accumulation of blood that is under pres-
sure, contains little parenchymatous debris, and dis-
places the adjoining cerebral structures (Fig. 4.13A,
C, D). The outer boundaries of the lesion are irregu-
lar and small petechial hemorrhages are present
FIGURE 4.11 Arteriolosclerosis: narrowing of
along its borders.
the lumen, concentric smooth muscle cell prolifera-
The bleeding may remain localized, or it may
tion, and the presence of foamy macrophages in the
expand rapidly, resulting in increased intracranial
arterial wall.
pressure and brain herniation. Rupture into the
ventricles with subsequent passage of blood into
wall (lipohyalinosis) (Fig. 4.11). Fibrinoid necrosis the subarachnoid space and basal cisterns can also
occurs in malignant hypertension. occur. Less often, the hemorrhage bursts directly
These microvascular lesions may lead to occlu- through the cerebral cortex into the SAS, though
sion of arterioles and to lacunar infarcts (cf. 3.2.3) this is much more common with CAA-related IPHs.
or to weakening of the vessel leading to rupture This is not surprising because they are caused by a
and IPH. meningocortical form of microvascular disease.
As already mentioned, hypertensive IPH is due In time, over the course of 2 to 14 days after the
to the rupture of small intracerebral arterioles 50 to initial bleed, the hemorrhage begins to lyse and there
200 μm in diameter, the walls of which have been is an acute inflammatory response that then evolves
weakened by replacement of the normal media to phagocytosis of the breakdown products largely
(muscular and elastic components) by collagenous by blood-derived scavenger cells. Macroscopic
fibrous tissue. In classic studies, Charcot-Bouchard autopsy studies of patients who survive the intra-
(C-B) microaneurysms have been described in the cranial hemorrhage beyond a month show the site
affected arterioles (Fig. 4.12), although often they of the hemorrhage to be a cavity with remnants of
are difficult to find even when brain parenchyma resorbed blood imparting an orange/yellow margin
around a hypertensive hemorrhage is extensively and adjacent discolored and firm gliotic brain tissue
and carefully sampled. As well, C-B aneurysms are (Fig. 4.13B). This lesion may (especially after many
A B
FIGURE 4.12 Miliary aneurysm (Charcot-Bouchard). (A) Charcot-Bouchard microaneurysms as drawn by

J-M Charcot. “Location: Hemispheric gray matter. The vessel is 26/100 (1/4) mm wide; in spite of its size, the
wall is devoid of a muscle layer and is thickened.” (B) Microscopic appearance.
A B
C D
FIGURE 4.13 Basal ganglia hemorrhages. (A) Lateral basal ganglia hemorrhage. (B) Cystic scar of an old
capsulo-lenticular hemorrhage. (C) Massive hemorrhage. (D) Medial thalamic hemorrhage.
years) be difficult to distinguish from an old (hem- subthalamic nucleus and midbrain. Extension into
orrhagic) infarct. Microscopic sections around the the third ventricle is seen in over 50% of cases;
edges of the hematoma show hemosiderin-laden and (d) the massive hemorrhages destroying most
macrophages and reactive astrocytes. of the above-mentioned structures are relatively
infrequent. Increased intracranial pressure with
1.2.1.3 Topography Approximately 80% of herniation is commonly seen with massive hem-
hypertensive IPHs are situated in the cerebrum, orrhages and is infrequent in medial/thalamic
mostly in the basal ganglia (Fig. 4.13). hemorrhages.
• Hypertensive hemorrhages may also be seen
• Within the basal ganglia, the most common in the subcortical white matter. They may be
sites of involvement can be divided in four massive or localized small extravasations at the
groups: (a) the putamen and external capsule junction of the cortex and white matter (“slit
(lateral basal ganglia): these may extend superi- hemorrhages”).
orly and medially into the internal capsule and
lateral ventricle; (b) medial basal ganglia: these Intracerebellar hemorrhages (Fig. 4.14) rep-
always extend into the internal capsule and usu- resent about 10% of all hypertensive IPHs. The
ally the globus pallidus and frequently the third clinical evolution of these hemorrhages is that of a
ventricle; they may also involve the white mat- space-occupying mass in the posterior fossa, and
ter of the superior temporal gyrus; (c) medial/ rupture into the fourth ventricle may occur.
thalamic: these are less common (10% to 20% Brainstem hemorrhages (Fig. 4.15) represent
of hypertensive IPHs) and can involve the about 10% of hypertensive IPHs. These are most
internal capsule and caudate nucleus, rarely the often situated in the pontine tegmentum/basis

FIGURE 4.14 Intracerebellar hemorrhage. FIGURE 4.15 Brainstem hemorrhage.
pontis and can be clinically associated with the with moderate to severe CAA shows a considerably
“locked-in” state. higher prevalence of hemorrhagic (and sometimes
ischemic) lesions than is seen in cases without CAA.
Relatively rare familial forms of CAA are also
1. 2. 2. C E RE BRAL AM Y L O I D A N G I O PATH Y
found in various countries around the world.
This microvascular lesion is more commonly associ-
ated with cerebral hemorrhage than with ischemia. • In a circumscribed coastal region of the
The microscopic characteristics of the lesion consist Netherlands, an autosomal dominant form of severe
of deposition of amyloid within the media and/or CAA (hereditary cerebral hemorrhage with amyloido-
adventitia of small parenchymal and leptomenin- sis, Dutch type/HCHWA-D) is attributed to a unique
geal vessels. Amyloid has the unique physicochemi- APP gene mutation (at codon 693). Massive Aβ—
cal structure of beta-pleated fibrils, giving it specific deposition occurs within the media of cerebral arte-
staining and optical properties. Upon staining with rioles, and fatal or debilitating cerebral parenchymal
thioflavin T the deposits emit bright-green fluores- hemorrhages frequently ensue. Less prominent
cence under ultraviolet light. Amyloid stains red with senile plaque-like parenchymal Aβ—deposits may
Congo red and gives apple-green birefringence under also be present within cerebral cortex.
polarized light (Fig. 4.16A). Immunohistochemical • APP codon 692 and 694 mutations appear to
methods are now also often used to demonstrate the cause, respectively, a rare Flemish form of CAA
various types of amyloid deposits. The deposits have (also with frequent IPH) and AD with prominent
a characteristic ultrastructural fibrillary appearance CAA in a family reported from the state of Iowa.
and correspond to misfolded protein. The nature of • An Icelandic form of CAA leading to hemorrhagic
the amyloid deposit varies depending on the bio- stroke, hereditary cerebral hemorrhage with amyloido-
chemical nature of the protein (see below). sis, Icelandic type/HCHWA-I, results from mutation
in the gene encoding cystatin C/gamma-trace;
1.2.2.1. Etiology The most common form of hence this condition is also sometimes described
CAA is associated with deposition of Aβ—pro- as hereditary cystatin C amyloid angiopathy
tein, a small, 42 amino acids peptide cleaved from (HCCAA). It causes cerebral bleeds in young
the amyloid precursor protein (APP) and encoded and middle-aged adults. Brains from HCHWA-I
by a gene on chromosome 21. CAA has a strong patients show extensive deposition of gamma-trace
association with aging, Alzheimer disease (AD), protein within arteriolar walls, associated with
and other conditions such as Lewy body dementia. degeneration of the affected vessel walls.
In these conditions, to variable extents in different • Also, familial British and Danish forms of CAA
patient populations, there is excessive deposition of have been described and attributed to unique
Aβ in both the brain gray matter (as senile plaques mutations on the BR12 gene, situated on chro-
and diffuse deposits) and vessel walls (as CAA) (cf. mosome 13. These two and other genetically
Chapter 8) (Fig. 4.16B, C). The brain of patients determined forms of CAA (e.g., meningovascular
A B
FIGURE 4.16 CAA.Apple-green birefringence of the vessel wall under polarized light with Congo red stain
(A); immunocytochemistry for Aβ shows diffuse infiltration of the arteriolar wall by amyloid (B,C). There is
also involvement of the capillaries (dyshoric angiopathy), with amyloid appearing to be “leaking” from the capil-
lary wall into brain parenchyma (C).
amyloidosis associated with transthyretin deposition, angiopathy, also called type 1 of Thal, amyloid is
familial amyloidosis of the Finnish type caused by thought to be “leaking” from the capillary wall into
gelsolin deposition) are less consistently associ- brain parenchyma (Fig. 4.16C). Type 1 is always
ated with IPH than are the Dutch, Flemish, and found when type 2 is present, although sometimes
Icelandic familial variants of CAA. the presence of amyloid renders difficult the accu-
rate identification of the vessel type affected.
1.2.2.2. Pathology All regions of neocortex and Histologically there is infiltration of the media and
overlying meninges may be affected by CAA, with adventitia of small vessels by an acellular amorphous
minor variations in the distribution of affected arter- eosinophilic substance, which gives the vessel wall a
ies among lobes. While cerebellum and its meninges homogeneous pale appearance, often allowing the
are occasionally involved by CAA, the microvascular diagnosis to be made on routine stains. In addition,
abnormality is almost never found within deep cen- some affected vessels, particularly pia mater arteri-
tral gray matter, subcortical white matter, the brain- oles, have a “double- barrel” appearance (Fig. 4.17A).
stem, or spinal cord. CAA may be patchy within the Amyloid deposition in the arterial wall causes dam-
cerebral cortex and adjacent leptomeninges; it can age of the medial smooth muscle cells. These changes
be segmental in given small vessels. disrupt the vascular architecture and weaken the
The term CAA encompasses amyloid deposition affected arterial walls. A variety of secondary changes
within the walls of small and medium-sized venules, may be found in the affected vessels, including fibro-
arteries, and arterioles (congophilic angiopathy, also sis, microaneurysm formation, chronic (including
called type 2 of Thal) (Fig. 4.16B, C). In dyshoric granulomatous [Fig. 4.17B]) inflammation, fibrinoid

necrosis, thrombosis, and, very rarely, vessel wall cal- 1 .2 . 3. VASCULAR M ALFORM ATION S
cification. These CAA-associated microangiopathies
These may be found in the CNS parenchyma, over-
(CAA-AM), especially microaneurysm formation
lying meninges and dura, or (rarely) both.
and fibrinoid necrosis, appear to increase the likeli-
hood of vessel rupture leading to IPH.
1.2.3.1. Arteriovenous malformations AVMs
1.2.2.3. Complications of CAA The extent of are the most clinically important of these lesions;
amyloid deposition within vessel walls correlates they rarely become manifest clinically beyond the
with increasing risk of IPH. CAA is the cause of age of 60 years.
hemorrhages with highly distinctive clinicopatho- AVMs may cause intraparenchymal or/and sub-
logical features (Fig. 4.18). When the hemorrhage arachnoid hemorrhage. AVMs usually occur in the
occurs within the cortex, it may dissect into the MCA territory, often involving a wedge-shaped area
subarachnoid space; when at the junction with the of brain parenchyma and overlying leptomeninges,
subcortical white matter (“lobar” hemorrhages), the but may be seen anywhere in the central nervous
lesion may rupture into the lateral ventricles. This system (CNS), including posterior fossa structures,
“lobar” predilection reflects the topography of and even on the circle of Willis. An AVM represents
CAA, a cortical and meningeal vasculopathy. CAA an abnormal tangle of vessels with direct communica-
may be readily detected on neuropathological tion between one or more arteries of the brain or spi-
examination in neurosurgical specimens of frag- nal cord parenchyma and one or more draining veins,
ments of brain parenchyma evacuated together with without an intervening capillary bed. The shunt most
a hematoma. Evidence of cerebral bleeds of different often involves a core of abnormal channels, called the
ages (months or years) can be seen at postmortem nidus. Arteriovenous fistulas are single-hole arterio-
examination involving different lobes of both cere- venous shunts. The arterial feeders are supplied either
bral hemispheres. As many as one third of patients by brain arteries or by dural arteries. The venous
afflicted with CAA-related lobar hemorrhage may drainage may take place in the superficial or the deep
also have clinical evidence of hypertensive microan- draining systems of the brain. Also, the microscopic
giopathies, and features of associated arterioloscle- morphologic features of AVMs are quite distinctive
rosis may also be seen. (Fig. 4.19A). The lesion consists of a mass of vascu-
Less frequent manifestations of CAA include lar channels of variable mural thickness and diameter,
SAH without IPH, leukoencephalopathy (cf. 3.2.5), embedded within abnormal, gliotic, and occasionally
granulomatous angiitis (Fig. 4.17B), recurrent malformed brain parenchyma. The CNS parenchyma
transient neurological symptoms (possibly due to may show morphologic evidence of old hemorrhage,
microinfarcts and/or miliary hemorrhages in the but an absence of blood breakdown products does
cerebral cortex), and brain infarct. not rule out the possibility that the AVM has bled
A B
FIGURE 4.17 CAA. Infiltration of the vessel wall by the acellular amorphous eosinophilic amyloid sub-
stance; note “double barrel” appearance of a leptomeningeal arteriole (A) and inflammatory granulomatous
reaction (B).
A B
FIGURE 4.18 Lobar intracerebral hemorrhages in patients with CAA involving the right temporal lobe
(A) and the left parietal-occipital region (B).
prior to resection. Thrombosed and recanalized vas- A

cular channels are usually present within an AVM.
Other characteristic abnormalities include hyalinized,
sometimes calcified (rarely, ossified) arterial walls, or
abnormalities in the blood vessels characteristic of
intimal fibromuscular hyperplasia. However, “compli-
cated” atheromatous change (with cholesterol clefts,
necrosis, and hemosiderin-laden macrophages) is
almost never seen on the intimal aspect of AVM
channels. Patients with AVMs become symptomatic
following rupture of the abnormal vessels and bleed-
ing into brain tissue and/or the SAS, direct pressure
on adjacent brain substance, or because of a “steal” of
blood from adjacent structures in the setting of arte-
riovenous shunting. In 10% of patients with AVM
there may be one or more coexistent berry aneu-
rysms somewhere along the circle of Willis, usually in
an artery “feeding” the AVM, presumably because of
increased flow/pressure within its lumen. AVMs are
also rarely seen along the spinal cord, where they fre-
quently occur as dural arteriovenous fistulas. AVMs
are usually treated by excision or iatrogenic emboli- B
zation therapy (the latter performed with the hope
of occluding the AVM nidus). As well, iatrogenic
embolization materials of many sorts, often with a
brisk granulomatous inflammatory response, may be
seen within the vascular lumina of autopsy or surgical
AVM specimens.
1.2.3.2. Venous angiomas Venous angiomas

(VAs) consist of one or more dilated, often grossly
apparent veins and their smaller tributaries, lack-
ing an obvious arterial component. If the lesion is FIGURE 4.19 Vascular malformations. (A) Medial
a single tortuous vein (e.g., in the spinal subarach- frontal cerebral arteriovenous aneurysm. (B) Vein of
noid space), it is described as a “varix”(Fig. 4.19B). Galen aneurysm.

Component vessels of a VA are more dilated and
have thicker walls than normal veins, and brain
parenchyma between the vessels shows negligible
reactive changes or evidence of prior bleeding. The
lesion is most often discovered as an incidental find-
ing at postmortem examination.
1.2.3.3. Capillary telangiectases These are

also common incidental lesions found at autopsy.
They consist of multiple dilated capillaries without
alterations of the surrounding brain substance. On
macroscopic examination, both VAs and capillary
telangiectases appear as small, fairly well-defined FIGURE 4.20 Multiple lobar hemorrhages in a
hemorrhagic lesions that initially suggest a localized patient with leukemia.
region of bleeding (e.g., petechial hemorrhage).
1.2.3.4. Cavernous hemangiomas (caverno- surgically resected blood clot (in current practice
mas) Less common than AVMs, these appear as removed either by craniotomy or endoscopic meth-
closely packed blood vessels (of varying wall thick- ods) should always be studied carefully for a lesion
ness) without intervening CNS parenchyma. The that may have caused the IPH. Sometimes examina-
lesion is most often found in the pons or subcorti- tion of the specimen under a dissecting microscope
cal white matter. On occasion, a patient with a cav- may be helpful, so that brain fragments can more
ernoma may present with signs and symptoms of a easily be separated from blood clot. Evidence of
space-occupying lesion and/or a seizure disorder, microangiopathies (AS, CAA), fragments of a vas-
in which case the clinical differential diagnosis and cular malformation, (clinically unsuspected or undi-
distinction from a primary brain tumor may be dif- agnosed) primary or metastatic neoplasm, portion
ficult. Though cavernoma is ordinarily not the cause of an inflammatory/mycotic aneurysm, etc., may be
of a massive hemorrhage, on microscopic study the found in this way.
lesion is almost always surrounded by deposits of
hemosiderin, indicating slow or recurrent leakage of
blood from component abnormal vessels. Familial
syndromes of cavernous angiomas (especially
2. INFARCTION: PRINCIPAL
among Hispanic subjects) have been linked to genes PHYSIOPATHOLOGICAL
on chromosomes 3q, 7q, and 7p. MECHANISMS
The terms “cerebral infarct,” “cerebral softening,”
and “encephalomalacia” are used to denote an area
1. 2. 4. S Y S T E MI C DIS EA S E
of tissue necrosis localized to a particular territory
IPH may occur in the setting of systemic disease of vascular supply. In most cases, an infarct is due to
associated with bleeding disorders, including occlusion of a branch of the feeding arterial tree. It
thrombocytopenia, coagulopathy (either iatrogenic may also follow a severe decrease in blood flow in
or secondary to hepatic failure), hemophilia, dis- the absence of arterial occlusion. In venous infarc-
seminated intravascular coagulation (DIC), and tion, the tissue ischemia is due to the occlusion of a
leukemia (Fig. 4.20). Although, often, the intra- large vein and consequent stasis.
cranial hemorrhages that are seen in many of these
diseases manifest as multifocal extravasations of
blood throughout the brain, with associated sub-
arachnoid bleeding, in some cases, the lesions are
2.1. General Features
single and fairly circumscribed and may therefore Arterial occlusion or severe reduction of blood flow
mimic hematomas associated with hypertension of sufficient duration produces ischemic necrosis.
or CAA, in terms of both their extent and topogra- The gross and microscopic appearances associated
phy. As suggested above (in the context of CAA), with infarction are manifest by a series of sequential
though the tissue is irreparably damaged. From 8 to
48 hours (Fig. 4.21), the damaged brain becomes
discolored, and the demarcation between the white
and gray matter is indistinct. Edematous swelling is
apparent and is sometimes accompanied by vascular
congestion, which is more marked in the cortex. At
this stage, the softer consistency of the involved area
is the only feature that permits the infarct to be rec-
ognized macroscopically after 2 to 3 weeks of brain
formalin fixation. From 2 to 10 days in the course of
the evolution of an infarct, the swelling persists, pro-
gressively decreasing over time, while the softened
tissue becomes more friable and the boundaries of
the infarcted territory become better defined.
Microscopically, after 6 to 12 hours, the neurons
within the infarcted territory demonstrate the fea-
FIGURE 4.21 Recent anemic or pale infarct involv- tures of acute ischemic cell injury (i.e., the cytoplasm
ing the territory of the right anterior cerebral artery. is eosinophilic, the Nissl substance is dispersed, the
nucleus is shrunken, and the nucleolus is no longer
visible) (Fig. 1.2). In the cortex and white matter,
changes that are distinctive regardless of the site of the capillary blood vessels show endothelial swell-
the affected territory within the CNS. ing accompanied by vasogenic and cytotoxic edema
The main types of infarction generally recognized fluid and by some extravasation of red blood cells
are anemic, or pale, infarcts, in which the cellular reac- (even in anemic infarction). Glia also shows isch-
tions to ischemic necrosis predominate (Fig. 4.21), emic cell damage, and somewhat later myelinated
and hemorrhagic infarcts, wherein the lesions are fibers lose their usual tinctorial affinity. Between 24
associated with hemorrhagic phenomena; the latter and 48 hours there is evidence of an emigration of
especially involve the cortical ribbon and the basal neutrophils, which can be severe and may simulate
ganglia (Fig. 4.22). an acute infectious process (Fig. 4.23).
After 48 hours, the leukocytes are replaced by
macrophages. These cells, which are laden with
2.1.1. ANEMIC/PALE INFARCTION
breakdown products of myelin disintegration, clus-
On macroscopic examination, the lesions are poorly ter around the swollen capillary blood vessels walls.
circumscribed early in the course of the evolution The macrophage proliferation becomes considerably
of the infarct. In the first 6 hours or so, no visible more marked after 5 days. Cerebral edema is usually
alteration can be demonstrated with the naked eye, maximal 3 to 5 days after a large infarct and may (at
A B
FIGURE 4.22 Hemorrhagic infarcts (A and B).

run across the cavity. In the case of cortical infarcts,
very often, layer I of the (infarcted) cerebral cortex
persists with a dense accumulation of (gemisto-
cytic) astrocytes.
2 .1 . 2. HEM ORRHAGIC IN FARCTION

This type of infarction is classically regarded as dis-
tinct from anemic bland infarction, although as men-
tioned above, microscopic evidence of red blood cells
extravasation is often found in the latter, especially
at the outer border of the lesion. In hemorrhagic
infarction, patches or confluent areas of hemorrhage
FIGURE 4.23 Microscopic features of cerebral
are evident, particularly in the cortex. These hemor-
infarcts. Diffusely scattered and perivascular groups of
rhages may involve the entire extent of the ischemic
polymorphonuclear leukocytes after 35 hours.
region (Fig. 4.22A), and in the cerebral cortex they
predominate along boundary zones supplied by men-
this time) lead to fatal herniation, sometimes with ingeal arterial anastomoses; in middle cerebral artery
Duret brainstem hemorrhages. After 10 days, mac- occlusion, the basal ganglia are involved (Fig. 4.22B).
roscopically, liquefaction begins, and from the third It is generally accepted that an important pathoge-
week onward the process of cavitation becomes netic mechanism of hemorrhagic infarction holds
more evident. From then on, the area of necrosis is that tissue reperfusion occurs following thromboly-
replaced by yellowish sunken gray tissue. The mac- sis or mobilization of an occluding thromboembo-
rophage proliferation persists, although to a decreas- lism. Extravasation of blood to varying extent then
ing degree, during the subsequent months, and the occurs in a capillary bed irreversibly damaged by the
number of reactive (gemistocytic) astrocytes pro- ischemic insult (see Fig. 4.26F). Indeed, this type of
gressively increases. After a few months, the necrotic infarction most often follows cerebral embolization,
zone becomes a cystic cavity with ragged outlines, where breakdown of the occluding thrombus and
intersected by vascular connective tissue strands distal migration commonly occurs.
and covered by leptomeninges on its cortical surface
(Fig. 4.24). During the phase of scar formation, the
residual cystic cavity is surrounded by a glial prolif-
2.2. Pathophysiology and Etiology
eration, while a few macrophages remain along the Cerebral infarction caused by prolonged isch-
persisting vascular connective tissue strands that emia localized to a particular vascular territory is
A B
FIGURE 4.24 Old cystic infarct in the territory of the middle cerebral artery. (A) Left cerebral hemi-
sphere. (B) Coronal section: note the involvement of a large part of the middle cerebral artery, sparing the
temporal lobe.
commonly secondary to arterial occlusion. It may the vascular territory that is normally served by the
be due to either thrombosis, most often in the occluded artery (Fig. 4.26D, E). However, the extent
setting of atherosclerosis, or to embolization (of of this reinforcement varies from case to case, and
cardiac origin or via artery-to-artery embolism). anatomical variations from the norm are frequent
Atheroemboli (e.g., from a severely atheroscle- (Fig. 4.26B). Moreover, these anastomotic path-
rotic cervical artery) may be encountered within ways may themselves be occluded by atherosclerotic
infracted brain, though in a small minority of lesions or become incompetent as a result of throm-
cases. On neuropathological examination of cere- bus propagation (Fig. 4.26C).
bral infarcts where no arterial occlusion is seen,
the presumption is that (1) the occluding emboli 2.2.1.2 Site of occlusion
have undergone secondary lysis; (2) severe and Proximal occlusion of a blood vessel, such as the
prolonged hypotension involving arteries with internal carotid artery, may, because of collateral
extensive or multifocal atheromatous stenosis has flow from the contralateral arterial network and via
resulted in hypoperfusion of tissue; or (3) stenosis the ophthalmic artery, produce only a limited lesion.
has been the result of arterial spasm. Reirrigation is generally adequate in the proximal
The appearance and extent of the cerebral infarct territory, and the lesions will then predominate in
depends on a number of modifying hemodynamic the distal regions (“last fields of irrigation”) or at the
and etiological factors (Fig. 4.25 and 4.26). junction of two vascular territories (“watershed or
boundary-zone infarct”) (Fig. 4.26D). Should the
proximal arterial anastomotic network (i.e., circle
2.2.1. HEMODYNAMIC FACTORS
of Willis) be anatomically incompetent (Fig. 4.26B)
2.2.1.1. Presence and efficacy of anastomotic or pathologically occluded (Fig. 4.26C), the infarct
pathways of vascular supply In the course of arte- will then be massive and will involve the entire arte-
rial occlusion, the ischemic cerebral territory is par- rial territory.
tially reirrigated by arteries at the base of the brain In the case of distal occlusion involving an
(circle of Willis, ophthalmic artery) and by super- end-artery, such as the middle cerebral artery, collat-
ficial corticomeningeal anastomoses (Fig. 4.26A). eral flow is dependent on a superficial anastomotic
This potential arterial anastomotic reirrigation sup- network, which is often precarious, and as a result,
ply explains why, in most cases, the resulting area of the infarct proximal to the circle of Willis will usu-
cerebral softening remains limited to only the part of ally be extensive (Fig. 4.26E).
ATHEROSCLEROTIC
CARDIOPATHIES STENOSIS Atherosclerotic
stenosis of
Anatomical byways of Functional
EMBOLI Mural thrombus
abnormalities supply factors*
Complete
THROMBOSIS
Failure of substitution
OCCLUSION OF MAIN
+ byways of
ARTERIAL TRUNK
supply
Extension of
thrombus
Inadequacy of
OCCLUSION OF A
+ arterial cortico-
PERICEREBRAL ARTERY
meningeal anastomes
CEREBRAL
INFARCT
FIGURE 4.25 Etiological and pathophysiological factors determining cerebral infarcts. *Functional fac-
tors: decrease in caliber of ischemic arteries; drop in blood pressure; loss of autoregulation of arterial caliber.

SC
A B C
SA
DC
AC
D E F
a b
1 2
1 2
FIGURE 4.26 Anastomotic patters of collateral supply and corresponding extent of cerebral lesions (AC,
anastomotic vascular network; SC, superficial arterial circulation; DC, deep vascular territory; SA, superficial
meningeal anastomoses). (A) Arterial occlusion but with effective and adequate anastomotic substitution net-
work of supply: no infarction. (B) Arterial occlusion without anatomically effective anastomotic collateral supply
(AC): massive infarction of the corresponding cerebral territory. (C) Arterial occlusion extending beyond the
origin of the anastomotic collateral supply. Absence of collateral supply: massive infarction. (D) Occlusion
proximal to the anastomotic collateral supply. Insufficient collateral supply. Anemic infarct of variable extent
in the territory (2) distal to the junction of two vascular territories (last field of irrigation or watershed infarct)
and in border zone between superficial and deep vascular territories (1). (E) proximal occlusion of one divid-
ing branch; collateral supply provided by superficial meningeal anastomoses: limited proximal infarction.
(F) Embolic occlusion. Mobilization of thrombus from 1 to 2. Sudden occlusion in 1, resulting in total ischemia
of both deep and superficial vascular territories and in hemorrhages in the superficial territory when border
zones are undergoing reirrigation (b); secondary mobilization of the thrombus in 2, with hemorrhages due to
secondary extravasation of blood into the originally ischemic deep vascular territory.
2.2.1.3. Type of occlusion In general, throm- 2 .2 . 2. ETIOLOGICAL FACTORS

bosis that leads to gradual occlusion of a vessel
2.2.2.1. Atherosclerosis General features.
allows for compensatory mechanisms of collateral
Atherosclerosis is the principal etiological factor in
flow. The resulting infarct is then usually pale and of
the production of cerebral infarction. The structural
relatively limited extent.
features and development of atherosclerosis in the
In contrast, emboli often produce sudden
brain are comparable to those in other organs. With
occlusion, with cessation of flow and inadequate
regard to the brain, atherosclerosis affects chiefly
irrigation. Hence, the resulting infarct is usually
large intracranial blood vessels and the carotid
extensive. In addition, migration and second-
arteries in the neck, even though the latter are infre-
ary fragmentation of the embolus is frequent.
quently examined at necropsy. It predominates at
This accounts for the hemorrhagic component of
sites of bifurcation (particularly at the level of the
the infarct frequently observed in the proximal
carotid sinus), at sites of curvature of the arteries, and
part of the ischemic territory, which follows sud-
at sites where the arteries are anatomically fixed. The
den reentry of arterial blood into damaged tissue
distribution of atherosclerosis in the thoracocervical
(Fig. 4.26F).
arterial tree and in the circle of Willis is illustrated in
however, microatheroma may be encountered (e.g.,
in parenchymal arteries within the basal ganglia, espe-
cially in subjects with severe basal atherosclerosis).
Increase in the size of the atherosclerotic
plaque and focal lesions, such as intramural hem-
orrhage, calcification, and mural thrombosis,
leads to increasing arterial stenosis (Fig. 4.28). It
is generally believed that the latter must involve
more than 75% of the original lumen of the artery
to cause a clinically significant decrease of blood
flow. The evolution of arterial stenosis is variable
(Fig. 4.29). The main complication lies in the
development of arterial thrombosis secondary to
local changes. Thrombosis may occlude the arte-
rial lumen completely and, as a result, a new event
may take place, namely anterograde extension of
a so-called stagnation thrombus, usually into the
first sizable collateral branch. The thrombus is ulti-
mately replaced by loose-textured connective tis-
sue in which new vessels of variable permeability
Lesions in increasing frequency. may develop. In many cases, the mural thrombus
can fragment and, in doing so, gives rise to arterial
emboli (artery-to-artery emboli). These emboli are
believed to account for cerebrovascular accidents
FIGURE 4.27 Frequency and severity of ath- from which some degree of recovery is possible,
erosclerotic lesions in the arterial cervico-cerebral particularly when the ischemic period is of short
arterial tree. duration (“transient ischemic attacks” [TIA]), or
which may be permanent when disintegration of
the classical diagram by Baker and Fisher (Fig. 4.27). the thrombus has not been sufficiently rapid.
The internal carotid arteries and the basilar artery are
the most heavily involved both at their origins and Atherosclerotic thrombosis (Figs. 4.27 to 4.29)
at their terminations. Atherosclerosis less severely
affects the most distal branches of the arterial tree • Internal carotid thrombosis develops in a setting of
compared to the vessels of the base of the brain; stenosing atheromatous lesions. These lesions are
A B
FIGURE 4.28 Stenosing atherosclerotic lesion. (A) Gross appearance of atherosclerosis of the basilar artery.
(B) Microscopic appearance, narrowing of the arterial lumen by arteriosclerotic lesions.

Stagnation
Atheromatous thrombus
plaque Mural
Emboli
(stenosis) thrombus
Occlusive
thrombus
FIGURE 4.29 Evolution of lesions caused by atheromatous carotid stenosis.
most often observed at the carotid bifurcation or at may also result from ascending extension of ver-
the level of the carotid sinus. A stagnation throm- tebral artery thrombosis and causes infarcts in the
bus is formed and usually extends rostrally to the midbrain or pons.
ostium of the first collateral branch, namely the • Thrombosis of a posterior cerebral artery is sel-
ophthalmic artery; collateral contribution through dom an isolated event. It usually occurs as the
the external carotid artery may ensure more or less result of anterograde extension of basilar artery
adequate perfusion of the proximal hemispheric thrombosis. When the posterior cerebral artery is
territory. The zone of infarction is then limited to a tributary of the internal carotid artery, its occlu-
the distal portion of the middle cerebral artery ter- sion may be secondary to extension from a throm-
ritory and, to a lesser extent, the anterior cerebral bosed carotid. As a result, these lesions frequently
territory. Anterograde extension of the thrombus result in massive hemispheric infarction.
beyond the ophthalmic artery, as well as beyond • Subclavian artery thrombosis may give rise to
the origin of the posterior communicating and the ischemic lesions in the vertebrobasilar territory
anterior cerebral arteries, will then result in mas- via diversion of the arterial flow (so-called subcla-
sive infarction. Less often, thrombosis takes place vian steal syndrome).
at the level of the carotid syphon (i.e., at the termi- • These artery-to-artery emboli play an important
nation of the internal carotid artery). Occlusion, role in the development of cerebral infarcts. They
due to atheromatous lesions in this terminal por- can arise from ulcerated plaques anywhere along
tion of the artery, is usually accompanied by retro- the arterial tree or from the aortic arch and spread
grade extension of the thrombus into the carotid distally. The most common sites of origin are the
sinus. When the lesion is old and organized, it may carotid sinus and the vertebral/basilar arteries.
be difficult to determine whether thrombosis of
the carotid artery originally took place at its distal Emboli of atherosclerotic origin (Fig. 4.29)
or proximal end.
• Isolated thrombosis of the middle or anterior • Platelet emboli frequently detach as small frag-
cerebral artery is much less common than internal ments from a thrombus and may cause transient
carotid thrombosis. It often follows extension of cerebral accidents or occlude terminal arterial
a carotid thrombus beyond the bifurcation of the branches.
internal carotid artery. • Fibrin emboli originate from a mural thrombus or
• Vertebral artery thrombosis may be clinically from fragmentation of a stagnation thrombus. They
and/or pathologically silent or may cause discrete often produce occlusion in the branches of larger
lesions, provided the thrombus does not reach the arteries (middle, anterior, or posterior cerebral) in a
ostium of the posterior inferior cerebellar artery setting of carotid or vertebrobasilar thrombosis.
and provided it is unilateral. • Purely atherosclerotic emboli most often are the
• Basilar artery thrombosis occurs in the setting result of spontaneous detachment of thrombotic
of atherosclerotic lesions, common at this site. It material from ulcerated plaques.
2.2.2.2. Cardiac emboli Cardiac (cardiogenic)
emboli are a frequent cause of arterial occlusion
(Fig. 4.30). They can originate from an atrial throm-
bus in mitral stenosis, from atrial vegetations and
atrial fibrillation from a mural thrombus in the
course of myocardial infarct, from various forms of
endocardial vegetations (e.g., bacterial endocarditis,
nonbacterial thrombotic endocarditis), or from a
cardiac prosthesis.
Emboli of other than those of cardiac origin are
less frequent.
2.2.2.3. Other Causes
• Arteritis is a rare cause of cerebral infarction.
Syphilitic arteritis, which affects especially FIGURE 4.30 Arterial embolus (superficial tempo-
the basal arteries, is seen infrequently today. ral artery). Note the normal appearance of the arterial
Meningovascular syphilis is characterized by a wall (H&E).
transmural plasma cell-rich infiltrate, associated
with intimal thickening. Tuberculous and other
bacterial meningitides, as well as meningitis caused Within the guidelines already outlined, the site and
by parasitic organisms, can produce occlusive arte- extent of the vascular occlusion will determine if the
ritic lesions (usually manifest as an endarteritis) infarct is to affect a greater or lesser portion of the
which may account for cerebral and spinal infarcts relevant vascular territory affected.
(cf. Chapter 5). In long-term survivors of HIV
infection, cerebral infarcts are rather frequent, for
reasons that are still unclear. “Collagen-vascular” 2.3.1 . CEREBRAL INFARCTS
diseases, especially polyarteritis nodosa, may The neuropathological analysis of cerebral infarcts
sometimes affect small superficial arterioles and, requires complete anatomical study of both the
more infrequently, the deep intracerebral or spinal carotid and the vertebrobasilar system from the
intramedullary vessels. The resulting parenchyma- aortic arch up to the cerebral branches (Fig. 4.31).
tous lesions consist of circumscribed and widely The study must also include a meticulous exami-
disseminated foci of softening. In children, otitis nation of the heart cavities, heart valves, and
media and rhinopharyngitis can occasionally be myocardium.
a cause of internal carotid occlusion, which may
result in cerebral infarction. 2.3.1.1. Infarcts of the carotid territory Brain
• Amyloid angiopathy of the cortical blood vessels infarction due to carotid occlusion may involve
may cause multiple disseminated cortical infarcts either the whole or only part of any of the territo-
(especially microinfarcts involving both cortex ries of distribution irrigated by the branches of the
and white matter), in addition to cerebral hemor- internal carotid artery (Fig. 4.32). Carotid artery
rhages, as discussed above (cf. 1.2.2). occlusion may result in a single infarct, but often
• Injuries to the neck or in the mouth may give rise enough, multiple infarcts that vary in size and age
to internal carotid occlusion. are the rule.
• Vascular malformations, especially arteriovenous
aneurysms, are sometimes associated with cere- • Infarct of the anterior cerebral artery territory (Fig.
bral infarcts (cf. 1.2.3). 4.33D). This area of vascular supply includes
the superior frontal gyrus, inferior and medial
surfaces of the frontal lobe extending back to
2.3. Topography the level of the precuneus, corpus callosum, and
Regardless of the specific cerebral or spinal territory anterior portions of the basal ganglia, which
involved by an infarct, the extent of the infarct will are variably supplied by the recurrent artery of
be determined by the general rules outlined above. Heubner. Because of collateral flow provided

to the superficial branches of the MCA results
from occlusion distal to the origin of the perforat-
Corticomeningeal ing branches (superior and inferior divisions)
anastomoses (Fig. 4.33A), whereas proximal vascular occlusion
Anastomoses of the by atherosclerosis is responsible for isolated deep
circle of Willis middle cerebral infarcts (Fig. 4.33B). Most often,
infarction involves only part of the vascular ter-
ritory (e.g., territory of the ascending branches).
Anastomosis via the This may result from occlusion of the terminal
ophthalmic artery
branches but more often results from proximal
occlusion of the internal carotid artery coupled
with adequate reirrigation of the proximal terri-
tory through vascular anastomoses at the base of
the brain.
• Infarct of the anterior choroidal artery territory
(Fig. 4.33E). The posterior part of the internal
capsule, pallidum, and optic tract are located
within this vascular territory. Infarction of this
deep area of supply, especially when recent, is
often difficult to detect because of the limited
extent of the involved territory. Isolated infarc-
tion of this area is quite rare; compromise of
FIGURE 4.31 The carotid-vertebral vascular tree this vascular territory more often is associated
and its chief anastomotic pathways. with total infarction of the middle cerebral terri-
tory, the affected region being part of a massive
infarct.
by the contralateral anterior cerebral artery via • Massive hemispheric infarct. The term describes an
the anterior communicating artery, infarcts of infarct that affects the entire territory supplied by
the anterior cerebral territory are less common the internal carotid artery (Fig. 4.33F, Fig. 4.34).
than those in the middle cerebral territory. The The infarct results from sudden occlusion of the
well-known anatomical variability of the circle terminal portion of the internal carotid artery,
of Willis at this site accounts for the differing either by an embolus or by a propagation of an
size and distribution of the infarct (e.g., a single internal carotid thrombus beyond the terminal
anterior cerebral artery associated with bilateral bifurcation of the artery, in the setting of a total
infarction) observed in clinical practice. In the absence of all potential sources of collateral sup-
case of internal carotid thrombosis with com- ply. The mere size of the large portion of the brain
promise of the territory supplied by the anterior that is rendered ischemic accounts for the wide-
cerebral artery, infarction is almost invariably spread edematous reaction and, consequently, the
associated with involvement of the middle cere- high frequency of temporal herniation (Fig. 4.33F,
bral territory (Fig. 4.33F). Fig. 4.34).
• Infarct of the middle cerebral artery territory. This • “Watershed” or boundary-zone infarcts (Fig. 4.35).
area of supply includes the lateral surface of the These involve mostly the boundaries between the
frontal and parietal lobes, insula, superior and anterior and middle cerebral territories, especially
middle temporal gyri, and deep striatal terri- posterior to the interparietal sulcus. This type of
tory. In most cases, occlusion of the proximal lesion is also seen sometimes in the distal fields
part of the middle cerebral artery results in total of irrigation between the middle, anterior, and
infarction of the middle cerebral artery territory posterior cerebral territories. Watershed infarcts
(Fig. 4.33C), since the superficial collateral arte- may also involve the zones of arterial supply
rial circulation is only able to provide minimal at the junction of the deep and superficial ter-
collateral flow. The occlusion is more often the ritories of the middle cerebral artery, thereby
result of embolization than of primary intravas- affecting the deep white matter and in particular
cular thrombosis. Cerebral infarction restricted the midportions of the centrum semiovale. This
A D
F
Posterior cerebral
artery
Anterior cerebral
artery
Middle cerebral
artery
Anterior choroidal
artery
H J
g, anterior
communicating
artery; h,
thalamic
perforating
arteries
FIGURE 4.32 Cerebral vascular territories. (A) Outer surface. (B) Inner surface. (C) Basal surface. (D–K)
Coronal slices from front to back.
type of infarction results from internal carotid granular appearance of the cerebral cortex is
thrombosis, particularly when the thrombosis is apparently the result of multiple, small chronic
bilateral, or follows prolonged episodes of arterial ischemic lesions manifest as punched-out foci
hypotension/shock. of cavitated cicatricial softening, and of focal
• Granular atrophy of the cerebral cortex of arte- glial scars affecting the cortex predominantly.
riopathic origin (Fig.4.36). This rare disorder is The lesions are often bilateral and involve the
characterized on macroscopic examination by watershed territories along the crest of the gyri at
an abnormality of the cerebral cortex whereby the junction of the middle and anterior cerebral
the gyral pattern over the convexities is thinned arteries, and may also affect the superficial water-
out and distorted, giving it a granular appear- shed territory between the middle and posterior
ance. The histopathological basis of the abnormal cerebral artery.

A B C
D E F
FIGURE 4.33 Principal topographical areas of distribution of infarcts in the internal carotid territory (Loyez
stain for myelin). (A) Recent right-sided superficial middle cerebral infarct. Note the presence of a small
associated infarct involving the corpus callosum and the cingulated gyrus (territory of the anterior cerebral
artery). (B) Recent, deep, right-sided middle cerebral infarct. Note its hemorrhagic character in association
with older, more superficial lesions (insula and claustrum). (C) Old, total, right-sided middle cerebral infarct.
(D) Right-sided anterior cerebral infarct. (E) Right-sided anterior choroidal infarct. (F) Recent, right-sided mas-
sive hemispheric infarct involving the whole territories of the anterior, middle, and anterior choroidal cerebral
arteries. Note right temporal herniation.
The distribution of the lesions is indicative of

global chronic watershed ischemia related to bilat-
eral internal carotid stenosis coupled with cardiac
insufficiency.
2.3.1.2. Infarcts of the vertebrobasilar terri-

tory (“posterior circulation”)
The same pathophysiological principles and neuro-
pathological features described above for the “ante-
rior” or carotid circulation also apply to infarcts in
the “posterior circulation.” In addition, the distinc-
tive anatomical aspects of the posterior arterial cir-
culation and its systems of collateral flow need to be
FIGURE 4.34 Recent massive hemispheric infarct. taken into account to further understand the clinico-
Gross appearance. pathological manifestations of these infarcts.
FIGURE 4.36 Granular atrophy; old ischemic
lesion involving the watershed territories at the junc-
tion of the middle and anterior cerebral territories at
the crest of the gyrus along the frontal superior sulcus
(Loyez stain).
FIGURE 4.35 Old infarct at the junction of the left
anterior and middle cerebral territories
inferomedial surface of the occipital lobe, of the
cuneus, and especially of the calcarine cortex, as
The posterior circulation system consists of well as part of Ammon’s horn (the hippocampus).
a median axis, the basilar artery, formed by the The infarct is the result of occlusion of the posterior
junction of two vertebral arteries originating from cerebral artery beyond its junction with the poste-
the subclavian arteries, which undergo a tortuous rior communicating artery. The arterial occlusion
course through the foramina transversaria, and is generally embolic in origin, and most often sec-
of two terminal branches, the posterior cerebral ondary to preexisting vertebrobasilar thrombosis.
arteries. There are considerable anatomical varia- Infarcts of the deep territory of the posterior cere-
tions of this vascular arrangement. The caliber of bral artery most often affect either the thalamoge-
the vertebral artery, the integrity of the posterior niculate territory (i.e., the ventrolateral thalamus
communicating artery, which may be narrowed or and the pulvinar) or the paramedian thalamic terri-
hypoplastic, and the caliber of the proximal poste- tory (i.e., the intralaminar nuclei). In the latter situa-
rior cerebral artery ultimately determine the flow tion, a bilateral butterfly-shaped lesion may develop
patterns through the circle of Willis. with unilateral origin of the paramedianartery and is
Variable anastomotic communications exist associated with variable involvement of the mesen-
with the internal carotid arteries, through the pos- cephalon (i.e., a thalamomesencephalic infarct).
terior communicating arteries, with branches of • Infarcts of the brainstem (Fig. 4.38). In the major-
the external carotid and subclavian arteries, and ity of cases, brainstem infarction is secondary to
between the vertebral arteries themselves through atherosclerotic thrombosis of the vertebral or
the spinal perimedullary arterial network. basilar artery. These infarcts may also be secondary
Finally, there are lateral anastomotic rings formed to embolization of cardiac origin. The general pat-
between the cerebellar arteries. tern of arterial supply of the brainstem is such that
These special anatomical features account for there is a relatively stereotyped arterial intraparen-
the commonly observed patterns of infarction that chymal vascular network, whereas the arborization
result from occlusive arterial disease in the vertebro- in the SAS of the extraparenchymal feeding vessels
basilar axis that are manifest as bilateral, multifocal, is highly variable and complex. Accordingly, the
and asymmetrical lesions. patterns of infarction often defy classification, but
for purposes of simplification they could roughly
• Infarcts of the posterior cerebral artery territory be subdivided into the following types:
(Fig. 4.37). Infarcts within this hemispheric terri- – Focal lesions corresponding to infarction of a
tory are often bilateral, producing necrosis of the specific vascular territory: these are the result

A B
FIGURE 4.37 Infarcts of the posterior cerebral territory (Loyez stain for myelin). (A) Occipital infarct
involving the calcarine cortex. (B) Recent infarct of the thalamogeniculate territory. Note involvement of
Ammon’s horn.
of occlusion of either paramedian branches – (B) the territory of the posterior inferior cer-
or circumferential branches of the basilar ebellar artery (PICA), distributed over the
artery: (A) paramedian infarcts—(1) midline ventral surface of the hemisphere; and
infarct of the midbrain tegmentum with or with- – (C) the inferior anterior cerebellar artery
out associated thalamic lesions (paramedian (AICA), which usually supplies the flocculus,
thalamic infarct); (2) paramedian infarct of the the middle cerebellar peduncle, and the infe-
pontine tegmentum; (3) paramedian infarct of rior lateral territory of the pons (Fig. 4.39C).
the medulla; (B)infarcts in the distribution of • Between 10% and 25% of cerebellar infarcts are
short circumferential branches: (1) infarct of the due to embolic vascular occlusion. The infarct
middle cerebellar peduncle; (2) infarct of the lat- can be confluent and involve most or all of the
eral medullary region (causing Wallenberg syn- territory supplied by one of the three major ves-
drome; usually due to occlusion of the PICA). sels that supply the cerebellum, or the ischemic
– Multifocal and diffuse lesions. These may insult may result in multiple foci of necrosis in
involve many vascular territories and sometimes the cerebellum with concomitant infarcts in the
consist of lesions of different ages. Single “geo- brainstem. Any of these lesions can behave as
graphic” lesions may also bridge the usual topo- space-occupying masses resulting in cerebellar
graphical limits of irrigation of a particular vessel herniation with brainstem compression. A surgi-
in this territory. cal pathologist may be surprised to find, at the
• Cerebellar infarcts (Fig.4.39) time of frozen section from a cerebellar “mass
– Cerebellar infarcts are three to five times lesion,” only infarcted cerebellar fragments.
more frequent than cerebellar hemorrhages. Border-zone infarcts, situated at the boundaries
The lesions frequently appear as territorial between the territories of distribution of the dif-
infarcts, the result of occlusion of the long ferent cerebellar arteries, are not uncommon.
circumferential branches of the vertebral
and basilar arteries (Fig. 4.39A). These may 2.3.1.3. Complications of therapy In the mod-
involve: ern era, aggressive therapy for acute stroke (espe-
– (A) the territory of the superior cerebellar cially ischemic stroke) is often carried out, and
artery (SCA), which comprises the superior a pathologist encountering tissue from the brain
portion of the cerebellum down to the dentate or blood vessels of an affected patient should be
nucleus and the posterolateral portion of the aware of this. Intravenous tissue plasminogen acti-
pontine tegmentum (Fig. 4.39C); vator (TPA) administered to a patient with acute
A B
C D
E F
FIGURE 4.38 Infarcts of the brain stem (Loyez stain for myelin). (A) Midbrain infarct. (B) Massive infarct
of the midbrain tegmentum. (C) Massive upper pontine infarct with right-sided paramedian predominance.
(D) Massive infarct of the basis pontis. (E) Central medullary infarct. (F) Lateral medullary infarct (causing
Wallenberg syndrome).
thrombosis may precipitate IPH; this is especially and such extractions may themselves be compli-
common in elderly individuals who have (clini- cated by subintimal dissection or arterial occlu-
cally unsuspected) CAA. Increasingly sophisticated sion. Various endovascular treatments may lead
devices are used to surgically extract intraluminal to intra-arterial embolization of “catheter sheath”
thromboemboli (e.g., from the MCA bifurcation), materials that can cause microvascular thrombosis,

A
A B C
A A A
B B B
1
C C C
2
D D D
3
B C
FIGURE 4.39 Cerebellar infarcts. (A) Diagram showing the full extension of lesions in cerebellar infarcts.
From top to bottom: Posterior view; lateral view; serial sections perpendicular to the brainstem axis through the
upper cerebellum and pons, middle cerebellum and lower pons, middle cerebellum and middle medulla oblon-
gata, lower cerebellum and medulla oblongata. A, posterior and inferior cerebellar artery (PICA) territory. B,
anterior and inferior cerebellar artery (AICA) territory. C, superior cerebellar artery (SCA) territory. (Modified
fromAmarenco P, Hauw JJ. Anatomie des artères cérébelleuses. Rev Neurol (Paris), 1989: 145:267–276 with per-
mission. See also Amarenco P, Hauw JJ, Caplan LR. Cerebellar Infarction. In: Lechtenberg R (ed.), Handbook of
Cerebellar Diseases. New York, Marcel Decker, 1993:251–290). (B) Right-sided recent pale infarct of the superior
cerebellar artery. (C) Left-sided hemorrhagic infarct of the posterior inferior cerebellar artery.
often with a foreign body giant cell reaction, and 2.3.2.1. Arterial organization of the spinal
brain infarcts. cord Distinctive features in the arterial supply of the
spinal cord determine the principal topographical
patterns of infarction following vascular occlusion
(Figs. 4.40 and 4.41). As in the brainstem, the extra-
2. 3. 2. S P I NAL I NT R A M ED U L L A RY
medullary arterial network is variable, whereas the
I N FA RC T S
intramedullary network is fairly constant.
Spinal intramedullary infarcts are much less com- The intramedullary arteries are principally
mon than cerebral infarcts. In cases of infarction of branches of the anterior spinal artery, which extends
the spinal cord, because it is technically difficult to downward along the ventral aspect of the spinal
carry out a thorough postmortem study of the blood cord and is responsible for the blood supply of the
supply of the spinal cord, clinicopathological corre- anterior two thirds of the cord, including most of
lation studies are often incomplete. the gray matter, except for the posterior portions
Posterior spinal Vertebral
territory artery
C1
Anterior spinal territory Radicular arteries supplying the
(stippled) central enargement (collaterals
Rostral from the subclavian and
territory vertebral arteries)
Aorta
ANTERIOR SPINAL ARTERY

T4
Middle Dorsal radicular artery
Peripheral territory territory
T6
FIGURE 4.40 The three transverse arterial territo-
Radicular artery supplying
ries of the spinal cord. the lumbar enlargement
Caudal (artery of Adamkiewicz)
territory
of the posterior horns in most cases. Two posterior
spinal arteries irrigate the dorsal third of the cord,
including the dorsal three fourths of the posterior
columns. A perimedullary anastomotic network
gives off a few branches to the subpial portions of S5
the cord. The extramedullary network, which is FIGURE 4.41 The three principal longitudinal arte-
complex and variable, is formed from multiple and rial territories of the spinal cord.
anastomosing branches of the radicular arteries.
Furthermore, on the longitudinal axis, following
territories are recognized: part of the posterior columns (i.e., at the bound-
ary between the anterior and posterior spinal ter-
• A superior, or cervicothoracic, territory corre- ritories) (Fig. 4.42B, C).
sponding to the cervical and upper two or three • Anterior spinal artery infarction involves a greater
thoracic segments and supplied by arterial twigs or lesser portion of the anterior spinal territory
originating from the vertebral arteries or from and especially the ventral horns (Fig. 4.43). It
branches of the subclavian arteries is the most frequent type of infarct in the spinal
• An intermediary or middle thoracic terri- cord. Cord infarcts in the anterior spinal artery
tory extending from T4 to T8 with a poor distribution have been described at almost any
blood supply segmental level but are most often seen in the
• An inferior, or thoracolumbar, territory whose lumbar region; this is probably because of the spe-
abundant vascularization is supplied by a single cial vulnerability of this territory, which ordinarily
lumbar artery (i.e., the artery of the lumbar depends on a single artery with limited collateral
enlargement, or artery of Adamkiewicz). This supply from the delicate middle thoracic arterial
artery ordinarily takes a leftward course, running network.
along the lower thoracic or upper lumbar nerve • Infarcts of the posterior spinal territory
roots, and can be reinforced by an upper or a (Fig. 4.44) are considerably rarer.
lower branch.
2.3.2.3. Microscopic features
2.3.2.2. Topographical features Histopathologically the cellular evolution of the
• Massive infarction (Fig. 4.42A) usually occurs ischemic lesion is comparable to what has been
in the middle thoracic zone, which is normally described above for cerebral infarcts. In other words,
poorly vascularized. It is presumably the result of hours after the insult there is an initial edematous
sudden total ischemia, when reirrigation of the stage involving the intracellular and extracellular
middle thoracic segments by the abundant cervi- compartments. This is followed by death and dis-
cal and lumbar networks is inadequate. The infarct integration of all constituents with secondary liq-
extends over several segments and often extends uefaction necrosis. Then an inflammatory cellular
proximally and distally in the form of a fusiform response occurs with tissue resorption through the
or pencil-like zone of tissue necrosis involving the mobilization of macrophages and, in the end, cavita-
centromedian portions just adjacent to the ventral tion and surrounding gliosis.

A B
C6
Upper fusiform
extension
T4 Total transverse
infarct
Lower fusiform
extension
T9
FIGURE 4.42 Transverse infarcts of the spinal cord. (A) Maximal extent of the lesions (Loyez stain for
myelin). (B) Diagram of fusiform extensions of the lesion. (C) Upper fusiform extension of the lesion (Loyez
stain for myelin).
FIGURE 4.43 Focal infarct of the spinal cord FIGURE 4.44 Focal infarct of the spinal cord (Loyez
(Loyez stain for myelin). Anterior spinal artery infarct. stain for myelin). Posterior spinal artery infarct.
2.3.2.4. Etiology Atherosclerosis and arterial variable depth, some reaching the deep white mat-
thrombosis involving either the feeding vessels or the ter as medullary branches. Other perforators enter
aorta play an important role. Vascular supply to the spi- the brain at the base (supplying the basal ganglia and
nal cord may be compromised because of obstruction thalamus), and yet others irrigate the brainstem aris-
of the orifices of the intercostal and lumbar arteries or ing from long and short circumferential branches.
via an aortic aneurysm. For the most part, these are end-arteries with lim-
Ordinarily, it is difficult to demonstrate an arte- ited collateral anastomoses until the capillary net-
rial embolic occlusion as the etiological factor of a work is reached.
spinal cord infarct, the exception being the case of
cholesterol emboli originating from ulcerated aortic
atheromatous plaques. Also, there are several case 3.1. Vascular Diseases Affecting the
reports on record where cartilaginous emboli fol- Small Blood Vessels
lowing relatively minor trauma to the spine have
Important disorders in this category include hyperten-
been implicated in spinal cord infarction.
sive cerebrovascular disease (discussed above: cf.1.2.1)
Rarely, primary angiitis of the CNS may prefer-
and cerebral amyloid angiopathy (cf. 1.2.2).
entially or predominantly involve the spinal cord.
Less common entities include cerebral autoso-
Other established predisposing factors in the
mal dominant arteriopathy with subcortical infarcts
pathogenesis of spinal cord infarction include tho-
and leukoencephalopathy (CADASIL) and other
racoabdominal surgery, aortography, and dissecting
rare disorders of small vessels.
aneurysm of the aorta.
3. SMALL VESSEL DISEASE 3.1.1 . CADASIL

The two broad categories of cerebrovascular diseases CADASIL is a hereditary disease of the brain vessels
described above, large hemorrhages and infarctions, due to a mutation of the Notch 3 gene on chromosome
account for the majority of cerebrovascular cases 19. It is characterized by deposition of pathognomonic
that come to medical attention. As indicated, these granular osmiophilic material (GOM) in the media of
conditions result in focal or multifocal injury affect- vessels throughout the body (Fig. 4.45D, E), including
ing relatively large areas of the brain and are related dermal arteries (where the deposit can easily be iden-
to arterial rupture or arterial occlusion. Apart from tified on skin biopsy by electron microscopy). Though
these, there remain a number of diseases in which the GOMs are suspected by routine light microscopy,
vascular lesions affect relatively small blood vessels, their presence must be confirmed by electron micros-
often at many sites throughout the neuraxis and are copy. The extracellular domain cleaved from Notch 3
associated with ischemic and/or hemorrhagic mani- in response to ligand binding accumulates outside the
festations. In some, the principal clinical manifesta- degenerating vascular smooth muscle cells and can
tions are those of focal neurological deficits, whereas be identified immunohistochemically. At the cellular
in others syndromes of dementia (with or without level, the topographical distribution of these deposits
associated degenerative diseases; cf. Chapter 8) or differs from that of the granular deposits (Fig. 4.45C),
encephalopathies predominate. The armamentarium and they are associated with degeneration of vascu-
of new radiological imaging methods has enhanced lar smooth muscle cells with progressive wall thick-
awareness of these important causes of neurologi- ening/fibrosis and luminal narrowing of small and
cal morbidity. Some of these affect predominantly medium-sized penetrating arteries. This vascular dis-
or exclusively the CNS, whereas others are systemic ease gives rise to multiple small infarcts involving the
vascular disorders that involve the brain and spinal white matter or deep gray matter, ordinarily not asso-
cord along with other organ systems. ciated with a hemorrhagic component. The cerebral
For purposes of classification, and conceptually, cortex is less often affected.
these are disorders of the “microcirculation” and Other rare hereditary cerebral and/or retinal vas-
small blood vessels in general. The so-called “small cular diseases have been described, and for some, a
arteries ”or arterioles include perforators with diam- gene mutation has been identified. These include cere-
eters from 40 to 400 μm. Some emerge from the bral autosomal recessive arteriopathy with subcorti-
leptomeningeal arteries, enter the brain parenchyma cal infarcts and leukoencephalopathy (CARASIL)
from the surface of the brain, and extend within to a and hereditary vascular retinopathy, cerebroretinal

A B
D E
FIGURE 4.45 CADASIL. (A) Gross appearance of the subcortical infarcts and leukoencephalopathy

(Woelcke stain). (B) Gross appearance of status cribrosus at the cortico-subcortical junction in the pole of the
temporal lobe and fronto-orbital cortex. (C) White matter arteriole, immunostaining of the extracellular domain
of Notch 3. Note positive deposit around the lumen and the vascular smooth muscle cells clearly different from
the unstained granular deposit deeper in the arteriolar wall. (D) Granular osmiophilic material in arterial walls
on semi-thin section and (E) at ultrastructural examination.
vasculopathy, hereditary endotheliopathy with unifying histopathological features in these condi-
retinopathy, nephropathy, and stroke (HERNS). tions are the presence of intramural inflammation
CARASIL, thus far found only in Japanese patients, and destruction of the vascular wall, manifesting in
results from mutations in the HTRA1 gene 9 on chro- some conditions as fibrinoid necrosis in the early
mosome 10q, which encodes a serine protease that stages of the disease. Recognized among these
appears to regulate the expression of vascular growth disorders are infectious vasculitides secondary to
factors. The result of mutations in this gene is pro- direct invasion of blood vessel walls by microorgan-
found intimal hyperplasia affecting parenchymal and isms and noninfectious CNS vasculitides, wherein
leptomeningeal arteries, leading to a severe ischemic the primary mechanism of injury is presumed to be
leukoencephalopathy. HERNS results from a muta- immunopathological.
tion in the trex 1 gene on 3p21, but the precise mecha-
nism of the resultant microangiopathy and multifocal 3.1.3.1. Infectious vasculitides Infectious vas-
(predominantly white matter) microinfarcts and lacu- culitides due to direct infection of blood vessels by
nar infarcts is poorly understood. Neuropathological microorganisms have been described in viral infec-
studies are mostly lacking or limited to single cases. tions (HIV, VZV, EBV, HSV, CMV—the latter espe-
Recently, growing interest has developed in a micro- cially in AIDS), bacterial infections (tuberculosis,
angiopathy associated with cerebral hemorrhages syphilis, mycoplasma, rickettsia), fungi (cryptococ-
and lacunar infarcts, resulting from mutations in the cosis), or parasitoses (cysticercosis) (cf. Chapter 5).
COL4A1 gene.
3.1.3.2. Non-infectious CNS vasculitides

3.1.2. SMALL VESSEL DISEASE IN OTHER
These may arbitrarily be divided into primary or
RARE SYSTEMIC DISORDERS
secondary forms.
Small vessel disease is also a part of some systemic Primary angiitis of the CNS is defined as vascu-
disorders, including mitochondrial encephalopathy, litis occurring predominantly in the CNS in the
lactic acidosis, and stroke-like episodes (MELAS) (cf. absence of systemic inflammatory diseases, infec-
Chapter 10) or merosin-negative congenital muscu- tions, neoplasms or exposure to drugs. The disease
lar dystrophies (cf. Chapter 12), in which a leukoen- affects, in a segmental distribution, multiple small
cephalopathy is a frequent and characteristic feature. and medium-sized arterioles and venules through-
out the brain and, to a lesser extent, the spinal
cord. Histologically, the typical acute/subacute
3.1.3. ACUTE INFLAMMATION OF SMALL
lesion consists of perivascular aggregates of multi-
VESSELS: CNS VASCULITIS WITH OR
nucleated giant cells and macrophages, which can
WI THOUT SYSTEMIC MANIFESTATIONS
extend into the vessel wall (Fig. 4.46). Sometimes,
In a wide variety of inflammatory diseases of the the vascular lesions are characterized by a predom-
CNS, small blood vessels may be affected. The inance of lymphohistiocytic infiltrates, without
A B
FIGURE 4.46 Primary angiitis of the CNS. Infiltration of the vessel walls by histiocytes, giant cells, and mono-
nuclear cells involving a leptomeningeal and a perforating artery (A); an intraparenchymal artery (B).

giant cells or mononuclear cells. Rarely, foci of 3.2. Parenchymal Changes Associated
necrosis are seen adjacent to the affected vessels. with Diseases of Small Arteries
Chronic lesions consist of thickening and fibrosis
of the vessel wall without significant inflamma- Of interest in these conditions is the correlation
tory infiltrates. Acute lesions often coexist with between the findings of neuroimaging data and neu-
more chronic healing or healed lesions. When ropathology in small hemorrhages, microbleeds,
CNS vasculitis/angiitis is identified in an older lacunes, status cribrosus (état criblé), and arterio-
subject (60+ years), angiitis secondary to CAA pathic leukoencephalopathies.
must be suspected and further evaluated with
appropriate immunohistochemical examination
of the specimen (using anti- Aβ primary antibod- 3 .2 . 1. SM ALL IN TRAPAREN CHYM AL
ies). CAA-associated angiitis (Aβ-related angiitis H EM ORRHAGES
[ABRA]) is usually characterized by a prominent As discussed above, large IPHs (cf. 1.2) are most
granulomatous transmural inflammatory infiltrate. often associated with hypertensive cerebrovascu-
Secondary inflammation of CNS blood ves- lar disease (cf. 1.2.1) and/or with cerebral amyloid
sels includes manifestations of systemic diseases, angiopathy (cf. 1.2.2). Smaller intracerebral hemor-
malignancy-related vasculitis, and drug-induced rhages, 10 to 20 mm in diameter, also occur. These
vasculitis. In secondary angiitis of the CNS the neu- are cavitated and destructive, usually with a regu-
rological syndrome is associated with a systemic lar outline (Fig. 4.47C). Their walls are the site of
disease, including systemic lupus erythematosus, ochre-yellow pigmentation that corresponds to the
polyarteritis nodosa, Wegener granulomatosis, and abundant presence of hemosiderin-laden macro-
Churg-Strauss syndrome; neurological manifesta- phages (Fig. 4.47D), which are also found inside the
tions have been described in the context of Sjögren cavity. They may be solitary and located in the basal
syndrome and Behçet disease. Diagnosis relies ganglia or, more seldom, in the hemispheric white
mostly on clinical assessment, imaging studies, and matter. However, multiple subcortical small “slit
laboratory analysis by immunological serological hemorrhages” may be seen in hypertensive patients.
tests. Brain biopsy is rarely utilized as a diagnos- Historically, they have been considered to be due
tic test. Neuropathological autopsy studies have to the rupture of microaneurysms, but lipohyali-
shown that the characteristic histopathological fea- nosis and amyloid degeneration of the vessel wall
tures of the vasculitis in these disorders are rather have also been implicated. Imaging and pathologi-
nonspecific and consist of variable perivascular cal studies now allow them to be distinguished from
and intravascular chronic inflammatory infiltrates cerebral “microbleeds” (cf. 3.2.2).
with mural fibrosis, thickening, and variable lumi-
nal compromise.
Vasculitides of the nervous system may 3 .2 . 2. CEREBRAL “M ICROBLEEDS”
occur in patients with neoplasia. They predomi- Cerebral microbleeds (CMBs) are small (less
nantly involve the peripheral nervous system (cf. than 5 to 10 mm in diameter), well-demarcated,
Chapter 13). CNS vasculitis is particularly associ- hypointense, rounded small lesions seen on MRI
ated with Hodgkin disease. In most cases it pres- sequences sensitive to magnetic susceptibility
ents as granulomatous angiitis. The neurological effects. Radiological studies suggest that CMBs are
symptoms may precede the diagnosis of the under- an imaging marker for small vessel pathology within
lying neoplasm, and brain biopsy is necessary for brain, especially CAA. They are observed more
definite diagnosis. frequently with increasing age. They occur mainly
Drug-induced vasculitis has been studied by in primary intracerebral hemorrhage patients and
radiological imaging methods but there are very are less frequent in patients with ischemic cerebro-
few confirmatory neuropathological studies. The vascular disease. They appear to be a predictor of
reported cases of biopsy/autopsy-proven cerebral recurrent vascular events. The neuropathological
vasculitis in cocaine abusers have shown a necrotiz- correlate of these imaging studies is in the process of
ing angiitis affecting cerebral arteries and arterioles being analyzed. Iron deposits have been seen in the
(in some, documentation of multiple drugs, includ- capillary wall, at the abluminal endothelial surface,
ing amphetamines, was documented). in association with pericytes, and in perivascular
A B
C D
E F
FIGURE 4.47 Cerebral lacunes. (A, C, E) Macroscopic features. (A) Lacune. (C) Small cavitated IPH (also
called type 2 lacune). (E) État criblé. (B, D, F) Microscopic features. (B) Lacune. (D) Small cavitated IPH.
(F) État criblé.
macrophages on the arterial side of the microcir- commonly found. Neuropathologic examination
culation. They are also found at some distance of may, in addition, reveal other lesions, such as small
evolved vessels, apparently in the extracellular space. vascular malformations (capillary hemangiomas
They are seen in association with amyloid angiopa- and capillary telangiectases.
thy as well as arterial hypertension, in the subcorti-
cal white matter as well as in the basal ganglia. At
3.2.3 . L ACUNAR INFARCTS
the latter sites, the identification of the nature of
the mineral deposits by MRI study can be prob- These are small, deep infarcts due to occlusion
lematic because other vessel mineral deposits are of small penetrating arteries originating from

the circle of Willis, its main branches at the base 3 .2 . 5. ARTERIOPATHIC
of the brain, and basilar artery. They have been L EU KOEN CEPHALOPATHIES
sometimes classified as type 1 lacunes. Old lesions
Diffuse white matter lesions can be seen in certain
appear as irregular, ragged cavities that on micro-
forms of vascular diseases. The neuropathological
scopic examination have all the characteristics of
appearance of these disorders is diffuse myelin pal-
ischemic necrosis. A lacunar cavity contains small
lor of the cerebral white matter, best demonstrated
amounts of parenchymatous debris and lipid- or
on whole brain sections stained for myelin. Often
hemosiderin-laden macrophages (Fig. 4.47B). The
enough, the subcortical U fibers, the interhemi-
cavities are traversed by blood vessels of small cali-
spheric commissures (corpus callosum and anterior
ber and are surrounded by variably severe astrocytic
commissure), and the internal capsule are spared
gliosis, often including gemistocytic astrocytes.
(Fig. 4.48A, B). On microscopic examination, the
Lacunes may be solitary or multiple; they involve
principal abnormalities are an ill-defined, incom-
preferentially the basal ganglia (Fig. 4.47A), the
plete myelin loss, intramyelinic edema, and abnor-
internal capsule, and basis pontis. Their diameter
malities of oligodendrocytes (Fig. 4.48C). These are
is variable, ranging from a small cavity to one that
associated with dilatation of the perivascular spaces
reaches 15 mm in diameter. In the majority of cases,
and diffuse reactive gliosis.
lacunar infarcts are the result of vascular occlusion
Binswanger arteriopathic subcortical encepha-
secondary to segmental arteriolosclerosis in the
lopathy is an arteriopathic leukoencephalopathy
setting of systemic hypertension, though in prac-
occurring in hypertensive patients. In addition
tice the “guilty” occluded arteriole is rarely iden-
to the previously described white matter lesions,
tified. They may also be related to atherosclerosis
numerous small chronic ischemic cavities are seen
involving arterial trunks when a plaque occludes
in the white matter and deep gray matter (lacunes)
the ostium of the artery. Artery-to-artery emboli
(Fig. 4.48A), and the arterioles of these regions
or emboli of cardiac origin may infrequently cause
are the seat of severe arteriosclerotic lesions
lacunar infarcts. Some lacunar infarcts may be the
(Fig. 4.48D).
result of resorbed small hemorrhages.
In CAA, similar lesions can be seen, although
there are no lacunes or infarcts in the white matter.
Amyloid angiopathy is present in the cerebral cortex
3. 2. 4. É TAT C R I BL É ( S TATU S and leptomeninges, and microinfarcts and miliary
C R I B ROSUS ) hemorrhages may be found in the cortex.
This condition is defined as a dilatation of the peri- Arteriopathic leukoencephalopathy is a feature
vascular spaces containing CSF. The resulting cavi- of CADASIL. In this condition, subcortical infarcts
ties have a rounded and smooth outline. They always or lacunes are frequent in the white matter and basal
contain in cross-section vessels with an open lumen ganglia (Fig. 4.45A).
(Fig. 4.47F). The cavity is lined by the pial cells that
form the outer walls of the Virchow-Robin space, 4. VASCULAR PATHOLOGY OF
which is greatly expanded and surrounds the blood
vessels. The adjoining brain parenchyma is devoid of
VENOUS ORIGIN
gliosis. Abnormalities within the cerebral venous sys-
No single mechanism has been put forth to tem that lead to cerebrovascular disease are most
explain état criblé, although it is mostly a second- often related to pathological processes in connec-
ary lesion. État criblé may be seen in association tion with infectious diseases in the brain; indeed,
with disease processes that result in loss of brain cerebral phlebitis is most often secondary to
tissue (degenerative or vascular), where it is mani- infectious lesions. In addition, important causes
fest adjacent to advanced or chronic lesions. Status of venous-related cerebrovascular disease occur
cribrosus often involves the basal ganglia and in a number of systemic diseases associated with
thalamus (Fig. 4.47E). Rarely, it may involve the coagulopathies. The result of venous occlusion is
cortico-subcortical junction, particularly in the tem- circulatory stasis, followed by diapedesis of red
poral lobe, in CADASIL (Fig. 4.45B). blood cells and IPH proximal to the site of vascular
A B
C D
FIGURE 4.48 Binswanger arteriopathic subcortical encephalopathy. (A, B) Macroscopic appearance with

Loyez stain for myelin. Note the presence of myelin pallor of the deep white matter and lacunes in the basal
ganglia (A) and in the posterior white matter (B). (C, D) Microscopic features (H&E). Edema and glial swelling
(C), dilatation of perivascular space and arteriolar hyalinosis (D).
occlusion. A venous infarct is the final outcome

of this process. In contrast to arterial hemor-
rhagic infarcts, which predominate in the cortex,
hemorrhage in venous infarction involves simul-
taneously the leptomeninges, the cortex, and the
white matter. In superior sagittal sinus thrombosis
(Fig. 4.49), hemorrhagic lesions involve symmet-
rically the hemispheric white matter and mostly
affect the centrum semiovale. Vein of Galen throm-
bosis is associated with venous infarction involving
the periventricular regions and the portions of the
thalamus. In superficial phlebitis, lesions are often
FIGURE 4.49 Bilateral venous infarction resulting seen in the hemispheric gray matter and the under-
from thrombosis of the superior sagittal sinus. lying white matter.

5
Infections of the Central Nervous System
F R ANÇOISE GRAY, KU M T H O N G WO N G , FRA N CE SC O S C A R AV IL L I, A N D L E R O Y R . S H A R E R
A WIDE variety of pathogenic infectious organisms— in diagnosis and treatment that have been made in
bacteria, fungi, parasites, viruses, prions— recent years.
may affect the central nervous system (CNS).
Organisms can be classified as pathogenic or
opportunistic; infections by the former group cause 1. BACTERIAL INFECTIONS
diseases in every individual and those by the lat- Depending on their virulence/pathogenicity deter-
ter affect patients with lower resistance. Infectious minants, bacteria can induce (a) purulent lesions
agents can enter the CNS in many ways: through involving the recruitment and lysis of polymorphs,
the blood, by retrograde spread via peripheral (b) cellular inflammatory reactions with influx of
nerves, or by direct invasion. The hematogenous mononucleated leukocytes, or (c) inflammatory
route is the most common, either by direct spread edema due to toxins and other inflammatory sub-
or via host cells. stances released by bacterial secretion or lysis, in the
The brain and spinal cord are relatively well absence of bacterial replication.
protected from infective agents by the skull and
vertebral column, by the meninges, and by the
blood–brain barrier. However, once the pathogen
1.1. Pyogenic Infections
enters the CNS, host defense mechanisms are sub- The bone, dura mater, arachnoid, and pia mater
optimal to control its replication and pathogenicity. delimit four compartments and tend to pre-
In addition, immunodeficiency conditions in the vent the spread of infection from one to another.
host are increasingly frequent. This may account for Accordingly, infections can occur in each of the four
the continuing high mortality and morbidity rates compartments—epidural, subdural, subarachnoid,
from infections of the CNS despite the advances and intraparenchymal.
114 •
1.1.1. EPIDURAL ABSCESSES A variety of bacterial species, gram-positive or
gram-negative, aerobic or anaerobic, can be incrimi-
Infection of the epidural space is rare. It usually
nated in acute bacterial meningitis. Some species
causes circumscribed abscesses and is localized
are most often found in children older than 1 year
more commonly to the epidural space of the verte-
and in adults, and infection results from either oti-
bral canal than to the intracranial epidural space. It
tis or a primary respiratory infection (sinusitis, rhi-
spreads frequently from an osteomyelitis secondary
nopharyngitis, or pneumonia); three major agents,
to frontal or mastoid sinusitis, trauma, or surgery
pneumococcus (Streptococcus pneumoniae), menin-
and may complicate epidural analgesia. Spinal epi-
gococcus, and Haemophilus influenzae each account
dural abscesses usually extend over several vertebral
for one third of the recorded cases. Other species,
levels. Intracranial epidural abscesses are biconvex,
such as Streptococcus agalactiae, Escherichia coli,
sharply outlined by the skull and the displaced dura.
Citrobacter koseri, and Listeria monocytogenes, are
most frequently isolated in young children or new-
1.1.2. SUBDURAL ABSCESSES OR borns, and they can be transmitted from mother to
EMPYEMA infant.
The purulent exudate may be seen macroscopi-
Infection of the subdural space most often extends cally in the leptomeninges (Fig. 5.1). Microscopically,
from an adjacent sinusitis, otitis, or osteomyelitis. large numbers of polymorphs invade the leptomen-
Infection from a purulent leptomeningitis is the ingeal and Virchow-Robin spaces (Fig. 5.2). Bacteria
main cause of subdural empyema in infants. The may be seen either free or within polymorphs. Later,
infections tend to spread over the convexities but in the absence of early resolution, the polymorphs
are prevented by the falx from crossing the midline. degenerate and disappear, to be replaced by a fibrin-
In most cases an empyema is situated over the ten- ous exudate containing lymphocytes, plasma cells,
torium, occasionally adjacent to the falx cerebri. histiocytes, and macrophages. After a few weeks, the
Empyema occurs less commonly in the posterior exudate organizes into fibrous connective tissue.
fossa, and rarely in the spinal canal. All the CNS structures in contact with the cere-
brospinal fluid (CSF) participate in the infectious
process. Thus, (a) there is a polymorphic inflam-
1.1.3. ACUTE BACTERIAL MENINGITIS
matory cellular infiltrate in the walls of the lepto-
Purulent infection of the leptomeningeal spaces is meningeal blood vessels, mainly the veins, that may
the most frequent pyogenic infection of the CNS. undergo thrombosis and cause cerebral infarcts;
The overwhelming majority of cases of pyogenic (b) there is cellular infiltration of the cranial nerves
meningitis are secondary to hematogenous dissemi- and spinal roots, sometimes with degeneration
nation of bacteria. Meningitis may also complicate of the myelinated fibers; and (c) there is invasion
trauma, surgery, or developmental malformations. of the ventricular walls with consequent purulent
FIGURE 5.1 Gross appearance of purulent FIGURE 5.2 Microscopic appearance of purulent

leptomeningitis. leptomeningitis (H&E).
Chapter 5 Infections of the Central Nervous System • 115

FIGURE 5.4 Parietal lobe abscess arising at the
cortico-subcortical junction with central necrosis,
surrounding granulation tissue, and peripheral
FIGURE 5.3 Purulent ventriculitis. capsule.
ventriculitis (Fig. 5.3). The process may also spread of hematogenous origin tend to occur at junctions
to the subpial and subependymal neural paren- between the gray and white matter (Fig. 5.4) and are
chyma. Cerebral abscesses secondary to purulent often multiple. They are secondary to septic emboli
meningitis are not unusual in infants and newborns. from bacterial endocarditis or chronic suppurative
The production of a fibrinocellular exudate and its intrathoracic infection. Paradoxical cerebral septic
subsequent fibrous organization may obstruct the emboli may also occur in congenital cyanotic heart
path of outflow of the CSF and result in the develop- disease. Abscesses resulting from direct spread from
ment of hydrocephalus, and even pyocephalus. an adjacent suppurative focus are usually situated in
Listeria monocytogenes infections deserve sepa- the temporal lobe (Fig. 5.5A) or in the cerebellum
rate mention because of the frequency with which following otitis media or mastoiditis, or in the fron-
microabscesses (“Listeria nodules”), localized par- tal lobe following sinusitis.
ticularly in the brainstem, are associated with this The initial stage of focal cerebritis (day 1 to 3
type of purulent meningitis. after inoculation) appears macroscopically as an
ill-defined region of hyperemia surrounded by
edema. Microscopically it is characterized by early
1. 1. 4. BRAI N ABS C ES S ES
parenchymal necrosis with vascular congestion,
Brain abscess is the second most common infection petechial hemorrhages, microthromboses, perivas-
of the CNS after bacterial meningitis and is the most cular fibrinous exudate, and infiltration by poly-
frequent space-occupying infection. Neuroimaging morphs. Surrounding edema is invariably associated
has greatly helped the diagnosis of brain abscess, and adds to the mass effect of the abscess itself.
resulting in a significant decrease of the mortality Late cerebritis (day 4 to 9) is characterized by a
rate. It has also become possible to treat many cases necrotic purulent center resulting from the con-
with antibiotics alone. fluence of adjacent foci of necrosis. The pus is
As in leptomeningitis, the source of infec- surrounded by a narrow, irregular layer of inflamma-
tion producing brain abscesses may be local or tory granulation tissue infiltrated by polymorphs,
blood-borne, resulting in particular localizations. lymphocytes and some macrophages. The perivas-
Posttraumatic abscesses occur at the site of cra- cular spaces in the vicinity become cuffed with poly-
niocerebral wounds or neurosurgery. Abscesses morphs and lymphocytes.
The early abscess capsule appears at day 10 to 13 wall. Despite the name, mycotic aneurysms are usu-
and is made up of granulation tissue, which includes ally due to pyogenic bacteria rather than to fungi.
lymphocytes, plasma cells, monocytes and mac- A mycotic aneurysm may rupture, causing hemor-
rophages, numerous newly formed blood vessels, rhages into the brain or subarachnoid space, and
and scattered fibroblasts. The developing capsule is meningitis.
at first poorly defined; it is thickest on its cortical
surface and often very thin or even deficient on its
ventricular surface. For this reason, abscesses tend 1.1.6 . SUPPURATIVE INTRACRANIAL
to expand inward and rupture into the ventricular PHLEBITIS
system, resulting in ventriculitis. Septic intracranial thrombophlebitis most fre-
As time passes (day 14 and later), the capsule quently follows infection of paranasal sinuses, mid-
becomes firmer and can be stripped easily from the sur- dle ear, mastoid, face, or oropharynx. The infection
rounding edematous white matter. Microscopically, spreads centrally along the emissary veins. Septic
more fibroblasts appear, so that a well-encapsulated thrombophlebitis may also occur in association with
abscess consists of five layers: a necrotic center epidural abscess, subdural empyema, or meningitis.
invaded by macrophages; granulation tissue with pro- Septic intracranial phlebitis may cause hemorrhagic
liferating fibroblasts and capillaries, and long, radially infarction. In addition, local suppuration may pro-
orientated blood vessels; a zone of lymphocytes and duce venous hemorrhage, venous necrosis, epidural
plasma cells in granulation tissue; dense fibrous tissue abscess, subdural empyema, meningitis, and brain
with embedded astrocytes; and a surrounding edem- abscess.
atous area of gliosis (Fig. 5.5B).
The two major and most serious complications
of brain abscesses are raised intracranial pressure 1.2. Tuberculosis
with the risk of cerebral herniation, and rupture of 1.2.1 . TUBERCUL OUS EPIDURAL OR
the abscess into a ventricle, resulting in ventricular SUB DURAL ABSCESSES
empyema.
Epidural tuberculous abscess is a recognized com-
plication of tuberculosis of the spine (Pott disease),
1.1.5. SEPTIC EMBOLISM involving either the vertebral bodies or the interver-
tebral discs. Subdural tuberculous abscess is also a
Apart from cerebral abscesses, septic emboli, when- frequent occurrence.
ever of sufficient size, may cause cerebral infarction
that is liable to become infected by extension from
1.2.2 . TUBERCUL OUS MENINGITIS
the septic embolus. Implantation of a septic embolus
in a cerebral artery may result in a mycotic aneurysm Tuberculous meningitis is the most common
due to local infection and weakening of the arterial form of tuberculosis of the CNS. In most cases, it
A B
FIGURE 5.5 Temporal lobe abscess with purulent necrosis in the center and surrounding granulation tissue.
(A) Gross appearance. (B) Microscopic appearance (HES).

complicates the initial hematogenous dissemina- of involvement of the perforating blood vessels
tion that follows primary infection; it may also fol- (Fig. 5.8B).
low late reactivation of latent infection elsewhere in In treated patients dying several weeks after onset
the body. Tuberculous meningitis may be associated of the illness, the exudate is more fibrous. It is espe-
with miliary tuberculosis. cially thick over the base (Fig. 5.9A) of the brain and
Unlike purulent meningitis, which spreads over in the cisterna ambiens, where it may obstruct the
the cerebral convexities, in tuberculous meningitis, flow of CSF and lead to hydrocephalus (Fig. 5.9B).
the meninges over the base are most often involved.
There may be some gray-green opacity of the menin- 1 .2 . 3. TUBERCULOM AS OF BRAIN AN D
ges over the cerebral convexities, but a much thicker S P IN AL CORD
exudate fills the basal cisterns, covering the basis
pontis and extending into the Sylvian fissures and Tuberculomas were formerly a very common type of
cisterna magna (Fig. 5.6). The spinal cord may also intracranial mass lesion and remain a serious prob-
be enveloped by exudate. Tubercles are not easily lem in areas of the world where tuberculosis is rife.
found in the exudate, but they can sometimes be Tuberculomas may be single but are more often
seen under the banks of the Sylvian fissures and near multiple (Fig. 5.10A). Their sites of predilection are
the pre- and post-central veins over the convexities. the cerebellum, the pontine tegmentum, and the para-
Microscopically, the inflammatory infiltrate central lobule. They have occasionally been described
involves the leptomeninges and the subpial regions, as in the spinal cord. They are spherical or multilobular
well as the ependyma and subependymal parenchyma. lesions with a caseous center, necrotic but firm and of
It is mostly composed of lymphocytes, mononuclear a creamy color, surrounded by a granulomatous reac-
cells, and epithelioid nodules with few giant cells and tion that includes giant cells, lymphocytes, and fibro-
tubercles. The latter consist of a central area of case- sis of variable extent (Fig. 5.10B). There is much less
ous necrosis surrounded by an epithelioid macro- swelling than around cerebral abscesses.
phage reaction with a peripheral ring of lymphocytes Tuberculomas, particularly of supratentorial
(Fig. 5.7). Acid-fast bacilli may be abundant or scanty. location, may spontaneously become cystic, fibrous,
Arterial lesions of reactive endarteritis obliterans or calcified; bacilli may be difficult to detect, and
(Fig. 5.8A) are constant and are frequently respon- inflammatory exudates can be scant. Tuberculomas
sible for the production of ischemic parenchymal may rupture into the meninges.
lesions, particularly within the basal ganglia because
1 .2 . 4. TUBERCULOUS ABSCESS
True abscesses of the brain, as opposed to tubercu-
lomas, are composed of a necrotic center containing
FIGURE 5.7 Tuberculous meningitis. Tubercles

FIGURE 5.6 Tuberculous meningitis. Thick exu- consisting of a central area of caseous necrosis sur-
date involving the basal meninges. (Courtesy of Pr. rounded by an epithelioid macrophage reaction with a
Leila Chimelli) peripheral ring of lymphocytes.
A pus in which Mycobacterium tuberculosis are abun-
dant. They are surrounded by a capsule similar to
that in pyogenic abscesses, without the characteris-
tic granulomatous reaction. Tuberculous abscesses
of the CNS are usually multiple. In true abscesses,
the absence of a granulomatous epithelioid reac-
tion suggests the failure of immune mechanisms.
Tuberculous abscesses are now seen most often in
patients with AIDS.
1.3. Atypical Mycobacteriosis

B Nontuberculous mycobacteria (“atypical myco-
bacteria”) were considered in the past to be sap-
rophytic organisms. The Mycobacterium avium
complex, including M. avium and M. intracellulare,
is now recognized as one of the more common
causes of opportunistic infection in AIDS patients,
in whom it produces disseminated systemic infec-
tion. However, in most cases with generalized
M. avium-intracellulare infection, involvement of
the CNS is asymptomatic. Neuropathological
examination only reveals diffuse perivascular mac-
rophages containing clusters of mycobacteria posi-
tive for acid-fast and periodic acid-Schiff (PAS)
stain. Symptomatic infection of the CNS due to
M. avium-intracellulare or M. fortuitum and brain
abscesses due to M. kansasii have been recorded in
rare case reports in patients with AIDS.
FIGURE 5.8 Tuberculous meningitis. (A) Marked

vascular changes forming endarteritis obliterans 1.4. Whipple Disease
(H&E). (B) Arterial lesions causing extensive cerebral Whipple disease is a multisystem disorder often
infarction (Loyez stain). involving the intestine, caused by a gram-positive
actinomycete, Tropheryma whipplei. Involvement
A B
FIGURE 5.9 Chronic tuberculous meningitis. (A) Massive fibrous infiltration of the basal meninges. (B) Basal
obstruction with ventricular dilatation.

A B
FIGURE 5.10 Tuberculomas. (A) Gross appearance of multiple tuberculomas in the thalamus.

(B) Microscopic appearance. The caseous center is surrounded by a granulomatous reaction (H&E).
of the CNS is uncommon and is usually associated usually secondary to a focus elsewhere in the body,
with systemic disease. In rare instances, Whipple spreading to the nervous system either by direct
disease may be confined to the brain. extension or via the bloodstream. Multilocular
At neuropathological examination, small lesions abscesses are formed, with a central necrotic inflam-
are disseminated throughout the entire CNS but matory exudate containing polymorphs, necrotic
are especially abundant in the cortex, with a pre- debris, and colonies of branching organisms form-
dilection for the subpial regions, the basal ganglia, ing “sulfur granules,” surrounded by granulation
the hypothalamic nuclei, the periaqueductal gray tissue.
matter, the nuclei of the brainstem, and the dentate
nuclei of the cerebellum. They may become conflu-
ent to form more extensive foci. 1.6. Nocardiosis
Microscopically, there are meningeal and paren- Nocardia asteroides is a ubiquitous aerobic organ-
chymal lymphocytes and multinucleated cells ism that in the majority of cases produces infection
(Fig. 5.11A). The macrophages with lipid-filled in immunosuppressed patients. The nervous sys-
cytoplasm contain tiny sickle-shaped inclusions that tem is usually invaded through the hematogenous
are positive for PAS (Fig. 5.11B), Gram, and methe- route from a primary pulmonary lesion. In the
namine silver stain. The bacteria are also present brain, Nocardia produces abscesses or meningitis.
extracellularly in the tissue. By electron microscopy, Microscopically, the abscesses have fibrous walls and
lamellar, partially degraded bacterial cell walls and consist of polymorphs. The organism appears as thin
better-preserved bacilli are present in macrophages, branching filaments, about 1 μm in diameter. They
astrocytes, and pericytes. cannot be recognized in routinely stained prepara-
tions but can be identified using a modified Grocott
methenamine-silver stain or also on Gram stain,
1.5. Actinomycosis where they are gram positive. Nocardia is one of the
Actinomyces are small anaerobic gram-positive most common causes of bacterial brain abscess in
organisms whose appearance as thin, branching fila- people with AIDS, in whom brain abscesses are not
ments has long led to their inclusion (with Nocardia) especially common.
among fungi. Actinomyces have a worldwide distri-
bution but occur predominantly in rural areas. Most
infections in man are produced by Actinomyces israeli
1.7. Neurosyphilis
and A. bovis and are acquired from organisms situ- Involvement of the CNS is a sequela of primary
ated in the oral cavity or in the large intestine; they luetic disease that either has been undetected or
invade the tissues through a break in the mucosa. has been inadequately treated. Although invasion
Bone (mainly the mandible) is the most commonly of the leptomeninges during secondary syphilis
affected site. Lesions of the CNS are rare and are is relatively common, symptomatic neurosyphilis
A B
FIGURE 5.11 Whipple disease. (A) Perivascular accumulation of lipid-laden macrophages surrounded by

reactive astrocytosis (H&E). (B) The foamy macrophages contain PAS-positive inclusions in the cytoplasm.
occurs predominantly at the tertiary stage of the attached to both the dura mater and the brain
disease. Classically, neurosyphilis may be separated and consist of round, red-tan-gray lesions that
into meningovascular (inflammatory) syndromes, are focally firm and rubbery, with a central area
occurring within a few years of infection, and paren- of necrosis (Fig. 5.12). Microscopically, they
chymatous (degenerative) syndromes, which have a consist of central gummatous necrosis with
latency of decades. However, considerable overlap ghost-like outlines of dead cells. This is sur-
of these syndromes is observed commonly. rounded by a granulomatous reaction including
epithelioid cells and fibroblasts with scat-
tered multinucleated foreign body giant cells.
1.7.1. MENINGOVASCULAR Spirochetes are rarely demonstrable since the
NEUROSYPHILIS gumma represents a hyperimmune form of tis-
This is due to a combination of chronic meningi- sue necrosis.
tis, multifocal arteritis, and gummatous necrotic
lesions.
• Chronic meningitis composed of lymphocytes

and plasma cells often leads to fibrous organiza-
tion and ultimate occlusion of the CSF pathways
with consequent hydrocephalus. Extension of
the inflammatory process into cranial and spinal
nerves and periarteritis may also cause optic atro-
phy or cranial nerve palsies.
• The vascular component of meningovascular
syphilis, “Heubner arteritis,” consists of an
infiltration of the arterial wall by lymphocytes
and plasma cells associated with intimal prolif-
eration (endarteritis obliterans). This arteritis
involves large and medium-sized blood vessels;
it may cause ischemic lesions in the brain or
spinal cord.
• Cerebral gummas are seen rarely in Europe
and North America; they seldom occur in the
meninges. They can involve the cerebral convex-
ity but may be found in the cerebral midbrain, FIGURE 5.12 Cerebral gumma in an AIDS patient.
hypothalamus, and spinal cord. They are usually (Courtesy of Dr. Marius Valsamis)

1. 7. 2. PARE NC HYMATO U S characterized by Wallerian degeneration of the dor-
N E U R O S Y P HI L I S sal columns. Unlike in GPI, no inflammatory reac-
tion is demonstrable in the cord parenchyma, and
This takes two forms: paretic dementia (general
T. pallidum is absent.
paralysis of the insane [GPI]) and tabes dorsalis.
Both forms may coexist as “tabo-paresis.”
In former days, in patients dying after several 1 .7 . 3. SYPHILIS AN D HIV IN FECTION
years of GPI dementia, the brain showed character-
istic macroscopic changes; it was shrunken and firm Neurosyphilis is not uncommon in patients with
and covered by a thick and opaque pia-arachnoid. AIDS. Co-infection with HIV may modify the clini-
These lesions were most marked frontally, decreas- cal spectrum of syphilis. Patients with HIV infec-
ing posteriorly. The ventricles were enlarged, and the tion are likely to progress rapidly to symptomatic
ependyma showed diffuse granular ependymitis. At neurosyphilis and to show an accelerated disease
the present time, GPI is rarely seen. In the healed course; treatment failure is also more frequent. The
stages of the disease, the brain is usually grossly nor- most common manifestations of symptomatic neu-
mal except perhaps for ependymal granulations. rosyphilis in HIV-infected patients are syphilitic
On microscopic examination, there is meningeal meningitis and meningovascular syphilis. General
thickening and striking involvement of the cerebral paresis, syphilitic meningomyelitis, syphilitic poly-
cortex, which is atrophic with loss of the normal lam- radiculopathy, and cerebral gummas have been
inar pattern. There is neuronal loss with proliferation reported in occasional cases.
of reactive astrocytes and rod-shaped microglia. The
lesions are distributed in scattered foci of different
age, giving a “bush-fire” or windswept appearance. 1.8. Borreliosis
Perivascular cuffing by lymphocytes and plasma cells This condition is due to an infection by a spirochete
is found in the cortex and leptomeninges. Specific sil- of the Borrelia group, which is transmitted to a human
ver impregnation may occasionally demonstrate the by insect bites. Examples include relapsing fever and
spirochetal organism of Treponema pallidum. Lyme disease. The latter is a multisystem disorder
Tabes dorsalis consists of degeneration of the due to the spirochete B. burgdorferi. It involves the
posterior columns (Fig. 5.13) and spinal nerve roots skin, cardiovascular system, joints, and central and
with involvement of the dorsal roots and ganglia. It is peripheral nervous system. Neurological signs usu-
apparently the result of inflammatory meningovas- ally develop several weeks after a tick bite, which may
cular lesions localized to the subarachnoid portion cause erythema chronicum migrans, and culminate
of the dorsal nerve roots. Spinal cord involvement in lymphocytic meningitis, which is rich in plasma
is secondary to radiculo-ganglionic lesions. It is cells. Involvement of the spinal and/or cranial nerve
roots is frequent. Encephalomyelitic complications
are much rarer. Tertiary neurological complications
occurring years after inoculation include axonal
neuropathies and low-grade encephalopathy. The
pathogenesis of CNS lesions is unclear; it may be
an immunopathological process rather than a direct
effect caused by bacterial invasion.
1.9. Brucellosis
Brucellosis, or Malta fever, is a zoonosis transmitted
to humans by raw dairy products or by direct con-
tact with animal products (such as the placenta).
The disease is endemic in cattle-breeding countries.
Leptomeningeal involvement is common in the sep-
FIGURE 5.13 Tabes dorsalis. Horizontal section ticemic phase of the disease. Either spontaneously
of the lumbar cord showing the degeneration of the or after inadequate treatment, the disease may give
posterior columns (Loyez stain). rise to subacute neurological manifestations, either
infectious or hyperergic. The different forms of neu- proliferation. Coalescence of granulomas may form
robrucellosis correspond to a variety of clinicopath- larger meningeal or parenchymatous masses, simu-
ological features, including meningoencephalitis, lating neoplasms.
meningomyelitis, and meningomyelitis-radiculitis,
with frequent involvement of the cranial nerves, par-
ticularly the acoustic nerves.
1.11. Chronic Pachymeningitis
In rare instances, there can be a chronic inflammatory
condition of the cerebral dura, which causes thickening
1.10. Sarcoidosis of the dura, with a mixed inflammatory cell infiltrate
Sarcoidosis is a granulomatous multisystem disor- consisting of plasma cells, lymphocytes, and occa-
der of unknown etiology. The lung is predominantly sional eosinophils. The inflammation often has a stori-
affected; skeletal muscle or peripheral nerve involve- form or whorled appearance, and germinal centers can
ment is not uncommon; CNS involvement occurs in also be seen. Cultures of this inflammatory lesion are
about 5% of cases. negative, and microorganisms cannot be demonstrated
The lesions may affect any part of the CNS but within them with special staining techniques. These
involve preferentially the base of the brain, especially lesions of the dura resemble similar inflammation of
the suprasellar and the hypothalamic regions, the the orbit, in some instances referred to as inflammatory
optic nerves and the optic chiasm, the basal ganglia, pseudotumor. Some patients with this disorder may
and the posterior fossa. Hydrocephalus may result have elevated levels of IgG4 in serum, and a diagnostic
from thickening of the basal meninges or aqueductal feature is considered to be the presence of 30 or more
obstruction by a periventricular parenchymal lesion. IgG4-positive plasma cells per high-power field on
The sarcoid granulomas consist of a central immunohistochemistry. This disorder is thought to be
mass of epithelioid cells and multinucleated giant part of the spectrum of IgG4-related disease.
cells surrounded by lymphocytes, monocytes,
and fibroblasts (Fig. 5.14A). The granulomatous
changes involve predominantly the leptomeninges;
1.12. Toxin-Induced Neurological
they are often perivascular and may extend to the
Disease
underlying parenchyma along the Virchow-Robin In addition to direct invasion of the CNS, bacteria
spaces. Cerebral vasculitis may give rise to vascular can cause neurological damage indirectly by produc-
occlusion and brain infarction. Within the brain, ing neurotoxic substances. A number of neurotoxins
granulomas may be confined to the perivascu- have been identified in specific bacterial infections
lar spaces (Fig. 5.14B). Parenchymal lesions may (diphtheria, tetanus, botulism); in other instances
also involve the periventricular areas, particularly (shigellosis, Bordetella pertussis infection, melioido-
around the third ventricle, and the choroid plexus; sis, legionellosis, etc.), because of the clinical fea-
they are often surrounded by marked astrocytic tures and persistent negative cultures of the CSF,
A B
FIGURE 5.14 Sarcoidosis. (A) Intraparenchymatous epithelioid granulomas (H&E). (B) Perivascular granu-

loma including lymphocytes, monocytes, and multinucleated cells. Note marked reactive astrocytosis (H&E).

A B
FIGURE 5.15 Aspergillosis. (A) Gross appearance, coronal section of the frontal lobes showing multiple hem-
orrhagic abscesses. (B) Presence of branching and septate hyphae (methenamine silver).
the possibility of a toxin-induced involvement of the 2. MYCOSES AND PARASITIC

CNS has been postulated. In either case, although
the encephalopathy may be lethal, there are few neu-
INFECTIONS
ropathological descriptions, and CNS changes are A number of different fungi, protozoa, and metazoa
usually discrete or nonspecific. may affect the central and peripheral nervous system.
A C
B D
FIGURE 5.16 Cryptococcosis. (A) Cryptococcus meningitis, gross appearance: chronic meningitis involv-

ing the basal leptomeningitis. (B) Cryptococcus meningitis in an immunocompetent patient, with marked
lymphocytic and giant cell inflammation (H&E). (C) Parenchymal cysts in an AIDS patient (Loyez stain).
(D) Microscopic appearance: dilatation of the perivascular space forming a cystic cavity filled with cryptococci.
Note the absence of inflammation or astrocytic reaction in the surrounding parenchyma (H&E).
These infections used to be relatively uncommon associated with hepatic and/or pulmonary
in everyday neuropathological practice in indus- involvement.
trialized countries and were restricted to certain • Free-living organisms may produce primary
geographical areas or involved small groups of indi- meningoencephalitis (by Naegleria fowleri) and
viduals. However, increased intercontinental travel, granulomatous encephalitis (Acanthamoeba and
loosening of health controls, and the AIDS epidemic Leptomyxid).
have made it possible for some infections to spread – Primary meningoencephalitis due to
into previously nonaffected areas. On the other Naegleria fowleri is usually contracted during
hand, the incidence of some opportunistic infec- the summer by healthy young people swim-
tions (in particular mycoses and toxoplasmosis) has ming in infected water. Parasites reach the
increased in the last decades owing to a considerable CNS through the nasal mucosa and the olfac-
increase in the number of immunocompromised tory epithelium. The pathology consists of
individuals. encephalitis with hemorrhagic necrosis, iden-
tifiable parasites, and basal leptomeningitis.
Virtually all cases are fatal.
2.1. Mycotic Infections – Granulomatous encephalitis presents with brain
Although fungal infections of the CNS are usually swelling, with moderate meningitis and conflu-
secondary to a primary focus elsewhere (respiratory ent areas of hemorrhagic necrosis. Histologically
system; gastrointestinal tract) or to a direct exten- it is a chronic vasculitis with the presence of
sion from the sinuses or bone, in some instances parasites and occasionally a granulomatous reac-
they may represent the only localization. In his- tion (Fig. 5.17).
tological specimens, organisms may be present as
yeasts (up to 20 μm in diameter), branching hyphae,
2.2.2 . CEREBRAL MAL ARIA
sometimes considerably long, or pseudohyphae of
intermediate size. These morphologic differences Responsible for 800,000 deaths a year in Africa
determine the type and size of the lesions: menin- alone, it is prevalent in 100 countries. There is
gitis in infections by the smallest; extensive infarcts marked heterogeneity between cases, probably
following occlusion of the vessels by the largest reflecting host susceptibility.
fungi; and multiple small infarcts in case of infection Macroscopically the brain is swollen with
by organisms of intermediate size, with infection of dusky leptomeninges and on section it appears
the ischemic lesions in turn causing abscesses and pale or slate-gray. Microscopically the most com-
granulomas. mon feature is sequestration of parasitized blood
The classical distinction of fungi into pathogens cells within cerebral microvessels, which also con-
and opportunists is not absolute, as some of them tain dark malarial pigment (Fig. 5.18A). Petechial
can manifest in both ways. hemorrhages of various types are also frequent.
The main fungal infections that may affect the Focal necrosis within the white matter is fol-
CNS are summarized in Table 5.1 lowed by a gliotic reaction (Dürck granuloma)
(Fig. 5.18B).
2.2. Protozoal Infections

2.2.3 . TOXOPL ASMOSIS
The main protozoa responsible for human infections
can be classified as summarized in Table 5.2. Feline species, particularly the domestic cat, are the
definitive host of the protozoan Toxoplasma gondii.
Toxoplasmosis in humans can present as congenital
2.2.1. AMEBIASIS toxoplasmosis (cf. Chapter 11) and as acquired/pri-
mary toxoplasmosis in adults.
In man, cerebral lesions are produced by Entamoeba Congenital toxoplasmosis is secondary to trans-
histolytica and by free-living amoebae. placental infection. There are diffuse necrotic and
inflammatory lesions of the cortex and white matter
• Entamoeba histolytica is rarely responsible for that are accompanied by calcifications, especially in
hematogenous brain abscesses that are usually the periventricular regions.

Table 5.1. Main Fungal Infections Affecting the CNS
MYCOSIS ORGANISM T YPE OF AC TION GEOGR APHICAL PRIMARY FOCUS N E U R O PAT H O L O G Y

DIS T RIBU TION
Aspergillosis Aspergillus: flavus, Predominantly Ubiquitous Usually secondary Abscesses and granulomas; vascular
fumigatus -niger, opportunist to foci in lungs and involvement, with extensive
oryzae gastrointestinal tract. hemorrhage (Fig. 5.15A). Branching
and septate hyphae (Fig. 5.15B).
Blastomycosis Blastomyces Predominantly North America, Africa Primary focus in Meningeal lesions, epiduritis,
dermatitidis pathogen, mainly in lungs. pachymeningitis, purulent or
agricultural workers granulomatous meningitis (mimicking
tuberculosis).
Central, basophilic body with wall;
single bud.
Candidiasis Candida albicans Opportunist, mainly Ubiquitous Saprophyte in Abscesses or granulomas; vascular
Other species in premature infants, digestive and genital involvement. Sometimes meningitis.
immunosuppressed mucosae. Chains of elongated cylindrical
and diabetic patients pseudohyphae.
Chromomycosis Alternaria, Both in Ubiquitous Primary focus usually Meningitis, abscesses, or diffuse
Heterogenous group Cladophialophora, immunocompetent and in the skin. encephalitis.
of organisms that Curvularia, immunocompromised Mainly hyphae, more seldom spores.
appear pigmented Exophilia, Fonsecaea, patients
microscopically or in Madurella,
cultures Phialophora,
Rhinocladiella
Cladosporiosis Cladosporium Predominantly Ubiquitous Isolated from Abscesses or meningitis.
trichoides pathogen skin, conjunctiva, Hyphae.
(bantianum) lymph nodes,
gastrointestinal and
urinary tract.
Coccidioidomycosis Coccidioides immitis Predominantly South America, Mexico, Primary foci in lungs. Basal meningitis with nodules;
pathogen southwestern United vasculitis.
States Hyphae.
Cryptococcosis Cryptococcus Predominantly Ubiquitous, but Usually secondary to Meningitis with occasional tubercles.
(Fig. 5.16) neoformans opportunist predominates in a focus in the lungs. Amount of inflammation depends on
southern United States degree of immunosuppression.
and Australia Spores with capsule.
Histoplasmosis Histoplasma Pathogen, but for CNS Ubiquitous, but Secondary to Meningitis with vasculitis. Granulomas
capsulatum infections it acts as common in the United pulmonary infection. are rare. Small ovoid budding bodies,
opportunist States intracellular.
Paracoccodioidomycosis Paracoccidioides Predominantly Brazil Primary focus in the Space-occupying lesions; meningitis.
brasiliensis pathogen lungs. Multiple budding.
Pseudoallescheriosis Pseudoallescheria Opportunist Ubiquitous Associated with Meningitis and abscesses; vasculitis.
boydii (immunodeficiency, disorders of the Sometimes granulomas.
diabetes) respiratory system. Septate hyphae and clamidospores.
Zygomycosis Rhizopus, Mucor, Opportunist, mainly Ubiquitous Secondary to focus in Necrosis and polymorphs with giant
Absidia diabetic patients, but skin, nasal mucosa or cells. Vasculitis with hemorrhage.
also drug users, patients lungs. Broad branching, nonseptate hyphae.
on antibiotics and
corticosteroids.
Table 5.2. Main Protozoa Responsible hemispheres, particularly the basal ganglia and
for Human Infections the cortico-subcortical junction (Fig. 5.19A).
These lesions contain central, eosinophilic, and
1. Amebiasis acellular pseudo-ischemic necrosis surrounded
a. Entamoeba histolytica: cerebral amebic by a cellular inflammatory reaction, usually with
abscesses polymorphs. Parasites are seen either within
b. Primary amebic encephalitis pseudocysts (bradyzoites) (Fig. 5.19D) or as
i. Primary amebic meningoencephalitis free forms (tachyzoites) (Fig. 5.19C). Associated
(Naegleria fowleri) hemorrhages are frequent. These abscesses can
undergo transformation during the illness and in
ii. Granulomatous amebic encephalitis
the course of treatment and appear at postmortem
(Acanthamoeba spp. and Leptomyxid)
as (1) necrotizing (Fig. 5.19A) or (2) organiz-
iii. Acanthamoeba keratitis ing (Fig. 5.19B) abscesses or 3) chronic “treated”
2. Cerebral malaria (Plasmodium falciparum lesions with a central cystic space. Rarely, in AIDS
infection) patients, diff use “septicemic” encephalitic forms
3. Toxoplasmosis (Toxoplasma gondii infection) may occur with dissemination of microglial nod-
4. Trypanosomiasis ules in some cases containing encysted bradyzo-
a. African trypanosomiasis (Trypanosoma brucei ites or tachyzoites.
spp.)
b. South American trypanosomiasis
2 .2 . 4. TRYPAN OSOM IASIS
(Trypanosoma cruzi)
African trypanosomiasis is caused by T. brucei sub-
species transmitted to human by the tsetse fly. It is
In immunocompetent individuals, CNS characterized neuropathologically by meningoen-
involvement is uncommon; it is usually benign cephalitis. There is perivascular inflammation with
and most often asymptomatic. In contrast, toxo- microglial nodules. Mott cells, characteristic of this
plasmosis is often fatal in immunocompromised form, are plasma cells with prominent eosinophilic
patients (HIV, posttransplantation, congenital cytoplasmic Russell bodies. No parasites are usually
immunodeficiencies). Cerebral toxoplasmo- seen in the brain tissue.
sis is one of the most frequent CNS complica- South American trypanosomiasis (Chagas dis-
tions of AIDS and represents the main cause of ease) remains a health problem in many areas of
focal and space-occupying cerebral lesions in Central and South America, where it affects up to
these patients. Typically, it presents as multiple 18 million individuals. The agent, Trypanosoma
abscesses involving predominantly the cerebral cruzi, is responsible for both an acute and a chronic
disease. The former can be asymptomatic or can
present as a mild meningoencephalitis with microg-
lial nodules in the brain, sometimes containing
parasites. The chronic form includes a “chagasic”
encephalopathy with neuronal loss and focal inflam-
matory changes and, more commonly, a peripheral
autonomic and occasionally somatosensory neu-
ropathy with ganglion cell loss. In AIDS patients,
T. cruzi infection may cause multifocal necrotizing
encephalitis in which abundant amastigote parasites
are present, particularly within glial cells and neu-
rons (Fig. 5.20).
FIGURE 5.17 Amebiasis, granulomatous

2.3. Metazoal Infections
encephalitis. Chronic vasculitis with presence of The major helmintic infections of the CNS can be
parasites (H&E). classified as summarized in Table 5.3.
A B
FIGURE 5.18 Cerebral malaria. (A) Sequestration of parasitized blood cells within cerebral microvessels,
which also contain dark malarial pigment. (B) Dürck granuloma (H&E).
2.3.1. CYSTICERCOSIS of the pig tapeworm; the disease occurs between

2 months and 30 years after initial infection. The
Cysticercosis is the most common parasitic infection
number of cysts in the CNS varies from one to sev-
of the CNS and is endemic in all countries, particu-
eral hundred (Fig. 5.21A). All of the cysts have similar
larly in Latin America. It is caused by the larval stage
A B
C D
FIGURE 5.19 Toxoplasmosis. (A) Multiple necrotizing abscesses, some of which are hemorrhagic involving the
basal ganglia and the cortico-subcortical junction. (B) Organizing abscesses with central necrosis and hyperemic
border in the genu of corpus callosum and in the white matter of the right frontal lobe. (C) Free tachyzoites at the
periphery of a necrotic lesion (H&E). (D) Numerous pseudocysts (bradyzoites) around a necrotic lesion (H&E).

appearance; and (3) inner reticular or fibrillary
(Fig. 5.21C). A granulomatous reaction with fibrosis
and calcification occurs only if the organism dies.
2 .3 . 2. HYDATIDOSIS
Hydatid cyst is endemic in the Mediterranean regions
and the Middle East, as well as in Latin America. Dogs
and other canids are the definitive hosts. Cysts in the
brain are usually solitary and unilocular and their wall
consists of two layers (1) the outer, laminated, cuticu-
lar layer and (2) the inner germinal layer.
FIGURE 5.20 Trypanosomiasis. Abundant amasti-
gote parasites are present within glial cells in a case of
2 .3 . 3. SCHISTOSOM IASIS
multifocal necrotizing encephalitis (H&E). (Courtesy
of Pr. Leila Chimelli) Schistosomiasis is caused by flukes of the genus
Schistosoma, which have man and other mam-
structure; they contain a single scolex with four suck- mals as definitive hosts. The infection is endemic
ers and a double row of hooklets (Fig. 5.21B). The in South America, the Middle and Far East, and
cyst wall consists of three layers: (1) outer or cutic- Africa. CNS lesions involve predominantly the spi-
ular; (2) middle cellular with a pseudoepithelial nal cord. Macroscopic changes are uncommon.
Histological examination reveals three main appear-
ances: (1) necrotic-exudative with variable number
Table 5.3. Major Helminthic Infections of eggs; the area is surrounded by eosinophils, lym-
of the CNS phocytes, plasma cells, and macrophages; (2) a pro-
1. Cestodes ductive stage where eggs have lost the embryo; and
(3) a late stage with a granulomatous reaction and
a. Neurocysticercosis (Taenia solium)
giant cells (Fig. 5.22).
b. Hydatid cyst (Echinococcus granulosus)
c. Coenuriasis (Taenia multiceps)
d. Sparganosis (Spirometra) 2 .3 . 4. EOSIN OPHILIC M EN IN GITIS
2. Trematodes These are due to infection by Angiostrongylus can-
a. Paragonimiasis (Paragonimus westermani) tonensis or Gnathostoma spinigerum. Larvae may be
b. Schistosomiasis (Schistosoma mansoni, demonstrated in the brain or meninges, which show
japonicum, haematobium, mekongi) a predominantly eosinophilic infiltrate.
c. Other trematode infections
3. Nematodes 2 .3 . 5. TOXOCARIASIS
a. Eosinophilic meningoencephalitis
Toxocara canis is a common agent and important
i. Angiostrongylus cantonensis
canine zoonosis that occurs worldwide. It may occa-
ii. Gnathostoma spinigerum sionally affect humans, particularly children. The
b. Toxocariasis (visceral larva migrans) death of the parasite in the brain is followed by a
i. Other forms of larva migrans nonencapsulated granulomatous reaction consist-
ii. Trichinella spiralis ing of lymphocytes, eosinophils, plasma cells, fibro-
c. Human filariasis. Loa-loa blasts, and epithelioid and giant cells.
ii. Dracunculus medinensis
iii. Onchocerca vulvulus 2 .3 . 6. TRICHIN OSIS
d. Nematodes and immunosuppression This infection exists in North and South America,
i. Strongyloides stercoralis but outbreaks have been reported also in Europe
A B
FIGURE 5.21 Cysticercosis. (A) Gross appearance: two cystic cavities containing a parasite are present in the
thalamus and insular cortex (courtesy of Pr. Leila Chimelli). (B) Microscopic appearance of the scolex with suck-
ers and a double row of hooklets. (C) Higher magnification showing the three layers of the cyst walls (HES).
and in some Mediterranean countries. Involvement small hemorrhages. Histological findings include
of the striated muscle is the main complication (cf. granulomatous nodules, predominating in the white
Chapter 12). Involvement of the CNS is uncom- matter and consisting of lymphocytes, microglia,
mon. Macroscopic features may be limited to non- and histiocytes. Larvae are only rarely identified in
purulent meningitis, mild edema, and occasional nodules, suggesting an immune-mediated patho-
genesis of the lesions.
2.3.7 . STRONGYL OIDES STERCORAL IS

INFECTION
Strongyloides stercoralis infection should be consid-
ered in the presence of severe immunosuppression
during which larval infection can affect every organ.
In these circumstances larvae can be seen in the
subarachnoid spaces, and microinfarcts may be pro-
duced by obstruction of capillaries by the parasite.
3. VIRAL INFECTIONS
FIGURE 5.22 Schistosomiasis. Eggs within a granu- The lesions of the CNS induced by viral infections
lomatous reaction with giant cells (H&E). may result from various mechanisms. Some of them

are nonspecific and are due to immuno-allergic 3 .1 . 2. ACUTE DISSEM IN ATED
reactions that are secondary to the viral infec- ENCEPHALOM YELITIS (ADEM ) OR ACUTE
tion; they involve the leptomeninges and espe- D I SSEM IN ATED LEUKOEN CEPHALITIS,
cially the white matter (leukoencephalitides). O R ACUTE POSTIN FECTIOUS/
Other, more specific lesions are directly caused P O STVACCIN IAL PERIVEN OUS
by the infection of the CNS by the virus. They ENCEPHALITIS
involve mainly, but not exclusively, the gray matter
Postinfectious encephalitis may complicate a variety
(polioencephalitides).
of systemic viral diseases, including measles, mumps,
Most viral encephalitides run an acute course.
chickenpox, rubella, influenza, and infectious mono-
However, special immunological phenomena may
nucleosis caused by Epstein-Barr virus (EBV). It was
modify the course of the disease and result in the
also well documented following smallpox or rabies
development of a latent infection, notably as in her-
vaccination. It closely resembles experimental aller-
pes, or a persistent infection, as in subacute scleros-
gic encephalomyelitis produced by injecting experi-
ing panencephalitis, which is presumably caused
mental animals with myelin proteins and adjuvant
by a defective measles virus. In AIDS, infection
and is believed to be due to a T-cell–mediated hyper-
by the retrovirus human immunodeficiency virus
sensitivity reaction. Clinically, it presents as an acute
(HIV) causes both a subacute encephalitis and
disseminated encephalomyelitis that is separated by
immunodeficiency.
a latent period of a few days to 3 weeks duration after
the causative viral infection or vaccination.
3.1. Nonspecific CNS The histological features are highly stereotypi-
Involvement in Viral Infections cal and consist of infiltrates of lymphocytes, plasma
cells, and macrophages around the venules of the
3. 1. 1. ACUT E V I R AL LY M P H O C Y TI C neural parenchyma. These involve mainly the white
M E N I NGI T I S OR ASEP TI C M EN I NG I TI S matter, where they are associated with perivenous
This response is common with several types of foci of demyelination (Fig. 5.23A, B) with rela-
viral infections, mainly enteroviruses (echovirus, tive sparing of the axons (cf. Chapter 7, section 4).
coxsackieviruses, enterovirus 71), but also mumps There may also be small perivascular hemorrhages.
virus, herpes simplex virus (HSV-2), arboviruses, Arteries are relatively free of inflammation, but there
lymphocytic choriomeningitis (LCM) virus, mea- are often inflammatory cells in the leptomeninges.
sles, parainfluenza, adenoviruses, and others.
It is characterized by vascular congestion and a
scanty infiltrate of lymphocytes in the leptomen- 3 .1 . 3. ACUTE HEM ORRHAGIC
inges, in the perivascular spaces surrounding some L EU KOEN CEPHALOPATHY OF HURST
of the superficial cortical blood vessels, and in the This is a fulminant, usually fatal, disorder, regarded
choroid plexus. by some as a hyperacute form of ADEM. It is
A B
FIGURE 5.23 Acute perivenous encephalitis. (A) Perivenous foci of demyelination in the white matter (Loyez
stain). (B) Higher magnification showing perivenous inflammatory infiltrates (Klüver-Barrera stain).
in one or more of the cell types in the CNS—
neurons, glial cells, or macrophages/microglial
cells, depending upon cell tropism. Some viruses
have a rather restricted or narrow cell tropism in
the CNS—for example, JC virus infecting oligo-
dendroglial cells in progressive multifocal leu-
koencephalitis (PML) and poliomyelitis viruses
infecting lower motor neurons. Other viruses have
wide cell tropism, infecting most of the cells in
the CNS, including endothelial cells, which is the
case for many of the herpes viruses. Cell tropism
is largely determined by cell receptors that allow
entry of virus into the cell.
FIGURE 5.24 Gross appearance of acute hemor- Whatever the causative virus, the basic neuro-
rhagic leukoencephalopathy. pathological picture of viral encephalitis includes
the following:
characterized by the presence of numerous scattered
hemorrhagic foci, which are more prominent in the • Involvement of the neuronal cell bodies, resulting
cerebral (Fig. 5.24) and cerebellar white matter and in their destruction and engulfment by macro-
in the pons. Microscopically, many small blood ves- phages (neuronophagia) (Fig. 5.25A)
sels undergo fibrinoid necrosis and are surrounded • Perivascular cuffing of inflammatory cells, mainly
by a narrow zone of necrotic tissue and a larger zone lymphocytes, macrophages, and plasma cells
of hemorrhage (ring- or ball-shaped perivascular (Fig. 5.25B)
hemorrhages). Still-recognizable vessels are veins • Microglial proliferation with the formation of
or venules, and they may be surrounded by fibrin microglial nodules and the appearance of rod cells
and an inflammatory infiltrate including neutrophils (Fig. 5.25C)
and mononuclear cells. Some neurites within the • In some cases, intranuclear or intracytoplasmic
infiltrate are demyelinated but many show axonal inclusion bodies are indicative of the presence of
fragmentation. virus in neurons and/or glia.
According to the type of the responsible virus

3.2. Infective viral encephalitis one may separate encephalitis due to RNA viruses
and encephalomyelitis (enterovirus, arbovirus, rabies, paramyxovirus,
Viral encephalitis—in the strict meaning of the term— rubivirus, and retrovirus), encephalitis due to
is due to infection of the brain by a virus. However, DNA viruses (herpes viruses, papovaviruses), and
quite often, viral infection also involves the meninges encephalitis suspected of being due to as yet uniden-
(meningoencephalitis) and/or the spinal cord (enceph- tified viruses (encephalitis lethargica, Behçet uveo-
alomyelitis, meningoencephalomyelitis) as well as the meningoencephalitis, chronic localized encephalitis
nerve roots (meningoencephalomyeloradiculitis). of Rasmussen).
Nervous system involvement is always second-
ary to infection elsewhere in the body. In fact, most
3.2.1 . ENCEPHAL ITIDES DUE TO RNA
viral infections of the CNS are rare complications
VIR USES
of common systemic viral diseases. The portal of
entry that has been directly exposed to infection 3.2.1.1. Poliomyelitis This is due to infection of
may be the skin (through direct contact or by an the CNS by a poliovirus, a small RNA virus of the
animal or insect bite), the airways (after inhala- genus Enterovirus.
tion), or the alimentary tract (after ingestion). The The most frequent form of the disease, “acute
virus may spread to the CNS directly along the anterior poliomyelitis,” is characterized by lytic
olfactory or peripheral nerves, or by the hematog- infection of the motor neurons. The lesions selec-
enous route in the course of viremia. This is fol- tively involve the motor neurons of the anterior
lowed by obligatory intracellular viral replication horns and the cranial nerve nuclei but may extend

A B
FIGURE 5.25 Chief microscopic features of encephalitis. (A) Neuronophagia (Nissl stain). (B) Lymphocytic

perivascular cuffing (Nissl stain). (C) Proliferation of rod-shaped microglia (H&E).
to the frontal gyri, the hypothalamus, the reticular populations, poliomyelitis is usually caused either
formation, and the posterior horns. As a result of by the rare reversion to neurovirulence of attenu-
viral infection and lysis of the neurons, there is neu- ated vaccine-related strains of poliovirus, or by other
ronophagia and microglial nodules with microg- groups of enteroviruses, especially group A cox-
lial/macrophage cell proliferation. Inflammation sackieviruses and enterovirus 71. The latter, a cause
in the leptomeninges and affected gray matter is of hand, foot, and mouth disease, has also been
intense (Fig. 5.26A, B). There is edema and vas- responsible for fulminant fatal brainstem encepha-
cular congestion, which may be associated with litis in children.
perivascular hemorrhages and, occasionally, focal
necrosis. 3.2.1.2 Arbovirus (arthropod-borne virus)
Following resolution, the residual lesions consist encephalitides These encephalitides are transmit-
of atrophy of the anterior horns with neuronal loss ted by insects and have a distinct geographical dis-
and astrocytic gliosis. There is atrophy and fibrosis tribution often indicated by the name of the virus.
of the anterior nerve roots, which appear thin and The best-known forms of the mosquito-borne
grayish at gross examination. The corresponding encephalitides include St. Louis encephalitis and the
skeletal muscles show wasting with severe denerva- Eastern, Western, and Venezuelan equine encepha-
tion atrophy. litides in America, Japanese B encephalitis in the
The introduction of vaccines for poliomyeli- Far East, Murray Valley encephalitis in Australia,
tis viruses has resulted in a sharp decline in the and West Nile fever primarily in Africa but also in
incidence of poliomyelitis. However, outbreaks Europe, Asia, and America. In these various forms
of paralytic infection by wild-type poliovirus the typical lesions of encephalitis are widely distrib-
still occur in developing countries. In vaccinated uted throughout the neuraxis.
A B
FIGURE 5.26 Poliomyelitis. (A) Horizontal section of the cervical level of the spinal cord showing inflam-
mation in the anterior horns. (B) Higher magnification showing neuronophagia, microglial proliferation, and
perivascular cuffing of lymphocytes (H&E).
In Japanese encephalitis, which is the most disparity between the abundance of virus and the
important of the arboviral encephalitides in terms limited degree of inflammation.
of global incidence, morbidity, and mortality,
the inflammation tends to be particularly severe 3.2.1.4. Measles encephalitides Measles
in the thalamus, substantia nigra, pons, medulla, virus, a paramyxovirus, like influenza and mumps,
and spinal cord and is occasionally necrotizing is known to cause two rare forms of encepha-
(Fig. 5.27A, B). litis: subacute sclerosing panencephalitis and
Tick-borne encephalitides, which include immunosuppressive measles encephalitis. In addi-
Russian spring–summer encephalitis and Central tion, it may provoke postinfectious encephalitis
European encephalitis, are characterized by menin- (cf. 3.1.2).
goencephalitic lesions and by involvement of the Subacute sclerosing panencephalitis occurs in chil-
lower cranial nerves and anterior horns, especially at dren, several years after an episode of measles. About
cervical levels. half of the patients are known to have had measles
In these encephalitides, inclusions are not before the age of 2 years. The lesions involve both
detectable by light microscopy, but some have the gray and the white matter. In the gray matter,
been observed ultrastructurally, and in many the the cortex is predominantly affected, but involve-
virus can be demonstrated immunohistochemically ment of the basal ganglia, mainly the thalamus, is
(Fig.5.27C). frequent and there may occasionally be extension
to the brainstem. Microscopic examination shows
3.2.1.3. Rabies Rabies is caused by a rhabdo- the features of subacute encephalitis. There is neu-
virus that is transmitted to humans by the bite of a ronal loss, occasional neuronophagia, and astrocytic
rabid animal. The animal reservoir includes foxes, and microglial reaction. Inclusion bodies may be
skunks, coyotes, jackals, and bats. However, the dog found in neuronal and glial nuclei (Fig. 5.29A). The
remains the main source of human infection. The white matter lesions are variable, including marked
disease may present as “furious” rabies or “dumb” astrocytic proliferation with inclusions in the glial
(paralytic) rabies. Once declared, the disease is nuclei and patchy myelin loss. Leptomeningeal,
almost always fatal. perivascular, and parenchymal inflammatory infil-
On neuropathological examination, rabies is trates are present both in the gray and white matter.
characterized by the presence in neurons of diag- In late cases, there may be considerable neuronal
nostic cytoplasmic inclusions called Negri bodies loss with atrophy of the cortex and basal ganglia;
(Fig. 5.28A, B). These are mainly found in the pyra- neurofibrillary degeneration of the Alzheimer type
midal neurons of the hippocampus and in Purkinje has been reported. The white matter shows thinning
cells. Accompanying lesions include leptomeningeal and demyelination with severe gliosis (Fig. 5.29B).
and perivascular inflammation, microglial nod- Inflammatory cells may be very scanty, as may be
ules (Babès nodules), and microglial hyperplasia. inclusion bodies, which may be better detected
These lesions are variable, but there may be striking immunohistochemically.

A B
FIGURE 5.27 Japanese encephalitis. (A) Gross appearance of necrotic lesions in the thalamus (courtesy of Pr.
S.K. Shankar and Dr. A. Mahadevan). (B) Necrolytic lesions in the neuronal areas. (C) Viral antigens in neurons
around edematous/necrolytic areas.
Although measles virus has been demonstrated A viral mutation resulting in defective M-protein
to be the causative agent by electron microscopy expression enabling the virus to elude the host
(Fig. 5.30), in tissue culture, and by immunologi- immune response has been postulated.
cal and virological assays, the pathogenesis of this Measles inclusion body encephalitis develops
type of prolonged viral infection remains uncertain. within months of the initial systemic infection in
A B
FIGURE 5.28 Rabies. (A) Negri bodies in a pyramidal neuron of the hippocampus (H&E). (B) Negri bodies
in a Purkinje cell stained in red using a specific antibody.
A
B
FIGURE 5.30 Electron microscopy showing
intranuclear tubular formations characteristic of
measles myxovirus in a case of subacute sclerosing
panencephalitis.
to a lesser extent astrocytes and oligodendrocytes.

Occasionally, multinucleated giant cells containing
virus may be found. There may be accompanying
inflammatory infiltrates and reactive astrocytes and
microglia, but these may be very scanty, even absent,
and the presence of inclusions may thus be missed.
3.2.1.5. Henipaviruses Henipavirus is a

new genus of RNA viruses belonging to the
Paramyxoviridae family that emerged to cause severe
human encephalitis in the 1990s. The genus com-
prised the two closely related, fruit bat-originated
viruses, Hendra virus and Nipah virus. Important
intermediate hosts for transmission to humans were
FIGURE 5.29 Subacute sclerosing panencephalitis. horses and pigs, respectively. Both viruses appear
(A) Intranuclear inclusion bodies in neurons (H&E). to cause similar acute and relapsing henipavirus
(B) Massive demyelination of the white matter and encephalitides.
severe cortical atrophy (Loyez stain).
patients with impaired cell-mediated immunity.

In AIDS patients, similar changes have also been
reported to occur after measles vaccination.
The brain may be normal or may show extensive
zones of necrosis of gray and white matter. The diag-
nosis can be made only on microscopic examination.
The lesions may be focal or widespread throughout
the brain; involvement of the spinal cord has been
found in children with AIDS. The diagnostic feature
is the presence of eosinophilic inclusion bodies that
are readily seen on routine stain (Fig. 5.31) but can
also be demonstrated by immunohistochemistry FIGURE 5.31 Measles inclusion body encephalitis.
and electron microscopy. These are mostly intra- Presence of numerous eosinophilic intranuclear inclu-
nuclear and involve predominantly neurons, and sion bodies (H&E).

Acute henipavirus encephalitis is character- and often viral inclusions, antigens (Fig. 5.32D), and
ized by disseminated small vessel vasculopathy and RNA can be demonstrated in adjacent neurons and
parenchymal pathology mainly in the CNS, but these more rarely in glial cells. Hence, necrotic plaques are
features are also found in extra-CNS organs such probably caused by a dual pathogenic mechanism
as lung, kidney, heart, etc. Vasculopathy consists of microinfarction and neuronal infection. In some
of true vasculitis with intramural necrosis, inflam- cases, focal neuronophagia, microglial nodule for-
mation, and endothelial ulceration (Fig. 5.32A). mation, clusters of foamy macrophages, perivascular
Vascular occlusion by vasculitis-induced thrombosis cuffing, and meningitis can be found.
or thromboembolism is readily observed and there In contrast to acute henipavirus encephalitis,
may be perivascular hemorrhage. Occasionally, mul- where there is systemic involvement, the pathology
tinucleated giant cells or syncytia arising from the of relapsing henipavirus encephalitis is confined to
endothelial surface can be found (Fig. 5.32B). Viral the CNS, and vasculopathy is absent throughout. In
inclusions, antigens, RNA, and nucleocapsids can affected neuronal areas and adjacent white matter,
be detected in vascular endothelium, multinucle- extensive confluent parenchymal necrosis, edema,
ated giant cells, and smooth muscle. and inflammation are observed. Reactive gliosis and
Parenchymal pathology of acute encephalitis prominent vascular proliferation in areas of severe
comprises discrete necrotic or more subtle vacuolar, neuronal loss were also seen. Severe meningitis may
plaque-like lesions often found adjacent to blood ves- be found in many areas. Like in acute henipavirus
sels with vasculopathy (Fig. 5.32C). These lesions are encephalitis, viral inclusions, antigens, and RNA can
characterized by necrosis, edema, and inflammation, be demonstrated in neurons and glial cells.
A B
C D
FIGURE 5.32 Acute Nipah encephalitis: (A) Vasculopathy consisting of true vasculitis and
thrombo-occlusion of vessel (Wong KT. Acta Neuropathol 2010; 120: 317–325; reproduced with kind
permission from Springer). (B) Multinucleated syncytia arising from the endothelial surface. (C) Necrotic
plaque with adajcent thrombotic vessel. (D) Viral antigens in neurons (Figures B–D, Wong KT et al. Am J Pathol
2002; 161: 2153–2167 reproduced with permission from Elsevier).
3.2.1.6. Progressive rubella panencephalitis can also freely cross the blood–brain barrier, gain-
This is a very rare delayed complication of congenital ing entry into the CNS parenchyma.
or childhood rubella infection. At neuropathological CNS neurological complications of HIV infec-
examination, there is widespread neuronal loss with tion are frequent and result from various mecha-
gliosis and leptomeningeal and perivascular inflam- nisms. Apart from lesions directly related to infection
mation containing lymphocytes and macrophages, of the CNS by the virus, opportunistic infections
and vasculitis with fibrinoid necrosis and mineral and lymphomas may occur as a result of the immu-
deposition. There is also extensive myelin destruc- nodeficiency syndrome; HIV-associated systemic
tion with relative sparing of axons. Inclusion bodies disorders may also cause neuropathological changes.
are not found, and rubella virus is not detected by They include cerebrovascular disease (marantic
either electron microscopy or molecular techniques. endocarditis, thrombocytopenia, coagulopathy, and
The lesions may result from vasculitis produced by cerebral atherosclerosis), metabolic and nutritional
immune complex deposition. abnormalities (hypoxia, vitamin deficiencies caus-
ing Wernicke encephalopathy and, possibly, vacu-
3.2.1.7. Infection by the human immunodefi olar myelopathy, as well as electrolyte disturbances
ciency virus (HIV-1) HIV-1 is a retrovirus of the responsible for central pontine myelinolysis), liver
lentivirus subfamily, properly classified as an immu- failure causing hepatic encephalopathy, or increased
nodeficiency virus, a subgroup of lentiviruses that levels of circulating pro-inflammatory cytokines
also includes HIV-2 as well as the closely related likely to be responsible for multifocal necrotizing
simian immunodeficiency virus (SIV). HIV-1 leukoencephalopathy. Finally, neurological compli-
infects cells that carry on their surface the CD4 cations of treatment, particularly those involving the
antigen, which is present both on CD4+ helper peripheral nervous system, are increasingly frequent.
T-lymphocytes and monocytes/macrophages, HIV-induced CNS lesions are defined as original
with the chemokine receptor CCR5 serving as an and specific changes that had never been observed
important co-receptor for HIV-1 on monocyte/ before the AIDS epidemic, and are found only
macrophage cells. On the one hand, infection of in HIV-infected individuals, without evidence of
CD4+ lymphocytes leads to their destruction and another cause. They include HIV encephalitis result-
cell-mediated immunodeficiency (the acquired ing from direct infection of the CNS by the virus,
immune deficiency syndrome [AIDS]). On the HIV leukoencephalopathy, and diffuse poliodystro-
other hand, HIV-1 can invade the CNS via infected phy, which may be variably associated.
macrophages, which represent a major cell type
capable of supporting viral replication and thus • HIV encephalitis (HIVE) due to productive infec-
potentially serving both as a reservoir for the virus tion of the CNS by the virus is the most character-
and as an agent for its dissemination. Viral particles istic. It includes marked astrocytic and microglial
A B
FIGURE 5.33 HIV encephalitis. (A) Presence of abundant multinucleated giant cells (H&E).

(B) Immunocytochemistry using an anti-HIV p24 antibody demonstrates the presence of HIV antigen in the
cytoplasm of a multinucleated giant cell.

activation with frequent multinucleated giant None of these HIV-induced CNS lesions can be
cells (MGC) (Fig. 5.33A) and abundant viral load precisely correlated with the specific progressive
demonstrated by either immunocytochemistry cognitive/motor syndrome termed HIV-associated
(Fig. 5.33B) or in situ hybridization. MGCs have neurocognitive disorder [HAND], suggesting that
been proposed as the hallmark of HIV encephali- HAND more likely reflects a specific neuronal dys-
tis. These cells are of macrophage lineage, contain function resulting from the combined effects of sev-
HIV in their cytoplasm, and result from the fusing eral neurotoxic factors, including those produced by
capacity of the virus. Thus, their presence pro- HIV itself as well as substances produced by acti-
vides evidence of productive HIV infection and of vated glial and microglial cells, some of which may
a cytopathic effect of the virus. The lesions consist be reversible.
of multiple disseminated foci that may affect any
part of the CNS but are more frequently found in 3.2.1.8. Human T-cell leukemia/lymphotro-
the deep white matter and basal ganglia. phic virus-1 (HTLV-1)-associated myelopathy
• Involvement of the white matter, HIV leukoencepha- HTLV-1, an oncogenic retrovirus (oncovirus) that
lopathy, is also a prominent feature of HIV-specific can cause T-cell leukemia, was the first human retro-
neuropathology (Fig. 5.34). It is often but not virus to be identified. It is endemic in the Caribbean,
invariably associated with HIV encephalitis. It is the southern United States, South America, parts
characterized both by diffuse myelin pallor with- of Africa, and Japan. In rare cases, it may cause
out true demyelination involving predominantly a myelopathy, HTLV-I-associated myelopathy
the deep white matter and usually sparing of the [HAM], characterized by progressive spastic para-
U fibers, and by widespread axonal damage. The paresis with sphincter and sensory disturbances.
white matter pallor is thought to be secondary to In longstanding cases of HAM, there may be
alterations in the blood–brain barrier. macroscopic meningeal thickening, spinal cord
• Involvement of the gray matter, diffuse poliodys- atrophy, and degeneration of the lateral columns.
trophy, is characterized by diffuse reactive astro- Microscopic examination shows myelin loss and
cytosis, and microglial activation in the cerebral some axonal degeneration in the long tracts of the
gray matter. It is associated with neuronal loss spinal cord, particularly in the lateral columns. There
resulting, at least partly, from an apoptotic process is fibrosis and lymphocytic infiltration of the lepto-
and, when severe, may cause macroscopic cortical meninges and astrocytosis and mononuclear inflam-
atrophy. mation in the spinal cord, more marked in the lower
thoracic region.
3 .2 . 2. EN CEPHALITIDES DUE TO DN A
V I RUSES
These include encephalitis due to herpes viruses and
Papova viruses. The main herpes viruses causing
CNS infection in humans include herpes simplex
virus (HSV) type 1 and type 2 (human herpes virus
types 1 and 2 [HHV1 and HHV2]), varicella-zoster
virus (VZV or HHV3), and cytomegalovirus
(HHV5). The main human infection caused by
Papova viruses is progressive multifocal leukoen-
cephalitis (PML) due to JC virus.
3.2.2.1. HSV encephalitis HSV is the most

common cause of sporadic acute encephalitis. Most
cases are due to infection by HSV type 1, but in
immunosuppressed individuals and neonates, HSV
FIGURE 5.34 HIV leukoencephalopathy (Loyez type 2 may also cause encephalitis. Following a pri-
stain). mary infection (oropharyngeal for HIV-1, genital
for HIV-2), HSV establishes a latent infection in of meningeal, perivascular, and scanty parenchymal
the sensory ganglia, with periodic reactivation of inflammation with scattered cells (neurons and glial
the virus leading to recurrent lesions at mucocu- cells) containing intranuclear inclusion bodies. The
taneous junctions, at or near the site of primary presence of HSV may be identified by immunohis-
infection. The mechanism of entry of HSV-1 into tochemistry or electron microscopy (Fig. 5.35D). At
the CNS to cause encephalitis is debated (spread a more advanced stage the lesions are more charac-
along olfactory nerve fibers either during primary teristic and include foci of hemorrhage and necrosis
nasopharyngeal infection or after reactivation of a with parenchymal infiltration by lymphocytes and
latent virus in the olfactory bulbs, reactivation of macrophages (Fig. 5.35B). Changes more character-
a latent virus in the trigeminal ganglia and axonal istic of meningoencephalitis (mononuclear inflam-
spread into the brain, or reactivation of a previously mation of the leptomeninges, perivascular cuffing,
established latent infection in the CNS, mainly in neuronophagia, and diffuse microglial hyperplasia)
the temporal lobes). are also present. Nuclear inclusions (Fig. 5.35C) are
In patients who die at the acute stage of the disease, usually sparse, and the virus is more easily identified
gross examination has shown generalized swelling by immunohistochemistry. Early diagnosis is essen-
and bilateral asymmetric necrotic and hemorrhagic tial so that treatment with antiviral therapy, usu-
lesions involving predominantly the temporal lobes ally acyclovir, can be initiated promptly, in order to
and the limbic regions (Fig. 5.35A) (insulae, cingu- achieve a therapeutic response. The untreated case
late gyri, and posterior orbital frontal cortex). On fatality rate is very high, approaching 80%, with a
microscopic examination, the earliest lesions consist significant reduction of mortality in people who are
A B
C D
FIGURE 5.35 Herpes virus encephalitis. (A) Necrosis of the left temporal lobe (the right temporal lobe
was surgically excised). (B) Microscopic appearance: necrosis with parenchymal infiltration by macrophages.
Note the presence of hemorrhage and perivascular cuffing by lymphocytes (H&E). (C) Characteristic Cowdry
intranuclear inclusion bodies (H&E). (D) Electron micrograph showing typical “target-like” intranuclear viral
particles.

treated. Reactivation of encephalitis after therapy
has been reported.
In long-term survivors of untreated or unsuc-
cessfully treated herpes encephalitis, the affected
parts of the brain are shrunken and cavitated, with
yellow-brown discoloration. The entire parenchyma
is replaced by cavitated glial scar tissue. Occasional
clusters of lymphocytes are still seen in the lepto-
meninges and brain parenchyma. The virus is no
longer demonstrable by culture, immunohistochem-
istry, or electron microscopy, but viral DNA may be
identified by polymerase chain reaction (PCR).
Neonatal HSV encephalitis differs from the
adult disease in that it is usually due to HSV-2 and FIGURE 5.36 Cytomegalic cell in a case of CMV
causes more generalized encephalitis without any encephalitis in an AIDS patient (Nissl stain).
predilection for any part of the brain. It also pres-
ents as necrotizing encephalitis. Nuclear inclusions, 3.2.2.3. CMV infection In children, early fetal
viral antigen, and DNA are usually demonstrable in infection may result in necrotizing encephalitis or
abundance. ventriculoencephalitis. Residual lesions in those
surviving the acute neonatal illness include micro-
cephaly, microgyria, porencephalic cysts, hydro-
3.2.2.2. VZV infection Primary infection by
cephalus, and periventricular calcifications.
VZV causes chickenpox. Latent infection is subse-
In adults, CMV may cause an opportunistic
quently established in the dorsal root or trigeminal
infection. Diffuse, nonnecrotic encephalitic lesions
ganglia. Reactivation of latent virus usually mani-
consisting of a dissemination of microglial nodules,
fests as shingles.
some of which contain characteristic cytomegalic
The pathological changes in zoster infection are
cells (Fig. 5.36), have been described, especially in
usually limited to the dorsal root ganglia or to the
transplant recipients. In AIDS patients, in addition
ganglia of a sensory cranial nerve and the nerve root,
to microglial nodule encephalitis, other lesions have
but changes may extend to the corresponding meta-
been observed, including necrotizing ventriculoen-
meric segment of the spinal cord, where there can
cephalitis, necrotizing encephalitis with large cystic
be intense lymphocytic inflammation that may be
foci of encephalomalacia, and acute meningomy-
associated with vasculitis and necrosis. Arteritis of
eloradiculitis, the last usually with numerous poly-
large arteries may cause extensive infarction of neu-
morphs. Cytomegalic cells containing intranuclear
ral tissue.
and intracytoplasmic inclusion bodies are numer-
In immunocompromised patients, particularly
ous and involve all types of cells (neurons, glial
AIDS patients, several patterns of VZV encephalitis
cells, endothelial cells, or macrophages). The virus
and myeloradiculitis have been described, includ-
may be identified by immunohistochemistry, in situ
ing multifocal lesions predominantly involving the
hybridization, or electron microscopy, but these are
white matter, likely to be due to hematogenous
usually not necessary for the diagnosis, since the
spread of the virus; ventriculitis secondary to ven-
appearance of the infected cells on routine stains is
tricular spread; encephalitis involving the visual sys-
so characteristic.
tem or the brainstem; and myeloradiculitis resulting
from spread from ophthalmic, trigeminal, or dorsal
root zoster. In all cases, inflammatory necrotizing 3.2.2.4. Progressive multifocal leukoen-
lesions are associated with vasculitis. Intranuclear cephalitis The disease is due to infection by the JC
inclusion bodies are present, and the virus may virus. This is an opportunistic infection occurring
be identified by immunohistochemistry or in situ most often in patients with immunodeficiency,
hybridization. In addition, granulomatous, necrotiz- particularly AIDS. The virus infects specifically
ing, or noninflammatory (endarteritis obliterans) oligodendrocytes, causing a demyelinating dis-
lesions involving small or large intracranial vessels ease. The lesions are usually bilateral but may
may cause infarcts or hemorrhages. be asymmetrical. They involve predominantly
the subcortical hemispheric white matter, espe- inclusions are particularly abundant and may be
cially in the parieto-occipital regions, but the cer- found in cells other than oligodendrocytes.
ebellum, brainstem, and even spinal cord may be
affected. They form limited spotty foci that very
3.2.3 . ENCEPHAL ITIS OF
often coalesce to form larger confluent demyelin-
UNCERTAIN ORIGIN
ating areas (Fig. 5.37A). They contain lipid-laden
macrophages and only scanty perivascular lym- 3.2.3.1. Encephalitis lethargica (epidemic
phocytes. The presence of giant astrocytes with encephalitis of von Economo) This supposed viral
bizarre hyperchromatic nuclei (Fig. 5.37B) and disease was rampant from 1916 to 1930 but attempts,
oligodendrocytes with enlarged nuclei containing with the limited techniques then available, to impli-
viral inclusions (Fig. 5.37C) is a striking and very cate a virus, as well as efforts to relate the encephalitis
characteristic feature. The virus may be identified with the contemporaneous pandemic of influenza,
in oligodendrocytes by immunocytochemistry, in were unsuccessful. The disorder was characterized by
situ hybridization, or electron microscopy. preferential involvement of the midbrain and basal
Since the AIDS epidemic, there has been a con- ganglia. In a large number of cases, a postencephalitic
siderable increase in the incidence of PML. The parkinsonism has been the sequela.
disorder is relatively frequent in AIDS patients, in
whom the lesions may be particularly severe, with 3.2.3.2. Behçet uveomeningoencephalitis Uveo-
sometimes necrotic, very extensive changes involv- meningoencephalitides present as inflammatory
ing particularly the cerebellum (Fig. 5.37D). Viral encephalitis, meningitis, and uveal lesions
A B
C D
FIGURE 5.37 Progressive multifocal leukoencephalitis. (A) Gross appearance, confluent demyelination in

the subcortical white matter of the parietal lobe (Loyez stain). (B) Presence of giant “bizarre” astrocytes in a
demyelinated area (H&E). (C) Presence of abnormal oligodendrocytes with enlarged nuclei containing viral
inclusions (H&E). (D) Extensive demyelination of the cerebellum and pons in an AIDS patient (Loyez stain).

involving the choroid, ciliary body, and iris. The with this hypothesis. Other supporting data include
etiology is uncertain. Behçet disease is a rare dis- the demonstration by in situ hybridization of
ease that most commonly presents as recurrent Epstein-Barr virus and CMV reported in some stud-
ulceration of the mouth and genitalia accompa- ies, though not confirmed by others.
nied by uveitis or iridocyclitis. An encephalitic Autoimmune mechanisms of injury, including
syndrome may occur occasionally consisting of immune complex deposits and vasculitis, have also
multifocal necrotizing lesions that involve pre- been postulated. Antibodies to GluR3 have been
dominantly the thalamus, hypothalamus, and identified in RS, but these may be nonspecific. More
midbrain. The inflammatory changes are often recently, direct T-cell–mediated cytotoxicity against
necrotic and sometimes hemorrhagic. Vasculitis the neurons has been demonstrated.
is considered to be the underlying lesion, but The observation of cortical dysplasia, tuberous
cerebral blood vessel changes are nonspecific. sclerosis, cavernous angioma, and tumors in patients
Attempts to demonstrate a virus as the cause of with RS has raised the possibility that these lesions
Behçet disease have failed. may be instrumental in inducing seizures, altering
the blood–brain barrier, which could, in turn, trig-
ger a viral or autoimmune disorder.
3.2.3.3. Chronic localized encephalitis of
Rasmussen This rare, devastating disorder is char-
acterized by progressive, unilateral neurological
4. RICKETTSIOSIS
deficit with sudden onset of seizures, usually in Some forms of rickettsial infection (murine/
childhood, that are refractory to treatment. They are endemic typhus due to R. prowazeki, exanthematic/
of partial complex type and become generalized and epidemic typhus due to R. typhi, Rocky Mountain
associated with hemiplegia, hemianopia, and intel- spotted fever due to R. rickettsii) may cause enceph-
lectual deterioration. alitides characterized histologically by perivascular
Macroscopic changes vary from case to case and mononuclear cuffing and microglial nodules that
are predominantly unilateral. They consist of cere- preferentially involve the gray matter of the cere-
bral atrophy, which may be patchy, and dusky dis- bral hemispheres and the brainstem. The agents,
coloration of the cortex (Fig. 5.38A). Histological which are obligatory intracellular microorganisms
examination confirms the largely unilateral distribu- that have the staining property of gram-negative
tion of the lesions, although bilateral involvement bacilli, may be demonstrated in the cytoplasm of
also occurs. Lesions are more diffuse and severe than endothelial cells.
can be assumed from macroscopic observation and
have a concentric distribution. They are necrotic and
destructive in their center, whereas at the periphery 5. OPPORTUNISTIC INFECTIONS
they have all the features of active encephalitis. They By definition, an opportunistic infection (OI) is an
include thickening of the leptomeninges with mild infection that takes the opportunity of a deficiency
lymphocytic infiltration and accompanying intrapa- in the immune response of the host to develop. It
renchymal cuffing of the vessels by lymphocytes and may be either a primary infection or a reactivation
macrophages (Fig. 5.38B). Microglial nodules and of a latent infection. Classically, OIs are due to
neuronophagia are ubiquitous (Fig. 5.38C–E), and saprophytic organisms that do not cause diseases
the former are seen also in the white matter. In older in immunocompetent individuals and that differ
lesions, there may be thinning of the cortex with loss from primary pathogens by several characteristics
of neurons and spongiosis, severe glial reaction, and (Table 5.4). However, one tends to include in this
less intense inflammatory clusters. group infections by common pathogens such as
The pathogenesis of Rasmussen Syndrome (RS) tuberculosis, syphilis, measles, or VZV, which may
is unknown. The possibility of an infectious etiol- behave as OIs in patients with impaired lympho-
ogy is raised by some studies, which have shown cyte function. One may also extend the concept
similarities between RS and the epilepsy seen of OIs to some neoplasms related to a specific
in Kozhevnikov encephalitis, a tick-borne viral viral infection that develop only in immunocom-
encephalitis with intractable seizures seen almost promised individuals, such as Kaposi sarcoma of
exclusively in Russia. The presence of an infectious AIDS patients, related to infection by HHV type
ipsilateral uveitis and chorioiditis is also consistent 8 (also known as Kaposi-sarcoma-associated virus
A B
C D
FIGURE 5.38 Rasmussen encephalitis. (A) Gross appearance. (B) Intraparenchymal perivascular cuffing

by lymphocytes and macrophages (H&E). (C) Nodule of neuronophagia. (D) Microglial nodule (H&E).
(E) Proliferation of rod cell microglia (immunocytochemistry for CD68).
[KSHV]), and primary brain lymphoma related age of the population as well as from a growing num-
to infection by EBV or HHV type 4, occurring in ber and longer survival of patients with debilitating
AIDS patients and organ transplant recipients. diseases such as diabetes, alcoholism, and lymphoid
In addition to the exceptional congenital and idio- neoplasms. In addition, many patients have received
pathic immunodeficiency disorders, there has been immunosuppressive drugs for rheumatic and neo-
a dramatically increasing number of patients with plastic diseases, and for organ transplantation. Finally,
acquired immunodeficiencies in the past 20 years. the occurrence of the AIDS epidemic has represented
This situation has resulted from the steadily increasing a major cause of acquired immunodeficiency.

Table 5.4. Differential Characteristics of Primary and Opportunistic Pathogens
P R I M A R Y PAT H O G E N S O P P O R T U N I S T I C PAT H O G E N S
• Induce specific diseases in • Induce atypical infections in immunocompromised

immunocompetent hosts with identified patients—present in wide environmental reservoirs or
reservoirs and routes of infection in commensal (endogenous) flora
• Interact with specific cellular or humoral • Lack defined cellular or humoral hostreceptors
target molecules
• Share specific virulence/pathogenicity • May express potentially virulent and pathogenic
determinants molecules (constitutive or inducible), once they have
colonized the host
• Can be transmitted from host to host and • Are acquired from the environment, from food sources,
induce the same disease (potential for or from the endogenous flora, and, for nosocomial
epidemics) infections, are communicable to susceptible contacts
• Clonal origin with limited genetic variability. • Genetic diversity and plasticity, which hamper
Induce specific immune responses, allowing indirect diagnosis and specific immunotherapies
for specific immunological diagnoses and and vaccines. High frequency of genetic variations
vaccines. and rearrangements, allowing acquired resistance to
antimicrobial agents.
Different types of immunodeficiency may be with lymphoid neoplasms (Hodgkin diseases or

associated with particular OIs, as described in the lymphoid leukemia) or other malignancies treated
following sections. with chemotherapy, or in patients on prolonged,
high-dose corticosteroid therapy.
In addition to mycoses (aspergillosis, cryptococ-
5.1. Opportunistic Infections cosis) and bacterial infections (listeriosis, nocar-
of the CNS in Patients with diosis), other cerebral OIs may occur, including
Granulocytic Disorders toxoplasmosis, PML, and CMV infection. Primary
Severe depletion of granulocytes is usually the conse- malignant non-Hodgkin lymphomas of the brain,
quence of decreased or absent production in the bone related to EBV infection, may also be seen. It is of
marrow. This may occur in myeloid leukemia or more historical interest that these tumors were first recog-
often in the course of treatment with cytotoxic drugs. nized as an opportunistic event in patients who had
More rarely severe granulocytopenia may result from undergone renal transplantation.
peripheral sequestration as in hypersplenism, or as an
idiosyncratic reaction to medication. In people who
develop severe granulocytopenia, the most common
5.3. Opportunistic Infections
OIs are mycoses, particularly those due to Aspergillus
of the CNS in Patients with
sp. and Candida sp., and to certain bacterial infections,
Lymphocytic Disorders,
particularly Pseudomonas aeruginosa, Listeria monocy-
Particularly in AIDS
togenes, and Nocardia asteroides. Prior to the introduction of highly active
anti-retroviral therapy (HAART) or combination
therapy including an HIV protease inhibitor, OIs
5.2. Opportunistic Infections secondary to the depletion in CD4+ T-cells caus-
of the CNS in Patients with ing the cell-mediated immunodeficiency syndrome
Combined Granulocytic and characteristic of AIDS were the more frequent com-
Lymphocytic Disorders plication of the disease. They usually occurred dur-
Immunodeficiency resulting from both granulo- ing the late stages, in full-blown AIDS, in people with
cytic and lymphocytic impairment is the rule in depletion of CD4 cells and with high viral loads,
transplant recipients. It may also occur in patients and they included multiple parasitic (Toxoplasma),
fungal (cryptococcal), bacterial (mycobacterial), of anti-Toxoplasma therapy. Cryptococcal menin-
and viral (cytomegalovirus, PML) infections, as gitis and PML are also rare in children with AIDS.
well as primary brain lymphomas. Unlike the situ- The most common opportunistic pathogen in this
ation with granulocytopenia, these patients, by age group, even in young children, continues to be
and large, did not have frequent infections due to CMV. In addition, children with AIDS are also at
Aspergillus sp. While bacterial infections were rare, risk for developing bacterial meningitis, including
it should be noted that a brain abscess in a patient that caused by S. pneumoniae.
with AIDS who did not have bacterial endocarditis The introduction of HAART has dramatically
was more likely to be due to Nocardia sp. than to any modified the course and prognosis of HIV disease.
other agent. In the developed world, where HAART is readily
The occurrence of many OIs in immunosup- available and where there have been progressive
pressed patients, particularly in those with AIDS, improvements in the management of OIs in general,
has modified the presentation of these complica- the incidence of CNS OIs has declined dramatically
tions and has consequently made their diagnosis from the 1980s, and epidemiological studies have
difficult for the following reasons: (1) There is an shown that AIDS-defining events are no longer the
increased range of organisms involved. (2) A par- major causes of death in HIV-infected patients. The
ticular patient may have successive or simultane- benefit is mainly due to a decrease of HIV viral load
ous infections by different agents. (3) There can and a restored functional immune system.
be involvement of several organs at the same time However, besides those related to drug toxicity,
with an increased incidence of neurological dis- new types of complications have occurred. On the
ease. (4) There is generally a reduced inflammatory one hand, “burnt-out” forms of treatable infections
reaction. in which no inflammation and no infectious agent
The occurrence of OIs of the CNS in AIDS could be detected have become more frequent. “Scar
patients varies with the geographical location where lesions” have been found with increasing frequency
the patient has lived, with the age of the patient, and in clinically and biologically cured patients who died
with therapy both for OIs and for HIV infection itself. from other causes. In other instances, despite effi-
With regard to geographical location, several cient treatment, the disease continued to progress
points can be made. Cerebral toxoplasmosis is clinically and often radiologically. This pattern was
more frequent in France and in Germany than it is particularly prevalent in patients with severe, mul-
in either the United States or the United Kingdom. tifocal toxoplasmosis, PML, or HIVE when treat-
In addition, this CNS complication has been ment had been administered too late in the course
reported in patients from sub-Saharan Africa, South of the disease, after irreversible cerebral destruction
America, and India. CNS histoplasmosis, blasto- had occurred with secondary progressive Wallerian
mycosis, and coccidioidomycosis are much more degeneration. On the other hand, new inflammatory
frequent in America than in Europe. Acute or reac- lesions related to the restoration of the immune system
tivated cerebral trypanosomiasis causing devastat- appeared. An “immune reconstitution inflammatory
ing necrotic lesions occurs only in South America. syndrome” (IRIS) was identified with four diagnos-
Mycobacterium tuberculosis infection of the CNS is tic criteria: (1) patients with AIDS; (2) efficiently
especially common in patients with AIDS living in treated by HAART; (3) presenting symptoms
developing countries that have a high incidence of consistent with an infectious/inflammatory condi-
tuberculosis, particularly in Africa. tion that appeared while on antiretroviral therapy;
Children up to 13 years of age in general have (4) symptoms that could not be explained by a
a lower incidence of CNS OIs than do adults; this newly acquired infection, the expected course of a
phenomenon is particularly manifest in AIDS, prob- previously recognized infection, or side effects of
ably because children have had less time than adults therapy. In the CNS, IRIS caused paradoxical exac-
to be exposed to common opportunist pathogens. erbation of tuberculosis and cryptococcal infection,
This is especially true for toxoplasmosis, which is a as well as of CMV retinitis. In some patients with
much less common cause of CNS mass lesion than PML or HIVE, onset or worsening of neurological
is primary brain lymphoma in children with AIDS signs following HAART institution was associated
in the United States. For this reason, it is recom- with contrast enhancement on MRI, suggestive of
mended that children with mass lesions in the CNS an unusually intense inflammation with impair-
be biopsied at presentation rather than after a trial ment of the blood–brain barrier. Neuropathological

studies confirmed intense inflammation with an Also, people with undiagnosed or unsuspected
influx of CD8+ lymphocytes variably associated HIV infection are still at risk of presenting with a
with an acute worsening of the underlying infection CNS OI, as are HIV-infected individuals who are
(HIV or JC Virus) and a nonspecific immunopatho- not compliant with their antiretroviral and pro-
logical reaction of the ADEM or Multiple Sclerosis phylactic therapy. In addition, this complication of
type. In most cases, this correlated with prolonged AIDS can be seen in people who develop resistance
survival and was interpreted as a marker of both mutations of HIV to antiretroviral agents. Finally,
improved immune status and outcome; however, in and of great importance, CNS OIs also continue to
rare instances, it coincided with clinical and radio- be a major problem in developing countries, where
logical aggravation and death. these types of therapy are often not available.
6
Human Prion Diseases
J A M E S W. I R ONS I DE , MATTH EW P. F R O S C H , A N D B ERNA RD INO G H ETTI
PRION DISEASES, also known as transmissible 1. BIOLOGY OF PRIONS

spongiform encephalopathies, are rare fatal neu-
rodegenerative disorders with a unique biological 1.1. The Infectious Agent
mechanism.
The human prion diseases are distinct from The transmissible agent in prion diseases is differ-
other neurodegenerative disorders in that they may ent from any known infectious pathogen both in its
be sporadic (idiopathic), inherited, or acquired structure and its remarkable resistance to conven-
(Table 6.1). These diseases are characterized patho- tional forms of decontamination. While attempting
logically by varying combinations of spongiform to identify the agent responsible for scrapie (a prion
change (vacuolation of the gray matter due to dis- disease affecting animals, particularly sheep and
tention and swelling of neuronal cell processes), goats), it was determined that the agent was smaller
neuronal loss, reactive gliosis (involving microglia than conventional viruses, did not have RNA or
and astrocytes), and prion protein (PrP) deposi- DNA, and accumulated in the central nervous sys-
tion. These features are markedly variable from tem (CNS). The prion hypothesis, proposed by
case to case and within different brain regions in a Prusiner in 1982, stated that the transmissible agent
single case. The diagnosis of prion diseases requires (prion) was a protein with a molecular weight of 27
a neuropathological examination combined with to 30 kD and was partially resistant to proteolytic
biochemical and genetic analysis. Prion diseases are cleavage and consistently associated with infectiv-
also seen in other mammals with implications for ity in purified extracts of scrapie-infected brain. It
spread to humans; the unusual biological properties was subsequently demonstrated that this protein
of the infectious agents are also associated with pro- was an abnormal isoform of a protein that normally
teins in organisms extending even to yeast. occurs in the mammalian brain. The normal protein
• 149
Table 6.1. Classification of Human Prion Diseases
Idiopathic Sporadic Creutzfeldt-Jakob disease
Sporadic fatal insomnia
Variably protease-sensitive prionopathy
Familial Familial Creutzfeldt-Jakob disease

Gerstmann-Sträussler-Scheinker disease and variants
Prion disease with cerebral amyloid angiopathy
Prion diseases associated with octapeptide repeat region insertional
mutations (variable phenotype)
Fatal familial insomnia
Acquired From human: Kuru

Iatrogenic Creutzfeldt-Jakob disease
From bovine: Variant Creutzfeldt-Jakob disease
is encoded by the PRNP gene located on the short been identified, of which the most significant are
arm of chromosome 20. M129V and E219K, since these affect susceptibil-
ity to prion diseases (Table 6.2).
1.2. The Normal Prion

Protein (PrPc) 1.3. The Abnormal Prion Protein (PrPsc)
The normal prion protein (PrPc) is a 253-residue In prion diseases, an abnormal isoform of the
peptide, which is translated from a single exon prion protein, designated PrPSc, accumulates in the
within the prion protein gene (PRNP). The peptide CNS (alternative terms include PrPCJD, referring to
undergoes a series of posttranslational modifica- Creutzfeldt-Jakob disease, and PrPres, referring to the
tions, including cleavage of a signal peptide, addi- property of proteinase K resistance). PrPSc has an
tion of up to two N-linked oligosaccharide chains identical amino acid sequence and the same molec-
(at residues 181 and197), and attachment of a ular weight as PrPc but has a much longer half-life
GPI anchor. The protein contains five octapeptide and is partially resistant to proteolytic digestion
repeats from codons 51 to 91. Four putative alpha (Fig. 6.1A). Structural studies have indicated that
helices in PrPc are located between codons 109 and PrPSc has a predominant beta-pleated sheet struc-
122, 129 and 140,178 and 191, and 202 and 218. ture, with loss of the alpha helix regions that is pres-
Most PrPc is membrane-associated and has a short ent in PrPc. These structural differences are thought
half-life. As with other proteins, it is sensitive to to confer resistance to proteolytic degradation, and
proteolytic digestion in standard in vitro conditions also allow PrPSc to aggregate and accumulate as amy-
(commonly assessed using the bacterial enzyme, loid within the CNS. In the prion hypothesis, PrPc
proteinase K). PrPc is expressed in a wide vari- is converted to PrPSc, which then accumulates in the
ety of tissues, but the highest levels of expression CNS and is neurotoxic, ultimately resulting in the
are found within neurons in the CNS. The precise targeted death of groups of neurons within the brain,
function of the normal protein is uncertain, but eventually leading to the death of the organism.
studies on engineered PrPc-null mice, which do not The mechanisms and sites of conversion are not
express PrPc, have indicated that it has a likely role fully understood. Conversion of PrPc to PrPSc can
in synaptic function and long-term potentiation, be achieved in cell-free systems, including in vitro
and may be involved in the control of circadian amplification systems such as the protein misfolding
rhythms. PrPc can act as a copper binding protein, cyclical amplification (PMCA) reaction. This reac-
and a protective role in oxidative cell stress has also tion not only amplifies a PrPSc “seed” by converting
been proposed. Several PRNP polymorphisms have a PrPc “substrate,” but it can also amplify infectivity.
Table 6.2. Prion Protein Gene This work, and other recent studies using recombi-
Polymorphisms in the Normal Population nant technology to create infectious PrPSc de novo,
and in Prion Diseases further supports the prion hypothesis.
Similarly, the mechanisms of neurotoxicity of
PRION PROTEIN PrPSc are not fully understood, although a range of
G E N E C O D O N 12 9 possibilities exist, from a direct toxic effect on neu-
P O LY M O R P H I S M S ( % ) rons to indirect toxicity mediated by microglia and
possibly astrocytes. No pathological changes occur
MM MV VV outside the CNS in prion diseases, although in some
diseases, PrPSc can be identified in the peripheral
Normal population 39 50 11 nervous system and in lymphoid tissues (see below).
Sporadic CJD 62 19 19
Variant CJD 100 – –
1.4. Diagnostic Methods for
M, methionine; V, valine; CJD, Creutzfeldt-Jakob disease Detecting PrPsc
A The resistance of PrPSc to protease digestion forms the
basis for its biochemical detection, which lies at the
Proteinase K − + heart of confirming the diagnosis of prion diseases.
When tissue homogenates are examined by Western
diglycosylated blot analysis with antibodies to PrP, samples con-
monoglycosylated taining PrPSc will show immunoreactivity even after
nonoglycosylated treatment with proteinase K, while PrPc is completely
digested. Although resistant to complete digestion,
PrPSc is partially cleaved in the experimental system;
B there are two common sites of cleavage, resulting in
CJD S S V fragments of different lengths. The size of the immu-
Codon 129 MM VV MM noreactive protein fragment that remains after prote-
ase digestion, along with the pattern of glycosylation, is
used to define PrPSc isotypes (Fig.6.1). Experimental
∗
animals inoculated with a particular isotype of PrPSc
21kDa — will typically present with a disease that is character-
— 19kDa
ized by the same isotype; this relationship has given
Type 1 2A 2B
rise to the use of the term “strain” to characterize indi-
FIGURE 6.1 Western blot analysis. (A) Western vidual PrPSc forms. There is no current uniformity in
blot analysis of prion protein (PrP) in variant CJD the nomenclature or classification of PrPSc isotypes;
brain tissue with (+) or without (-) prior digestion the relationship between isotype and disease pattern
with proteinase K. Proteinase K results in complete is only moderately predictable, and the identification
degradation of PrPC and in N-terminal truncation of of multiple PrPSc isotypes in some cases of sporadic
PrPSc. The remaining protease-resistant PrP (PrPres) CJD makes it difficult to establish these correlations
occurs in di-, mono-, and non-glycosylated forms. with great certainty at present
(B) Western blot analysis of protease-resistant prion
protein (PrPres) in sporadic (S) and variant (V) CJD
brain. Nonglycosylated PrPres occurs as either a 21kDa 2. THE HUMAN PRION
band (termed type 1) or a more extensively truncated DISEASES
19kDa band (termed type 2). Variant CJD exhibits
a characteristic predominance of the diglycosylated
2.1. Sporadic Creutzfeldt-Jakob
band (*), and this protein isotype is termed type 2B
to distinguish it from the type 2A isotype seen in
Disease (sCJD)
sporadic CJD, where the diglycosylated form does not sCJD is the most commonly diagnosed human
predominate. The cases shown were homozygous for prion disease, occurring with a relatively uniform
methionine (MM) or valine (VV) at codon 129 of the incidence of around 1 to 2 individuals per million
PRNP gene. per annum in the countries in which it has been
Chapter 6 Human Prion Diseases • 151

studied. Although a wide range of ages at onset but recent reports have indicated that a past his-
has been reported, most cases of sCJD occur in tory of surgery (not specifically neurosurgery)
the seventh decade of life, with males and females appears to be significantly higher in patients with
being affected equally. The disease usually presents sCJD than in controls. Analysis of the PRNP has
as a rapidly progressive dementia accompanied by shown that most patients with sCJD are methio-
other neurological abnormalities, among which nine homozygotes at codon 129, in contrast to the
ataxia, myoclonus, visual abnormalities, and pyra- normal population (Table 6.2). This finding has
midal and extrapyramidal signs are common. The been reproduced consistently in many countries,
duration of the clinical illness of sCJD is typically but the significance of this genetic predisposing
about half a year, but both shorter and in some factor remains uncertain.
cases markedly longer clinical courses have been Clinical and pathological heterogeneity has long
observed. been associated with sCJD, and a wide range of acro-
Use of a combination of diagnostic tests can assist nyms have been applied to some of these clinical sub-
in identifying cases of sCJD. These include the elec- groups (e.g. Heidenhain variant with a short clinical
troencephalogram (EEG), which shows a character- history and cortical blindness as a prominent feature;
istic abnormality with periodic triphasic complexes Brownell-Oppenheimer variant with prominent cer-
in approximately 65% of patients, although not at all ebellar ataxia). Recent studies on large cohorts of
phases of the illness. Elevated levels of the chaper- patients with sCJD have identified an association
one protein 14-3-3 in the cerebrospinal fluid (CSF) between the clinicopathological phenotype, the
can also be seen, although this is also seen in other PRNP codon 129 genotype, and the PrPSc isotype on
settings. Imaging studies can also assist in making Western blot analysis.
the diagnosis of sCJD, with restricted diffusion and Cases of sCJD exhibit the typical neuropatho-
hyperintensity on FLAIR sequences evident in ana- logical features of prion diseases (Fig. 6.2A , B). As
tomically involved regions such as cerebral cortex discussed above, the typical histological features in
and striatum. These imaging changes typically prog- the six major subgroups of sCJD are summarized
ress along with clinical signs and symptoms during in Table 6.3. It is interesting to note that within one
the course of the disease. subgroup (MM2) there appear to be two distinct
The etiology of sCJD is unknown. It has been clinical presentations: one with features character-
suggested that this disease might occur as a con- istic of sCJD, the other with features indicative of
sequence of a random stochastic event, which progressive thalamic and hypothalamic dysfunction.
results in the generation or spontaneous con- In this latter subgroup, the term “thalamic variant of
version of PrPSc within the brain. Case-control sCJD” is sometimes applied, although more recently
studies have failed to identify any consistent pre- a proposal has been made to name cases within the
disposing factors in terms of occupation or diet, subgroup as fatal sporadic insomnia.
A B
FIGURE 6.2 Sporadic CJD: microscopic features. (A) Spongiform change in the cerebral cortex in sporadic
CJD MM1 consists of multiple small vacuoles in the gray matter that occasionally join to form larger cyst-like
spaces (H&E). (B) Immunocytochemistry for PrP in the same case as Figure 6.1A shows accumulation of PrP in
amorphous deposits around areas of spongiform change.
Table 6.3. Summary of Genotypes and Phenotypes of Sporadic Human Prion Diseases
CLINICAL PRNP PR N P C O D O N P R P RES PROPOSED PRP-

DISE ASE M U TAT I O N 12 9 ISOT YPE IMMUNOHIS TOCHEMIS T RY
C O R R E L AT E
Sporadic None MM, MV Type 1A Synaptic and coarse granular

CJD(Myoclonic, staining in cortex
Heidenhain
variants)
Sporadic CJD None VV Type 2A Plaque-like, focal and
(Brownell- perineuronal staining
Oppenheimer
variant)
Sporadic None MV Type 2A Amyloid plaques in the
CJD(Kuru-plaque cerebellum
variant)
Sporadic None MM Type 2A Staining faint and variable
CJD(Sporadic fatal
insomnia)
Sporadic None MM Type 2A (basic Cortical perivacuolar staining
CJD(Cortical glycans)
variant)
Sporadic CJD None VV Type 1A Faint synaptic staining
Variant CJD None MM Type 2B Florid and cluster plaques
M, methionine; V, valine
2.2. Variably protease-sensitive and spongiform change and microplaques are pres-
prionopathy ent in the cerebellar cortex (Fig.6.3A–C). The most
striking feature of VPSPr is the biochemistry of the
In 2008, 11 cases of a novel form of prion disease disease-associated prion protein in the brain on
now known as variably protease-sensitive prion- Western blot examination (Fig.6.3D). This shows
opathy (VPSPr) was reported in the United States. a ladder-like electrophoretic profile with five major
They had different clinical features from sCJD, with bands, in which the 7-8 kDa band may predomi-
features including behavioral and mood changes, nate. This appearance is in marked contrast to other
language deficits (including aphasia), cognitive human prion diseases.
impairment, and motor signs including parkinson- The identification and characterization of this
ism. The disease duration is longer than in sCJD (up novel disorder is still underway; the results of exper-
to 45 months), and in some cases a family history imental transmission studies are awaited, which
of a neurological disease was obtained. However, should allow a clearer understanding of the bio-
analysis of the PRNP gene in these patients found logical properties of the abnormal prion protein in
no pathogenic mutations. Subsequently around 30 this disorder, and its relationship to other forms of
cases have been identified in a wider range of coun- human prion disease.
tries, in which all three PRNP codon 129 genotypes
were affected. Interestingly, the clinical features and
to some extent the brain pathology vary according
to the PRNP codon 129 genotype.
2.3. Familial prion diseases
Spongiform change is present, particularly in the Familial prion diseases occur as autosomal domi-
neocortical and subcortical regions of the cerebrum, nant disorders with high penetrance and include

A B
C D
]
JD 10
v C r [X
sC r
SP
SP
JD
JD
VP
VP
vC
40
30
20
FIGURE 6.3 Variably protease-sensitive prionopathy (VPSPr). VPSPr shows spongiform change in the
frontal cortex (A), focal fine vacuolation in the cerebellar cortex (B), and microplaques in the cerebellar cortex
on immunohistochemistry for prion protein (C). Western blot analysis of protease-resistant prion protein in
VPSPr compared to that of variant Creutzfeldt-Jakob disease (vCJD) and sporadic Creutzfeldt-Jakob disease
(sCJD) shows a faint ladder of higher-molecular-weight bands in addition to the prominent ~8kDa band (*) that
characterizes VPSPr (D).
a wide range of clinicopathological phenotypes, and disease duration. For this reason, it has been
which are categorized as familial Creutzfeldt-Jakob proposed that mutations that cause familial forms
disease (fCJD), Gerstmann-Sträussler-Scheinker are to be identified with both the details of the muta-
disease (GSS), variable phenotypes, and fatal famil- tion and the codon 129 context.
ial insomnia (FFI). The first genetic abnormality
to be identified in a familial prion disease was the
2 .3 . 1. FAM ILIAL CJD
PRNP P102L mutation in GSS in 1989. Since then,
over 40 different PRNP mutations, including mis- In fCJD, the range of clinical and pathological
sense, deletion, nonsense, and insertion, have been phenotypes resembles those observed for sCJD.
identified. The insertional mutations are in the octa- Some cases, initially suspected to be sCJD because
peptide repeat region. In addition to mutations, the of the apparent absence of a positive family his-
polymorphic codon 129 on both the mutant and tory, have subsequently been found to be associ-
nonmutated alleles of PRNP can strongly influence ated with a PRNP mutation. The most common
disease phenotype: the amino acid at codon 129 on PRNP haplotypes to be associated with fCJD are
the same allele as the disease-causing mutation can the E200K-129M and D178N-129V (Table 6.4).
influence the clinical and pathological features of the Phenotypic variability does occur within affected
disease, while the amino acid at codon 129 on the families in terms of both the clinical and pathologi-
other allele predominantly influences age of onset cal features of the disease.
Table 6.4. Most Common Haplotypes and Phenotypes of Familial Human Prion
Diseases
CL INICA L DISE ASE PRNP H A PL OT Y PE P R P RESI S O T Y P E HIS TOLOGICA L

C O R R E L AT E S
Gerstmann- P102L-129M Type 1Band 8kD Spongiform change, synaptic

Sträussler- PrP, amyloid plaques
Scheinker disease 8 kD only PrP-amyloid plaques, no
spongiform changes
P105L-129VA117V- 8 kD Multicentric amyloid plaques,
129VH187R-129V no spongiform changes
F198S-129VQ217R-129V 8 kD Multicentric amyloid plaques,
no spongiform changes and
neurofibrillary tangles
Fatal familial insomnia D178N-129M Type 2B Thalamic atrophy, inferior
olivary gliosis
Familial D178N-129V Type 1B Cortical spongiform
Creutzfeldt-Jakob degeneration
disease E200K-129M Type 1B Diffuse PrP staining
E200K-129V Type 2B Diffuse PrP staining in
cortex, focal deposits in the
cerebellum, or plaque-like
deposits in the cerebellum
M, methionine; V, valine
2.3.2. GERSTMANN-STRÄUSSLER- vascular wall accumulation of this material can be

SCHEINKER DISEASE seen in the rare setting of stop mutations in PRNP
(Y145stop, Y226stop). In these cases, the clinical
GSS is a progressive cerebellar syndrome, accompa-
course is usually a relatively prolonged progressive
nied by pyramidal signs and progressive cognitive
cognitive decline leading to dementia, while the
decline, which may result in dementia. The shared
common histological feature is the vascular and
histological feature in GSS is the presence of mul-
perivascular amyloid deposits, minimal spongiform
ticentric PrP-amyloid plaques in the cerebral and
change, and tangle accumulation in neurons near the
cerebellar cortex, while spongiform change may
affected vessels. Interestingly, this pattern of disease
or may not be present (Fig.6.4A, B). A number of
does not always result from truncation mutations in
point mutations resulting in a similar clinicopatho-
PrP, as another missense mutation (Q227stop) gives
logical phenotype has been described (Table 6.4).
rise to a pattern more in keeping with GSS, again
The F198S and Q217R mutations are associated
with abundant tangles.
with neocortical neurofibrillary tangles (similar to
those found in Alzheimer disease) in addition to
widespread multicentric and unicentric PrP amy- 2.3.4 . PRION DISEASES ASSOCIATED
loid plaques. WIT H OCTAPEPTIDE REPEAT REGION
INSERTIONAL MUTATIONS (VARIABL E
PHE NOTYPES)
2.3.3. PRION DISEASE WITH CEREBRAL
In patients with insertional mutations in the octa-
AMYLOID ANGIOPATHY (PRP-CAA)
peptide repeat region of the PRNP, the clinical mani-
While PrP-amyloid deposits in are found the paren- festations are highly variable both in terms of disease
chyma in some forms of prion disease, selective duration and in the disease phenotype. In general,

A B
FIGURE 6.4 Gerstmann-Sträussler-Scheinker disease. Immunocytochemistry for PrP shows multicentric PrP

plaques in the cerebellar molecular layer (A,B), with smaller plaques in the granular layer (A).
patients with up to four additional copies of the shared across FFI kindreds, is D178N—which had
octapeptide repeats have a clinical phenotype simi- already been demonstrated to cause fCJD. It was
lar to sCJD, with rapidly progressive dementia and recognized that D178N-129M results in FFI, while
characteristic EEG abnormalities. In patients with D178N-129V results in fCJD. Phenotypic variabil-
a larger number of extra repeats, the clinical pheno- ity has been described within FFI, usually under the
type is more variable, often with progressive ataxia influence of the codon 129 genotype on the nonmu-
and other movement disorders. Histologically, these tated allele.
cases often show unusual linear PrP deposits in the
molecular layer of the cerebellum (Fig. 6.5); how-
ever, the other histological features are somewhat 2.4. Acquired Prion Diseases
more variable. 2 .4 . 1. KURU
Kuru was described as an endemic disease among
2. 3. 5. FATAL FAMI LI A L I NS O M NI A the Fore tribe of Papua New Guinea in the 1950s.
The disease was characterized by progressive ataxia
FFI is a disorder characterized by sleep disturbance,
and tremor with marked emotional instability, but
dysautonomia, and motor signs, with cognitive
abnormalities, which are often relatively mild but
tend to increase with the duration of the disease. The
neuropathology of FFI is characterized by severe
neuronal loss and gliosis in the anterior thalamic
nuclei (Fig. 6.6A–C) and in the hypothalamus, in
the absence of spongiform change and PrPSc depo-
sition. Neuronal loss and gliosis are also evident in
the inferior olivary nuclei (Fig. 6.6D) and to a lesser
but variable extent, in the cerebral and cerebel-
lar cortex. Spongiform changes can be remarkably
difficult to detect in this disorder but are usually
apparent on careful study of the cerebellar cortex.
In some cases, tissue blots obtained from sections
of paraffin-embedded tissue may help to identify
PrPSc deposition, particularly in the entorhinal cor-
tex (Fig. 6.6E). FIGURE 6.5 Prion disease with octapeptide repeat
The discovery that FFI is caused by a mutation in region insertional mutations. Immunocytochemistry
PRNP highlights the impact of codon 129 on disease for PrP shows linear PrP deposits in the molecular
phenotype (Table 6.4). The identified mutation, layer of the cerebellum.
rapidly progressive dementia was not a common presence of the amyloid deposits in the cerebellum
feature. The disease was associated with ritualistic (Fig.6.7B) but also has demonstrated diffuse depos-
cannibalism, and since this practice has been dis- its, which are not identifiable on routine stains.
couraged, the incidence of disease has declined sig-
nificantly. The disease is now extinct, and some of
2.4.2 . IATROGENIC CJD
the last symptomatic patients sustained incubation
periods of around 40 years. In 1974, the occurrence of iatrogenic CJD (iCJD)
The pathology of Kuru is similar to that of the was reported in a recipient of a corneal transplant.
sporadic CJD VV2 and MV2 subsets, with amy- Since then, well over 400 cases of human transmis-
loid plaques, so-called “Kuru plaques,” present in sion of CJD have been identified; the majority of
the cerebellum, particularly in the granular cell these have been recipients of autopsy-derived human
layer (Fig. 6.7A), and spongiform change noted pituitary hormones (mostly growth hormone) or
in the cerebellum, basal ganglia, and thalamus, human dura mater grafts. A summary of the routes
with a variable distribution in the cerebral cortex. of transmission of iCJD is given in Table 6.5. There
Immunocytochemistry for PrP has highlighted the is a relationship between the route of infection and
A B C
D E
FIGURE 6.6 Fatal familial insomnia. (A, B) Coronal section of the right thalamus through the mammil-
lary bodies showing atrophy of the anterior and medial nuclei in a FFI case (A) compared to a normal control
(B) (courtesy Pr. Danielle Seilhean). (C) Microscopic appearance of the medial thalamus: neuronal loss and
gliosis. Note the absence of spongiosis (H&E). (D) Immunocytochemistry for GFAP showing neuronal loss and
gliosis in the medullary olive. (E) PET immunoblotting shows PrP deposition in the entorhinal cortex (courtesy
of Pr. F. Scaravilli).

A B
FIGURE 6.7 Kuru. (A) Kuru plaque in the molecular layer of the cerebellum (H&E). (B) Small rounded
PrP amyloid plaques, well identified on PrP immunostain, are a characteristic feature in the granular layer of the
cerebellum.
incubation times: a central route of infection has Histologically, iCJD is similar to sCJD, although the
the shortest incubation times, while the peripheral cerebellar pathology in the pituitary hormone recipi-
route of infection (particularly in growth hormone ents tends to be more severe than in sCJD (Fig. 6.8).
recipients) has a longer incubation period. In general, iCJD has developed more frequently in
The clinical features of iCJD are variable; some the setting of homozygosity at codon 129. There is
patients (particularly those with a “central” route an intriguing observation that cases from the United
of transmission) resemble sCJD, whereas others Kingdom are more commonly 129VV, while those
(including the human pituitary hormone recipients) from France are more commonly 129MM; this may
often present with a progressive cerebellar ataxia reflect differences in the original contaminating agent.
and other focal neurological symptoms as well as
dementia occurring only later in the illness.
2.5. Variant CJD
In 1996, a novel form of prion disease with unusual
clinical, biological, and pathological features was
Table 6.5 Routes of Iatrogenic identified by the National CJD Surveillance Unit in
Transmission of Creutzfeldt-Jakob the United Kingdom. A causative relationship with
Disease
SOURCE OF N U M B E R O F I N C U B AT I O N
INF EC TION REPORTED PERIOD (M)
CASES
Neurosurgical 4 12–28
instruments
Intracerebral 2 16–20
electrodes
Dura mater graft 215 18–216
Corneal graft 2 16–320
Human growth 227 550–456
hormone
Human 4 144–192 FIGURE 6.8 Iatrogenic CJD. In iatrogenic CJD in
gonadotrophin a growth hormone recipient, the cerebellum contains
small “kuru-type” plaques as well as more diffuse PrP
Courtesy of Dr. L. Schonberger, 2011 deposits, well identified on PrP immunostain.
the epidemic of bovine spongiform encephalopathy
(BSE) in cattle seemed likely. Since then, just over
200 patients with this disease, subsequently known
as variant CJD (vCJD), have been identified.
Clinically, there is a relatively young age at onset
(mean 27 years, range 12 to 74). The lengthy dura-
tion of illness (13 months) and clinical presentation
are also characteristic. The latter includes psychiatric
and/or sensory manifestations at onset, followed by
severe progressive ataxia, extrapyramidal and pyra-
midal signs, and a progressive dementia, which in
some cases was severe. In vCJD, the EEG is abnormal
but does not exhibit the characteristic abnormalities
seen in sCJD. Cranial MRI scans show a symmetrical
area of hyperintensity on FLAIR sequences in the
posterior thalamus (the “pulvinar sign”) (Fig. 6.9),
which is highly characteristic and has been incorpo- FIGURE 6.9 Axial MRI FLAIR image at the level
rated into the clinical diagnostic criteria for vCJD. of the basal ganglia, showing bilateral hyperintensity
Analysis of CSF 14-3-3 levels has not proved useful of the pulvinar and dorsomedial thalamic nuclei in
in making the diagnosis of vCJD, but detection of variant CJD.
elevated CSF phosphorylated tau has been shown to
contribute to establishing such a diagnosis.
Pathologically, vCJD differs from other forms that most human cases of vCJD result from expo-
of human prion disease by the presence of large sure to BSE through the food chain (i.e., by the con-
numbers of “florid” plaques with a widespread dis- sumption of contaminated meat products). There is
tribution in the cerebral cortex (Fig. 6.10A , B) and also evidence to suggest from a case-control study
in the cerebellum. These lesions comprise a central that consumption of certain meat products is higher
eosinophilic amyloid core with radiating bundles of in patients with vCJD than in controls.
amyloid fibrils, surrounded by spongiform change. Since the most likely route of exposure to BSE
Apart from the florid plaques, other characteris- in humans is the oral route, studies have been per-
tic neuropathological features of vCJD include formed on tissues outside the CNS to investigate
extensive PrPSc accumulation both as small cluster the peripheral pathogenesis of this disease. PrPSc is
plaques and diffuse deposits (Fig. 6.10C, D), with detectable in follicular dendritic cells within germi-
spongiform changes most marked in the caudate nal centers in lymphoid tissues including the tonsil
nucleus and putamen. In the thalamus, there is (Fig. 6.10E), lymph nodes, spleen, thymus, and the
extensive neuronal loss and gliosis in the posterior gut-associated lymphoid tissues in the appendix and
nuclei, corresponding to the abnormalities on MRI. small intestine. On the basis of this finding, it has
Western blot analysis of the brain in vCJD shows been proposed that a tonsil biopsy is an important
a characteristic PrPSc isotype, with a predominant diagnostic test for patients suspected of having vCJD,
diglycosylated band and an unglycosylated band particularly when the characteristic MRI changes are
that migrates around 21 kD (see Fig. 6.1B). This gly- absent. Recent investigations have confirmed the
cosylation pattern is similar to that seen on Western presence of infectivity in the spleen and tonsil of
blots for PrPSc in cattle with BSE and in other species individuals with vCJD; however, the level of infectiv-
(e.g., cats) that have been infected with BSE. ity is two to three times lower than that in the brain.
At the time of the original description, it was sug- The potential number of future cases of vCJD is
gested that the most likely hypothesis for the emer- highly uncertain; estimates range from a few hun-
gence of vCJD is exposure of the human population dred to many thousands. At the time of writing, 225
to the BSE agent. A number of independent investi- cases of vCJD have been reported worldwide, 176
gations have demonstrated that the structural char- of them in the United Kingdom. Since all patients
acteristics of the transmissible agent in vCJD are with definite vCJD are homozygous for methionine
quite similar to those for BSE but share no similari- at codon 129 (129MM), estimates are restricted
ties with those of sCJD. On this basis, it is assumed to that genotype. However, vCJD infection has

A B
C D
FIGURE 6.10 Variant CJD, microscopic features. (A, B) The florid plaque in the cerebral cortex in vari-
ant CJD comprises a dense core with a paler outer layer of amyloid fibrils, surrounded by spongiform change
(H&E). (C, D) Immunocytochemistry for PrP shows strong staining of the florid plaques, as well as multiple
smaller plaques and diffuse PrP deposits. (E) PrP accumulation in the tonsil in variant CJD within follicular
dendritic cells and macrophages in a germinal center is demonstrated by PrP immunocytochemistry.
been transmitted on four occasions in the United but with no evidence of a neurological disorder; at
Kingdom by blood transfusion from asymptomatic autopsy, PrPSc was detected in the spleen and lymph
donors who subsequently died from vCJD. Three of nodes, although not in the brain and spinal cord. It
the four recipients were 129MM and later died from remains possible that cases of vCJD may yet emerge
vCJD, but the fourth recipient was a heterozygote after a longer incubation period in individuals with
(129MV). This recipient died from other causes genotypes other that 129MM.
7
Multiple Sclerosis and Related Inflammatory
Demyelinating Diseases
H A NS LAS S M ANN, R AYMO N D A . S O B EL , A N D D A N IELLE SEILH EA N
INFL AMMATORY DEMYELINATING dis- by remyelination due to recruitment and differentia-

eases are defined by the selective destruction of tion of oligodendrocyte progenitor cells. In contrast,
myelin sheaths and oligodendrocytes, which arises spontaneous regeneration of axons and neurons
in a background of acute or chronic inflammation. does not occur in the affected central nervous system
There is a spectrum of inflammatory demyelinating (CNS). There is evidence that inflammation drives
diseases that includes multiple sclerosis (MS), acute the formation of lesions in inflammatory demyelin-
disseminated encephalomyelitis (ADEM), concen- ating diseases, but the cause of chronic inflamma-
tric sclerosis (Baló disease), and neuromyelitis optica tion (i.e. either of primary autoimmune nature or as
(NMO). These diseases have distinct pathology and a reaction to a chronic infectious or other injurious
pathogenesis but share some common pathologi- process) is still unresolved.
cal features and molecular pathways of tissue injury.
Within typical demyelinating lesions, myelin sheaths
are completely lost, while axons are in part preserved; 1. MULTIPLE SCLEROSIS
they appear naked and are embedded within glial The clinical spectrum of MS is highly variable. It
scar tissue. However, as demonstrated even in the is determined by the location of lesions within the
earliest descriptions of the pathology of MS, axons CNS and the disease stage. The disease most com-
are affected and variably lost in all lesions. In contrast monly starts with episodes of neurological deficit
to demyelination, neuroaxonal degeneration is the that generally resolve but are followed by phases
major correlate of irreversible functional deficits in of relapses (relapsing/remitting MS [RRMS]).
affected patients. Slow impulse conduction is pos- After about 10 years of disease duration, this pat-
sible in demyelinated axons and demyelination and tern switches to a phase of less episodic and unin-
oligodendrocyte loss can, at least in part, be repaired terrupted progression (secondary progressive MS
• 161
[SPMS]). In a minority of patients, the relapsing matter. Inflammatory infiltrates mainly consist of
stage of the disease is absent and the patients show T-lymphocytes, of which CD8+ cells outnumber
uninterrupted progression from the onset (primary CD4+ ones. CD8+ T-cells show dominant clonal
progressive MS [PPMS]). Acute MS (Marburg expansion, suggesting the expansion of this particu-
type) is a fulminant, usually monophasic disease lar cell type through local recognition of their cog-
that leads to death of the patient within 1 year nate antigen(s). B-lymphocytes are also components
after onset. of the infiltrates and contribute to about 1% to 10%
There are several features of the clinical picture of the total lymphocyte population. These cells and
that are particularly important for interpretation of plasma cells are mainly present in the leptomeninges
the pathology and understanding the pathogenesis and perivascular Virchow Robin spaces, while their
of the disease. In RRMS, clinical disease is largely infiltration into the parenchyma is less common.
characterized by new lesions in the white matter Inflammation in the MS brain is accompanied by
that show contrast enhancement on magnetic reso- additional recruitment of monocytes and macro-
nance imaging (MRI) (i.e. reflecting inflammation phages and even more abundantly by activation of
and blood–brain barrier damage). In this stage, the local microglia population. Active demyelination
anti-inflammatory and immunosuppressive treat- and tissue injury is invariably associated with the
ments are most effective. The progressive stage of presence of activated microglia and macrophages.
the disease mainly occurs later in life; the onset of At the sites of inflammation, and in particular
disease in PPMS generally occurs at the same age as within active lesions, molecules that are involved
when disease in other patients switches from RRMS in induction, propagation, and control of the
to SPMS. In the progressive stage, clinical deteriora- inflammatory process are expressed. They include
tion does not correlate as well with new white mat- class I and class II major histocompatibility complex
ter lesions, and enhancing lesions in MRI are rare molecules (necessary for antigen presentation for
or absent. The speed of progression of the disease is T-cells), adhesion molecules, chemokines and their
surprisingly uniform and poorly related to the num- receptors (which are important for recruitment and
ber and clinical severity of previous relapses. Most migration of inflammatory cells), cytokines (which
importantly, anti-inflammatory or immunosuppres- are involved in propagation or termination of the
sive treatments are ineffective at this stage of the dis- inflammatory process), Fc-receptors and comple-
ease. Thus, from a clinical point of view, MS seems ment (involved in antibody-mediated cell injury),
to start as an inflammatory disease that gives rise to and molecules involved in macrophage toxicity
new white matter lesions, whereas it may transform (e.g., cytotoxic cytokines, proteases, and enzymes
into a neurodegenerative disease in the progressive responsible for the production of reactive oxygen
phase. As will be discussed below, this view seems and nitric oxide species).
to be too simplistic in light of the knowledge on the Inflammation is most extensive in active lesions
pathology of the disease. at early stages of MS (acute and RRMS) but is invari-
ably also present in patients at the progressive stage
of the disease, when there is ongoing active demy-
1.1. Pathology of MS elination and neurodegeneration. At very late stages
The pathology of MS is defined by the triad of inflam- of the disease, inflammation may decline to levels
mation, demyelination, and glial scar formation. observed in age-matched controls. In these patients
no active demyelination is seen and active neurode-
generation is minimal. These observations suggest
1. 1. 1. I NF L AMMAT IO N that there may be no ongoing neurodegeneration in
MS patients in the absence of inflammation.
Inflammation can be present in all stages of MS.
Inflammatory infiltrates are present around small
1 .1 . 2. DEM YELIN ATED LESION S IN THE
veins and venules in the centers of active white
W H ITE M ATTER
matter lesions. Parenchymal infiltration by inflam-
matory cells is generally associated with active Focal demyelinated plaques in the white matter
demyelination or neurodegeneration in discrete are the hallmark of MS pathology. They occur at
lesions known as plaques and, to a variable extent, any sites of the brain and spinal cord but are more
in the more normal-appearing white and gray frequently located in certain sites that include the
periventricular and subcortical cerebral white mat- fan-shaped appearance with the tip of the triangle
ter, the optic nerves, chiasm, and tracts, the periven- pointing toward the central gray matter. There is no
tricular regions of the brainstem, the cerebellum, predilection of plaques for specific neuroanatomical
and the spinal cord (Figs. 7.1 and 7.2). In the spi- tracts, functional systems, neurons using a particular
nal cord, the lesions generally show a triangular, neurotransmitter, or vascular territories. However,
A B
D E
FIGURE 7.1 Principal topographical features of MS lesions (Loyez stain for myelin). (A) Right cerebral
hemisphere: disseminated plaques. (B) Cerebral hemispheres through the parieto-occipital region; note the
confluent periventricular distribution of the lesions. (C) Demyelination in the optic chiasm. (D) Left cerebellar
hemisphere and pons: plaques in the anterior aspect of the fourth ventricle and in the cerebellar white matter.
(E) Plaques involving the spinal cord. Note the absence of Wallerian degeneration. Although a plaque is present
in the right cerebrospinal tract at the thoracic level, there is no consequent demyelination at the lumbar level.
Chapter 7 Multiple Sclerosis and Related Inflammatory Demyelinating Diseases • 163

A B
FIGURE 7.2 Distribution of demyelinated lesions in the MS brain (secondary progressive MS). Focal white
matter lesions are the hallmark of MS pathology. They are easily depicted in fresh brain slices and on sections
stained for myelin. (A): Hemispheric brain sections stained with Luxol fast blue. The lesions tend to accumulate
in the periventricular white matter, while smaller lesions are seen in the depth of the white matter and subcor-
tical. (B): Detailed lesion map, which includes besides the white matter lesions (green) and also gray matter
lesions. Cortical lesions are present as cortico-subcortical lesions, as small intracortical lesions, and most abun-
dantly as band-like subpial lesions (red lesions). In addition, lesions are present in deep gray matter nuclei (blue
lesions). Subpial cortical lesions are predominantly found in invaginations of the brain surface (sulci, insular
cortex, cingulate cortex, and hippocampus).
areas with a high density of venules and veins are Reactive glial cells (astrocytes and microglia) are
more likely to be affected, and a topographical rela- intimately involved in the pathology of MS lesions.
tionship between plaques and draining veins was Perivascular cells and parenchymal microglia show
demonstrated in the earliest descriptions of the evidence of immune activation, and astrocytes show
disease. marked hypertrophy and proliferation. Astrogliosis
On gross examination of the CNS, the plaques is maximal at the edge of the plaque. Toward the
become more visible after a brief exposure to center of the plaque, gliosis tends to become more
room air; they are localized predominantly in the fibrillary and, in older lesions, forms a dense glial
white matter but may also extend into gray mat- scar consisting of expanded and thickened arboriza-
ter. They appear as rounded, geographical, sharply tion of astrocytic processes (Fig. 7.6).
demarcated zones (Fig. 7.3). Recent lesions tend
to be pink or yellowish, whereas older lesions tend
to have sharp borders and are grayish or trans-
lucent and firm. On microscopic examination,
plaques are characterized by loss of myelin in dis-
crete, well-circumscribed areas; this results in a
punched-out appearance when sections are stained
for myelin (e.g. Heidenhain-Woelcke, Loyez, or
Luxol fast blue stains) (Figs. 7.1 , 7.2 and 7.4). Silver
impregnation preparations demonstrate a network
of variably reduced but relatively preserved axons
in the plaque with some axonal swellings or “spher-
oids” that indicate acute axon injury. Overall axonal
density can be reduced by 60% on average within
chronic lesions compared to the surrounding white FIGURE 7.3 Gross appearance of MS. Coronal sec-
matter. Also, in a given case, the extent of axonal loss tion of the parieto-occipital region; note the periven-
is variable from one lesion to another (Fig. 7.5). tricular distribution of the plaques.
B
A D
FIGURE 7.4 Structural features of white matter lesions. (A) Periventricular lesion in continuity with a large
white matter plaque. The plaque contains a demyelinated center (DM), a small region of remyelination (shadow
plaque areas, RM), and a broad zone of lesional activity (active). (B): Profound perivascular inflammation is
seen in the center of the plaque. (C): The active zone of the lesion contains numerous macrophages with early
(Luxol fast blue-positive) myelin degradation products. (D): The zone of remyelination (RM) contains myelin
sheaths, which are thinner than those in the normal-appearing white matter (NAWM).
B C D
E F G
FIGURE 7.5 Axonal pathology in MS lesions. (A): Low-magnification picture of the periventricular white matter
that contains numerous demyelinated plaques. The different staining intensity in the Bielschowsky silver impregnation
reflects the different degree of axonal loss in the lesions. (B, C, D): In sections stained for phosphorylated neurofila-
ment, the different axonal content between normal-appearing white matter (B), active plaques (C), and inactive
plaque center (D) is clearly visible. (E, F, G): Immunocytochemistry for amyloid precursor protein (APP) depicts
injured axons with disturbed fast axonal transport. This is rare or absent in the normal-appearing white matter (E); it is
pronounced in active lesions (F), where it is also reflected by numerous axon spheroids or end bulbs, seen in sections
stained for neurofilament (F). In the inactive plaque center, a single dystrophic axon is seen (G).

A B C
FIGURE 7.6 Astrocytic gliosis in MS lesions. (A):Several chronic focal white matter lesions are present in
the internal and external capsule. (B): Fibrillary gliosis is best visualized by Holzer stain, showing intense blue
staining in the plaque areas. (C)Right: Massive protoplasmatic gliosis with enlarged astrocytic cell bodies show-
ing a high immunoreactivity for glial fibrillary acidic protein (GFAP). This occurs on the background of massive
inflammation and active demyelination.
Actively demyelinating MS lesions (Fig. 7.7) immunohistochemistry to demonstrate amyloid

are seen as both classical active plaques and slowly precursor protein (APP) in axonal swellings and end
expanding lesions. Classical active plaques are mainly bulbs. Perivascular inflammatory infiltrates and dis-
seen in acute and RRMS. They are characterized by persed T cells are also present in slowly expanding
marked inflammation and blood–brain barrier dam- lesions but are not associated with any increase of
age. They are heavily infiltrated with macrophages, vascular permeability for serum proteins. In inactive
which contain early myelin degradation products lesions (Fig. 7.8), demyelinated areas are sharply
that have staining properties similar to those of nor- demarcated from the surrounding normal-appearing
mal myelin (e.g. appearing as blue granules in sec- white matter. They may contain some foci of inflam-
tions stained with Luxol fast blue). Macrophages are matory infiltrates and acutely injured axons, but
either dispersed throughout the whole lesion (as is they lack the rim of activated microglia and ongoing
seen in acute plaques) (Fig. 7.7B) or concentrated at demyelination at the outer limit of the lesion.
the margin in chronic active plaques (Fig. 7.4). The Remyelination in MS lesions is variable; when it
outer rim of chronic active plaques varies in thickness does occur, the thickness of the individual myelin
and contains large numbers of oligodendrocyte pro- sheaths never regains its original, normal diameter.
genitor cells or newly differentiated re-myelinating Remyelination may be restricted to the outer mar-
oligodendrocytes; myelin sheaths in these areas are gins of the lesion (Fig. 7.4, A, D) or may be pres-
in the initial stage of dissolution and are associated ent throughout. When remyelination is present
with activated microglia. These peripheral regions throughout the plaque, the lesion is referred to as a
are the advancing edge of demyelination and tissue “shadow plaque;” these are sharply demarcated areas
injury. Macrophages remaining in the center of the of myelin pallor due to widespread reduction in the
plaques express low levels of pro-inflammatory acti- thickness of the individual myelin sheaths. Although
vation markers (e.g. inducible nitric oxide synthase the extent of remyelination in most MS patients is
or NADPH oxidases), and they contain breakdown limited, rarely it can be quite considerable.
products of the late stages of myelin degradation (i.e.
oil red O-positive neutral lipids, Fig. 7.7D).
1 .1 . 3. M S LESION S IN CEREBRAL
In contrast, slowly expanding lesions are mainly
C O RTEX AN D DEEP GRAY M ATTER
seen in patients with progressive disease (PPMS,
SPMS). These lesions are centered around an inac- Since the initial recognition of MS as a distinct path-
tive demyelinated lesion core with profound fibril- ological entity, it has been regarded as a primarily a
lary gliosis (Fig. 7.8) and are surrounded by a small disease of the white matter. However, with the intro-
rim of activated microglia, few macrophages with duction of more sensitive tools for the immunohis-
early myelin debris, and a variable extent of acute tochemical analysis of myelin proteins, it has now
axonal injury. Axonal injury is best detected using become clear that extensive demyelination also can
A B
C D
FIGURE 7.7 Microscopic features of MS in active lesions. (A) Perivascular lymphocytic infiltrate associated

with macrophage infiltration and reactive astrocytosis. (B) Bodian silver impregnation combined with Luxol fast
blue shows diffuse infiltration by macrophages containing Luxol-positive myelin debris and relative preservation
of axons. (C) Immunostaining of neurofilaments in the same plaque as in (B) showing axonal swellings. (D) Oil
red O stain in a frozen section of an active MS plaque showing the sudanophilic (orthochromatic) catabolism
of the myelin. Macrophages containing late myelin degradation products, neutral lipids, strongly stained by
Oil red O.
occur in the gray matter, particularly in the cerebral cor- spaces and the cortical parenchyma, and blood–brain
tex (Figs. 7.1 and 7.9). Cortical demyelination is scant barrier leakage is minimal or absent. Active subpial
in the early stages but increases with disease progres- cortical lesions are associated with inflammation in
sion. Three different types of cortical lesions have been the adjacent leptomeninges, either as diffuse men-
described: cortico-subcortical, intracortical perivascu- ingeal infiltrates or as lymphocyte aggregates, which
lar, and band-like subpial lesions. Subpial lesions are the may show features of secondary B-cell follicles. Active
most abundant in patients with progressive MS. They demyelination in the cortex occurs at sites of microglial
affect the outer cortical layers and can span over several activation, which in chronic lesions demarcate them
cortical gyri and sulci. They are preferentially located from the surrounding normal-appearing gray matter.
within invaginations of the brain surface, such as corti-
cal sulci, insular, cingulate, or temporal cortex includ-
1.1.4 . PATHOL OGY OF THE
ing the hippocampus, and cerebellar cortex. Like white
NORMAL - APPEARING WHITE AND
matter plaques, cortical plaques show primary demy-
GRAY MATTER
elination with relative sparing of axons and neurons.
When they arise in early stages of MS, inflammation Although focal demyelinated plaques are the hall-
is prominent in active lesions. However, in progressive mark of MS pathology, there are profound dif-
MS, inflammatory cells are sparse in the perivascular fuse alterations in the normal-appearing white

A B
FIGURE 7.8 Microscopic features of MS in inactive lesions. (A) Gliosis with Rosenthal fibers and absence of
inflammation. Note rare perivascular remaining macrophages. (B) Bodian silver impregnation combined with
Luxol fast blue at the periphery of an old plaque shows myelin–axonal dissociation with relative preservation of
axons. Note the normal staining of myelin on the left. (C) Metallic impregnation preparation shows fibrillary
gliosis in the center of an old plaque but no axons.
and gray matter. They consist of perivascular 1.2. Etiology and

and less conspicuous parenchymal inflammatory pathogenesis of MS
infiltrates, microglial nodules, diffuse rarefaction
of myelin and axons, and diffuse astrogliosis. In There is little doubt that inflammation drives the
late stages of MS, this gives rise to severe white disease process in MS, but it is entirely unclear
and gray matter atrophy with expansion of cere- what induces and propagates the inflammatory
brospinal fluid spaces. These diffuse brain and process. Most researchers in the field favor the
spinal cord changes can be in part explained by autoimmune hypothesis. This view is supported
Wallerian degeneration following axonal transec- by the fact that a disease model with similarities in
tion within demyelinated plaques. However, dif- clinical presentation, pathology, and immunology
fuse white matter atrophy does not correlate with (i.e. experimental autoimmune encephalomyelitis)
the number, distribution, and extent of damage can be induced in experimental animals sensitized
of focal white matter plaques and correlates only with brain or myelin antigens. Furthermore, analo-
in part with the extent of cortical demyelination. gous autoimmune T-cells and autoantibodies can
It therefore appears that diffuse white and gray be detected in MS patients. An alternative view is
matter changes occur independently from focal that chronic inflammation is driven by infection(s),
demyelination in the white and gray matter. which either trigger T-cell autoimmunity in the
peripheral immune system or even persist in the
able to propagate further oxidative injury. In addi-
tion, genetic deletions of mitochondrial DNA,
which can also be induced by radicals, tend to clon-
ally expand in injured cells, such as neurons. Thus,
increasing mitochondrial dysfunction renders these
cells more susceptible to further damage. Given the
characteristic features of progressive MS, it is not
surprising that current anti-inflammatory or immu-
nomodulatory treatments are not effective at this
stage, despite the key role played by inflammation
along the course of the disease.
2. ACUTE MULTIPLE SCLEROSIS

The designation “Marburg type” has been given to
MS that follows a rapidly progressive, monopha-
sic course and is usually fatal in a few months and
always within 1 year of onset. It is most common
FIGURE 7.9 Cortical lesions in the MS brain. in children and young adults but has also been
Cortical lesions are not easily seen in sections stained described in older patients.
with conventional myelin stains but are clearly visible Neuropathological examination shows multiple
on immunocytochemistry for major myelin proteins. plaques, the edges of which may be poorly defined,
Besides widespread subpial demyelination there are making them difficult to see macroscopically. All
also smaller perivascular intracortical lesions. the plaques are active, hypercellular with promi-
nent perivascular lymphocytic cuffing, numerous
brain tissue. Epidemiological and immunological foamy macrophages, and scattered reactive astro-
evidence suggests that Epstein-Barr virus could be cytes. Edema may be present in the surrounding
involved in MS pathogenesis, although its direct role white matter with mass effect in occasional cases.
in the pathogenesis of the disease, inside or outside Necrotic changes may be found, and in cases with a
the nervous system, has not been proven to date. more prolonged course, they may result in cavitary
Chronic inflammation induces a complex cascade lesions (Fig. 7.10). Some of these cases have now
of immune mechanisms, which may evoke differ- been reclassified as ADEM (see below).
ent mechanisms of tissue injury involving cytotoxic In the so-called “Schilder type” of MS, which is
T-cells, autoantibodies, and products of activated mostly encountered in children and runs a relatively
macrophages and microglia. In addition, the genetic progressive course, the lesions are characterized by
makeup of the tissue in which an immune response extensive, acute plaques with clear-cut borders, often
occurs may additionally determine its susceptibility asymmetrical and sparing the subcortical white mat-
to immune-mediated damage. ter (Fig. 7.11). Axonal lesions may be prominent, and
Various patterns of demyelination are found Wallerian degeneration is frequent. Some of the cases
in active lesions at the early stages of MS. One of originally described by Schilder included various
the most important involves mitochondrial injury forms of MS but also included what is now known as
induced by reactive oxygen and nitric oxide spe- adrenoleukodystrophy and perhaps other diseases as
cies. Nevertheless, during disease progression, well. “Transitional sclerosis” has also been described
tissue injury tends to become more and more inde- wherein extensive hemispheric lesions may be associ-
pendent from inflammation, which seems partly ated with typical disseminated plaques.
trapped behind a closed or repaired blood–brain
barrier. The human brain accumulates iron (mainly 3. BALÓ CONCENTRIC
in oligodendrocytes) with aging. In active lesions,
the release of iron from intracellular stores into an SCLEROSIS
environment of oxidative damage gives rise to the Baló disease is a rare variant of inflammatory demy-
formation of highly toxic hydroxyl radicals that are elinating diseases. The clinical course is generally

A A
FIGURE 7.11 Acute “Schilder-type” MS. Wide

hemispheric periventricular plaques. Note the presence
of smaller plaques at a distance from large lesions.
FIGURE 7.10 Cavitating MS. Wide, clear-cut
periventricular plaques with sharp borders around the
early chronic MS. The mechanisms of tissue injury
right frontal horn (A) and inferior aspect of corpus
in these lesions are not fully understood, but it seems
callosum (B).
likely that demyelination, as in other MS lesions,
occurs through mitochondrial injury (cf. supra), and
subacute, very severe and often fatal, resulting in the preserved concentric rings of myelinated tissue
profound neurological deterioration within months may be protected by hypoxic tissue preconditioning.
after disease onset. It is characterized by the alter-
nation of demyelinated foci with zones in which
4. ACUTE DISSEMINATED
the myelin is preserved, thereby resulting in a con-
centric or irregular pattern of demyelination (Fig. ENCEPHALOMYELITIS
7.12). The demyelinating lesions have all the histo- This disease has several different names, including
logical features of acute plaques and axonal injury is acute disseminated encephalomyelitis (ADEM),
often prominent. Rare cavitating forms have been acute disseminated leukoencephalitis, and acute
reported. Baló disease is generally regarded as a vari- postinfectious/postvaccinial perivenous encephali-
ant of MS, since single layers of concentric demy- tis. A particularly severe variant is acute hemorrhagic
elination are seen within acute plaques of acute and leukoencephalopathy of Hurst (see Chapter 5). In
A
FIGURE 7.13 Acute disseminated (postinfectious)

encephalomyelitis (ADEM). Lesions in the cerebellar
white matter of a patient with postinfectious measles
encephalomyelitis. On immunostain for myelin pro-
teins, there is marked perivascular inflammation with
some perivascular demyelination. Unlike in MS, large
confluent plaques of demyelination are absent.
infiltrates and centering sleeves of demyelination,

without confluent MS-like plaques (Fig. 7.13). The
disorder is thought to be an autoimmune-mediated
complication of a non-CNS infection and its patho-
genesis seems mainly to be driven by T-lymphocytes.
In some patients, circulating demyelinating antibod-
ies (e.g. against myelin oligodendrocyte glycopro-
tein) are present.
5. NEUROMYELITIS OPTICA
FIGURE 7.12 Concentric sclerosis of Baló type. NMO has for long been regarded as a subtype of MS
The lesions of Baló disease are characterized by alter- but recently has been considered to be a separate
nating rings of myelinated and demyelinated white disease. In the majority of NMO patients, there are
matter. (A) A 5-cm-in-diameter lesion located in the autoantibodies against the astrocytic water channel
frontal white matter is identified by immunostain for aquaporin 4 that can be detected in the serum. The
myelin proteins. Smaller lesions with some concentric presence of these antibodies has an extremely high
layering of myelinated and demyelinated tissue are specificity (100%) and a very high sensitivity (70%
sometimes also seen in conventional MS patients with to 90%); they have been shown to be pathogenic
severe active disease. (B) Two lesions in the occipital after transfer into experimental animals.
white matter, one periventricular and one with a char- The pathology of NMO is in some respects differ-
acteristic concentric pattern (Loyez stain for myelin). ent from that seen in MS. Lesions mainly target the
spinal cord and the optic system and also can be dem-
contrast to typical MS, this is a monophasic illness onstrated as thin sleeves of tissue injury around the
that may occur spontaneously or may follow an third and fourth ventricles. In the spinal cord, the cen-
infection (e.g. measles) or a vaccination. It affects tral gray matter is more severely affected than the white
children more frequently than adults. In patients matter and the lesions are extensive along the length
who survive, there is usually rapid recovery, often of the cord, spanning several segments (Fig. 7.14).
without neurological sequelae. The CNS lesions Microscopic examination shows dense infiltrates of
are characterized by small perivenous inflammatory T-cells, less often B-cells, and macrophages, but in

A B C
FIGURE 7.14 Neuromyelitis optica (NMO). (A): NMO lesions in the spinal cord are mainly located in the
center, massively involving the gray matter but leaving the subpial white matter largely unaffected. These lesions
typically are longitudinally extensive, spanning several segments of the spinal cord. (B): A very typical feature
of NMO lesions is the extensive destruction and loss of astrocytes, reflecting areas devoid of GFAP reactiv-
ity. (C):The inflammatory infiltrates in active NMO lesions contain very high numbers of polymorphonuclear
leukocytes. In addition, deposition of immunoglobulins and activated complement (C9neo; red) is seen in a
perivascular rosette pattern, reflecting the astrocytic glia limitans and the distal astrocyte processes.
contrast to MS lesions, polymorphonuclear leukocytes compatible with an inflammatory demyelinat-

are abundant in active lesions. At sites of active tissue ing disease. Patients who come to biopsy under
injury, massive deposition of immunoglobulins and these circumstances are individuals with single
activated complement are seen on astrocytes and their tumor-like lesions in the brain or spinal cord in
processes in a rosette-like staining pattern that mainly whom a potential neoplasm has to be excluded.
targets the perivascular and subpial astrocyte foot The differential diagnosis in such biopsies is broad
processes. Astrocytes are in part destroyed through and difficult. In addition to inflammatory demy-
complement-mediated cellular injury mechanisms; elinating diseases it includes virus-induced lesions
they may survive in the periphery of the lesions but are of the white matter and a variety of metabolic
devoid of aquaporin 4 expression. Demyelination and diseases.
axonal loss, which is prominent in chronic, established As a first step, inflammation, demyelination,
NMO lesions, follow the destruction of astrocytes. and axonal destruction have to be assessed in
Overall, NMO lesions are much more destructive routine sections stained with H&E, Luxol fast
than classical MS lesions, frequently resulting in cystic blue, and silver impregnation. This also allows
damage of the spinal cord tissue, as well as brain tissue, distinguishing between primary demyelinating
when affected. and destructive lesions. Then, the extent of demy-
elination (perivenous versus confluent) has to be
established. Vasculitic changes, B-cell neoplasms,
6. DIAGNOSIS OF and viral inclusions in astrocytes and oligoden-
INFLAMMATORY drocytes have to be excluded and intracellular
DEMYELINATING DISEASES accumulation of proteins or lipids, suggesting
metabolic (storage) diseases, assessed. Only when
IN BRAIN BIOPSIES all these conditions have been excluded can the
Neuropathologists are sometimes called upon diagnosis of an MS-like inflammatory demyelinat-
to examine biopsy specimens containing lesions ing disease be made.
8
Pathology of Degenerative Diseases of the
Nervous System
C H A R LE S DUY C K AE RTS , JA MES L O W E, A N D MATTH EW FRO SCH
1. INTRODUCTION AND tangles or Lewy bodies, or may be extracellular,

forming “plaques” such as the neuritic plaques of
BACKGROUND Alzheimer disease (AD).
Degenerative diseases of the nervous system are
characterized by several common factors that serve Degenerative diseases were once enigmatic
to separate them from other disorders: conditions with little understanding of pathogen-
esis. The combination of cell biology to under-
• These diseases affect specific neuronal groups, stand shared processes and insights from genetics
often spatially separated but functionally linked, has resulted in a reorganization of the classification
with clinical features determined by the involved schemes for some disorders. A common thread that
structures. runs across degenerative diseases is the accumula-
• The histopathological changes are generally char- tion of protein aggregates, often associated with tox-
acterized by neuronal loss in the affected regions icity and failure of clearance by cellular degradation
with a variable astrocytic and microglial reaction. pathways. These aggregates are also evident on his-
Neurons are thought to die through nonnecrotic, tological examination, and for this reason the disor-
often apoptotic processes. ders are sometimes referred to as “proteinopathies.”
• Specific proteins accumulate in many of the For some diseases, there are now well-characterized
degenerative diseases. These accumulations may genetic abnormalities; in some diseases all cases
be intracellular in neurons or glia, giving rise are associated with mutations, while in others both
to distinctive inclusions such as neurofibrillary inherited and sporadic forms occur.
• 173
2. CLASSIFICATION • Tauopathy: Disorders characterized by
accumulation of the alternatively spliced
There are several approaches to classification, each hav- microtubule-associated protein tau (encoded
ing advantages. The one adopted here classifies disor- by the MAPT gene). In some of these disorders,
ders according to the dominant pattern of initial clinical there are mutations in the tau gene, including
features, into five broad categories: degenerations of missense mutations as well as mutations that alter
the cerebral cortex (dementia), movement disorders, splicing. Tau isoforms can contain either three
cerebellar ataxia, motor neuron disease and condi- (3R) or four (4R) of the microtubule-binding
tions associated with autonomic failure (Table 8.1). domains. Among the tauopathies are diseases
It is essential to realize that, with disease progression, characterized by inclusions with 3R tau (Pick
there is great overlap in the symptoms manifested by disease), 4R tau (progressive supranuclear palsy
patients with neurodegenerative disease. As an exam- [PSP], corticobasal degeneration [CBD], argyro-
ple, a patient with a hyperkinetic syndrome movement philic grain disease), both 3R and 4R tau (AD, in
disorder (e.g.,Huntington disease) may develop cere- combination with deposits of Aβ); the character-
bral cortical pathology leading to dementia. istic inclusions in the various forms of frontotem-
Cutting across this symptom-based scheme poral lobar degeneration (FTLD) may have 3R,
occurs commonly in neurodegenerative diseases 4R, or the combination of the two.
characterized by protein accumulation. When group- • α-synucleinopathy: Disorders in which there is
ing diseases on this basis, categories would include: accumulation of the synaptic vesicle-associated
protein α-synuclein. There can be aggregates
visible on routine sections, or the accumula-
Table 8.1. Classification of tions require immunohistochemistry to reveal
Neurodegenerative Diseases them. This group includes Parkinson disease,
other Lewy body diseases, and multiple system
Cortical Degenerations
atrophy.
Alzheimer disease • Diseases with accumulation of TAR
Frontotemporal lobar degeneration DNA-binding protein 43 (TDP-43): TDP-43
Dementia with Lewy bodies is a RNA/DNA-binding protein implicated in
alternative splicing, transcriptional regulation,
Movement Disorders
mRNA stabilization, and microRNA process-
Akinetic/rigid syndromes ing. The full-length protein is normally pres-
Parkinson disease ent in the nucleus. In pathological conditions,
Progressive supranuclear palsy the protein, fragmented, phosphorylated, and
Corticobasal degeneration ubiquitinated, accumulates in the cytoplasm of
Multiple system atrophy (striatonigral the cell body, principally of neurons, but also
degeneration) of glia. It may also be found in neurites. Such
accumulations define a subset of frontotemporal
Hyperkinetic syndromes
lobar degenerations, collectively referred to as
Huntingtonchorea FTLD-TDP.
Choreoacancythosis • Polyglutamine diseases: Various cellular pro-
Cerebellar ataxias teins contain a polyglutamine tract encoded
by repeats of CAG in the coding region of the
Inherited
corresponding gene. When one of these repeats
Sporadic expands, the protein contains a lengthened
Diseases of motor systems polyglutamine tract, generally accumulating as
Motor neuron diseases neuronal intranuclear inclusions (NIIs). This
group includes Huntington disease as well as
Hereditary spastic paraparesis
some of the dominantly inherited spinocer-
Autonomic Disorders ebellar ataxias; typically, a greater degree of
Parkinson disease repeat expansion is associated with younger
age of onset and increased severity. Uniquely
Multiple system atrophy (Shy-Drager syndrome)
among the degenerative diseases, these diseases
exist only as genetically determined forms. 3.1.1 . GROSS APPEARANCE
The proteins associated with these diseases are
The shrinkage of cortical gyri and widening of sulci
not structurally or functionally related to one
is often striking. Cortical atrophy involves predomi-
another, apart from the presence of the polyglu-
nantly the hippocampus (Fig. 8.1), the parahip-
tamine tracts.
pocampal gyrus and the temporal amygdala, with
parietal and frontal lobes being next most severely
affected. The occipital lobe is generally spared. In
3. PATHOLOGY OF some cases, especially late-onset types, the cerebral
DEGENERATIVE DISEASES atrophy is inconstant and often mild, marked by a
OF THE CEREBRAL CORTEX symmetrical slight reduction in the volume of the
temporal gyri. On cut surface, the ventricular dila-
AND DEMENTIAS tation, generally of moderate degree, parallels the
Dementing diseases, with their clinical diagnostic severity of the cortical atrophy. Depigmentation of
features of decline in cognitive function across mul- the locus coeruleus in the face of relative preserva-
tiple modalities, are associated with processes affect- tion of the substantia nigra is also typical.
ing the cerebral cortex. The degenerative changes
may be accompanied by cerebrovascular disease,
3.1.2 . MICROSCOPIC L ESIONS
which contributes to cognitive impairment. The
main causes of dementia and an indication of their Senile plaques and neurofibrillary tangles are the
frequency are presented in Table 8.2. lesions required to make the diagnosis of AD.
Synaptic loss is early and constant. It correlates with
clinical dysfunction but is difficult to assess, as is the
neuronal loss. While both senile plaques and neu-
3.1. Alzheimer disease
rofibrillary tangles form, as a result of the biological
AD is the most common of the degenerative diseases changes that characterize AD, they are not in them-
and increases in incidence with age. Most patients selves specific for the disease. It is the combination
present with memory failure and develop deficits of Aβ deposits, senile plaques, and neurofibrillary
in other cognitive domains, commonly including tangles, all with appropriate density and distribu-
apraxia, aphasia, and agnosia. tion that allows a neuropathological diagnosis to
Table 8.2. Main Causes of Dementia and Their Frequency
DISORDER FREQUENCY
Alzheimer disease
Sporadic Very common
Familial Uncommon
Vascular and mixed dementia Very common
Dementia with Lewy bodies
Pure without AD changes Rare
Common (with AD changes) Common
Frontotemporal lobar degeneration
Pick disease Uncommon
FTLD with MAPT mutations Uncommon
FTLD-TDP Not rare
FTLD with motor neuron disease Not rare
FTLD-FUS Uncommon
Argyrophilic grains Common lesion; uncommonly diagnosed clinically
Chapter 8 Pathology of Degenerative Diseases of the Nervous System • 175

FIGURE 8.1 Alzheimer disease. On the right is the hippocampus from a patient with AD. On the left is that
from an age-matched individual with no cognitive abnormality. Note atrophy of cortex, shrinkage of white mat-
ter, and widening of the temporal horn of the left lateral ventricle.
be made. The clinical diagnostic criteria for the stages) typically follows a predictable sequence: 1,
diagnosis of AD have changed and now rely less on isocortex; 2, hippocampus; 3, basal ganglia; 4, mes-
the demonstration of severe dementia, considering encephalon; 5, pons and cerebellum.
rather earlier stages of the illness when cognitive
impairment is milder. Correspondingly, there has 3.1.2.2. Plaques Senile (or neuritic) plaques
been a need to shift neuropathological criteria to (Fig. 8.2A–C) consist of a core and a corona. The core
identify the burden and distribution of lesions that is an extracellular deposit of Aβ, while the corona is
are associated with the underlying disease process made of degenerating neurites, mainly axons, immu-
but are not typically associated with end-stage neu- noreactive for tau protein and highlighted on silver
rological impairment. staining methods such as Bielschowsky or Gallyas
(Fig. 8.2C), and enlarged ubiquitin-positive “dystro-
3.1.2.1. Aβ deposits The Aβ peptide is a 40-42 phic” neurites.
amino acid fragment from a normal neuronal pro- The Aβ peptide in the core of the senile plaque is
tein termed APP (amyloid precursor protein). The misfolded, enriched in β-pleated sheets, and has all
peptide is generated by sequential cleavage of APP of the features of amyloid (Fig. 8.2B); for example,
in the extracellular domain (by a protease known as it shows an apple-green birefringence after Congo
BACE) followed by an intramembranous cleavage red stain, is fluorescent after thioflavin S staining,
(by an enzymatic complex known as γ-secretase, and appears fibrillar at electron microscopy exami-
which includes presenilin). Generation of Aβ from nation. The neuritic plaque also elicits an astrocytic
APP is considered critical for the initiation of AD and microglial reaction. Neuritic plaques and diffuse
pathogenesis since mutations in APP that accelerate deposits are typically found in neocortex, entorhinal
generation of Aβ cause familial forms of AD, as do cortex, and hippocampus, while striatum and cere-
mutations in presenilin, which increase the rate of bellum show only diffuse deposits. Neuritic plaque
generation of Aβ or shift toward longer forms of Aβ. burden in neocortical areas is typically reported in
The recent discovery that an APP mutation that hin- the semiquantitative CERAD method, separated
ders the generation of Aβ is protective against AD into sparse, moderate, and abundant.
has further strengthened this argument.
The Aβ is highly prone to aggregate; small aggre- 3.1.2.3. Neurofibrillary tangles, neuronal and
gates (termed oligomers) are the currently suspected synaptic loss Neurofibrillary tangles are intracel-
critical mediator for eliciting cellular and synaptic lular inclusion bodies, primarily containing tau as
dysfunction. Within the brain, aggregates of Aβ well as other proteins (Fig. 8.3). Tau is a microtu-
are extracellular deposits that commonly elicit sig- bule binding protein, but, in tangles, it has separated
nificant local reaction (neuritic plaques, see below). from the microtubules and is hyperphosphorylated
Diffuse deposits of Aβ are also present in AD; at a variety of serine and threonine residues. Tangles
these are wispy, larger, but less dense than plaques, may be detected by immunostaining for tau pro-
and have convoluted shapes. They are not seen on tein, as well as silver impregnation techniques such
hematoxylin and eosin or Congo red stains but are as Bielschowsky or Gallyas stains (see Fig. 1.10).
immunolabeled by Aβ antibodies. The progression When nerve cells die, tangles may be left behind in
of amyloid pathology within the brain (termed Thal the neuropil as so-called “ghost tangles.” Nerve cell
A B
FIGURE 8.2 Alzheimer disease plaques. (A) With H&E staining, focal plaques can be sometimes seen as
compact, rounded alterations in the neuropil. (B) Immunostaining for the Aβ peptide positively stains the core
of the plaque. (C) Tau immunostaining reveals neurites containing tau protein surrounding the central amyloid
core material.
processes (mainly dendrites) in the cortical neuropil

may accumulate tau protein, in which case they are
called neuropil threads. Nerve cell processes run-
ning through neuritic plaques also accumulate tau
protein and are then termed degenerating neurites.
Both tangles and degenerating neurites contain a
mixture of 3R and 4R forms of tau.
A scheme known as Braak & Braak staging is used
to characterize the distribution of neurofibrillary
pathology with good correlation to clinical status.
In general, tangles and neuropil threads first occur
in the entorhinal cortex (Stage I), progress through
the subiculum (Stage II) into the hippocampus,
first through CA1 (Stage III) and on through the FIGURE 8.3 Alzheimer disease tangles. Tau
remainder of the pyramidal cell layer (Stage IV), immunostaining shows neurofibrillary tangles within
before reaching association neocortex (Stage V) and neuronal cell bodies. In addition, the neurites around
finally extending to the primary motor and sensory plaques detected by tau immunostaining as fine
neocortex (Stage VI). In addition, neurofibrillary threads in the cortex are termed neuropil threads.

changes are also found in some other brain regions, 3 .1 . 3. DIAGN OSTIC CRITERIA AN D
including the amygdala, limbic nuclei of the thala- S TAGIN G OF AD
mus (anterior complex, laterodorsal nucleus,
As the pathological processes of AD begin in the
and some intralaminar nuclei), nucleus basalis of
brain many years before the emergence of dementia,
Meynert, reticular formation of the mesencephalon,
it is not surprising that these lesions (Aβ deposits,
locus coeruleus, raphe nucleus, and selected subnu-
neuritic plaques, and tangles) may be seen in sub-
clei of the substantia nigra.
jects without subjective or objective evidence of
In the same areas where tangles develop, neuro-
cognitive decline—although typically with a lower
nal cell loss, varying according to the severity of the
burden of lesions and a more restricted distribution.
disease, may also be seen. Synaptophysin immuno-
As presented above, there are three scales by which
reactivity is decreased at an early stage of AD, and
the lesions of AD are assessed: tangles are consid-
this finding is related to loss of synapses.
ered by the Braak staging scheme for AD, Aβ depos-
its by the Thal stages, and neuritic plaques according
3.1.2.4. Amyloid angiopathy Accumulation of
to the CERAD system. With the most recent con-
Aβ peptide in the vessel walls causes amyloid angiop-
sensus proposal, by definition, Alzheimer disease
athy (Fig. 8.4). It is especially seen in the neocortex
neuropathological changes necessarily include Aβ
(occipital, temporal, parietal, frontal, in decreasing
deposits with any combination of neuritic plaques
frequency) and later in Ammon’s horn and cerebel-
and tangles. Progression and increasing burden
lum. The amyloid deposit results in irregular thick-
along these histological scoring scales are associ-
ening of the terminal vascular bed. It may affect
ated with a greater probability of cognitive impair-
capillaries and then extends into the adjacent paren-
ment in affected individuals. At one extreme are
chyma (dyshoric angiopathy). Involvement of the
subjects with Thal phase 1 Aβ deposits, with low
capillary walls is seen particularly in a subgroup of
Braak stages and sparse neuritic plaques (CERAD),
patients who are of the ApoE ε4 genotype. Amyloid
who are expected to be cognitively intact. At the
vascular deposits may also affect small arteries and
other are cases with widespread Aβ deposits (Thal
veins in the meninges and superficial layers of the
phase 5) and abundant neuritic plaques and tangles
cortex (congophilic angiopathy). Cerebral amyloid
throughout the neocortex and mesial temporal lobe
angiopathy may also be seen in non-demented,
(Braak V or VI).
aged individuals, causing cerebral hemorrhages or
microscopic infarcts (see Chapter 4). It is a nearly
constant finding in patients with AD, although the
3 .1 . 4. M OLECULAR PATHOLOGY
vessel damage is only seldom associated with hem-
orrhage in this disorder. As mentioned above, recognition of the central
pathogenetic role of Aβ in AD has been driven by
observations from genetics. Several factors are rec-
ognized to promote or cause amyloid deposition.
Rare early-onset familial cases of AD are caused by
mutations in—or duplication of—the APP gene
on chromosome 21. It is believed that the associa-
tion between Down syndrome and AD relates to
the presence of three copies of the APP gene, due
to the trisomy 21. Mutations in genes coding for the
presenilins (PS1, PS2), which are components of
γ-secretase, are also recognized to cause early-onset
familial AD. These proteins are involved in the path-
ways of cleavage of APP, with mutations giving rise
to excess production of AE peptide. Genotype at the
apolipoprotein E (apoE) locus influences the risk
of AD: individuals with copies of the apoE4 allele
FIGURE 8.4 Alzheimer disease amyloid angiopa- have a roughly four- to five-fold increased risk of
thy. Immunostaining for Aβ peptide shows affected developing AD for each copy of the allele they carry
vessels. compared to those carrying apoE2 or apoE3 alleles.
Genetic studies continue to identify potential other pathological findings; for instance, one study of
contributing risk factor alleles, although each of well-characterized subjects with PPA found that, at
these makes only a small contribution to the risk autopsy, approximately half had AD and half had a
of developing AD. It is important to recognize that, form of FTLD, with a roughly even split between
even though tangles form an essential part of the his- FTLD-tau and FTLD-TPD43.
topathological findings of AD, mutations in the gene
encoding tau (the primary protein of tangles) do not
result in AD. 3.2.1 . F TL D- TAU
These diseases are defined by the combination of
3.2. Frontotemporal Lobar lobar degeneration and of inclusions containing 3R
Degenerations tau, 4R tau, or both forms. This group includes Pick
disease, tauopathies with mutation of the tau gene
Several diseases are characterized by neurodegen- (MAPT), and other tauopathies without MAPT
eration concentrated on the frontal and temporal mutation. Additionally, two disorders that are pri-
lobes with relative sparing of the parietal and occipi- marily classified as movement disorders (PSP and
tal lobes. The clinical features relate to behavioral CBD) may also include cognitive changes with lobar
disturbances or language dysfunction, with memory atrophy and tau-containing inclusions. They are dis-
dysfunction occurring later in the course of the cussed below with the akinetic movement disorders
disease. It is this distinct pattern of progression of (4.12 and 4.1.3).
clinical symptoms, albeit with other clinical mani-
festation, that helps distinguish these patients from
those with AD. The clinical condition is typically 3.2.1.1. Pick disease Pick disease is a sporadic
referred to as frontotemporal dementia (FTD); the dementia, characteristically beginning in the fifth
pathological substrate is FTLD. and sixth decades of life. The behavioral changes
Histopathological findings, as well as genetic are severe. This clinical pattern of symptoms corre-
underpinnings, have refined the classification of sponds to the distribution of lesions, involving pre-
FTLDs over the past decade. These diseases are now dominantly the frontal lobes early in the course of
characterized based on the type of protein inclu- the disease.
sions observed in neurons as well as mutational sta-
tus, if known. Current classification is based on the 3.2.1.1.1. Gross appearance Grossly the cerebral
presence of inclusions containing predominantly or atrophy, which is often so severe as to be described
exclusively one of three markers, shown by immu- as “knife-edge” atrophy, is circumscribed and most
nohistochemistry: tau, in various combinations evident in the frontal lobes; even when it involves
of 3R and 4R tau (FTLD-tau); TDP-43, a DNA/ the temporal lobe, it typically spares the poste-
RNA binding protein (FLTD-TDP43); and FUS rior third of the superior temporal gyrus. Severe
(FTLD-FUS). Within each of these groups, genetic involvement of the hippocampus may be present
markers and the distribution pattern of inclu- and may be responsible for memory loss. The pari-
sions are heterogeneous. A relationship between etal cortex is seldom involved, and the occipital
FTLD-TDP43 and FTLD-FUS and amyotrophic cortex is always spared. In keeping with this pattern
lateral sclerosis (ALS), in terms of histopathological of lobar involvement, there is greater dilatation of
findings, genetic causes, and clinical presentation, the anterior portion of the frontal and temporal
has been recognized in recent studies. horns of the lateral ventricles. This may be accen-
Characteristic clinical symptoms can be used tuated when, in some cases, there is also striatal
to group forms of FTLD; these reflect the ana- atrophy.
tomical distribution of neuronal loss rather than
the inclusion type. Among the major patterns of 3.2.1.1.2. Microscopic lesions Involved regions of
presentation, the three best characterized are the cerebral cortex show massive neuronal loss, associ-
behavioral variant (bvFTLD), primary progressive ated with dense astrocytic gliosis, usually accom-
non-fluent aphasia (PPA), and semantic dementia. panied by cortical microvacuolation. White matter
Importantly, however, there is still a lack of consis- in the involved gyri shows the expected secondary
tent correlation between clinical presentation and attenuation. Pick disease is characterized by the

mutations can be grouped into those that alter the
splicing of the mRNA for tau and those that are
point mutations changing the structure of the pro-
tein in other ways. The altered splicing results in
a shift of the balance between 3R and 4R tau, and
this disequilibrium is believed to contribute to the
initiation of the cellular dysfunction. The underly-
ing mechanisms relating the point mutations to the
disease are less clear.
The disease is characterized by a diffuse atrophy
of the frontal and temporal lobes, correlated with
corresponding cognitive changes. Parkinsonism
may accompany the dementia (hence the term fron-
FIGURE 8.5 Pick disease. Pick bodies are faintly totemporal dementia with parkinsonism linked to
visible with H&E staining. They appear as rounded, chromosome 17: FTDP-17, MAPT being localized
slightly basophilic inclusions in the neuronal cell body. on chromosome 17, used before the isolation of the
various tau mutations).
presence of Pick bodies—rounded, homogeneous
neuronal cytoplasmic inclusions, faintly visible on 3.2.1.2.1. Gross appearance The frontotemporal
H&E staining (Fig. 8.5). Immunohistochemical atrophy and the ventricular dilation are of variable
staining shows that these inclusions contain 3R tau severity. The caudate nucleus may be atrophic. The
(Fig. 8.6A , B). Pick bodies are also strongly argyro- substantia nigra is sometimes pale.
philic and well detected using appropriate silver
stains (Fig. 1.12). Ballooned neurons (sometimes 3.2.1.2.2. Microscopic lesions In involved corti-
referred to as Pick cells) are also frequent (Fig. 8.7). cal regions, there is extensive neuronal loss with
When deep gray matter structures are involved, there reactive gliosis. Glial tau inclusions are quite com-
is comparable neuronal loss and gliosis but not the mon (Fig. 8.8A). Tangles are present in remaining
accumulation of Pick bodies. Such changes are most neurons and in less affected regions. Neurons also
common in the head of the caudate, although they accumulate tau diffusely, in abnormal conforma-
may also be found in putamen, pallidum, and portions, referred to as “pre-tangles” (Fig. 8.8B). In
tions of the thalamus. addition, there is commonly vacuolation of the
upper layers of the cortex. Western blots and immu-
3.2.1.2. FTLD with MAPT mutations nohistochemistry can characterize the forms of tau
Mutations in the MAPT gene that encodes tau present in the inclusions—which can be 3R, 4R, or
are found in familial forms of FTLD-tau. These the combination. Additionally, glial tau inclusions
A B
FIGURE 8.6 Pick bodies are spherical tau-positive inclusions, seen in the neocortex (A) and in the dentate
gyrus of the hippocampus (B).
3.2.2 . F TL D ASSOCIATED WITH
TDP - 4 3 - POSITIVE L ESIONS (F TL D- TDP)
FTLD with tau-negative, TDP-43-positive inclu-
sions (FTLD-TDP) may account for half the
autopsy-confirmed FTLD cases. Several genetic
loci harbor causative mutations for FTLD-TDP
and include the genes for TDP43 (an RNA binding
protein), progranulin, and C9orf72. Additionally,
sporadic forms of this disease also occur, with compa-
rable clinical features. Overall, the types of inclusions
that define a subtype of FTLD are not strongly cor-
related with the clinical presentation. FTLD-TDP is
FIGURE 8.7 Pick disease. Swollen cortical neu- often associated with ALS (vide infra). This is partic-
rons are a characteristic but nonspecific feature of ularly true for those cases associated with mutations
disease (H&E). in TDP-43 and the more frequent cases linked to
expansion of the hexanucleotide repeat in C9orf72.
Progranulin-linked FTLD-TDP is never associated
are quite common. These can occur diffusely in with ALS. Another genetic locus, valosin-containing
white matter, but also in patterns that involve astro- protein (VCP), has been identified in the setting
cytes within gray matter. There is moderate histo- of familial FTLD with the added clinical features
logical overlap in some cases between the lesions of inclusion body myositis and Paget disease of the
of FTLD-tau and those seen in forms of parkinso- bone (but without an associated link to ALS).
nian syndromes with tau-containing inclusions, as
mentioned above. Thus the tau-containing lesions
3.2.2.1 Gross appearance As with other forms
observed may resemble the tangles of AD, the
of FTLD, the frontotemporal atrophy is generally
tufted astrocyte of PSP, or the astrocytic plaque
most severe in anatomical regions that correspond
of CBD.
to the clinically observed functional deficits. There
is commonly ventricular dilation and there may be
3.2.1.3. FTLD-tau without tau mutation atrophy of the caudate nucleus (Fig. 8.9).
Some cases of FTLD-tau are neither associated
with MAPT mutations nor with Pick pathology, 3.2.2.2 Microscopic findings Superficial cor-
although neither gross nor microscopic appear- tical vacuolation is commonly observed, particu-
ance can differentiate them from cases with MAPT larly in layer II of the frontal cortex (Fig. 8.10). In
mutations. some cases, the neuronal loss is severe, involving
A B
FIGURE 8.8 Frontotemporal degeneration with parkinsonism linked to mutations of the tau gene. P301L
MAPT mutation, polyclonal anti-tau antibody. (A) Tau accumulation in an astrocyte. (B) Same case, pretangle
in the cerebral cortex.

neuronal inclusions are located in the cell body
(so-called neuronal cytoplasmic inclusions [NCIs])
(Figs. 8.12A and 8.13A), in the nucleus (NIIs)
(Fig. 8.12B), or in the neurites (Fig. 8.11A); glial
inclusions are also observed in affected regions. In
the inclusions, TDP-43 is phosphorylated and ubiq-
uitinated. The inclusions are most abundant in the
frontal and temporal cortex, in the striatum, and in
the dentate gyrus of the hippocampus (Figs. 8.11B
and 8.12A).
Different classification schemes have been pro-
posed for FTLD-TDP taking into account the
appearance, abundance, and distribution of inclu-
sions, and also attempting some correlation with
FIGURE 8.9 Frontotemporal lobar degeneration. underlying genetic alterations, but less so with the
There is severe cerebral atrophy with marked temporal clinical phenotype:
lobe involvement, especially marked in its medial
aspect (including hippocampus). • Type A shows the presence of many
TDP-43-positive NCIs (Fig. 8.12A) and short
neurites, both mostly in upper cortical layers.
all the cortical layers with microvacuolation and These are accompanied by needle-like NIIs
astrocytic gliosis. TDP-43 is normally a nuclear (Fig. 8.12B). This pattern is associated with muta-
protein. The staining of neuronal nuclei is uniform tion in the progranulin gene.
by immunohistochemistry; in the face of inclusion • Type B shows predominantly NCI (not lim-
formation, there is relative nuclear clearing and ited to upper cortical layers) (Fig. 8.13A) with
accumulation of TDP in abnormal cellular topogra- some neurites, but missing NIIs. This pattern
phy. In FTLD-TDP, immunohistochemistry shows is more commonly associated with the behav-
ubiquitin- and TDP-43-positive intraneuronal ioral variant of FTLD, with ALS (Fig. 8.13C),
inclusions of various types and with variable distri- and with expansion of the hexanucleotide
bution (Figs. 8.11, 8.12, and 8.13). TDP-43-positive repeat in C9orf72. In this case, it is selectively
associated with ubiquitin- and p62-positive,
TDP43-negative NCIs in the granule cells of the
cerebellum (Fig. 8.13B).
• Type C shows many long dystrophic neurites, less
abundant NCI, and very few NIIs. This type is
often associated with semantic dementia.
• Type D shows predominantly the lentiform NII,
with abundant short neurites but scant NCI.
This pattern is associated with the rare mutations
in VCP.
3 .2 . 3. FTLD- FUS
In rare cases, the neuronal inclusions are tau and
TDP-43 negative but are labeled by antibodies
directed against the RNA-binding protein FUS
(fused in sarcoma). This observation grew out
FIGURE 8.10 Frontotemporal lobar degeneration. of the demonstration that mutations in this gene
Neuronal loss and microvacuolation in the superficial were associated with some familial forms of ALS,
cortical layers is often seen. In more advanced cases and awareness of the relationship between ALS
(as here) there is severe neuronal loss and transcorti- and FTLD. Within the set of FLTD-FUS cases,
cal vacuolation (H&E). some have no other distinguishing characteristics
A B
FIGURE 8.11 Frontotemporal lobar degeneration. (A) Ubiquitin-immunoreactive inclusions in layer II neu-

rons as well as accumulation in small neuritis. (B) Ubiquitin-immunoreactive inclusions in hippocampal dentate
granule cells.
and were previously known as atypical FTLD-U 3.2.4 . F TL D- UPS

(because the inclusions contained ubiquitin but not
In a few families with FTLD, the inclusions are detect-
the other recognized markers). Two other sporadic
able only by immunohistochemistry directed against
disorders fit into the category of FTLD-FUS: neu-
proteins belonging to the ubiquitin-proteasomal
ronal intermediate filament inclusion disease and
degradation system. The inclusions in these brains
basophilic inclusion body disease. The first of
are characterized by the presence of ubiquitin and
these can mimic Pick disease with spherical neu-
p62 (a protein that binds to polyubiquitinated pro-
ronal cytoplasmic inclusions, approximately the
teins and assists in transporting them toward the pro-
size of the nucleus, found in the cerebral cortex,
teasome and for autophagy). This neuropathological
basal nuclei, and brainstem. As the name implies,
pattern is associated with mutations in the gene for
the inclusions contain neurofilament proteins as
CHMP2B (charged multivesicular body protein 2B).
well as FUS and are tau negative. The latter has a
heterogeneous clinical phenotype that can include
behavioral-variant FTLD, with manifestations of
3.2.5. FTD LACKING INCLUSIONS (FTLD-NI)
lower motor neuron degeneration and extrapyra-
midal signs; again, there are neuronal cytoplasmic In a few cases of FTD, there is no cytoplasmic or
inclusions that are inconstantly ubiquitin positive nuclear inclusion detected. These cases are classified
but intensely FUS positive. as FTLD-ni (for no inclusion).
A B
FIGURE 8.12 Mutation of the progranulin gene (PGRN). (A) Ubiquitin- and TDP-43-positive neuronal
cytoplasmic inclusion in the dentate gyrus. (B)Ubiquitin- and TDP-43-positive neuronal intranuclear inclusion
with typical cat’s-eye appearance.

A B
FIGURE 8.13 C9ORF72 mutation. (A) TDP 43 antibody. The nucleus in the upper part of the field is nor-
mally immunostained. The nucleus in the lower part of the field is negative and is associated with a cytoplasmic
inclusion. (B) In the cerebellum, a typical ubiquitin- and P62-positive inclusion is negative for TDP-43. (C) In
the same case, an ubiquitin-positive skein-like inclusion is present in a motor neuron.
3.3. Dementia with Lewy Bodies remains unclear, it is likely that each can contribute
to cognitive impairment.
Dementia commonly emerges as an additional com-
ponent of the illness in individuals with Parkinson
disease (vide infra). There is somewhat arbitrary 3 .3 . 1. GROSS APPEARAN CE
separation between dementia with Lewy bodies
Cerebral atrophy is generally not as severe as that
(DLB, which becomes manifest within a year of
seen in a case of AD of equivalent cognitive impair-
the onset of parkinsonism or in advance of it) and
ment, with brain weight in the normal range.
Parkinson disease dementia (where the dementia
There is usually pallor of the substantia nigra and
follows the establishment of a Parkinson disease
of the locus coeruleus, as would be seen in typical
diagnosis by more than a year). In either setting, the
Parkinson disease. Atrophy of the limbic system may
dementia is a progressive disorder with early hallu-
be prominent.
cinations and prominent fluctuations in cognition.
Neuropathological changes include the presence
of Lewy bodies and Lewy neurites in the cerebral
3 .3 . 2. M ICROSCOPIC FIN DIN GS
cortex as well as in the brainstem. These are often
accompanied by some degree of AD neuropatho- Neuronal loss and gliosis are usually restricted
logical changes, often with a moderate plaque bur- to brainstem regions, particularly the substantia
den but relatively lower tangle burden. Although nigra and locus coeruleus. The severity of injury is
the etiological relationship between the processes typically comparable to that observed in Parkinson
disease, along with Lewy bodies—eosinophilic, be localized atrophy of the ambient gyrus, and the
laminated cytoplasmic neuronal inclusions. In con- accumulation of grains appears to begin there, with
trast to these changes, the cerebral neocortex, hip- progressive involvement through medial temporal
pocampus, and amygdala are usually unremarkable lobe structures and thence to other limbic regions
with routine staining methods. With immunohis- such as cingulate and insular cortices.
tochemistry directed against α-synuclein, another
picture emerges. The brainstem Lewy bodies are
highlighted and their wider distribution in the retic- 3.5. Hippocampal sclerosis
ular formation becomes evident, along with the pres- Some aged subjects have memory loss as their pre-
ence of immunoreactive dystrophic neurites (Lewy dominant symptom, often leading to a presumptive
neurites). In the deeper layers of the cerebral cortex clinical diagnosis of AD. While the typical findings
(particularly temporal, insular, and cingulate corti- of AD are present in some, others have plaques but
ces) there are ill-defined cytoplasmic inclusions that limited tangle distribution in a manner less likely
are indistinct compared to the counterpart lesions in to explain the cognitive impairment. In these cases,
the brainstem, but stain comparably for α-synuclein there can be neuronal loss and gliosis limited to the
(Fig. 8.14A , B). These are also accompanied by CA1 sector of the hippocampus but lacking the
Lewy neurites in the cortical neuropil and a super- marked destructive changes that would suggest a
ficial spongiosis involving the outer several cortical prior ischemic event (or epileptic seizures). In this
layers. In the amygdala, Lewy bodies are detected in clinicopathological setting, TDP-43-containing
neurons, while in the hippocampus Lewy neurites in inclusions are commonly identified, suggesting a
CA2-3 can be the only finding (Fig. 8.15). As men- link to FTLD-TDP.
tioned above, most brains with DLB also show some
plaques and tangles, although in most instances the
lesions are not nearly as severe as in AD. 3.6. Vascular dementia/Vascular
cognitive impairment
3.3.3. DIAGNOSTIC CLASSIFICATION It is being increasingly recognized that injury to
the brain parenchyma associated with a wide range
Lewy body diseases (DLB and Parkinson disease) of vascular lesions may be a substrate for cognitive
can be neuropathologically stratified into three impairment and even dementia. The types of vas-
groups: brainstem, when Lewy bodies are restricted cular lesions that can contribute to loss of normal
to brainstem structures; transitional, when there cognition include large-territory infarcts leading to
is involvement of limbic structures; and neocorti- massive tissue destruction (multi-infarct demen-
cal, when there is additional involvement of the tia); small infarct(s) localized in strategic areas (e.g.,
neocortex. In the current diagnostic criteria, it is thalamus); diffuse white matter injury, as can been
recommended to systematically assess Alzheimer seen in the setting of poorly managed hypertension
pathology in order to evaluate the probability (high, (a pattern sometimes referred to as Binswanger leu-
intermediate, or low) that Lewy pathology is respon- koencephalopathy), with amyloid angiopathy, or
sible for the cognitive deficit. with diffuse small vessel diseases such as CADASIL
(see Chapter 4). While pure vascular-based cogni-
tive impairment is relatively infrequent, vascular
3.4. Argyrophilic grain disease co-morbidity commonly contributes to the demen-
Lacking a distinctive clinical picture that reliably tia in individuals who also have neurodegenerative
allows for diagnosis, argyrophilic grain disease is diseases, particularly with AD.
largely defined on neuropathological grounds—that
is, by the presence of small, silver-positive inclusions
containing 4R-tau in neurites along with inclusions 3.7. Other causes of dementia
in oligodendrocytes with similar staining character- Dementia can be seen as a component of neurode-
istics (“coiled bodies”). These pathological findings generative diseases that are discussed elsewhere in
in argyrophilic grain disease are not consistently this chapter because the primary burden of the dis-
associated with clinical evidence of cognitive impair- ease process is borne by other functional systems.
ment. Recent studies have suggested that there can Examples that will be encountered in subsequent

A B
FIGURE 8.14 Dementia with Lewy bodies. (A) Cortical Lewy bodies are immunoreactive for alpha synu-
clein. (B) Cortical Lewy bodies may also be detected by anti-ubiquitin.
sections include some of the movement disorders, “movement disorders” is commonly reserved for
such as the trinucleotide-disorder Huntington dis- those diseases in which dysfunction of the basal gan-
ease, as well as the tauopathy progressive supranu- glia circuitry results in either decreased or increased
clear palsy. Dementia is also a prominent component motor output.
of prion diseases (Chapter 6), bacterial infections The functional organization of the basal ganglia
including syphilis and Whipple disease (Chapter 5), (commonly defined to include the circuitry of the
and viral diseases, such as the HIV-associated neu- striatum, globus pallidus, the subthalamic nucleus,
rocognitive disorder (Chapter 5). Patients with the substantia nigra, and interconnecting white
certain types of storage disorders can develop matter tracts) serves to modulate the planning and
cognitive impairment leading to dementia, such execution of movement through two stereotypi-
as Kufs disease and adult-onset Tay-Sachs disease cal competing pathways. Because of this dynamic
(Chapter 10). balance, loss of neurons that shift the balance can
either allow the residual circuitry to decrease motor
capacity (akinetic movement disorders) or increase
4. MOVEMENT DISORDERS it (hyperkinetic movement disorders).
While numerous brain regions contribute to plan-
ning and execution of motor output, the term
4.1. Akinetic rigid syndromes
These disorders are characterized by the presence of
rigidity, bradykinesia, and tremor—a clinical triad
known as parkinsonism, although not all affected
individuals will manifest all features. The most
common disorder in this group is Parkinson dis-
ease. Other diseases may manifest a similar clinical
picture but show additional features and are desig-
nated, for example, as “Parkinson plus” syndromes,
or as atypical parkinsonism. A critical component of
these movement disorders is related to loss of stria-
tal dopamine, and associated abnormalities of the
nigrostriatal system.
FIGURE 8.15 Dementia with Lewy bodies. Lewy 4 .1 . 1. PARKIN SON DISEASE

neurites may be detected in both demented as well as
non-demented patients with Lewy body disease by The most common of the akinetic movement dis-
ubiquitin immunostaining. orders, Parkinson disease, is a degenerative disease
mainly seen in older adults. The diagnosis is based characteristic of the disease may extend supraten-
on the presence of the parkinsonian triad (rest- torially to cortical regions, and the disease can be
ing tremor, rigidity, and bradykinesia), character- expressed clinically as a dementia (DLB, see above),
istic progression of the disease, and symptomatic often with the characteristic fluctuations and visual
response to treatment with agents that increase stria- hallucinations.
tal dopamine. In addition to the movement disorder,
other common components of the illness include
4.1.1.1. Gross appearance The brain weight is
autonomic dysfunction, depression or behavioral
ordinarily within normal limits for age in Parkinson
changes, and sleep disturbances. REM sleep behav-
disease; the most striking findings are pallor of the
ioral disorder is a relatively frequent antecedent to
substantia nigra in the midbrain (Fig. 8.16) as well
the onset of symptomatic parkinsonism.
as pallor of the locus coeruleus in the upper pons.
The annual incidence of Parkinson disease ranges
from about 7.0 to 19 per 100,000 and the prevalence
from about 30 to 190 per 100,000; the majority of 4.1.1.2. Microscopic lesions The brain-
cases are sporadic, although there are rare familial stem structures with pallor visualized on mac-
forms. Patients with familial forms may have domi- roscopic examination show neuronal loss and
nant or recessive inheritance patterns. From the astrocytic gliosis, recognized best in the pars com-
study of these familial forms have come important pacta of the substantia nigra (Fig. 8.17) and the
insights into the pathways critical for development coeruleus-subcoeruleus area. Neuromelanin pig-
of Parkinson disease and the nature of the diagnostic ment may be seen in macrophages or free in the neu-
pathologic hallmark of Parkinson disease, the Lewy ropil. Remaining neurons in these nuclei contain
body (the intraneuronal cytoplasmic inclusion Lewy bodies in varying abundance.
body primarily composed of α-synuclein already Other regions may be affected by Lewy body
seen in DLB) (Fig. 8.14A). With the recognition of pathology and may relate to other clinical features
α-synuclein as a marker of neuronal abnormalities in of disease. Changes in the dorsal vagal nucleus are
Parkinson disease, it has become clear that the dis- commonly observed, and patients may manifest
ease involves much of the brainstem and can prog- dysphagia. The nucleus basalis of Meynert and the
ress to involve cortical regions. In fact, it appears amygdaloid body are frequently affected. Lewy bod-
that the changes that mark Parkinson disease begin ies may be seen in the cerebral cortex, and extensive
in the medulla and only gradually progress rostrally pathology has been related to DLB, as discussed
to the brainstem, with the clinical onset of akinetic above. Lewy bodies may also be encountered in the
movement disorders when the substantia nigra neurons of the intermediolateral columns of the
begins to be moderately involved. Lewy body Braak spinal cord, sympathetic and parasympathetic gan-
stages (from 1 to 6) have been devised to describe glia, the enteric nervous system, the cardiac plexus,
this progression. The neuropathological changes the pelvic plexus, and the adrenal medulla—the
A B
FIGURE 8.16 Parkinson disease. Macroscopic appearance: Midbrain showing pallor of the substantia nigra
(A), compared with substantia nigra from an unaffected individual (B). The pallor is the result of loss of neurons
containing neuromelanin.

for the detection of Lewy bodies and Lewy neuritis,
which can otherwise be inconspicuous.
4.1.1.3 Molecular and cell biology of

Parkinson disease Several familial forms of
Parkinson disease have been documented, and the
genes for some have been characterized. Mutations
in the gene encoding α-synuclein and in the gene
of the leucine-rich repeat kinase 2 (LRRK2) have
been linked to autosomal dominant familial forms
of Parkinson disease. There are also kindreds with
Parkinson disease caused by duplication or trip-
FIGURE 8.17 Photomicrograph of the sub- lication of the α-synuclein locus. Mutations of
stantia nigra showing loss of pigmented neurons the gene of parkin (E3 ubiquitin ligase) and the
and astrocytic gliosis. Pigment can be seen in mitochondrial-associated proteins DJ-1, PINK1,
macrophages (H&E). and ATP13A2 cause autosomal recessive parkinson-
ism; these forms usually present before age 40 and
are sensitive to L-dopa therapy. In these recessive
involvement of these structures can be presumed to forms, Lewy bodies are absent, although neuronal
be the basis of the autonomic dysfunction seen in loss is severe in the substantia nigra.
some patients. The best-characterized genetic risk factor for the
In some affected brain regions, one may observe, development of Parkinson disease is the presence of
in addition to the typical Lewy bodies situated in a mutated allele of the GBA gene, which encodes the
the neuronal perikarya (Fig. 1.13A, B) hyaline aci- enzyme β-glucocerebrosidase and is the recessive locus
dophilic inclusions. The outline and the halo may be for Gaucher disease, a lysosomal storage disorder.
less distinctly defined; they are elongated and are sit- While the underlying mechanism of this relationship
uated in the cell processes (intraneuritic Lewy bodies is not known, these mutations are found in approxi-
or Lewy neurites) (Fig. 1.13C, D). Finally, the corti- mately 10% of cases of sporadic Parkinson disease.
cal (cerebral) Lewy bodies are situated in the peri-
karyon of cortical neurons, may not be spherical, and
are less eosinophilic; they have neither central core 4 .1 . 2. PROGRESSIVE
nor peripheral halo (Fig. 1.13E, F). The presence of S U PRAN UCLEAR PALSY
α-synuclein within these inclusions (Fig. 8.18) has
PSP, or Steele-Richardson-Olszewski syndrome, is
led to the recommendation that immunohistochem-
clinically characterized by parkinsonism associated
istry against this normal synaptic protein be used
with supranuclear ophthalmoplegia. Additionally,
the parkinsonism is usually without tremor but
with hypertonia, retrocollis (rather than flexion
as in Parkinson disease), and axial rigidity (rather
than greater involvement of the extremities as in
Parkinson disease). Pseudobulbar palsy and cogni-
tive abnormality leading to dementia are common.
The average age of onset is about 64 years, with a
prevalence of about 7 per 100,000. In general, these
individuals obtain only minimal symptomatic ben-
efit from therapeutic approaches to elevate striatal
dopamine, in contrast to patients with Parkinson
disease.
4.1.2.1 Gross appearance The most strik-

FIGURE 8.18 Immunohistochemistry for alpha ing abnormality that can be observed is atrophy
synuclein showing Lewy bodies in a nigral neuron. of the midbrain and pontine tegmentum. There is
commonly pallor of the substantia nigra and locus seen but are not specific and may be seen in other
coeruleus as in Parkinson disease, but with variable neurodegenerative conditions. Accumulation
atrophy of the globus pallidus. The cerebral cortex of tau protein in oligodendrocytes, which also
is usually spared, although in cases with prominent occurs in PSP but is less specific of it, is known as
cognitive impairment there may also be frontotem- “coiled body.”
poral atrophy.
4.1.2.3. Genetics and cell biology Nearly
all cases of PSP are sporadic, although there are
4.1.2.2. Microscopic lesions The diagnostic
rare cases in which MAPT mutations are pres-
features of PSP are the combination of regional
ent. The aggregates of tau in neurons and glia in
neuronal loss and astrocytic gliosis, with neuronal
PSP are primarily composed of the 4R isoform
and glial accumulation of tau protein, as highlighted
(4Rtau). While MAPT mutations are rare causes
best by immunohistochemistry. There is a high
of PSP, there is a strong risk association for the
lesion burden in basal ganglia (substantia nigra, the
H1 haplotype of the MAPT locus as defined by a
globus pallidus, and the subthalamic nucleus) as
series of genetic markers that are in strong linkage
well as the brainstem (superior colliculus, pretec-
disequilibrium.
tal areas, periaqueductal grey matter, and the mes-
encephalic and pontine reticular formations). In
addition, there can be moderate involvement of the
4.1.3 . CORTICOBASAL DEGENERATION
cerebellar dentate nucleus, locus coeruleus, oculo-
motor nuclei, pontine nuclei, the reticular forma- CBD is a clinicopathological entity in which there is
tion in the medulla, inferior olivary complex, and degeneration of cortical areas and of the basal gan-
the thalamus. glia (including the substantia nigra). It is related to
In these affected regions, the neuronal loss and PSP, with accumulation of 4R tau in neurons and
gliosis is accompanied by tau-containing inclu- glia, although the distinction between the two can
sions in both neurons and glia. Within neurons, tau be made both at the clinical level through distinct
protein forms neurofibrillary tangles, which have a patterns of symptoms and at the neuropathological
characteristic globose appearance (Fig. 8.19A , B). level by the distinct distribution of lesion burden
Tufted astrocytes, considered to be highly char- and lesion character.
acteristic of the disease, develop in affected areas, The disease presents with rigidity, clumsiness,
are usually abundant in the putamen, and are com- stiffness, or jerking of the arm or, less commonly,
monly found in the cerebral cortex, mostly motor a leg. There is early asymmetry in these movement
and premotor areas of the frontal lobe (Fig. 8.20A). abnormalities, and it is common for patients to
The length of their processes contains tau protein develop progressive apraxia and the so-called “alien
and they are often binucleated. Thorn-shaped astro- limb” phenomenon in which a limb moves with-
cytes (Fig. 8.20B) (see Chapter1) are commonly out their voluntary control in association with the
A B
FIGURE 8.19 (A) Neuron containing a globose neurofibrillary tangle (H&E). (B) Neuron containing a glo-
bose neurofibrillary tangle detected by immunostaining for tau protein.

A B
FIGURE 8.20 Glial pathology in progressive supranuclear palsy. (A) Fairly specific finding of tufted astro-
cytes seen in gray matter (Gallyas silver stain). (B) Thorn-shaped astrocytes are commonly seen but not entirely
specific.
feeling that the offending limb does not belong to 4.1.3.2. Microscopic lesions The characteristic
them. Difficulty in walking develops due to apraxia features include the combination of neuronal loss,
of leg movement together with pyramidal defi- astrocytic gliosis, and 4R-tau-containing inclusions
cits caused by upper motor neuron involvement. in neurons and glia. In addition, in the cortex it is
Cognitive abnormalities occur in some patients possible to find swollen (“achromatic”) neurons
with aphasia and dementia of frontotemporal type. that have lost their Nissl substance (Fig. 8.21A,
In some patients, the cognitive abnormalities may B). In the substantia nigra, cell loss is associated
even predominate over the movement disorder. The with astrocytic gliosis. Remaining nigral cells show
biochemical and genetic associations of CBD are large globose, pale-staining neurofibrillary tangles
comparable to those of PSP. (Fig. 8.22). Immunostaining for tau protein shows
tangles in neurons as well as immunoreactivity in
4.1.3.1. Gross appearance Cortical atrophy many swollen neurons. Accumulation of tau pro-
is the typical finding, most prominent around the tein in astrocytes forms distinctive structures in gray
Sylvian fissure or with a frontotemporal distribu- matter areas termed astrocytic plaques: tau protein
tion, and often asymmetrical. The substantia nigra accumulates at the end of the astrocytic processes,
shows loss of pigment. There may be atrophy of the while the center of the plaque is devoid of tau immu-
basal ganglia. noreactivity (Fig. 8.23). They are conspicuous in the
cortex and in the putamen.
A B
FIGURE 8.21 Corticobasal degeneration. (A) Swollen achromatic neurons in the cerebral cortex (H&E).
(B) Swollen neurons show immunoreactivity for alpha B-crystalline, which is a useful method for detection.
acquired the others. This clinical aggregation was
further validated by the recognition that the neuro-
pathological finding of distinctive inclusion bodies
in glial cells was common to all these patients. These
inclusions were subsequently shown to contain
α-synuclein, leading to the classification of MSA as
a synucleinopathy, along with Parkinson disease and
DLB; no mutations in the gene for α-synuclein have
been found in MSA, which appears to exist only as a
sporadic disorder.
The clinical features of MSA may show a predom-
inance of the parkinsonian components (MSA-P) or
of the cerebellar ataxia (MSA-C); it is relatively rare
FIGURE 8.22 Corticobasal degeneration. Nigral to have the autonomic dysfunction be the sole man-
neurons contain pale areas that displace the neu- ifestation of the illness, although some features of
romelanin. These are large globose tangles composed autonomic disturbances are seen in nearly all cases.
of tau protein (H&E).
In addition to the extrapyramidal motor symptoms,
evidence of pyramidal involvement with hyperre-
4.1.4. MULTIPLE SYSTEM flexia is commonly seen. The tempo of progression
ATROPHY (MSA) is not strikingly different across the various clinical
As the term “multiple” implies, MSA is a degen- subtypes, and the disease is fatal in most patients
erative process that crosses functional systems and within a decade of the onset of symptoms.
hence does not fit well into only one of the clini-
cally discussed categories. We made the choice of 4.1.4.1. Gross appearance As would be
presenting this disorder in this sequence because expected from the spectrum of clinical presenta-
of the frequency of parkinsonism and because it tions, there can be a range of gross abnormalities
is, like Parkinson disease, included in the synucle- observed in cases of MSA. The best correlate of
inopathies. Three disorders (the parkinsonian MSA-P is the combination of pallor of the substan-
striatonigral degeneration, the ataxic olivopontocer- tia nigra with atrophy of the putamen, often asso-
ebellar atrophy [OPCA], and the autonomic failure ciated with a gray-green discoloration of the latter
of Shy-Drager syndrome), which were originally structure (Fig. 8.24). When a prominent cerebellar
thought to be distinct, were united after it was rec- component has been present (MSA-C), the cerebel-
ognized that affected individuals often began with lum, basis pontis, and inferior olivary complex are
one symptom complex but eventually gradually generally atrophied (see 5.1.2 and Fig. 8.30).
FIGURE 8.24 Multiple system atrophy.

FIGURE 8.23 Corticobasal degeneration. Macroscopic examination of the fixed brain shows
Astrocytic plaques can be detected in gray matter by shrinkage of basal ganglia and discoloration of the
tau immunostaining, as here, or by Gallyas staining. putamen, which takes on a gray-green discoloration.

4.1.4.2. Microscopic lesions Grossly and changes similar to those described in progressive
symptomatically involved brain regions show neu- supranuclear palsy. At microscopic examination,
ronal loss and astrocytic gliosis, and on routine neurofibrillary tangles are found in widespread dis-
stains (H&E, with or without Luxol fast blue) little tribution but particularly affect the substantia nigra,
else is evident. Use of silver stains such as Gallyas the locus coeruleus, and the nuclei of the reticular
(Fig. 8.25A) or Bodian (Fig. 8.25B), or immuno- formation, hypothalamus, and the nucleus basalis of
histochemistry of α-synuclein or of ubiquitin (Fig. Meynert. Affected regions show cell loss with astro-
8.26A, B) will show characteristic glial cytoplasmic cytic gliosis.
inclusions in oligodendroglia. They are widely dis-
tributed through the brain, and appear as crescentic- 4.1.5.2. Pharmacologic/toxic Extrapyramidal
or sickle-shaped structures in glial cells, partially disturbances can be seen in the course of treatment
wrapping the nucleus and extending away from it. with neuroleptics; the anatomical substrate is poorly
NCIs and NIIs may also be seen but are generally defined. Toxic exposure to a byproduct of illicit drug
much less obvious. synthesis, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyr-
idine (MPTP), resulted in a parkinsonian syndrome
with neuronal loss relatively selectively involving the
4. 1. 5. S E CONDARY PA R K I N S O NI A N substantia nigra.
S Y N DROME S
Functional disruption of the basal ganglia circuitry 4.1.5.3. Carbon monoxide poisoning With
and, in particular, of nigrostriatal projections may nonfatal exposure, there can be bilateral necro-
result in the development of a parkinsonian syn- sis of the superomedial part of the pallidum (see
drome. The diagnostic challenge is usually to Chapter 9). Lesions in the substantia nigra are
separate these syndromes from the primary neu- inconstant and usually moderate and involve the
rodegenerative diseases affecting the same brain pars reticulata of the nucleus rather than the dopa-
regions. minergic pars compacta.
4.1.5.1. Postencephalitic parkinsonism Posten- 4.1.5.4. Vascular disease The combination of

cephalitic parkinsonism followed a pandemic of hypertensive cerebrovascular disease involving the
encephalitis lethargica (von Economo disease) basal ganglia, with lacunes, as well as involvement of
between 1915 and 1927 (see Chapter 5). Half of the brainstem and white matter projections essential
the individuals who survived the acute encephalitic for basal ganglia circuitry, can result in parkinsonism.
phase of the illness developed a parkinsonian syn- In these cases, there is usually marked asymmetry
drome after a typical latent period of about 9 years. of symptoms reflecting the anatomical location of
Cases coming to medical attention in recent times discrete lesions, as well as pseudobulbar palsy when
are very rare. Macroscopic examination shows there is more widespread brainstem involvement.
A B
FIGURE 8.25 Multiple system atrophy. Glial cytoplasmic inclusions of multiple system atrophy, which have
been termed Papp-Lantos inclusions, can be detected by Gallyas staining (A) or Bodian silver impregnation (B).
A B
FIGURE 8.26 Multiple system atrophy. Alpha synuclein can be detected in glial cytoplasmic inclusions (A),
neuronal nuclear inclusions, and neuronal cytoplasm. The neuron shown in (B) has both nuclear and cytoplas-
mic inclusions.
4.1.5.5. Trauma Individuals exposed to trinucleotide (CAG) repeat in the gene. In patients
repeated traumatic injury, as seen particularly in with HD, the length of this repeat is expanded, with
professional boxers, can develop a parkinsonian syn- the average repeat length around 46 and a range of
drome, which often is associated with progressive 36 to 86. In general, the length of the repeat influ-
dementia (dementia pugilistica) (see Chapter 3). ences the age of onset of the illness, with longer
repeats associated with earlier onset. There is a
4.2. Hyperkinetic Movement propensity for expansion of the CAG repeat during
Disorders paternal transmission, such that this disease can
occur at younger and younger ages in subsequent
The clinical signs and symptoms of hyperkinetic generations, a phenomenon referred to as anticipa-
movement disorders are chorea, ballism, myoclo- tion. Unanswered questions remain in HD, includ-
nus, dystonia, and tics. Chorea is characterized by ing the determination of anatomical specificity
“dance-like,” non-rhythmic rapid involuntary move- given that the protein is widely expressed through-
ments. These disorders may be separated into two out the nervous system as well as the processes that
main groups, hereditary and sporadic, with a wide drive neurodegeneration. Proposed mechanisms
range of causes, the most common being the inher- contributing to pathology include loss of func-
ited condition Huntington disease. tion of huntingtin because of the expanded repeat,
gain of toxicity by mutant protein, transcriptional
4.2.1. HUNTINGTON DISEASE dysregulation caused by nuclear inclusions, excito-
toxicity, oxidative stress, impaired proteolysis, and
Huntington disease (HD) is an autosomal domi- stimulated apoptosis.
nant disorder, without a sporadic counterpart. Its
frequency varies in different populations, with levels 4.2.1.1 Gross appearance There is commonly
of between 4 and 7 per 100,000. The disease usu- mild to moderate cerebral atrophy. On cut surface,
ally starts in middle or late life, but it may become the main neuropathological abnormality is atrophy
manifest earlier in life (see further on). It is charac- of the caudate nucleus and putamen. At the earliest
terized by chorea and mental deterioration leading stages of the disease, the caudate atrophy is primar-
to dementia. In some juvenile or early-onset forms, ily seen in the posterior portion of the structure
chorea is replaced by hypertonia. (Grade 1), but with time there is evidence of vol-
HD is associated with a mutation in the gene ume loss from the caudate head as well (Grade 2).
coding for the huntingtin protein, located on the As the disease progresses further, the contour of the
distal portion of chromosome 4p. Huntingtin is caudate shifts from the normal convex bulge into the
widely expressed in a variety of tissues and con- lateral ventricle to flat (Grade 3) or even concave
tains a polyglutamine tract that varies in size from (Grade 4) outline (Fig. 8.27). Atrophy of the puta-
9 to 37 copies of the amino acid, encoded by a men follows the same overall gradient and tempo,

with changes seen in the globus pallidus in the later organelle membranes, particularly the endoplasmic
stages primarily. reticulum).
4.2.1.2. Microscopic lesions In the involved 4.2.2.2. Neurodegeneration with brain iron
regions of the striatum, there is neuronal loss with accumulation (NBAI) The combination of behav-
astrocytic gliosis. The initial burden of degeneration ioral changes with a progressive extrapyramidal
is borne by the medium spiny neurons, although in syndrome typically combining rigidity with hyper-
late stages of the illness most striatal neurons are kinesia, dystonia, and tremor is characteristic of this
lost. The cerebral cortex may show some degree of set of disorders, which can be caused by a series of
neuronal loss and gliosis, particularly in the setting different mutations. There are common histological
of greater cognitive impairment. features, including the presence of axonal spheroids
Immunohistochemistry for huntingtin or for the predominantly in the internal globus pallidus and
expanded polyglutamine tract or for ubiquitin shows substantia nigra, as well as increased levels of brain
accumulation of abnormal protein as nuclear inclu- iron, again primarily in these regions. Interestingly,
sion bodies. Abnormal protein also accumulates in coincident lesions such as Lewy bodies and tangles
cortical neurites (Fig. 8.28). Intranuclear inclusions are often found in the basal ganglia with the dis-
are relatively infrequent in striatal neurons but are eases. The ability to detect the elevated iron levels
more abundant in the cerebral cortex. through imaging methods has made it possible to
invoke the diagnosis at the time of clinical evalua-
tion; patients will show a characteristic “eye of the
4. 2. 2. OT HE R HYPE R K I NETI C D I S O R D ER S tiger” sign in the basal ganglia with T2-weighted
imaging.
4.2.2.1. HD-like diseases Individuals and Mutations in an enzyme involved in the synthesis
families have been identified with clinical and neu- of coenzyme A (pantothenate kinase 2) are found in
ropathological features of HD but without expan- many of the cases of NBAI, particularly those with
sion of the polyglutamine tract in the gene for adult onset, now termed NBAI1. When the disease
huntingtin. The best understood of these is known begins in early childhood, is it usually associated
as Huntington disease-like 2 (HDL2), in which the with more diffuse formation of axonal spheroids
genetic locus is an expansion of a CTG/CAG tract across the nervous system, hence the previous name
in the gene for junctophilin-3 (a protein involved in of infantile neuroaxonal dystrophy. This form of
the complexes linking the plasma membrane with the disease (NBAI2) is associated with regression
of milestones and emergence of combinations of
FIGURE 8.28 Huntington disease. Neurites can

FIGURE 8.27 Huntington disease. Loyez stain be detected in the cerebral cortex with immunostain-
showing atrophy of the caudate nucleus and putamen ing with anti-huntingtin or anti-ubiquitin. Neuronal
with dilation of frontal horn and cortical atrophy. nuclear inclusions are also identified by these stains.
hypotonia and rigidity as well as optic atrophy; a Table 8.3. Classification of Some
distinct genetic locus has been identified. Inherited Spinocerebellar and Cerebellar
Ataxias
4.2.2.3. Choreoacanthocytosis This disorder is
defined by the combination of chorea, dystonia, and Autosomal recessive cerebellar ataxia
tics with a hemolytic anemia including the presence Friedreich ataxia
of acanthocytes (“thorny” red blood cells detect- Ataxia with vitamin E deficiency
able on a blood smear). Usually showing recessive Ataxia-telangiectasia
inheritance, a range of mutations have been detected
Autosomal dominant cerebellar ataxia
in a chromosome 9q encoding a protein involved
in cellular trafficking of proteins, including in red Spinocerebellar ataxia (SCA1-31)
blood cell precursors. Acanthocytes can also be seen Dentato-rubro-pallido-luysial atrophy (DRPLA)
in association with movement abnormalities, with X-linked cerebellar ataxia
McLeod syndrome with mutations in the XK locus Fragile X tremor/ataxia syndrome
on the X chromosome that is also required for gen-
eration of the Kell blood antigen, Kx.
5.1.1 . CEREBEL L AR CORTICAL
5. CEREBELLAR ATROPHIES
DEGENERATIONS (ATAXIC Within this group of disorders, some diseases mani-
DISORDERS) fest relatively consistent patterns of tissue injury,
although some variability in the distribution and
Disorders that include neurodegeneration of the cer- severity of the neuropathological changes can be
ebellum can be variously classified either by the pat- seen from case to case. The common denominator
terns of inheritance and underlying genetic basis or by in all is degeneration of the cerebellar cortex, with
the patterns of cellular degeneration. While classifica- early and eventually severe loss of Purkinje cells
tions based on the topographical distribution of injury (Fig. 8.29B). Loss of Purkinje cells is associated
were used in the past, the emergence of genetic infor- with Bergmann gliosis—reactive proliferation of
mation has allowed neurologists and neuropatholo-
gists to use alternate methods of classification to draw
a greater understanding of the underlying basis of Table 8.4. Classification of Ataxias
cerebellar degeneration (Table 8.3). In addition to the
neurodegenerative disorders, cerebellar degeneration Primary cerebellar and spinocerebellar
may be seen in a variety of other conditions, including degenerations
toxic and metabolic disorders and infectious diseases Inherited
(Table 8.4). Knowledge of the cerebellar circuitry is Autosomal recessive
useful to understand the various classic descriptions Autosomal dominant
of cerebellar neurodegeneration; however, clinical and Sex-linked
neuropathological overlaps are frequent.
Sporadic
Multiple system atrophy (OPCA)
5.1. Types of Atrophy According
to the Topography of the Lesions Idiopathic cerebellar degeneration
in the Cerebellar Circuitry Secondary cerebellar and spinocerebellar
degenerations
Three main patterns of cerebellar degeneration are
recognized: Neurometabolic
Prion disease
• Cerebellar cortical atrophy Toxic
• Olivopontocerebellaratrophy Infectious
• Cerebellofugal atrophy Vascular
Paraneoplastic cerebellar degeneration
These are summarized in Figure 8.29.

A B
Axons of Dendrites of
granular neurons Purkinje cells
Granular Purkinje
neurons cells
Axons of
Mossy Purkinje cells
fibers
Climbing
fibers
Dentate nucleus
Middle of cerebellum
Inferior
cerebellar
cerebellar Superior MCP ICP
peduncle SCP
peduncle cerebellar
peduncle
Inferior
olive
C D
Dentate nucleus Dentate nucleus

of cerebellum
MCP ICP MCP ICP
SCP SCP
Inferior
olive
FIGURE 8.29 The principal lesions seen in various cerebellar atrophies: (A) normal cerebellum;

(B) cerebello-olivary atrophy; (C) olivopontocerebellar atrophy; (D) dentatorubral atrophy. The main afferent
pathways are in black and the main efferent pathways in red; lost pathways are stippled.
astrocytes at the interface of the Purkinje cell layer this finding is inconstant in the various forms of cer-
and the molecular layer. Early and subtle evidence ebellar degeneration.
of Purkinje cell loss may be demonstrated with the Structures that are functionally connected to
use of silver staining to reveal the processes of bas- the cerebellum are also commonly involved. The
ket cells that normally wrap around the cell bodies frequent involvement of spinal cord tracts, particu-
of Purkinje cells; when Purkinje cells are lost, these larly the spinocerebellar pathways, in the autosomal
processes remain as “empty baskets.” Granule cell dominant forms of diseases has led to the emergence
degeneration typically follows the loss of Purkinje of the term spinocerebellar ataxia (SCA)—a range of
cells, with marked loss of folial volume. As Purkinje disorders with several dozen distinct entities. Other
cells die, their projections to the deep nuclei are spinal cord tracts may also be involved, including the
lost and this phenomenon is demonstrable as pallor dorsal columns (which do not have direct connec-
in the fibers that wrap around the dentate nucleus tions with the cerebellar cortex). Within the brain-
(amiculum). Degenerative changes are also com- stem, there is commonly involvement of the inferior
mon in the deep nuclei of the cerebellum, although olivary nuclei and their fiber connections.
5.1.2. OLIVOPONTOCEREBELLAR • The cerebellar atrophy is characterized by severe
ATROPHIES degeneration of the cerebellar white matter with
astrocytic gliosis (to a large extent due to loss of
OPCA, classically regarded as the prototype of cer-
pontocerebellar fibers). The relative sparing of
ebellopetal atrophy, is characterized by selective
the amiculum of the dentate nucleus indicates the
involvement of the afferent fibers of pontine and oli-
preservation of Purkinje cell axons.
vary origin (Fig. 8.29C). The condition is character-
• Inferior olivary involvement is characterized by
ized by pontine and cerebellar lesions, with variable
neuronal cell loss and degeneration of the olivo-
degeneration of the inferior olives.
cerebellar fibers.
• Atrophy of the basis pontis is evident on macro- The neuropathological picture of OPCA is seen
scopic examination. There is neuronal loss from in several types of inherited spinocerebellar atrophy
the pontine nuclei and degeneration of the ponto- (such as SCA2) as well as multiple system atrophy,
cerebellar fibers, which constitute the middle cer- which is sporadic (4.1.4)
ebellar peduncles. In myelin stains, there is pallor
of the pontocerebellar fibers, which contrasts with
5.1.3 . CEREBEL L OF UGAL ATROPHIES
preserved staining of the uninvolved superior
cerebellar peduncles, tegmentum, and pyramidal Dentato-rubral atrophy is characterized by atrophy
tracts (Fig. 8.30). of the dentate nucleus and its efferent fibers in the
A B
FIGURE 8.30 Olivopontocerebellar atrophy in a case of MSA (Loyez stain for myelin). (A) Upper pons: mas-
sive myelin loss of pontocerebellar fibers sparing the superior cerebellar peduncles, tegmentum, and pyramidal
tracts. (B) Medulla: loss of olivocerebellar fibers; note the pale appearance of the median raphe due to loss of
crossing fibers. (C) Medulla and cerebellum: myelin loss of the cerebellar white matter with relative sparing of
the amiculum of the dentate nucleus.

superior cerebellar peduncles and of the red nucleus 5 .2 . 1. FRIEDREICH ATAXIA
(Fig. 8.29D). Spared Purkinje cell axons may form
A childhood-onset illness, FA typically mani-
large growth cones in the dentate nucleus, vis-
fests with some combination of clumsiness, gait
ible on H&E stain and responsible for the aspect
ataxia, and signs of sensory peripheral neuropathy.
of “grumose degeneration.” It may be associated
Weakness and spasticity often emerge and can be
with pallidal atrophy in the inherited condition
a source of significant morbidity. Skeletal changes
dentato-rubro-pallido-luysial atrophy.
including scoliosis and pes cavum are common, as is
a hypertrophic cardiomyopathy (seen in up to 75%
5. 1. 4. S E CONDARY C ER EB EL L A R of cases), as well as diabetes (seen in a third of cases).
AT R O PHI E S The disease is caused by mutations in the gene
on chromosome 9 coding for the protein frataxin.
Although strictly speaking the following patterns Normal frataxin is an 18 kDa mitochondrial protein
of pathology are not degenerative disease, they are with 210 amino acids involved in the regulation of
classically considered in this context. iron homeostasis in mitochondria. The most com-
mon mutation is expansion of an intronic GAA
5.1.4.1. Crossed cerebellar atrophy This uni- repeat in the gene, which may reach 1,000 copies,
lateral general atrophy of all the neocerebellar struc- with the normal length ranging from 6 to 34.
tures is secondary to massive destruction of the
efferent corticopontine pathways. It is a rare con- 5.2.1.1. Gross appearance The spinal cord and
sequence of extensive contralateral cerebral hemi- dorsal roots are consistently atrophic. The volume
spheric lesions and only seen when the survival after of the cerebellum is often unremarkable, but the
the initial lesions has been long. Crossed cerebellar degeneration of the dentate nucleus results in wid-
atrophy, which has been occasionally described in ening of the superior end of the fourth ventricle as
adults, is particularly obvious when the responsi- the superior cerebellar peduncles atrophy. Systemic
ble lesion has developed in utero or in the neonatal manifestations often include cardiomegaly and a
period. characteristic diffuse cardiac fibrosis, which is dis-
tinguishable from the scarring seen after myocardial
5.1.4.2. Pseudohypertrophy of the infe- infarction.
rior olive Palatal myoclonus (rhythmical move-
ments of the soft palate occurring 60 to 180 times 5.2.1.2. Microscopic findings Spinal cord
a minute) is associated with hypertrophy of the sensory input is severely affected with loss of large
inferior olive in which enlarged neurons may myelinated axons, dorsal root ganglion cells, and the
appear “fenestrated” (i.e. contain lacunae in their dorsal columns. Involvement of the spinocerebellar
cell body). Olive hypertrophy is secondary to a tracts is also characteristic (Fig. 8.31). Clarke’s col-
longstanding, usually vascular, contralateral lesion umns, from which the dorsal spinocerebellar tract
involving the dentate nucleus or the superior cer- arises, show neuronal loss and the dorsal spinocere-
ebellar peduncle, or to an ipsilateral lesion of the bellar tract appears degenerated, atrophied, and pale
central tegmental tract. in myelin stains. The ventral spinocerebellar tract is
generally less severely involved. There is severe neu-
5.2. Autosomal Recessive ronal loss in the dentate nuclei, and the cerebellar
Cerebellar Ataxias white matter is generally gliotic although the cer-
ebellar cortex is usually normal, as are the inferior
Cerebellar ataxias with autosomal recessive inheri- olives. The pyramidal tract often shows myelin pal-
tance are an important group of relatively rare dis- lor. Cardiomyopathy with fibrosis is frequently pres-
orders, with patients commonly showing early age ent and may lead to cardiac failure.
of onset and often with associated lesions outside
of the cerebellar system. The two most frequent
5 .2 . 2. ATAXIA- TELAN GIECTASIA
of these diseases (Friedreich ataxia [FA] and
ataxia-telangiectasia [AT]) will be considered here This is the most common cause of progressive
with another rare disorder that may be prevented by ataxia in infancy and is caused by mutations in a
adequate treatment (vitamin E). gene (ataxia-telangiectasia mutated [ATM]) on
A 5.2.3 . CEREBEL L AR ATAXIA WITH
ISO L ATED VITAMIN E DEF ICIENCY
This neurological condition has been described in
patients with mutations of the alpha-tocopherol trans-
fer protein gene, leading to low availability of vitamin
E. Symptoms are similar to that seen in FA. The dis-
ease has a relatively high prevalence in NorthAfrica.
Neuropathology shows axonal spheroids with
B degeneration at the rostral ends of the posterior
columns and lipofuscin accumulation in neurons,
especially those of dorsal root ganglia. There may
be Purkinje cell loss. Early treatment with vitamin E
prevents the occurrence of lesions.
C 5.3. Autosomal Dominant Cerebellar

Ataxias
About three dozen distinct forms of this complex
set of diseases are now recognized; they are col-
lectively termed spinocerebellar ataxias (SCA).
Within this heterogenous group of diseases, a set
of disorders are polyglutamine diseases, similar to
HD: SCA1, SCA2, SCA3, SCA6, SCA7, SCA17,
and dentato-rubro-pallido-luysian atrophy. Among
FIGURE 8.31 Friedreich ataxia (Loyez stain for
the other loci, a range of types of genetic mutation,
myelin). Sections of the spinal cord at cervical (A),
including frameshift mutations, point mutations,
thoracic (B), and lumbar (C) levels. Involvement of
deletions, expansion of noncoding repeats, and mis-
the spinocerebellar tracts, mostly dorsal, and of the
dorsal columns. Note the early involvement of the
sense mutations, have been described; for some, a
pyramidal tracts in this case. mapped locus but not an identified genetic altera-
tion has been identified. A summary of the pres-
ent classification of autosomal dominant cerebellar
chromosome 11q. The common symptoms (in ataxias is presented in Table 8.5.
relative order of appearance) are the combination While the detailed discussion of the patterns of
of oculomotor apraxia, cerebellar ataxia, and con- clinical symptomatology and gross and microscopic
junctival telangiectasias. Patients have increased pathological changes in each one of these diseases
sensitivity to injury from ionizing radiation, which is clearly well beyond the scope of this chapter, a
can be attributed to the role of the ATM protein few generalizations can be made. By and large, those
in the regulation of DNA repair mechanisms. This forms of SCA linked to expanded polyglutamine
dysfunction is also associated with some degree of tracts show some clinical similarities with HD: the
immunodeficiency as well as an increased risk of age of onset is inversely correlated with the length
leukemia and lymphoma. of the repeat; “anticipation” (see above) is due to
With progression of the disease, there is cerebel- expansion of the repeat during genetic transmis-
lar degeneration, typically involving the Purkinje sion. Intranuclear inclusions in neurons contain
cells as well as the dentate nucleus; dorsal column ubiquitinated proteins, including the expanded
involvement can be seen as well as lower motor polyglutamine portion of the mutated protein. Of
neuron degenerations. In addition, histological note, patients with two of the CAG-repeat forms of
examination shows bizarre large, irregular, and SCA (SCA17 and DRPLA) can also have a clinical
hyperchromatic nuclei associated with vascular presentation that mimics HD, with prominent cho-
endothelial cells. This form of vascular abnormality reoathetosis. In all of the SCAs, there is commonly
appears to be independent of the telangiectasias that involvement of a range of brain structures outside
contribute to the name of the entity. of the cerebellum—and this is the basis for the

Table 8.5. Autosomal Dominant Forms of Cerebellar Ataxia with Known Mutations
DISORDER CHROMOSOME PRODUCT T YPICA L DISE ASE T YPICAL

R E P E AT S NORMAL
R E P E AT S
SCA1 6p23 Ataxin-1 42 to 81 (CAG) 16 to 36

SCA2 12q24 Ataxin-2 35 to 64 (CAG) 15 to 24
SCA3/MJD 14q Ataxin-3 68 to 79 (CAG) 13 to 36
SCA4 16q22.1 Unknown
SCA5 11p12-q12 Unknown Anticipation seen
SCA6 19p CACNA1A 21 to 30 (CAG) 6 to 17
SCA7 3p21 Ataxin-7 38 to 130 (CAG) 7 to17
SCA8 13q21 Transcribed but 16 to 37 (CTG) 107 to 127
untranslated
SCA10 22q13 Transcribed but 800 to 4,500 (ATTCT) 10 to 22
untranslated
SCA11 15q14-21.3 Unknown
SCA12 5q31 PPP2R2B 66 to 93 < 29
SCA15 Unlinked Unknown
SCA16 8q23-24 Unknown
SCA17 6q27 TBP 63 (CAG) 25 to 42
SCA27 13 Fibroblast growth Point mutation
factor 14 (FGF14)
SCA28 18p11 ATPase family gene Missense mutation
3-like 2 (AFG3L2)
presence of additional symptoms of neurological can emerge in males and, less frequently, in obligate
dysfunction. For example, patients with SCA7 have carrier females. Characteristically, patients develop
associated retinal degeneration that can progress to progressive ataxia with onset in adult life, often
blindness. Combinations of pyramidal and extra- associated with tremor and parkinsonism. Sensory
pyramidal motor disturbances as well as peripheral nerves are commonly involved as well. While there
neuropathy and other signs referable to focal degen- may be gross atrophy of the cerebellum, microscopic
erative changes can be seen in the SCAs. findings include loss of Purkinje cells, widespread
changes in white matter with volume loss and vacu-
olization, and the presence of ubiquitin-positive
5.4. Fragile X Tremor/Ataxia intranuclear inclusions in neurons and glia.
Syndrome
The fragile X syndrome is one of the causes of men-
tal retardation, with the pathological expansion of a
5.5. Sporadic
noncoding trinucleotide repeat (CGG) in the frag-
Degenerative Ataxia
ile X mental retardation 1 (FMR1) gene being the Even with the increasing number of genetically
underlying mutation. When the repeat length is in determined forms of cerebellar system degenera-
the “premutation” range (typically described as 55 tion, some cases still fall outside of the currently
to 200 copies), a cerebellar degenerative disease established categories. While some patients with
progressive ataxia have multiple system atrophy While much of ALS appears to be sporadic,
(vide supra) in which other portions of the nervous familial forms account for about 5% to 10% of
system are involved, there remain others—typi- cases, with an ever-increasing spectrum of muta-
cally with idiopathic late-onset cerebellar ataxia, tions and genetic loci being identified. While auto-
associated with cerebellar cortical atrophy and somal dominant inheritance is most common, both
some involvement of afferent and efferent paths and recessive and X-linked patterns of inheritance also
nuclei. occur. Mutations involving superoxide dismutase
(SOD1) were among the first recognized to cause
familial ALS (fALS), with different point muta-
6. MOTOR NEURON tions associated with a range of disease spectrums,
DISEASES including both age of onset and rate of progression.
While the specific mechanism of cellular injury
Within the brain and spinal cord, a variety of neu-
from the mutant SOD1 remains unclear, it is gener-
rons are referred to as being motor neurons—there
ally believed to represent a novel gain-of-function
are the cholinergic neurons in brainstem nuclei
rather than being the consequence of loss of normal
and the anterior horn of the spinal cord that proj-
enzymatic activity. A range of other genetic loci have
ect directly to muscle endplates (also known as
been identified that can cause ALS, but of particular
lower motor neurons) as well as the large glutama-
interest are those that overlap with familial forms
tergic pyramidal neuronal of the precentral gyrus
of FTLD. As was considered above, associations of
that descend from the cortex to innervate the lower
ALS and forms of FTLD are relatively common, and
motor neurons (and these are known as upper
this relationship has been strengthened by the recog-
motor neurons). While a range of other neurons
nition that disease-associated mutations in TDP43,
contribute to motor output, it is the involvement of
FUS, and C9orf72 are linked to both processes.
these two sets of neurons that defines this category
of illnesses. In addition to the neurodegenerative
disorders, motor system degeneration may be seen 6.1.1 . GROSS APPEARANCE
in a variety of other conditions, including toxic and
Usually, the brain appears macroscopically normal.
metabolic disorders and infectious diseases.
Atrophy of the precentral gyrus can occur with long
survival, particularly when nutritional and ventila-
tor support has been provided. In patients who have
6.1. Amyotrophic Lateral Sclerosis developed clinical dementia, atrophy of frontal and
Amyotrophic lateral sclerosis (ALS) is characterized temporal lobes may be present. Gross evidence of
by degeneration of both upper motor neurons and changes in the descending corticospinal tracts is
lower motor neurons. While the balance between often evident in the medullary pyramids, while the
the severity and pace of involvement of these two atrophy of roots of the hypoglossal nerve reflects
sets of neurons may vary from case to case, the com- bulbar lower motor neuron involvement. Motor cra-
bination is characteristic of ALS. In many cases, the nial nerves associated with extraocular muscles (III,
disease begins with involvement of spinal lower IV, and VI) are not affected. The spinal cord is usu-
motor neurons manifesting as weakness in the arms ally thinner than normal, with discoloration of the
or legs. In others, ALS begins with bulbar symptoms lateral funiculus. Anterior nerve roots are generally
and may be termed progressive bulbar palsy. shrunken and gray in comparison with the posterior
Infrequently, the upper motor neurons may be sensory roots (Fig. 8.32).
predominantly involved in the face of preserved
lower motor neurons; this disorder is typically
6.1.2 . MICROSCOPIC L ESIONS
referred to as primary lateral sclerosis, drawing its
name from the changes in the descending cortico- The most prominent neuronal loss, with associated
spinal tracts of the lateral portion of the spinal cord. astrocytosis, is found in anterior horns of the spi-
The other pattern, with loss of lower but preserva- nal cord (Fig. 8.33), some brainstem motor nuclei,
tion of upper motor neurons and their associated and the motor cortex. Within these structures, the
corticospinal fibers, is referred to as progressive injury is relatively restricted to a specific population
muscular atrophy. of neurons: motor neurons in the spinal cord and

changes can be observed in these tracts at more
rostral levels, including the medullary pyramids
(Fig. 8.34A), the basis pontis, and the cerebral
peduncles. It is uncommon to be able to detect the
loss of these descending fibers at higher levels than
the upper brainstem, such as within the posterior
limb of the internal capsule.
Although the overall gross and microscopic
appearance of ALS is the same for sporadic and famil-
ial forms (including across the spectrum of different
mutations), it is possible to demonstrate differences
using immunohistochemistry directed against vari-
FIGURE 8.32 Motor neuron disease. On the ous proteins. It has been observed that aggregates of
left, the spinal cord viewed from the dorsal surface SOD1 in an abnormal conformation can be detected
shows normal-sized posterior (sensory) nerve roots. in anterior horn cells both in sporadic ALS and in the
In contrast, the spinal cord viewed from the ventral setting of SOD1-linked fALS, although this is little
surface(right) shows marked atrophy of anterior used in diagnostic practice. In contrast, immunohis-
(motor) nerve roots in a case of amyotrophic lateral tochemistry for ubiquitinated TDP-43-containing
sclerosis. inclusions will reveal aggregates of thread-like struc-
tures termed skeins in surviving motor neurons in
the setting of sporadic ALS or fALS associated with
the involved brainstem nuclei (hypoglossal nucleus, TDP-43 mutations or expansion of the hexanucleo-
nucleus ambiguus, motor nucleus of trigeminal tide repeat in C90rf72 but not in the setting of SOD1
nerve and of facial nerve), while in the motor cor- mutations (see Fig. 1.15). In contrast, ubiquiti-
tex, the large projecting pyramidal neurons of layer nated, TDP43-negative, FUS-positive inclusions are
V (Betz cells) are targeted. Even when it is difficult observed in the setting of FUS-linked fALS.
to determine whether there is loss of Betz cells, glio-
sis at the gray–white junction of the precentral gyrus
is commonly observed. 6.2. Spinal Muscular Atrophy
Associated with the loss of upper motor neurons, In this condition, spinal motor neurons progres-
the white matter of the spinal cord shows pallor in sively degenerate, with resulting severe weakness.
both the lateral and anterior corticospinal tracts, Primarily a pediatric disorder, the disease is similar
related to their degeneration. Pallor of myelin stain- to other degenerative diseases where the more severe
ing may also be seen in the corticospinal tracts as forms occur with earlier onset. The spectrum ranges
they descend in the brainstem (Fig. 8.34B). Similar from a neonatal and rapidly fatal form (SMA 0) to
an infrequently observed adult-onset form (SMA
4). The two best-recognized patterns are SMA 1
(Werdnig-Hoffmann disease), with onset during the
first 6 months of life, in which children never achieve
the developmental milestone of sitting, and SMA 3
(Kugelberg-Welander disease), with onset around
the second birthday, in which children start to walk
before the onset of motor weakness. As would be
expected, there is atrophy of skeletal muscles and of
anterior nerve roots along with loss of motor neu-
rons from the anterior horns of the spinal cord.
All of these different phenotypes of the disease
are linked to mutations in the pair of genes SMN1
and SMN2, which sit as an inverted repeat on the
FIGURE 8.33 Motor neuron disease. This long arm of chromosome 5 (5q13). In addition to
low-magnification view shows severe loss of motor the few single amino acid differences between the
neurons in the anterior horns of the spinal cord. protein products of the two genes, there is also a
A B
FIGURE 8.34 Amyotrophic lateral sclerosis. (A) Pallor of myelin staining of the medullary pyramid.
(B) Sections of the spinal cord at cervical, thoracic, and lumbar levels show pallor of myelin staining in
uncrossed and crossed pyramidal tracts (Loyez stain).
difference that decreases the efficiency of splic- 6.4. Hereditary Spastic

ing into the mRNA of exon 7 from SMN2. As a Paraparesis
result, the SMN2 gene is far less efficient at gener-
ating function SMN protein than the SMN1 gene. Hereditary spastic paraparesis is a genetically and clin-
The severity of the phenotype is associated with ically heterogeneous set of disorders in which patients
the number of copies of SMN2 present in the set- develop slowly progressive paraparesis beginning
ting of homozygous loss of SMN1. Currently novel with the legs and having more spasticity than weak-
therapeutic approaches to this disorder are focused ness. These symptoms reflect a length-dependent
on alteration of the splicing of SMN2 mRNA or axonal injury process involving the descending corti-
mutagenic conversion of the SMN2 gene into an cospinal tracts. There can be variability in age of onset
SMN1 gene. (even within kindreds), in severity, and in associated
other symptoms (sensory changes, cerebellar ataxia,
epilepsy, and intellectual deficit). Despite the het-
erogeneity, autosomal dominantly inherited forms
6.3. X-linked Spinal and Bulbar predominate, with mutations in the gene encoding
Muscular Atrophy (Kennedy spastin (SPG4/SPAST) being the most common
Disease) overall, although aspects of the complex clinical phe-
This disorder involves lower motor neurons of the notype can direct suspicion toward other known loci.
spinal cord and brainstem, with typical onset of There is degeneration of corticospinal tracts, most
symptoms in early to middle adult life. Men are marked in the lumbar and lower thoracic cord, with
predominantly affected, as the causative muta- preservation of anterior horn cells. In those cases with
tion is an expansion of a polyglutamine tract in clinical evidence of sensory changes, degeneration of
the androgen receptor, which is encoded by a gene dorsal columns may also be observed. In keeping with
on the X chromosome. Neurological involvement the length-dependent pattern of the disease, this is
typically includes weakness, muscle atrophy with most marked in the upper thoracic and cervical cord.
fasciculations, and decreased tone without spastic-
ity. Systemic findings such as gynecomastia and tes- 7. INVOLVEMENT
ticular atrophy emerge as well, as a consequence of
relative androgen insensitivity. Grossly, there can be OF THE CENTRAL
evidence of motor root atrophy both in the brain- AUTONOMIC SYSTEMS
stem and spinal cord. Microscopic examination IN DEGENERATIVE
reveals the corresponding loss of motor neurons
from these nuclei, with the appearance of ubiquiti-
DISORDERS
nated polyglutamate-containing intranuclear inclu- There are many causes of autonomic failure, which
sions in remaining neurons. may be divided into primary and secondary types.

Some are due to lesions of the central nervous sys- to develop over time. In both cases, autonomic dys-
tem and some to lesions in the peripheral nervous function is related to loss of cells from the interme-
system. Patients who have autonomic failure with diolateral column of the spinal cord. At autopsy of
parkinsonism almost always have either MSA with patients who have primary progressive autonomic
glial cytoplasmic inclusions or Lewy body pathol- failure without any other neurological symptoms,
ogy. In MSA cases, it is not uncommon for other the sympathetic ganglia may contain Lewy bodies
clinical features of MSA (such as cerebellar ataxia) or may show the characteristic inclusions of MSA.
9
Acquired Metabolic Disorders
L E I L A C HI M E LLI AND F R A N Ç O I S E G R AY
A WIDE range of systemic acquired metabolic of receptors for various excitatory amino acids may
diseases can also affect the central and/or periph- also play a role in some others.
eral nervous system (e.g. hypoxia, hypoglycemia,
disorders of serum electrolytes, vitamin deficien-
cies, and exogenous intoxications). By and large,
the morphologic manifestations of most of these
1. CEREBRAL HYPOXIA
diseases in the various organs of the body are non- The brain normally receives about 15% of the
specific. In the central nervous system (CNS), on cardiac output, consumes about 20% of the
the other hand, lesions may find expression via blood oxygen, and consumes about 10% to 20%
selective involvement of some brain regions with of the blood glucose. Different states of deficient
simultaneous complete preservation of others, a oxygen supply and utilization or deficient sub-
phenomenon often referred to as selective vulnerabil- strate may produce prominent cerebral hypoxic
ity. The pathogenesis of the predisposition to injury changes:
of some anatomical areas and/or of some specific,
largely neuronal, cell types varies considerably from • Anoxic or hypoxic hypoxia results from decreased
one disease to another and is undoubtedly multifac- pulmonary access to oxygen. This may be due
torial in all. Differences in the vascular patterns of to insufficient oxygen in the inspired air. It also
irrigation and resulting alterations in regional perfu- may result from upper airway obstruction or may
sion may explain, at least partly, the phenomenon of accompany pulmonary disorders that impede the
selective vulnerability in some disorders. Regional uptake of oxygen. In rare instances (i.e., hyper-
variations in the biochemical characteristics of neu- thermia) it may be due to increased metabolic
ronal populations or, most likely, in the distribution demand.
• 205
• Anemic hypoxia results from decreased oxygen
transport, either from reduced hemoglobin levels
or reduced capacity of the hemoglobin molecule
to transport oxygen, as occurs in carbon monox-
ide poisoning.
• Stagnant hypoxia results from reduction or ces-
sation of blood flow. This can be the result of
impaired cardiac output producing global isch-
emia, or can be localized as is the case in brain
infarcts. The cerebral lesions that result from
stagnant hypoxia are due to a combination of an
inadequate supply of oxygen and glucose and an
accumulation of lactic acid.
• Histotoxic hypoxia results from exposure to intoxi- FIGURE 9.1 Laminar cortical necrosis. This is often
most severe in the posterior frontal and parietal lobes.
cants, such as cyanide or hydrogen sulfide, which
render the neural parenchyma incapable of utiliz-
ing oxygen and substrates.
• Oxyachrestic hypoxia results from severe hypogly- The hippocampus (Ammon’s horn) often shows
cemia, where oxygen is not utilized because of the selective involvement by hypoxia. This is most evi-
severe metabolic substrate deficiency. dent in the CA1 sector (an area that corresponds
to what is anatomically defined as Sommer’s sec-
tor) (Fig. 9.2A, B). The CA3 area (also referred to
1.1. Basic Cellular Reactions as the endplate) is often less severely affected. The
to Injury CA2 area tends to be relatively resistant to hypoxic
changes. The regional variation in the susceptibil-
The basic cellular reactions to injury (see Chapter 1)
ity of the pyramidal hippocampal neurons is now
seen in cerebral hypoxia mostly involve neurons
best explained by implicating the distribution of
(ischemic nerve cell change); glial cells may also be
excitotoxic receptors as an important pathogenetic
affected and this may be manifest, for example, as
factor.
glial necrosis, reactive gliosis, or rod-shaped microg-
Among the basal ganglia, the pallidum (espe-
lia and macrophage proliferation.
cially the medial portion) (Fig. 9.3), the striatum,
especially the lateral half of the putamen, and the
thalamus are selectively vulnerable to hypoxia. The
1.2. Selective Tissue Lesions mammillary bodies may be especially vulnerable
The cellular changes resulting from hypoxia are when hypoxia occurs in infancy.
maximal in those areas of the brain that are regarded In the cerebellum, cortical involvement is frequent
as showing selective vulnerability. and affects chiefly the Purkinje cells with secondary
In the cerebral cortex, the neuronal changes are proliferation of Bergmann glia. The dentate nucleus
more pronounced in the third, fifth, and sixth layers is also frequently involved.
of the neocortex. In addition, the changes are more In the brainstem, the medullary olives are vulner-
severe in the depths of sulci than along the banks or able areas. In children, the brainstem is sometimes
the apices of the gyri. Widespread, severe destruc- severely damaged, especially the medial and lateral
tion of the deeper layers of the cortex leads to lami- reticular formations and the adjacent cranial nerve
nar (or pseudo-laminar) necrosis (Fig. 9.1). This nuclei.
descriptive term applies to a phenomenon whereby Various types of white matter lesions may be
the distribution of the necrosis is confined to one or seen in isolation in response to anoxia or in asso-
more layers of the isocortex and may be especially ciation with gray matter damage. Some white mat-
evident in the parietal and occipital lobes, where ter lesions consist predominantly of extravasation
impaired perfusion may exacerbate the effects of of edema fluid due to increased vascular perme-
hypoxia. In the most severe cases, the cortical necro- ability but with preservation of endothelial cells.
sis is not selective. These lesions currently are designated as reversible
A B
FIGURE 9.2 Cerebral anoxia, involvement of the hippocampus. (A) Gross appearance. (B) Microscopy. Note
the cell loss from the CA1 sector and to a lesser extent the endplate (Luxol fast blue myelin stain).
leukoencephalopathy and may be seen in hypoxia and that interval, a variable degree of cerebral swell-
other acquired metabolic disturbances or intoxica- ing may be observed. In cases of sudden death
tions. Other white matter lesions, often designated or where only moderate cerebral hypoxia has
collectively as hypoxic encephalopathy, consist of occurred, unquestionable signs of hypoxia may
varying proportions of demyelination and white be discerned solely on histological examination;
matter necrosis. The degree of severity of these these changes consist of ischemic neurons in the
lesions ranges from small, perivascular foci of demy- most vulnerable areas, where they are difficult to
elination, to focal plaque-like areas of demyelination detect before 4 to 12 hours of survival beyond the
and necrosis, and up to large confluent areas of insult.
demyelination and necrosis. The lesions tend to be Depending on the mechanism of cerebral anoxia,
most severe deep in the white matter and are often separate and distinctive patterns of ischemic changes
associated with relative preservation of the subcorti- are recognized.
cal “U” fibers (Fig. 9.4).
1.3. Variation of Lesions

According to Etiology
A survival time of approximately 48 hours is
necessary for macroscopically visible lesions of
cerebral hypoxia to become apparent. Before
FIGURE 9.4 Whole-brain section showing exten-

sive white matter demyelination with preservation of
FIGURE 9.3 Bilateral necrosis of the pallidum, the U fibers in hypoxic leukoencephalopathy (Loyez
gross appearance. stain).
Chapter 9 Acquired Metabolic Disorders • 207

1. 3. 1. C E RE BRAL I N FA R C TS carboxyhemoglobin; that hue is also imparted to
the external and cut surface of the brain (Fig. 9.6).
Cerebral infarcts are the result of localized ischemic
Scattered petechial hemorrhages also may be pres-
hypoxia due to vascular occlusion (see Chapter 4).
ent. With prolonged formalin fixation, the red dis-
Infarcts and/or ischemic lesions in the boundary
coloration becomes less prominent.
zone areas are the result of global oligemic hypoxia,
Some individuals who seem to recover clinically
especially in the setting of low cerebral blood flow of
from acute toxic exposure to CO may, some days to
sudden onset, even of short duration. These lesions
weeks later, develop a neurological syndrome that
are one of the possible consequences of acute heart
includes neuropsychiatric manifestations includ-
failure (cardiogenic shock), drug-induced hypoten-
ing personality changes, parkinsonism, dementia,
sion, or general anesthesia.
incontinence, and frank psychosis. In these cases,
different combinations of the neuropathological
1. 3. 2. C ARDI OVASCU L A R A R R ES T abnormalities described below may be found.
Pallidal necrosis is most often observed in fatal
Cardiovascular arrest exceeding three to four min- cases of CO intoxication occurring after some delay
utes at normal temperature ordinarily causes diffuse after the insult (6 or more days). Microscopic foci
cortical lesions and Ammon’s horn involvement; the of ischemic or hemorrhagic necrosis may develop
distribution and extent of damage in the basal gan- even sooner. The pallidal lesions are usually bilat-
glia and in the brainstem vary (Fig. 9.5). Comparable eral but are often asymmetrical. The necrosis usually
lesions are caused by profound hypoglycemia (vide involves the anterior portion and inner segment of
infra) and status epilepticus. the pallidum but may extend into the outer segment
or dorsally into the internal capsule. Although pal-
1. 3. 3. C ARBON MONO X I D E P O I S O NI N G lidal necrosis is characteristic of and frequently seen
in delayed deaths from CO, it may also be seen in
Carbon monoxide (CO) is produced by incom- other conditions associated with hypoxia or anoxia
plete combustion of carbon-containing substances. (Figs. 9.3, 9.7, and 9.8). The selective involvement
Humans are exposed to CO mainly through auto- of the globus pallidus in CO poisoning has been
mobile exhaust, improperly ventilated stoves or
heaters, and tobacco smoke. The toxic effects of
CO result primarily from the decreased capacity of
blood to transport oxygen.
At autopsy examination, the brain of an indi-
vidual who dies within a few hours of intoxication
is diffusely swollen and congested. The blood within
vessels has the characteristic cherry-red color of
FIGURE 9.6 Macroscopic image of the brain from

patient with acute CO poisoning. The postmortem
FIGURE 9.5 Diffuse cortical and basal ganglia blood CO saturation was 60%.The cherry-red color
lesions in a case of delayed death following cardiovas- of the carboxyhemoglobin imparts a red hue to the
cular arrest. entire brain.
FIGURE 9.7 Coronal section showing bilateral
pallidal necrosis. This can be seen following delayed
death from CO or other hypoxic conditions.
FIGURE 9.8 CO poisoning. Necrosis of the pal-

attributed to selective vulnerability of pallidal neu-
lidum and white matter necrosis in a case of Grinker
rons, the result of hypotension and impaired circu- myelinopathy (Loyez stain).
lation through the pallidal branches of the anterior
choroidal arteries, or the relatively high iron content
of this portion of the brain, which somehow renders
the structure especially susceptible. develop. If death occurs some time later, the brain
Other gray matter regions involved include the may show foci of necrosis in the basal ganglia and
neocortical and hippocampal neurons, and the cer- white matter and loss of Purkinje cells.
ebellar Purkinje cells and granule cells, where there
may be focal neuronal loss.
Lesions of the white matter are also encountered 1.3.5 . HYPOGLYCEMIA
in individuals who die some time after CO poi- Glucose is the principal source of energy in the
soning. These lesions consist of varying degrees of CNS. Neuronal stores of glucose and glycogen are
demyelination and associated necrosis. There may relatively small and need practically continuous
be small perivascular foci found in the deep white replenishment. A decrease of glucose level under
matter, large confluent areas that extend from the 1.5mmol/L (25 to 30mg/100mL) leads to brain
frontal to occipital poles in the periventricular white damage within one to two hours.
matter, or sharply demarcated foci of demyelination The most common cause of hypoglycemia is an
with relative sparing of axons in the deep white mat- excess of exogenous insulin. The effects of hypo-
ter (“Grinker’s myelinopathy”) (Fig. 9.8). All these glycemia are not due just to the energy deficit.
lesions tend to spare the arcuate fibers. Releases of aspartate and to a lesser extent release of
glutamate probably contribute to neuronal damage
through excitotoxic mechanisms.
1.3.4. CYANIDES
In acute hypoglycemia, the lesions are similar to
Cyanides are histotoxic or cytotoxic agents, the tox- those of acute hypoxia but not identical. In general,
icity of which is due to bonding between the cyanide the pattern of injury is that of selective degeneration
ion and the ferric iron of intracellular cytochrome of neurons rather than frank necrosis of all other cel-
oxidase. This reaction leads to cessation of cellular lular components. Affected neurons are shrunken
respiration. Acute intoxication can result from either with hypereosinophilic cytoplasm. Initially, the
ingestion or inhalation of cyanides and causes respi- nucleus is pyknotic, as seen in anoxia, but later may
ratory arrest. Rarely, survivors of cyanide intoxica- become eosinophilic and appears to blend in with
tion may develop parkinsonism or dystonia. the cytoplasm (nuclear dropout). The topography of
When death is acute, the brain may be edematous the lesions is roughly similar to that in hypoxia, but
and in some cases focal subarachnoid hemorrhages Purkinje cells may be relatively spared.

In long-term survivors of severe hypoglycemia
who then come to postmortem examination, the
cerebral cortex may appear thinned and the hippo-
campi shrunken and discolored. The white matter is
reduced in bulk and the ventricles are dilated. There
may be marked atrophy of the caudate nucleus and
putamen. On microscopic study, the cerebral cortex
shows laminar neuronal loss and gliosis associated
with capillary proliferation. There is often dense
subpial gliosis. The hippocampal pyramidal cell
layer and subiculum are replaced by a loose mesh-
work of glial tissue. The white matter is usually rar-
efied and gliotic. The caudate nucleus and putamen
are diffusely gliotic. The globus pallidus is relatively FIGURE 9.9 Cross-section of pons from patient
with CPM. Note the ill-defined brown discoloration
spared. Moderate neuronal loss and gliosis may be
of the demyelinative lesion.
evident in the thalamus. As in acute hypoglycemia,
the cerebellar cortex, including the Purkinje cells, is
relatively spared. complication of the rapid rise in osmolality that
accompanies excessively rapid correction or
1. 3. 6. HYPE R T HE RM I A
over-correction of chronic hyponatremia. The clini-
cal manifestations vary according to the size of the
Acute hyperthermia or heat stroke is a thermal lesion—from asymptomatic to coma. In life, the
insult to the cerebral thermoregulatory system con- diagnosis can be made by MRI.
trolling heat production and heat dissipation. The At autopsy, the typical CPM lesion appears as a
thermal insult may be endogenous in “exertional discolored, destructive area in the basis pontis that
heat stroke” or environmental “classic heat stroke.” may be centrally cavitated (Fig. 9.9). The lesions
It is also a feature of malignant hyperthermia, an are often triangular, T-shaped, or diamond-shaped
autosomal dominant disorder of the skeletal muscle and vary from a few millimeters across (Fig. 9.10)
characterized by a hypermetabolic response to com- to lesions that involve nearly the entire basis pontis.
monly used inhalation anesthetics and depolarizing Even when the lesion is extensive, generally at least
muscle relaxants. Clinically heat stroke is defined as a a thin rim of intact tissue with myelin preservation
syndrome characterized by elevated core body tem-
perature over 40° Celsius and neurological dysfunc-
tion. Neuropathological studies are relatively few.
Abnormalities similar to those of hypoxic–ischemic
damage, probably resulting from a combination of
cardiovascular collapse and an increased metabolic
rate, have been described. Severe diffuse loss of
Purkinje cells with consequent degeneration of the
cerebellar efferent pathways is known to occur, but
often in the absence of injury to Ammon’s horn and
other areas susceptible to hypoxia.
2. ELECTROLYTIC
DISTURBANCES
2.1. Central Pontine Myelinolysis
Central pontine myelinolysis (CPM) is a mono-
phasic demyelinating disease that predominantly FIGURE 9.10 Triangular lesion of limited CPM
involves the basis pontis. It usually occurs as a (Loyez stain).
anatomically by close apposition of gray and white
matter structures.
2.2. Disorders of Iron Metabolism

In primary or secondary hemochromatosis, the
blood–brain barrier provides effective protection
against the diffusion of protein-bound iron into
the CNS. Therefore, hemosiderin iron deposits are
limited to regions of the CNS devoid of the blood–
brain barrier, including the choroid plexuses, the
area postrema, the pineal gland, adenohypophy-
FIGURE 9.11 Large section of pons from a patient sis, dorsal root ganglia, and a number of vestigial
with extensive CPM (Loyez stain for myelin). remnants such as the paraphysis and the subforni-
cal organ. These regions have a gross rusty appear-
is present at the lateral and ventral margins of the ance and show marked Prussian blue reaction with
basis pontis (Fig. 9.11). Demyelination is usually ferrocyanide.
maximal in the middle and rostral portions of the
pons. Lesions may extend to the middle cerebellar 2.3. Disorders of Calcium
peduncles. Metabolism
Histologically, the CPM lesion is character-
ized by demyelination with relative preservation Massive perivascular deposits including calcium
of axons and neuronal perikarya (Fig. 9.12). Acute (Fig. 9.13A) but also iron (Fig. 9.13B) and other
lesions contain numerous lipid-laden macro- minerals may be observed in the basal ganglia and
phages but few or no inflammatory cell infiltrates. sometimes in the dentate nucleus, the white mat-
Occasionally foci of necrosis and cavitation are ter, and Ammon’s horn (so-called Fahr syndrome)
present in the center of the more severe lesions. in a variety of circumstances, including hypo-
Sometimes, especially in more severe cases, CPM parathyroidism and conditions accompanied by
is accompanied by extrapontine demyelinated hypercalcemia.
lesions. These may involve the subcortical white
matter, striatum, anterior commissure, internal and
external capsules, lateral geniculate bodies, and 3. VITAMIN DEFICIENCY
cerebellar folia. As is the case in the pons, these DISORDERS
extrapontine sites of involvement are characterized
3.1. Thiamine Deficiency
The Wernicke-Korsakoff syndrome is caused by
thiamine (vitamin B1) deficiency from inadequate
intake (beriberi, prolonged intravenous therapy
without vitamin supplementation), significant
nutritional deficit as in fasting or famine, gastric
absorption defect such as in hyperemesis gravidarum,
gastrointestinal neoplasms, and gastric plication for
morbid obesity.
The distribution of the lesions of Wernicke
encephalopathy is characteristic (Figs. 9.14 and
9.15] and accounts for the symptoms, which
include disturbances of wakefulness, hypertonia,
FIGURE 9.12 Microscopic section of pons from a and ocular palsies. They are found in the periventric-
patient with CPM. Note the intact neuron in the midst ular areas, including the medial aspect of the thala-
of an area of demyelination (Klüver-Barrera stain). mus, hypothalamus, and mammillary bodies, the

A B
FIGURE 9.13 (A) Massive perivascular mineral deposits in a case of Fahr disease (H&E). (B) Iron perivascu-
lar deposits in the same patient revealed by Perl’s method for iron.
periaqueductal region at the level of the third cranial adjacent to the ventricular system and around the
nerve, the reticular formations of the midbrain, cau- aqueduct usually remains unaffected.
dal portion of the corpora quadrigemina, and the At microscopy, the acute lesions display edema,
floor of the fourth ventricle. The mammillary bodies petechial hemorrhages, myelin loss, and reactive
are the most frequently affected structures and are astrocytosis. Neurons are generally preserved.
involved in virtually all cases. Swelling and hyperplasia of endothelial cells make
The changes vary with the stage and severity of the capillaries abnormally prominent (Fig. 9.18).
the disease. At gross examination, when patients The perivascular spaces may contain lipid-laden
die during the acute stages of the disease, petechial macrophages. Extravasated erythrocytes and
hemorrhages involve predominantly the mammil- hemosiderin-laden macrophages are seen in the
lary bodies (Fig. 9.16) and sometimes may be more cases with grossly discernible petechial hemor-
extensive (Fig. 9.15). In contrast, the lesions may rhages. In the chronic stages of the disease and in
be inconspicuous grossly. Patients with less severe, treated patients the affected regions may show little
chronic, or previously treated disease may have more than mild loss of neurons and gliosis. Central
mildly atrophic mammillary bodies that are gray to chromatolysis of neurons may result from associated
brown in color as a result of hemosiderin deposition niacin deficiency (see below).
(Fig. 9.17). A narrow band of tissue immediately Korsakoff psychosis is defined clinically as ret-
rograde amnesia and an impaired ability to acquire
new information and is usually encountered in
alcoholic patients with chronic Wernicke encepha-
lopathy. The pathological basis of that syndrome is
debated. It does not seem to result from the lesions
of the mammillary bodies only. Involvement of the
medial dorsal nuclei (Figs. 9.15A and 9.19) and/or
midline region of the thalamus plays an important
causative role, according to some authors.
Thiamine deficiency also produces peripheral neu-
ropathy, including beriberi neuropathy and at least
some cases of so-called alcoholic polyneuropathy.
3.2. Pellagra
Pellagra is clinically manifest typically by dermatitis,
diarrhea, and dementia. The disease has long been
FIGURE 9.14 Topographical distribution of the recognized among malnourished individuals who
lesions in Wernicke encephalopathy. depended on corn as a major part of their diet. It
A B
C D
FIGURE 9.15 Wernicke encephalopathy: topographical distribution of the lesions (Loyez stain).

(A) Periventricular hemorrhagic thalamic lesions. (B) Lesions in the tegmentum of the midbrain at the level of
the third cranial nerve nuclei. (C) Hemorrhages in the tegmentum of the upper pons. (D) Hemorrhagic lesions
in the medullary floor of the fourth ventricle.
FIGURE 9.16 Acute Wernicke encephalopathy. FIGURE 9.17 Shrunken, discolored mammillary

Note the petechial hemorrhages in the mammillary bodies in a patient who had been treated for previous
bodies and, to a lesser extent, the walls of the third episodes of Wernicke encephalopathy.
ventricle.

dorsal nucleus of the vagus, the gracile and cuneate
nuclei, the nucleus ambiguus, the trigeminal nerve
nuclei, the oculomotor nuclei, the reticular forma-
tions, and the anterior horn motor neurons of the
spinal cord. In some cases of niacin deficiency there
may be degeneration of the posterior columns and
corticospinal tracts.
3.3. Vitamin B12 deficiency

Vitamin B12 is obtained primarily from meat and
dairy products. The vitamin must be bound to
FIGURE 9.18 Microscopic appearance of the “intrinsic factor,” a glycoprotein produced by the
mammillary bodies from a patient with Wernicke gastric parietal cells, prior to being absorbed by the
encephalopathy. Note the petechial hemorrhages and body through the ileum. Most cases of vitamin B12
the swelling of the endothelial cells deficiency actually result from inadequate produc-
tion of intrinsic factor. In pernicious anemia, this is
due to autoimmune atrophic gastritis, more rarely to
results from lack of P-P (pellagra preventive) factor gastric neoplasms or gastrectomy. Vitamin B12 defi-
(nicotinic acid or niacin). It is now known that deficiency also can result from impaired ileal absorp-
ciency of niacin itself, or of tryptophan, an amino tion, in individuals with malabsorption syndromes,
acid precursor of niacin that is deficient in corn, intestinal tuberculosis, regional enteritis, or lympho-
leads to pellagra. The disease has become very rare mas. Rarely the cause of the deficiency is the result
as the result of enriching common foods, such as of competitive utilization of the vitamin within the
bread, with niacin. This vitamin deficiency is now intestine by the fish tapeworm (Diphyllobothrium
encountered most often in patients with chronic latum) or bacterial overgrowth in intestinal blind
alcoholism. In these patients the disease may be clin- loops or diverticula. Very similar changes (“vacu-
ically atypical, lacking the characteristic skin lesions. olar myelopathy”) have been observed in AIDS
The neuropathological changes resulting from patients, resulting from abnormalities of vitamin
niacin deficiency consist of isolated neuronal B12 metabolism.
changes of central chromatolysis type (Fig. 9.20), Vitamin B12 deficiency affects the hematopoi-
without associated glial or vascular alterations. They etic (megaloblastic anemia), gastrointestinal (glossi-
affect, in decreasing order of frequency, the Betz cells tis, anorexia, diarrhea, and weight loss), and nervous
of the cerebral motor cortex, the pontine nuclei, the systems. Neurological complications develop in 40%
of untreated cases and can occur in the absence of
hematological abnormalities. The neuroanatomical/
clinical syndrome of nervous system involvement
has been termed subacute combined degeneration of
the spinal cord.
The spinal cord from patients with longstand-
ing severe vitamin B12 deficiency may be mildly
shrunken, with discolored posterior and lateral col-
umns. Histologically, the earliest lesions consist of
vacuolar distention of myelin sheaths, resulting in
a characteristic spongy appearance of the affected
white matter. With further demyelination, lipid-laden
macrophages become scattered throughout the
lesions. Some of the axons traversing the lesions
FIGURE 9.19 Petechial hemorrhages and myelin undergo Wallerian degeneration. Initially astrocyto-
loss in the thalamus from a patient with Korsakoff sis is not marked, but dense gliosis may be seen in
syndrome. patients who have had the disease for a protracted
A B
FIGURE 9.20 Pellagra encephalopathy. Microscopic picture of cell chromatolysis (H&E). (A) In nuclei pon-
tis. (B) In the gracile nucleus.
period. The distribution of the lesions is remark- also determine the extent and severity of the toxic
ably constant. They are bilateral and symmetrical insult. Accordingly, the neuropathological picture is
and involve chiefly the long tracts of the spinal cord. highly variable, reflecting the selective vulnerability
Initial lesions are found in the central part of the pos- of some of the neural structures and the diversity of
terior column of the thoracic cord, from where they the underlying mechanisms (e.g., energy deficiency,
extend peripherally and affect the corticospinal and excitotoxicity). Some lesions may also result from
spinocerebellar tracts in the lateral columns. In severe visceral disturbances caused by the intoxication. In
cases, the lesions may involve virtually all the white some toxic encephalopathies the peripheral nervous
matter, including the anterior columns, only sparing system may also be affected.
the fibers adjacent to the gray matter. The severity Here we describe the most widely recognized
of the lesions usually decreases toward the cervical toxic substances that are known to produce lesions
and lumbar levels, in which they are restricted to of the CNS.
the dorsal and lateral columns, often sparing a small
peripheral zone (Fig. 9.21]. However, changes of sec-
ondary ascending and descending tract degeneration 4.1. Ethanol
may be associated at those levels. Rarely, the lesions Ethanol has many effects upon the CNS. It is well
extend rostrally into the medulla. Occasionally, simi- known that alcoholism potentiates infections, con-
lar mixed demyelinative and destructive lesions may tributes to traumatic injuries, and may increase the
be seen in the optic nerve and cerebral white matter. risk of stroke, especially hemorrhagic stroke.
4. TOXIC 4.1.1 . ACUTE AL COHOL INTOXICATION

ENCEPHALOPATHIES
Ingestion of large quantities of alcohol can lead
The nervous system is particularly susceptible to directly to death from cardiorespiratory paralysis.
noxious agents. There are several reasons for this. Blood alcohol levels over 450 to 500 mg/dL are
Neurons are continually active and are highly suscep- generally considered as potentially lethal, although
tible to energy deprivation; also, they are post-mitotic there is considerable individual variation. Autopsy
cells and cannot divide as a response to toxic insults. examination of the brain in fatal cases of acute alco-
It is also important to recognize that the suscepti- hol intoxication usually shows only cerebral edema.
bility of cells of the CNS to toxic substances in dif-
ferent anatomical regions is quite variable. These
4.1.2 . CEREBRAL L ESIONS IN CHRONIC
differences are attributable in part to the anatomical
ALC OHOL ISM
blood–brain barrier’s differential susceptibility to
some toxic substances. The type of exposure, dose, Whereas a direct neurotoxic effect of excessive alco-
age, gender and inherent, probably genetic factors hol consumption on the nervous system remains

A B
FIGURE 9.21 Subacute combined degeneration of the spinal cord. (A) Klüver-Barrera stain showing spongy
appearance of the white matter in the central part of the posterior column of the thoracic cord. (B) Bodian Luxol
stain showing vacuolar distention of myelin sheaths. (C) Loyez myelin stain showing demyelination of the pos-
terior and lateral columns of the spinal cord.
controversial, patients suffering from chronic alco- The clinical manifestations evolve slowly over
holism develop a wide range of visceral lesions that months to years and include truncal instability, a
have a serious impact on the nervous system: wide-based stance, and an ataxic gait. The vermal
atrophy can be demonstrated by CT and MRI,
• Hepatic encephalopathy may result from decom- but the degree of atrophy does not correlate well
pensated cirrhosis leading to hepatic coma and/or with the severity of the clinical manifestations. The
occurring in the setting of a portocaval shunt (see lesions involve the rostral vermis (Fig. 9.22) and
below). to a lesser extent the superior surface of the cer-
• Cerebral lesions due to vitamin deficiency include ebellar hemispheres (Fig. 9.23). The folia are pale,
Wernicke-Korsakoff encephalopathy secondary to sclerotic, and separated by widened inter-folial
deficiency of vitamin B1 absorption due to alco- sulci. The atrophy affects the crests of the folia
holic gastritis and pseudopellagra encephalopathy, more severely than the depths of the inter-folial
with which it is frequently associated (see above). sulci. Microscopically, the lesions consist of loss of
• Alcoholic cerebellar degeneration may occur as Purkinje cells with proliferation of Bergmann glia
an isolated lesion or in association with other and variable depopulation of the internal granular
alcohol-related lesions, such as Wernicke cells. They are associated with lesions of the dorsal
encephalopathy. Its pathogenesis is unclear. laminae of the inferior olives. The cerebellar white
Morphologically similar but generally milder matter remains relatively unaffected.
cerebellar vermal atrophy can also occur as • Central pontine myelinolysis was first described
an age-related phenomenon independent of in individuals with chronic alcoholism but may
alcoholism. also be seen in other conditions in which severe
commissure (Fig. 9.24B), centrum semiovale
(Fig. 9.24A), and middle cerebellar peduncles.
Histologically, the lesions show loss of myelin with
abundant lipid-laden macrophages and relative spar-
ing of axons.
• Morel’s laminar sclerosis is known to occur in
chronic alcoholism. It is characterized by a glial
astrocytic band-like proliferation localized to the
third cortical layer, especially in the lateral frontal
cortex. This disease is usually associated with,
and probably secondary to, the callosal lesions of
Marchiafava-Bignami disease.
FIGURE 9.22 Superior vermal atrophy from a
patient with chronic alcoholism.
4.2. Methanol
Methanol poisoning resulting from oral intake, most
metabolic or electrolytic disturbances are present often as a substitute for ethanol, may cause acute cere-
(see Section 2.1). bral and ocular lesions. Methanol itself is neurotoxic;
• Marchiafava-Bignami disease is a rare disorder, its catabolites, including formaldehyde and formic
the pathophysiology of which is unknown. It acid, are even more toxic. Formic acid and formates
is observed in the setting of chronic alcohol- block cellular respiration and contribute to the meta-
ism of long duration and great severity. Rarely, bolic acidosis that is characteristic of this intoxication.
Marchiafava-Bignami disease has been described The ocular pathology of the blindness has been
in association with Wernicke encephalopathy or investigated extensively. The lesions include princi-
CPM. The disease is usually diagnosed at autopsy, pally optic disc edema and retrolaminar and optic
but the lesions may be seen by CT and MRI. nerve necrosis.
Grossly and macroscopically the lesions are Pathological changes in the brain include cerebral
demyelinated or partially necrotic regions in the edema, demyelination, and necrosis of the subcorti-
interior of the corpus callosum, with relative pres- cal white matter, the lateral aspect of the putamen,
ervation of a thin strip of myelinated fibers on its and the claustrum (Fig. 9.25). The putaminal necro-
dorsal and ventral surfaces. The involvement is sis is often hemorrhagic and may evolve into a mas-
maximal in the genu and body of the corpus cal- sive hematoma. The necrosis of the claustrum is
losum (Fig. 9.24) and may be accompanied by generally non-hemorrhagic. The white matter lesions
similar involvement of the optic chiasm, anterior and the retrolaminar demyelination of the optic
nerves are believed to be due to histotoxic myelinoc-
lastic damage caused by formates. The pathogenesis
of the putaminal lesions remains unclear.
4.3. Ethylene glycol
Ethylene glycol is a dihydroxy alcohol that is widely
used as a solvent and a component of certain anti-
freezes and coolants. Intoxication with this compound
is encountered most often when it is consumed as a
substitute for ethanol or with suicidal intent. Ethylene
glycol is progressively oxidized to more toxic com-
pounds, including glycoaldehyde, glycolic acid, and
glyoxylic acid. A small proportion is also oxidized
FIGURE 9.23 Atrophy of the rostral vermis and to oxalic acid. The clinical manifestations include
superior surface of the cerebellar hemispheres in a encephalopathy, severe metabolic acidosis, cardiopul-
patient with chronic alcoholism. monary failure, and acute renal failure.

A B
FIGURE 9.24 Marchiafava-Bignami disease. (A) Gross appearance showing necrosis of the interior of the corpus
callosum. Note involvement of the adjacent white matter. Whole-brain sections showing necrosis and demyelination
of the corpus callosum and anterior commissure (B) and splenium of corpus callosum (C) (Loyez myelin stain).
Macroscopic examination of the brain in fatal cases around intraparenchymal blood vessels. Deposits of
shows edema, meningeal congestion, and, occasion- calcium oxalate may be seen in and around blood
ally, petechial hemorrhages. Microscopically, acute vessels in the meninges, neural parenchyma, and
inflammatory cells may be seen in the meninges and choroid plexus. These crystals are birefringent under
polarized light (Fig. 9.26A, B).
4.4. Phenytoin
Patients with seizure disorders who have been
treated with phenytoin for prolonged periods may
develop cerebellar cortical atrophy, which can
be documented by CT and MRI during life or at
autopsy. Histopathological studies have shown
folial atrophy, loss of Purkinje cells throughout the
cerebellum, and mild loss of internal granular layer
cells (Fig. 9.27). Whether the drug itself is the sole
factor that causes toxic damage to Purkinje cells
has been difficult to establish since loss of Purkinje
cells may also be the result of hypoxia during sei-
FIGURE 9.25 Methanol intoxication. Note the zures or from preexisting brain damage. Reports
bilateral necrosis of the putamen and claustrum. of patients with seizure control under long-term
A B
FIGURE 9.26 Microscopic sections showing cerebellar cortex and leptomeninges from a patient with ethyl-
ene glycol intoxication. (A) Note the refractile calcium oxalate crystals in the vessel walls (H&E). (B) Note the
birefringence of the same crystals when viewed with polarized light.
phenytoin treatment, and who develop cerebellar the morphologic changes that may be seen include
atrophy, support the view that phenytoin itself may edematous or hemorrhagic lesions. In the majority
be neurotoxic. of cases, the brain lesions are secondary to the multi-
ple visceral disturbances caused by the intoxication.
4.5. Intoxication by Heavy

Metals and Certain Metalloids 4.5.1 . AL UMINUM
Many different metals and certain metalloids, in The neurotoxicity of this element is controversial.
sufficient concentration and determined chemi- Various aluminum compounds, applied directly
cal form, are toxic to humans. It is usually difficult onto or injected into the cerebral cortex of certain
to correlate a particular type of lesions with a spe- laboratory animals, produce seizures and neurofibril-
cific etiology. In some hyperacute fatal forms of lary tangles, but these lesions are different from the
intoxication, the clinical course may be so rapid Alzheimer neurofibrillary tangles seen in humans.
that, at the time of autopsy examination, histologi- Aluminum toxicity was described most com-
cal changes have not yet become evident. Some of monly in patients undergoing chronic hemodialysis
and is due to exposure to aluminum in the dialysate
and the use of oral phosphate binding compounds
that contain aluminum.
Dialysis dementia is a syndrome now largely dis-
appeared through the purification, of the water used
in dialysis, characterized clinically by dyspraxia,
asterixis, myoclonus, and dementia. In fatal cases
the brain aluminum content may become elevated
to levels even greater than reported in Alzheimer
disease but neurofibrillary tangles are not present.
4.5.2 . ARSENIC
Arsenic intoxication is encountered most often as
FIGURE 9.27 Microscopic section of cerebellar the result of occupational exposure or after inges-
folium from a patient who had been on long-term tion with homicidal or suicidal intent. Acute triva-
treatment with high-dose phenytoin. Note the loss of lent arsenic poisoning is characterized by abdominal
Purkinje cells and the mild loss of internal granular pain, nausea, vomiting, and diarrhea followed by
cell layer neurons. renal failure. Death may occur in severe cases.

Chronic arsenic intoxication is manifest by gastro- 4 .5 . 5. M ERCURY
intestinal and dermatological symptoms. A mixed
Acute poisoning from inorganic mercury com-
sensory and motor neuropathy is a well-known and
pounds is manifest clinically predominantly by
often disabling sequela of both acute and chronic
gastrointestinal tract and renal tubular injury.
arsenical intoxication. Encephalopathy also has been
Pulmonary injury is caused by inhalation of metallic
reported with acute and chronic arsenic intoxica-
mercury vapors. Neurotoxicity is also a prominent
tion. Acute hemorrhagic leukoencephalopathy has
manifestation of chronic inorganic mercury poison-
been reported in patients treated with organic pen-
ing, and patients present with behavioral changes,
tavalent arsenicals. This may have been the result of
intention tremor, and movement disorders; periph-
a hypersensitivity reaction to the drug, rather than
eral neuropathy may also develop.
arsenic intoxication.
Organic mercury intoxication is usually caused
by ingestion of contaminated food. Some years
4. 5. 3. L E AD ago, reports from Japan described a large number
of patients who developed chronic organic mer-
Lead can enter the body through the gastrointes- cury intoxication by eating fish contaminated by
tinal and respiratory tracts and, when in organic methyl mercury (Minamata disease). Other large
compounds, through the skin. Lead encephalopa- outbreaks have resulted from the consumption of
thy is now encountered predominantly in young grain treated with an organic mercury fungicide. The
children who chew on items coated with lead paint. clinical manifestations in these cases included corti-
Acute encephalopathy produces irritability, seizures, cal blindness, impaired proprioception, movement
altered consciousness, and evidence of increased disorders, mental retardation, and quadriparesis.
intracranial pressure. The intoxication usually The neuropathology of organic and inorganic
responds to sedation and chelation therapy but can mercury poisoning is essentially indistinguishable.
lead to permanent damage. Many authors attribute The slight differences that may exist possibly reflect
the encephalopathy to vascular injury, which seems variations in the rate of entry of mercury into the
to be more severe in the immature nervous system. nervous system. The lesions observed involve the
At gross examination, the brains are diffusely neurons predominantly. There is cerebral atrophy
swollen. The histological changes include conges- involving mainly the anterior portions of the cal-
tion, petechial hemorrhages, and foci of necrosis. carine fissures with loss of neurons, especially the
Intraparenchymal capillaries may show necrosis, outer cortical layers, and gliosis. Cerebellar atrophy
thrombosis, and swelling of endothelial cells. There is also frequent, notably with loss of granule cell
is a proteinaceous exudate in the perivascular space neurons, mild loss of Purkinje cells, and prolifera-
extending into the adjacent brain tissue. Periodic tion of Bergmann glia.
acid-Schiff–positive globules may be seen within
the exudates and in astrocytes. Diffuse astrocytosis
has been reported even in the absence of capillary 4 .5 . 6. THALLIUM
changes.
Most cases of thallium intoxication result from acci-
dental or deliberate ingestion of thallium pesticides
used for insect and rodent control. The clinical pic-
4. 5. 4. MANGANE S E
ture resembles that of trivalent arsenical poisoning.
Manganese exposure may result from inhaling dust The only consistent abnormalities in the CNS are
in manganese mines or vapor released during fer- chromatolysis of spinal motor neurons and degen-
romanganese smelting. The clinical manifestations eration of the posterior columns, related to the sen-
include headaches, transient psychiatric distur- sorimotor distal axonopathy.
bances, and a hypokinetic extrapyramidal dysfunc-
tion that resembles Parkinson disease but is not
4 .5 . 7. TIN
responsive to L-dopa.
Pathological studies in humans are limited but Inorganic tin is not neurotoxic, but two organic
document degenerative lesions in the pallidum and tin compounds, triethyl-tin and trimethyl-tin, are.
subthalamic nucleus and, to a lesser extent, the stria- Triethyl-tin causes striking white matter edema
tum. The substantia nigra is involved in some cases. due to accumulation of fluid in vacuoles within
the myelin sheaths, which are separated along the Wilson hepatolenticular degeneration. It is charac-
intra-periodic lines (see Chapter 1 and Fig. 1.24C). terized by the presence of Alzheimer type II glia (see
Trimethyl-tin does not cause intra-myelinic edema Chapter 1 and Fig. 1.20). The lesions predominate
but is toxic to neurons in the hippocampus, the in the pallidum but may also involve the cerebral
entorhinal cortex, and the amygdala. cortex and the dentate nuclei.
5. CNS CHANGES 5.3. Multifocal Necrotizing

SECONDARY TO SYSTEMIC Leukoencephalopathy
DISEASES This condition is characterized by the develop-
ment of multiple, usually microscopic foci of necro-
5.1. Respiratory sis in the white matter. It often affects the basis
Encephalopathies pontis (focal pontine leukoencephalopathy). The
pathogenesis of the lesions observed is unclear.
The neuropathology of respiratory encephalopathy,
Affected individuals are predominantly those who
secondary to chronic bronchopulmonary disease
are found to have increased levels of circulating
and essentially due to hypoxia and hypercapnia, is
pro-inflammatory cytokines (e.g., patients with
characterized by diffuse vasodilatation, microscopic
AIDS, neoplasms treated with radiotherapy and
perivascular hemorrhages, and anoxic neuronal
often intrathecal chemotherapy, sepsis). In most
changes of variable intensity.
cases it is discovered at autopsy.
At postmortem examination, the brain of patients
By and large, the lesions are only visible on micro-
with who die soon after acute asphyxia shows con-
scopic examination and consist of well-demarcated
gestion of the meninges and cortex due to venous
areas of necrosis disseminated in the white matter,
and capillary dilatation (“lilac brain”) (Fig. 9-28).
but particularly involving the transverse pontine
Perivascular hemorrhages predominating in the
fibers (Fig. 9.29A). There is loss of myelin staining,
white matter may be seen.
proliferation of macrophages, and lesions of axons,
which appear swollen and fragmented and tend to
calcify (Fig. 9.29B).
5.2. Hepatic Encephalopathy
Hepatic encephalopathy occurs in the course
5.4. Paraneoplastic
of severe hepatic insufficiency in cases of severe
Encephalomyelopathies
hepatic cirrhosis or hepatitis, in association with
portocaval anastomosis and in individuals with Paraneoplastic CNS syndromes are neurological
disorders that are associated with systemic malig-
nancies and that are unlikely to be the direct result
of involvement by the neoplasm, say by compres-
sion, invasion, or metastasis. Excluded, by defini-
tion, are iatrogenic complications of radiotherapy or
chemotherapy and opportunistic infections related
to immunodepression secondary to the neoplastic
process itself, to treatment, or to both. Also set apart
are the metabolic or deficiency disorders and vas-
cular disorders associated with the development of
malignant disease.
Paraneoplastic syndromes can affect the cen-
tral, peripheral, or autonomic systems. The neuro-
logical symptoms may be the initial manifestation
of the neoplastic process and can be multifocal.
FIGURE 9.28 “Lilac brain” in a patient who died Comparable idiopathic autoimmune disorders of
from acute asphyxia. Note petechial hemorrhages and the CNS in which no systemic cancer is found have
laminar necrosis. also been described.

A B
FIGURE 9.29 Multifocal necrotizing leukoencephalopathy. (A) Whole-brain section of the pons showing

disseminated necrotic foci in the transverse pontine fibers (Klüver-Barrera). (B) Microscopic section showing a
necrotic lesion with vacuolation and central calcification (H&E).
By and large, many paraneoplastic syndromes have In recent decades, specific autoantibodies (IgGs)
been shown to develop in the setting of autoimmune and their target antigens have been identified that
mechanisms directed against an oncoantigen aberrantly are often but not exclusively associated with specific
expressed by the systemic tumor, which cross-react with neoplasms and neurological syndromes (Tables 9.1
antigens normally present in the nervous system. and 9.2).
Table 9.1. Paraneoplastic Antibodies, Antigens, Associated Neoplasm and

Neurological/Neuropathological Aspects
Antibodies targeting neural plasma membrane ion and water channels receptors and
synaptic proteins
AN TIBODY ANTIGEN TUMOR N E U R O PAT H O L O G I C A L

P R E S E N TAT I O N
VGK-complex Ab LGI1, CASPR2 Small cell lung carcinoma Limbic encephalitis

Thymoma Peripheral and autonomic
neuropathy
Carcinoma of breast, prostate Myoclonus
NMDA receptor Ab NR1 Ovarian teratoma Limbic encephalitis
AMPA receptor Ab GluR1,2 Thymic tumors Limbic encephalitis
Carcinoma of breast, lung
GABA-B receptor Ab GABA-B Small cell lung carcinoma Limbic encephalitis
Other neuroendocrine tumor
P/Q and N-type P/Q and N-type Small cell lung carcinoma Paraneoplastic
encephalomyelopathy
Calcium channel Ab Calcium channel Gynecological or breast carcinoma Neuropathies,
Lambert-Eaton syndrome
Muscle AChR Ab Muscle AChR Thymoma, thymic or Myasthenia gravis
lung carcinoma
Neuronal ganglionic Neuronal Adenocarcinoma, thymoma Peripheral and autonomic
neuropathy
AChR Ab Ganglionic AChR Small cell lung carcinoma Paraneoplastic
encephalomyelopathy
Table 9.2. Paraneoplastic Antibodies, Antigens, Associated Neoplasm and Clinical/
Neuropathological Aspects
Neuronal Nuclear, Cytoplasmic, and Nucleolar Antibodies
AN TIBODY ANTIGEN TUMOR N E U R O PAT H O L O G I C A L P R E S E N TAT I O N
ANNA-1 ELAVL (Hu) Small cell lung carcinoma Peripheral and autonomic neuropathy
Paraneoplastic encephalomyelopathy
ANNA-2 NOVA 1, 2 Small cell lung carcinoma, Cerebellar degeneration
(Ri) breast carcinoma Paraneoplastic encephalomyelopathy
ANNA-3 Unknown Lung or esophageal Paraneoplastic encephalomyelopathy
carcinomas Cerebellar degeneration
Small cell lung carcinoma
Peripheral neuropathy
AGNA SOX-1 Small cell carcinoma Lambert-Eaton syndrome
Mal, Ma2 PNMA1, Testicular (Ma2) Cerebellar degeneration
PNMA2
Breast, colon, testicular Brainstem encephalitis
(Ma1)
PCA-1 CDR2 (Yo) Müllerian adenocarcinoma Cerebellar degeneration
Breast carcinoma Paraneoplastic encephalomyelopathy
PCA-2 Unknown Small cell carcinoma Paraneoplastic encephalomyelopathy
Peripheral and autonomic neuropathy
Lambert-Eaton syndrome
PCA-Tr Unknown Hodgkin lymphoma Cerebellar degeneration
CRMP-5 IgG CRMP-5 Small cell carcinoma Cerebellar degeneration
Thymoma Paraneoplastic encephalomyelopathy
Peripheral and autonomic neuropathy
Amphiphysin Amphiphysin Small cell carcinoma Stiffness
IgG
Breast adenocarcinoma Paraneoplastic encephalomyelopathy
GAD65 Ab GAD65 Thymoma, renal, breast, Stiffness
or colon adenocarcinoma Paraneoplastic myelopathy
In some of these syndromes, the patient devel- degeneration is then mediated by cytotoxic T cells.
ops antibodies against neural cell surface receptors These disorders, accompanied by autoantibody
or channels, the antibodies have a pathogenic role, markers of neural peptide-specific cytotoxic effec-
and there can be a clinical improvement after early tor T cells, are generally poorly responsive to
immunotherapy. In other conditions, the antigens immunotherapy.
are not superficial but intracellular, and the immune The main neuropathological entities encoun-
reaction is cellular, through MHC class 1 mol- tered in CNS paraneoplastic syndromes are para-
ecules and cytotoxic T-cell mechanisms. Neuronal neoplastic cerebellar degeneration, paraneoplastic

A B
FIGURE 9.30 Paraneoplastic cerebellar degeneration. (A & B) Massive loss of Purkinje cells and prolifera-
tion of Bergmann glia (H&E). (C) Loss of Purkinje cells; preservation of basket fibers and of granular neurons
(Bielschowsky silver impregnation).
encephalomyelitis, and the opsoclonus-myoclonus 5 .4 . 2. PARAN EOPLASTIC

syndrome. ENCEPHALOM YELITIS
Subacute polioencephalomyelitis lesions involve
predominantly the gray matter and include, in vari-
5. 4. 1. PARANE OP L A S TI C C ER EB EL L A R
able proportion, neuronal loss, nodules of neuro-
D E G ENE RAT I ON
nophagia, proliferation of rod-shaped microglia,
The clinical course of the disease is generally sub- astrocytic gliosis, and infiltration by B and T lym-
acute and manifests as gait ataxia, incoordination, phocytes. The latter are mainly of the CD4 induc-
dysarthria, and often nystagmus. The cerebellum may tor/helper type in the perivascular cuffs and of the
be atrophic but is usually macroscopically normal. CD8 cytotoxic type in the parenchymal infiltration.
Histologically, there is massive, diffuse loss of the B cells may predominate in disorders accompanied
Purkinje cells with proliferation of the Bergmann glia by neural plasma membrane-reactive autoantibod-
(Fig. 9.30A) and sparing of the basket fibers and to ies. The lesions have a characteristic distribution
a lesser extent of the granular neurons (Fig. 9.30B). and show a predilection for the medial temporal
The degeneration of Purkinje cells axons often pro- cortex (limbic encephalitis), the rhombencephalon
duces myelin pallor of the amiculum of the dentate (medullary pontine encephalitis), the cerebellum,
nucleus (Fig. 9.31). Microglial nodules and perivas- the gray matter of the spinal cord (poliomyelitis),
cular mononuclear cuffs in the leptomeninges and and the spinal root ganglia. In some patients, lesions
parenchyma are frequent, but inflammation may be in these different anatomical locations may coex-
sparse or absent. ist; they may also be associated with inflammatory
A
FIGURE 9.31 Paraneoplastic cerebellar degeneration. Myelin pallor of the amiculum of the dentate nucleus,
which is the site of convergence of Purkinje cell axons (Loyez myelin stain).
A B
FIGURE 9.32. Limbic encephalitis. (A) Gross appearance: bilateral necrosis of the hippocampus and cere-
bral amygdala. (B) Microscopic section showing massive loss of pyramidal cells, astrocytic gliosis, and mono-
nuclear perivascular infiltrates. (C) Microscopic section showing nodules of neuronophagia, astrocytic gliosis,
and mononuclear infiltrates both perivascular and diffuse in the parenchyma. Note severe inflammation of the
leptomeninges.

manifest by numbness, paresthesias, dysesthesias,
and reduced or absent reflexes. The peripheral
nerves show axonal degeneration with varying
degrees of secondary segmental demyelination.
Additional pathological changes include degenera-
tion of posterior roots, degeneration and demyelin-
ation of the posterior columns of the spinal cord,
and degeneration of dorsal root ganglia (Fig. 9.34A).
Mild perivascular and intraparenchymal infiltrates
of mononuclear inflammatory cells are often pres-
ent. In the sensory ganglia, inflammatory cell infil-
trates may be especially prominent. The number of
ganglion cells is reduced and nodules of Nageotte
FIGURE 9.33 Medullary pontine paraneoplastic are found where the ganglion cells have been lost
encephalitis. Microscopic section showing nodules of (Fig. 9.34B). Autonomic ganglia may be involved
neuronophagia, proliferation of rod-shaped microglia, as well as dorsal root ganglia but show less severe
astrocytic gliosis, and mononuclear infiltration in the changes.
medullary olive.
5 .4 . 3. PARAN EOPLASTIC
lesions in the myenteric plexuses, the peripheral O P SOCLON US- M YOCLON US SYN DROM E
nerves, and/or the skeletal musculature.
Patients with paraneoplastic limbic encephalitis The opsoclonus-myoclonus syndrome is rare but
display behavioral changes, memory loss, and hal- is best known in association with neuroblastomas
lucinations. Limbic structures including the hip- in children. Even more rarely, the syndrome also
pocampi, cingulate gyri, insular cortex, amygdala, occurs in adults, in association with small cell car-
and parts of the temporal lobe may be affected cinoma of the lung or breast carcinoma. Autopsy
(Fig. 9.32A , B, C). The midbrain (Fig. 9.33) and examination of the brain of affected individuals may
thalamus may also show similar changes. show no histopathological abnormalities or may
Sensory neuropathy is a frequent component show Purkinje cell loss and/or mild periaqueductal
of an encephalomyeloneuropathy. Clinically it is infiltrates of inflammatory cells.
A B
FIGURE 9.34 Paraneoplastic sensory neuropathy. (A) Note demyelination of the posterior columns (Loyez
myelin stain). (B) Spinal ganglion: note loss of ganglion cells, proliferation of satellite cells, and interstitial lym-
phocytic infiltration.
10
Hereditary Metabolic Diseases
F R ÉD ÉR I C S E DE L, HA N S H . G O EB EL , A N D D O U G L A S C. A NTH O NY
1. INTRODUCTION One approach is the identification of two major

categories of disorders based on intracellular or
Hereditary metabolic diseases were originally identi- extracellular abnormalities in metabolites. The
fied based on the absence of specific enzyme activities first is a group of disorders in which the meta-
within distinct metabolic pathways. Identification of bolic derangements are most prominent inside
deficiency of enzymatic activity, often with accumu- the cell and often are linked to the dysfunction
lation of an intermediate metabolite within the path- of a single cellular organelle. These disorders may
way, eventually led to identification of the involved have increased intracellular levels of an interme-
gene. Therefore, the original classification of heredi- diate metabolite and may have intracellular accu-
tary metabolic disease was based on enzyme deficien- mulation of the metabolite, resulting in a so-called
cies. More recently, pedigrees with inherited diseases “storage” disease. The organelles most commonly
have been linked to specific genetic loci and, by iden- involved in these disorders are lysosomes, per-
tifying the involved gene, the protein sequences and oxisomes, mitochondria, and the cytoplasmic
putative protein functions have been established, compartment. In the second group of hereditary
without understanding the metabolic pathways that metabolic disorders, no intracellular accumulation
may be involved. This “reverse” genetics, includ- is identified. Instead, these disorders are viewed
ing findings from more recent methods such as full as systemic biochemical disorders in which bio-
exome or whole genome sequencing, has consider- chemical abnormalities are most prominent in the
ably increased the speed of discovery of inherited circulation or in the urine. These are classified by
metabolic diseases and expanded the categories of the biochemical pathways involved and are often
disease that are recognized. As a result, the classifica- identified by the presence of circulating small mol-
tion of inherited metabolic diseases is in flux. ecules or by genetic testing.
• 227
1.1. Biochemical abnormalities A past history of prolonged neonatal jaundice is
suggestive of disorders of cholesterol and bile acid
According to the metabolic pathway involved, inher- metabolism. Splenomegaly is highly suggestive of
ited metabolic diseases involving the nervous system some lipid storage diseases, such as Gaucher disease,
can be divided into several categories of biochemical Tangier disease, and Niemann-Pick disease (either
abnormality, many of which display some similari- type A, B or C). Other presentations are less specific
ties in clinical presentation, diagnostic methods, and for lipid metabolism disorders: cerebellar ataxias,
treatment strategies. dementia, psychiatric disorders, epilepsy, and spas-
tic paraparesis. A slow progression of symptoms,
1. 1. 1. ABNORMAL I TI ES I N EN ER G Y which corresponds to progressive lipid storage, is
M E TABOL I SM highly suggestive of these disorders.
Energy metabolism disorders include some that

directly affect the respiratory chain and others that 1 .1 . 3. IN TOXICATION SYN DROM ES
involve metabolic pathways required for energy Some metabolic disorders are associated with vari-
production. These defects include respiratory chain able clinical symptoms that correlate with the serum
disorders (that can be primary or secondary, as can levels of a small molecule or metabolite. These
occur in organic acidurias), pyruvate dehydrogenase include porphyrias, urea cycle defects, organic acid-
deficiency, Krebs cycle deficiencies, glucose trans- urias, and amino acidopathies. The onset of acute
port (GLUT1) deficiency, and β-oxidation defects, as symptoms that accompany the metabolic crisis is
well as disorders involving co-factors such as electron characteristic of these disorders and has led to their
transfer flavoprotein deficiency, vitamin E deficiency, designation as “intoxication” syndromes. However,
biotinidase deficiency, biotin-responsive thiamine in mild adult forms, symptoms can be progressive,
metabolism dysfunction, creatine deficiency syn- giving rise to leukoencephalopathies, epilepsy, psy-
dromes, and coenzyme Q synthesis defects. This chiatric disorders, or spastic paraparesis.
group includes the disorders of mitochondrial func-
tion (mitochondriopathies). Acute manifestations
1 .1 . 4. DISORDERS OF
are often triggered by infections and include Leigh
NEUROTRAN SM ITTER M ETABOLISM
syndrome, acute optic neuropathy, acute cerebel-
lar ataxia, or pseudo-strokes. Chronic presentations Disorders of neurotransmitter metabolism are
often involve muscles, cerebellum, basal ganglia mostly represented by defects in the synthesis of
(parkinsonism), cortex (epilepsy, myoclonus), or the serotonin and dopamine. Clinical signs are related
peripheral nervous system (axonal polyneuropathy). to dopamine deficiency (dystonia, parkinsonism,
In adults, these diseases rarely involve the brain white oculogyric crisis), noradrenergic deficiency (ptosis,
matter, and spastic paraparesis is very uncommon. myosis, hypotension), or serotonin deficiency (sleep
disturbance, dysthermia, behavioral disturbance).
Dopa-responsive dystonia or parkinsonism is highly
1. 1. 2. DI SOR DE R S O F L I P I D
suggestive. Diurnal fluctuations of symptoms are also
M E TABOL I SM
characteristic, with improvement in the morning and
Lipid metabolism disorders include some lysosomal worsening during the day. Diagnosis of these disor-
diseases, mainly sphingolipidoses (Krabbe disease, ders relies on analysis of neurotransmitter metabolism
metachromatic leukodystrophies, Niemann-Pick A, in the cerebrospinal fluid. Cerebral folate deficiency
B, and C, Fabry disease, Gaucher disease), peroxi- can be added to this group because it shares several
somal disorders (adrenomyeloneuropathy, Refsum clinical features and diagnostic methods, although
disease, disorders of pristanic acid metabolism, per- this syndrome is still highly heterogeneous.
oxisome biogenesis disorders), Tangier disease, and
cerebrotendinous xanthomatosis.
1 .1 . 5. DISORDERS OF M ETAL
Given the high content of lipids in the nervous
M ETABOLISM
system, these diseases can produce severe neuro-
logical symptoms. Leukodystrophies and demyelin- Metal storage disorders include Wilson disease, neuro-
ating polyneuropathies are hallmarks of disorders ferritinopathy, aceruloplasminemia, PANK2-associated
interfering with myelin formation or maintenance. neurodegeneration, PLA2G6 mutations, and a recently
identified disorder of manganese metabolism. The “leukodystrophies.” The latter disorders are charac-
hallmark of these diseases is an abnormality in metal terized by loss of myelin (demyelination) or abnor-
metabolism that may result in metal deposits, often mal myelin formation (hypomyelination), which is
in the basal ganglia, sometimes visible on brain MRI. often evident on MRI of the brain. Hereditary leu-
The main presentations are movement disorders kodystrophies, in which the production of myelin
because of the primary involvement of the basal gan- may be impaired due to abnormalities in the struc-
glia. Treatments, when they exist, are mainly based on ture of myelin or in myelin metabolism, are often
metal chelators. considered “dysmyelinating” disorders rather than
“demyelinating” diseases. Pathologically, however,
the process is characterized by the absence of myelin
1.2. Morphological classification with a relative preservation of axons.
Many of the biochemical pathways involved in As a consequence of the many metabolic path-
inherited metabolic diseases are associated with a ways involved and the different structures and
specific cellular organelle. There are three organ- regions affected, the clinical presentation of heredi-
elles commonly associated with the metabolic tary metabolic disease is highly variable. However,
disorders: lysosomes, peroxisomes, and mitochon- starting from the regions of the brain involved cer-
dria. As a general rule, disorders involving lysosomal tain types of metabolic disease are more likely and
proteins tend to involve catabolic pathways, and specific metabolic testing can be performed.
the lack of a lysosomal enzymatic function is often
associated with the accumulation of a metabolite 1. Involvement of white matter is particularly com-
for which the catabolic pathway is defective. The mon in leukodystrophies, and differential diag-
accumulation of the nondegraded metabolite in nostic considerations include Krabbe disease,
lysosomes is often referred to as a “storage” disease metachromatic leukodystrophy, cerebrotendi-
and may lead to distention of nerve cell bodies and nous xanthomatosis, Zellweger disease, adre-
their processes, glia, blood vessel walls, or cells out- noleukodystrophy, polyglucosan body disease,
side the nervous system. In particular, the liver and Canavan disease, and phenylketonuria.
spleen are involved in some storage diseases, with 2. Progressive involvement of the basal gan-
the presence of hepatosplenomegaly. glia, especially when mineral deposits are
Other disorders involve a separate cellular organ- detected by MRI, is common in disorders of
elle, the peroxisome. Like the lysosome, the peroxi- metal metabolism, and differential diagnos-
some is involved in specific catabolic pathways, and tic considerations include Wilson disease,
serum levels of metabolites from these pathways are Hallervorden-Spatz disease, aceruloplasmin-
often increased in peroxisomal disorders. However, emia, phospholipase A2 group VI (PLA2G6)
in contrast to lysosomal disorders, intracellular stor- mutation, neuroferritinopathy, and also disor-
age of the metabolite is not usually present. ders of dopamine synthesis.
Mitochondria are the third major organelle asso- 3. Degeneration of the cerebellar or hemispheric
ciated with specific metabolic disorders. Serum lev- cortex implies a neuronal storage disease or
els of intermediary metabolites are often normal, neuronal metabolic disorder; differential diag-
although impairment of oxidative phosphorylation nostic considerations include gangliosidoses,
may lead to elevations of lactic acid. In addition, the neuronopathic Gaucher disease, Niemann-Pick
inheritance has a Mendelian pattern for the mito- disease, neuronal ceroid lipofuscinoses, or
chondrial proteins encoded in nuclear DNA but a mucopolysaccharidoses.
maternal pattern of inheritance for genes encoded in 4. Predominant involvement of the peripheral
mitochondrial DNA (mtDNA). nervous system is common in a subset of dis-
orders: Tangier disease, Refsum disease, or the
porphyrias.
1.3. Clinical Findings 5. Predominant involvement of the vascular
Some hereditary metabolic disorders tend to affect system may be seen in Fabry disease and
neurons and may do so within certain regions homocystinuria.
or nuclei. Disorders that involve gray matter, or 6. Weakness and muscle atrophy are common in
neurons, have been termed “poliodystrophies,” metabolic myopathies and may be seen in glyco-
while those involving white matter are called genoses or mitochondrial myopathies.
Chapter 10 Hereditary Metabolic Diseases • 229

7. Acute encephalopathy is an uncommon pre- Sphingolipids are defined by the presence of a
sentation in hereditary metabolic diseases but ceramide (N-acylsphingosine) and either a sugar
may occur in mitochondrial encephalopathy or phosphocholine moiety. When a sugar moiety is
with lactic acidosis and stroke (MELAS), Leigh present (galactose or glucose), the metabolites are
disease, urea cycle disorders, or nonketotic cerebrosides; when a phosphocholine is present, the
hyperglycinemia. metabolite is sphingomyelin; when a sulfated sugar
is present, the metabolite is a sulfatide, and when
multiple sugar moieties, are present, including sialic
2. LYSOSOMAL acid (N-acetylneuraminic acid), the metabolites are
DISORDERS (LYSOSOMAL gangliosides.
STORAGE DISEASES)
These diseases are due to a deficiency of a specific 2 .1 . 1. GAUCHER DISEASE
lysosomal enzyme required for the lysosomal catab- ( G LUCOCEREBROSIDASE
olism of a particular metabolite, usually a complex D EFICIEN CY)
lipid or sphingolipid, and are often accompanied by Gaucher disease (or glucocerebrosidase deficiency)
the accumulation of the lipid (“storage disease”). is an autosomal recessive disease due to a deficiency
Current classifications most often refer to the lipid of acid beta-glucosidase (beta-glucocerebrosidase),
involved or to the enzyme deficiency responsible for which catabolizes glucosylceramide into ceramide
their accumulation rather than to clinical features. and glucose. The disease is characterized by the accu-
However, distinct clinical syndromes are recognized mulation of glucosylcerebroside within lysosomes
and often carry the eponyms of the author of the and involves the bone marrow, liver, and spleen.
first clinical description. The most common form (type I) has an onset in
The abnormalities commonly involve both the adults and the central nervous system (CNS) is not
cerebrum and cerebellum; they often consist of neu- affected. Involvement of the nervous system occurs
ronal storage, with enlargement of the neuronal cell only in the infantile severe (neuronopathic) form.
body initially but ultimately neuronal loss and glio- The gene (GBA; glucosidase, beta acid) is located
sis. When involvement of white matter is the pre- on chromosome 1q21, and mutations in this gene
dominant abnormality, the disorder may be referred are responsible for all clinical forms of the disease.
to as a leukodystrophy. In some lipid disorders, espe- Although specific mutations are associated with spe-
cially those involving myelin lipids, the brain lesions cific clinical phenotypes, there is no correlation with
are accompanied by peripheral nerve disease due to enzyme activity measured in vitro.
involvement of Schwann cells and peripheral myelin In the typical form (type I Gaucher disease),
sheaths. Storage of the metabolic product in lyso- hepatosplenomegaly is common, and pancytope-
somal storage diseases also often occurs in the heart, nia results from replacement of the marrow with
liver, kidney, spleen, or eye. Ocular storage may be storage cells. The storage cells are predominantly
seen on ophthalmic examination as a “cherry red” macrophages and are known as Gaucher cells. They
spot, due to storage within retinal ganglion cells; are found in large numbers outside the nervous sys-
involvement of viscera may be detected as hepato- tem, sometimes appearing to have almost replaced
splenomegaly or cardiomyopathy. the normal parenchyma of the liver, lymph nodes,
Deficiencies in specific lysosomal proteins cause marrow, and spleen. These large (30 to 40 μm)
the accumulation of sphingolipids (gangliosides, Gaucher cells are distended with cerebrosides, and
cerebrosides, and sulfatides), mucopolysaccharides, the parallel clefted vacuoles give the cells a distinct
and complex neutral lipids. appearance that has been described as resembling
crumpled tissue paper. By electron microscopy, the
cells contain tubular, sickle-shaped profiles measur-
2.1. Sphingolipidoses ing 12 to 30 nm.
Sphingolipidoses represent the most common In the neuronopathic form (type II Gaucher
group of neuronal lysosomal storage disease. The disease) and in the rare juvenile form with a pro-
catabolic enzyme defect impairs the lysosomal longed course characterized by dementia (type
catabolism of the sphingolipid, and accumulation III), Gaucher cells are present in the brain, where
of the sphingolipid is the most common result. they are distributed chiefly around blood vessels.
Accumulation of glucocerebroside within the neu- osmiophilic limiting membrane; they are variably
rons themselves is variable and usually discrete. needle- or splinter-shaped or gently curved, 10 to
Survival in type 1 Gaucher disease is variable, usu- 100 nm wide, and of indeterminate length.
ally depending on the severity of liver and bone mar- Involvement of the peripheral nervous system
row involvement. Type 2 neuronopathic Gaucher may also be found. The clinical manifestation refer-
disease has a severe and rapidly progressive course, able to the peripheral nervous system is hyporeflexia,
with death usually occurring before the age of 2. particularly in the childhood variants of the disease.
Loss of myelinated fibers and relative preservation
of unmyelinated axons are the outstanding findings,
2.1.2. KRABBE DISEASE
although segmental demyelination and remyelin-
( GALACTOCEREBROSIDASE
ation also occur. By electron microscopy, inclusions
DEFI CIENCY)
similar to those seen in globoid cells may be seen in
Krabbe disease (globoid-cell leukodystrophy; histiocytes and Schwann cells (Fig. 10.1C).
galactosyl-ceramide-beta-galactosidase deficiency) There is no storage of galactocerebroside in
is an autosomal recessive leukodystrophy due to the liver or spleen and no visceral enlargement or
a deficiency of the enzyme galactosyl ceramidase dysfunction.
(galactosyl-ceramide-ß-galactosidase, or galacto-
cerebrosidase [GALC]), which is necessary for
2.1.3 . NIEMANN- PICK DISEASE
the catabolism of galactosylceramide (galactocer-
(SP HINGOMYEL IN L IPIDOSIS)
ebroside), an integral component of myelin. The
gene, GALC, is located on chromosome 14q31.3 Niemann-Pick disease is an autosomal recessive
and encodes the enzyme. It is a rare condition and multiorgan storage disease with several forms,
is the only sphingolipidosis in which accumulation each form sharing the defining feature of accumu-
of the metabolite (galactocerebroside) does not lation of sphingomyelin (sphingomyelin lipidosis).
occur. Rather, the block in catabolism of galactocer- Sphingomyelinase is the enzyme that catalyzes
ebroside leads to shunting of galactocerebroside to the breakdown of sphingomyelin to phosphocho-
psychosine (galactosylsphingosine), with elevated line and ceramide. There are at least three distinct
levels of psychosine. The elevated levels of psycho- genetic loci and multiple distinct clinical forms
sine have a toxic effect on oligodendrocytes in tis- of the disease at the different loci. Clinical forms
sue culture experiments, and it has been postulated A and B involve the gene for acid sphingomyelinase
that psychosine impairs the maintenance of myelin. (chromosome 11p15.4-p15.1) and are the forms of
Instead of neuronal storage, there is destruction of “classic” Niemann-Pick disease with sphingomy-
white matter, resulting in an infantile leukodystro- elinase deficiency. However, there are two forms
phy. The onset is usually before the age of 6 months, of the disease, types C and D (Nova Scotia vari-
and the clinical course is usually rapidly progres- ant), which involve a separate gene, NPC1 (chro-
sive, with death usually occurring before the age of mosome 18q11.2). In both of these forms, there
2 years. is sphingomyelin storage (sphingomyelin lipido-
Demyelination is widespread, resulting in atro- sis), but the sphingomyelinase enzyme activity is
phy of the white matter of the cerebrum and cer- normal.
ebellum and marked fibrillary gliosis. A common The nervous system is prominently involved in
feature of the disease is the presence of rounded the acute infantile form (type A), which is most
macrophages with a large amount of cytoplasm, common in Ashkenazi Jewish populations. There is
known as “globoid” cells. They may measure up to severe hepatosplenomegaly, a cherry red spot of the
40 μm, with more irregular outlines, and are often retina, a diffuse reticular infiltration of the lungs, and
multinucleated. Globoid cells occur throughout a rapidly progressive encephalopathy. Hypotonia
the white matter of the CNS (but are not pres- may be present in the early course, but there is grad-
ent in the peripheral nervous system) and may be ual loss of motor function and intellectual deteriora-
found singly but are more often grouped to form tion. Death usually occurs by 3 years of age.
perivascular collections (Fig. 10.1A , B). By elec- Type B is more variable in presentation and
tron microscopy, globoid cells contain intracy- progression but much less severe than Type A. The
toplasmic inclusions, which appear as elongated patients do not have neurological involvement but
cleft-like empty spaces, sometimes bordered by an present with massive hepatosplenomegaly, often

A B
FIGURE 10.1 Krabbe disease. (A) Globoid cells (H&E). (B) Globoid cells with a perivascular distribution
(PAS). (C) Electron microscopy of peripheral nerve showing characteristic inclusions in a Schwann cell.
detected on routine physical examination. Survival of the brain with severe gliosis. Types C and D may
into adulthood is common. show atrophy, but the finding is more variable. In all
Type C is less common and has a slower clini- three forms (types A, C, and D), there are abundant
cal course; it may also involve the nervous system. large neurons with distended cytoplasm and many
However, the neurological manifestations appear small round clear vacuoles. Histochemical studies
later in the course of the disease. Type D (Nova performed on frozen sections may demonstrate the
Scotia variant), which may also involve the CNS, has presence of neutral lipids. Patients with onset of the
been reported as a separate type, but many sources disease in infancy, who have severe involvement of
now consider it a syngenic variant of type C that was
discovered in pedigrees from Nova Scotia. Type E
had been distinguished as an adult-onset disorder
but is now viewed as type B with late onset.
All of the forms of Niemann-Pick disease, regard-
less of the gene involved are characterized by the
presence of large macrophages with distended cyto-
plasm. These large cells have round clear vacuoles by
light microscopy and electron microscopy and have
been called “foam cells” (Fig. 10.2), regardless of
location. They are often detected on bone marrow
biopsy but also occur in the liver, spleen, and lymph
nodes. Involvement of the nervous system occurs in FIGURE 10.2 Niemann-Pick disease, electron
types A, C, and D. Type A shows marked atrophy microscopy of a foam cell.
the CNS, sometimes show evidence of peripheral (cornea verticillata). The disease commonly results
nervous system involvement. When peripheral ner- in life-threatening pathological changes in the
vous system involvement is present, it is character- kidneys, heart, and cerebral blood vessels, lead-
ized morphologically by the presence of lamellated ing to renal or cardiac failure or multiple strokes.
inclusions and empty vacuoles in the cytoplasm of Gastrointestinal dysfunction is likewise frequent;
Schwann cells and in endoneurial and perineurial this has been attributed to lipid inclusions in the
fibroblasts. myenteric plexus. Common symptoms suggesting
involvement of the peripheral nervous system are
recurrent attacks of severe pain in the hands or feet,
2.1.4. FARBER LIPOGRANULOMATOSIS
especially in the presence of heat, and absence of
( CERAMIDASE DEFI CIENCY)
sweating.
Farber lipogranulomatosis (ceramidase deficiency; Foam cells are found in the liver, spleen, and
Farber disease) is an autosomal recessive disor- lymph nodes as well as in renal and cutaneous epi-
der resulting from deficiency of acid ceramidase, a thelial cells. The storage material is sudanophilic,
lysosomal enzyme required for the catabolism of PAS-positive, and birefringent under polarized light,
ceramide into sphingosine and fatty acids. Ceramide with a Maltese-cross shape. By electron microscopy,
accumulates in various tissues, including the central the inclusions often have a myelin-like lamellated
and peripheral nervous system. The gene, located structure, sometimes in parallel arrays, sometimes in
on chromosome 8p22, encodes the acid ceramidase concentric layers, with a periodicity of 5 nm. Some
protein. of them are membrane-bound, others not. Some,
The characteristic feature of the disease is the instead of being lamellated, are in the form of dense
development of periarticular and perivascular nod- osmiophilic aggregates.
ules that are composed of lipid-filled macrophages, CNS involvement is apparently limited to the
typically accompanied by a granulomatous inflam- amygdala, hypothalamus, hippocampus, entorhi-
matory reaction. The nodules are often first detected nal cortex, and brainstem nuclei. Neurons in these
within the skin, where they form readily visible sub- areas have reticular foam cytoplasm with abundant
cutaneous nodules. Similar lipogranulomas may also storage material. Storage is also seen in astrocytes,
involve the joints, bones, and kidneys. In the CNS, endothelial cells, and smooth muscle cells around
the large neurons of the anterior horns of the spinal blood vessels. In peripheral nerves, inclusions may
cord and their homologues in the brainstem are the be found in the cytoplasm of perineurial cells, vascu-
main structures affected, and they appear distended lar endothelial cells, and smooth muscle cells in the
with lipid inclusions. Peripheral (sensory and auto- tunica media of arteries.
nomic) ganglion cells are also affected. Characteristic
inclusions (curvilinear tubular structures) are also
seen in capillary endothelial cells in the CNS. 2.1.6 . GANGL IOSIDOSES
The gangliosidoses are characterized by the accu-
mulation of gangliosides, which are composed of
2.1.5. FABRY DISEASE
ceramide linked to an oligosaccharide (up to four
( ALPHA-GALACTOSIDASE A DEFICIENCY,
hexose saccharides, either galactose or glucose)
ANGI OKERATOMA CORPORIS DIFFUSUM)
and one or more sialic acids (N-acetylneuraminic
Fabry disease is a rare X-linked disorder due to a acid, or NANA). Gangliosides stain intensely with
deficiency of the hydrolase enzyme α-galactosidase. myelin stains in histological sections (such as LFB)
This enzyme is encoded on the long arm of the X but do not stain appreciably with routine H&E, so
chromosome (Xq22.1). Alpha-galactosidase A defi- swollen neurons usually appear to have clear vacu-
ciency results in the accumulation of glycosphingo- oles on H&E-stained sections (Fig. 10.3A). By
lipids, particularly globotriaosylceramide, forming electron microscopy, the perikarya of neurons con-
abnormal intracellular lipid inclusions (foam cells), tain membranous cytoplasmic bodies, which may
especially in vascular endothelial and smooth have two appearances: circular concentric profiles
muscle cells. formed by alternating concentric electron-lucent
Clinically, Fabry disease is characterized by and electron-dense bands 5 to 6 nm wide, known as
the development of angiokeratomas of the skin membranous concentric bodies (MCBs), or oblong
and mucous membranes and by corneal changes profiles with alternating linear electron-lucent

A B
FIGURE 10.3 Tay-Sachs disease. (A) Swollen neurons with clear peripheral vacuoles (H&E). (B, C)
Membranous cytoplasmic bodies on electron microscopy.
and electron-dense bands, known as zebra bodies life. It presents with poor head control and other
(Fig. 10.3B, C). symptoms of psychomotor decline. In the early
stages, the head and brain are enlarged, but there
2.1.6.1. Tay-Sachs disease (hexosaminidase is no hepatosplenomegaly. Gradual decline occurs,
A deficiency, GM2-gangliosidosis B variant) and death usually occurs within 2 years. The neu-
Tay-Sachs disease is an autosomal recessive disease, ropathology is that of a neuronal storage disease,
formerly known as amaurotic idiocy (to empha- with greatly enlarged neurons with distended cyto-
size the blindness and intellectual deterioration). plasm and large clear vacuoles on H&E. The micro-
It is caused by mutations in the α subunit gene of scopic features are the same as other gangliosidoses
hexosaminidase A (HEXA, chromosome 15q23), (PAS-positive on frozen sections, PAS-negative on
with deficiencies in hexosaminidase A and S activi- routine sections, strongly LFB-positive, membra-
ties. Hexosaminidase A is composed of α and β nous concentric bodies on electron microscopy).
subunits (encoded by the HEXA and HEXB genes,
respectively). Hexosaminidase B is composed of 2.1.6.2. GM2 gangliosidosis type II (Sandhoff
two β subunits (HEXB gene), and hexosaminidase disease) and GM2 gangliosidosis AB variant
S is composed of two α subunits (HEXA gene). Sandhoff disease (GM2 gangliosidosis type II)
Mutations of the α gene, therefore, lead to deficien- results from mutations involving the HEXB gene
cies of both hexosaminidase A and S activities. (chromosome 5q13.3), causing deficiency of hex-
Tay-Sachs disease occurs predominantly in osaminidase A and B activities; hexosaminidase
Ashkenazi Jews, with a high mutation frequency S activity is preserved. Sandhoff disease does not
in that population. The onset is in infancy, usu- show any particular ethnic predominance and is
ally after birth but within the first few months of clinically indistinguishable from Tay-Sachs disease.
GM2 gangliosidosis AB variant, which is rare, is of onset are thought to be related to residual enzyme
clinically and histologically identical to Tay-Sachs activity associated with the two mutations affecting
disease, but there is normal hexosaminidase A and each allele, with the least enzyme activity associated
B activity. The disease is caused by mutations in with the late infantile form of the disease. The onset
the GM2 activator protein (GM2A; chromosome of symptoms in the disease may be during the infan-
5q33.1). tile or juvenile periods, or in adulthood. In the late
infantile form, clumsiness and spasticity are often
2.1.6.3. GM1 gangliosidosis type I early findings, with onset between 2 and 3 years
(beta-galactosidase-1 deficiency) GM1 gangliosi- of age. Progression is relentless, and death usually
dosis type I is an autosomal recessive neuronal stor- occurs in early childhood.
age disease caused by a deficiency of β-galactosidase Sulfatides accumulate in many tissues, and the
(GLB1, chromosome 3p22.3). Similar to Tay-Sachs deposits may be up to 20 or 30 μm in diameter.
disease, the onset is in infancy and there is early onset They are PAS-positive and metachromatic (stain
of hypotonia and cherry red spots. However, there brown with acidic cresyl violet [Fig. 10.4B] and pink
are also signs of systemic involvement, including with toluidine blue). By electron microscopy, these
corneal opacities, depression of the nasal bridge, and lysosomal inclusions have a lamellar structure with
hepatomegaly, features similar to Hurler disease, a a periodicity of 5.8 nm. They may be arranged con-
mucopolysaccharide storage disorder. The disorder centrically, but parallel prismatic bodies or rectilin-
is, therefore, sometimes known as pseudo-Hurler ear “tuffstone” bodies (Fig. 10.4C) are characteristic.
disease. The staining properties of the gangliosides On gross examination, the brain may be atrophic,
are similar to Tay-Sachs; however, storage material especially in longstanding cases. The entire white
may also be found in the liver, spleen, kidney, and matter shows loss of myelin, with sparing of the sub-
bone marrow. cortical fibers (Fig. 10.4A). Myelin is largely absent
throughout the entire centrum semiovale, and gliosis
is severe, with scattered macrophages. Metachromasia
2.1.7. METACHROMATIC
is identified in the macrophages, which tend to
LEUKODYSTROPHY (ARYLSULFATASE
have a perivascular location. In the peripheral ner-
A DEFICIENCY) AND RELATED
vous system, there is demyelination and there may
DISORDERS
be some onion bulb formation. Schwann cells and
Metachromatic leukodystrophy (MLD) is an auto- macrophages, and occasionally axons, may contain
somal recessive disorder resulting from a deficiency metachromatic material. Electron microscopy in
of lysosomal arylsulfatase A activity, which cata- peripheral nerve shows the characteristic inclusions.
lyzes the catabolism of the sphingolipid, galactocer- Two important variants are known that involve
ebroside sulfate (a sulfatide), to the corresponding separate genetic loci: activator protein saposin B and
nonsulfated sphingolipid. These lipids are integral sulfatase-modifying factor-1. Mutations involving
components of myelin sheaths, both in the central the activator protein, saposin B (prosaposin gene,
and peripheral nervous systems; deficiency of the PSAP located on chromosome 10q22.1), lead to a
enzyme activity creates an excessive accumulation clinical appearance that is indistinguishable from
of sulfatides, which in turn results in breakdown arylsulfatase A deficiency, but in which arylsulfatase
of myelin and phagocytosis of its disintegration activity is normal (metachromatic leukodystrophy
products. due to saposin B deficiency). Multiple sulfatase
These sulfatides have an unusual staining prop- deficiency (Austin disease) is caused by mutations
erty, known as metachromasia. When certain dyes in the sulfatase-modifying factor 1 gene and leads
bind to sulfatides, the absorption spectrum of the to an absence of arylsulfatases A, B, and C activity.
dye shifts to a different color. This chemical prop- The sulfatide accumulation is accompanied by an
erty led to the distinction between this disorder, a accumulation of mucopolysaccharides, and patients
metachromatic leukodystrophy, and the majority have some facial and bony features that resemble
of leukodystrophies, which are “orthochromatic” or Hurler disease. There are also benign mutations in
“sudanophilic” leukodystrophies. the arylsulfatase A gene, which lead to pseudodefi-
The disease most often occurs due to mutations ciency of arylsulfatase A activity. These mutations,
in the arylsulfatase gene (ARSA), located on chro- although characterized biochemically by greatly
mosome 22q13.33. Differences in severity and age reduced enzyme activity, are not associated with

A B
FIGURE 10.4 Metachromatic leukodystrophy. (A) Massive demyelination of the white matter sparing the U
fibers in the right parieto-occipital region (Loyez). (B) Metachromasia of the white matter, which stains brown
with acidic cresyl violet. (C) Sulfatide inclusion by electron microscopy.
neurological disease, and pseudodeficiency of aryl- The histopathological findings consist of

sulfatase activity may be present in up to 2% of some an association of nervous system changes with
populations. alterations in the blood vessel walls. In the cere-
bral cortex and cerebellum, the appearance of
the swollen neurons is comparable to that seen in
2.2. Mucopolysaccharidoses gangliosidoses, with the presence of zebra bodies
The nervous system and especially neurons are (Fig. 10.5A) and other structures that are inter-
involved only in certain forms of mucopolysac- mediary to the membranous cytoplasmic bodies
charidosis. In such cases, a systemic disturbance of of Tay-Sachs disease. Capillary pericytes may
acid mucopolysaccharides, or glycosaminoglycans show marked vacuolation (Fig.10.5B), which cor-
(which are excreted in the urine), is accompanied responds to the excessive accumulation of glycos-
by a neuronal lipid storage disorder that closely aminoglycans. Vacuolization is found in the CNS,
resembles the gangliosidoses. Because of the sec- in various visceral organs (including the liver,
ondary nature of the gangliosidosis, this group of myocardium, and bone marrow), and in lympho-
diseases is not a form of neurolipidosis, but it should cytes. The vacuoles appear to be of lysosomal
be stressed that in some forms the neuronal changes origin, as suggested by the demonstration of acid
dominate the pathological findings. phosphatase.
A B
FIGURE 10.5 Mucopolysaccharidosis. (A) Zebra body in Hurler disease. (B) Vacuoles in a pericyte.
The mucopolysaccharidoses that involve the and lymph nodes. The foam cells are derived from
CNS to the greatest extent are: macrophages and have large clear vacuoles. In the
CNS, choroid plexus, leptomeninges, and Purkinje
• Hurler syndrome (type IH mucopolysaccharido- cells are often affected. Death usually occurs before
sis, α-L-iduronidase deficiency; dermatan sulfate the age of 1 year.
and heparan sulfate storage; gene locus 4p16.3)
with facial and skeletal deformities (gargoylism), 2.3.2 . TANGIER DISEASE
corneal opacities, and nervous system lesions
• Hunter syndrome (type II mucopolysaccharido- Tangier disease (high-density lipoprotein deficiency
sis; iduronate-2-sulfatase deficiency; dermatan type I, analphalipoproteinemia) is an autosomal
sulfate and heparan sulfate storage; gene locus recessive multiorgan disease affecting cells of the
Xq28), similar to Hurler disease, with similar lymphoreticular type, cornea, and the peripheral
deposition of glycosaminoglycans, but with nervous system due to mutations in the ATP-binding
X-linked inheritance and absence of corneal cassette 1 (ABCA1) gene. The gene is located on
opacities chromosome 9q31.1 and encodes an ATP-binding
• Type III A mucopolysaccharidosis (Sanfilippo cassette transporter, an important protein involved in
disease; heparan sulfate storage; heparan sulfate regulating the intracellular transport of cholesterol.
N-sulfatase deficiency; gene locus 17q25.3), The disease is characterized by near or total
which is histologically similar to types I and II, absence of circulating alpha lipoproteins. Histiocytes,
but in which only heparan sulfate accumulates in which may be encountered in lymphoid tissues
excessive amounts. and bone marrow, transform to “foam cells” due to
cholesterol ester accumulation. Tonsil hypertrophy,
hepatomegaly, and splenomegaly are common, and
2.3. Enzymes involved in metabolism of nearly all patients have some degree of neuromus-
cholesterol, other lipids, and lipoproteins cular dysfunction during the course of the illness.
About one third of patients come to medical atten-
2.3.1. WOLMAN DISEASE (LYSOSOMAL
tion because of peripheral neuropathy.
ACI D LIPASE DEFICIENCY)
Neuropathological features vary with each of
Wolman disease (lysosomal acid lipase deficiency) three fairly distinct clinical syndromes. Sural nerve
is an autosomal recessive infantile disease with hepa- biopsies from patients with peripheral neuropathy,
tosplenomegaly, gastrointestinal signs, and progres- characterized by remittent and relapsing asymmetri-
sive neurological deterioration caused by mutations cal polyneuropathy, have shown striking evidence
of the lysosomal acid lipase gene (LIPA, chromo- of segmental demyelination and remyelination
some 10q23.31) and accumulation of cholesterol and very little overall fiber loss. Patients with a dis-
and triglycerides. Calcification of the adrenals is tal symmetrical polyneuropathy have loss of large
accompanied by lesions in the intestinal mucosa and myelinated fibers and a relative increase in very
by the presence of “foam cells” in the liver, spleen, small fibers, with evidence of remyelination and

fiber regeneration (sprouting). In patients with a young adult life and progresses slowly. The disease is
syringomyelia-like syndrome, mostly middle-aged caused by mutations of the CYP27A1 gene or chro-
adults, there has been severe loss of small myelin- mosome 2q35, which encodes polypeptide 1 of the
ated and unmyelinated fibers, with a tendency for cytochrome P450, subfamily XXVIIA, required for
the large myelinated fibers to be relatively spared. sterol 27-hydroxylase activity. This enzyme activity
Accumulation of lipid droplets in Schwann cells is is required for hydroxylation of a variety of sterols at
a constant feature. the 27position. In a few cases of cerebrotendinous
xanthomatosis, there has been evidence of a periph-
2.3.3. ABETALIPOPROTEINEMIA eral neuropathy clinically and pathologically on
( BASSEN-KORNZWEIG DISEASE) nerve biopsy. The changes in the nerves have been
those of relative loss of large myelinated fibers and
This rare autosomal recessive syndrome is character- segmental demyelination and remyelination with
ized by a combination of malabsorption of lipids, a some onion bulb formation.
chronic progressive peripheral neuropathy, pigmen-
tary degeneration of the retina, and acanthocytosis
2.3. 5 . CEROID L IPOF USCINOSIS,
(burr cells) affecting red blood cells. Signs of cer-
NEURONAL (CL N, BATTEN DISEASE,
ebellar dysfunction (intention tremor, nystagmus)
KUF S DISEASE)
are frequently seen in association with peripheral
neuropathy characterized by prominent sensory The neuronal ceroid lipofuscinoses are now classified
impairment, muscular weakness, and atrophy (lead- as ceroid lipofuscinosis, neuronal (CLN), and are
ing to kyphoscoliosis and pes cavus in some cases). the most frequent type of neurodegenerative disease
The disease results from mutations of a gene on in children. These disorders are marked by neuronal
chromosome 4q23 that encodes the microsomal tri- loss and ubiquitous accumulation of intracellular
glyceride transfer protein (MTP). This protein cata- lipopigments. Juvenile and late infantile forms of the
lyzes transport of lipids between membrane surfaces disease are the most common, but there is also a rare
and is required for assembly of very-low-density adult form (Kufs disease). The frequency is 0.1 to
lipoprotein (VLDL) particles in the liver, and in the 7/100,000 live births. They are autosomal recessive
absence of functional MTP, the apolipoprotein is progressive disorders of uniformly fatal outcome
never assembled and released from the liver. and are characterized by lysosomal accumulation of
The peripheral neuropathy is characterized by lipid pigments that are positive for acid phosphatase
marked loss of myelinated axons, especially large and autofluorescent by light microscopy.
ones, and involvement of the posterior horns of the Infantile, late-infantile, juvenile, and adult forms
spinal cord. Retinal pathology entails loss of photo- are defined based on the age of onset of clinical
receptors and pigmentary retinopathy with mobili- symptoms. While the juvenile form is the most fre-
zation of retinal pigment epithelial cells, which enter quent one in Northern Europe and North America,
the sensory retina to produce brownish pigmenta- the late infantile form is the most frequent one in
tion. The formation of finely granular lipopigments Southern Europe and South America. The infantile
in peripheral nerve and skeletal muscle fibers resem- form, however, predominates in Finland as one of the
bles that seen in vitamin E or alpha-tocopherol defi- hereditary diseases of Finnish heritage and, though
ciencies, and tocopherol therapy has been found more rarely, may be encountered worldwide. The
beneficial for Bassen-Kornzweig disease patients. former classification of the neuronal ceroid lipofus-
cinoses, according to clinical subtypes, has recently
been replaced by one based on genetic defects, now
2.3.4. CEREBROTENDINOUS
numbering CLN1 to CLN10 (Table 10.1). In the
XANTHOMATOSIS
three early childhood forms (CLN1, CLN2, and
Cerebrotendinous xanthomatosis is an autosomal CLN10), three different proteases (palmitoyl pro-
recessive disorder of sterol metabolism that results tein thioesterase 1 [PPT1], tripeptidyl peptidase
in extensive lipid deposition, mainly in large ten- 1 [TPP1], and cathepsin D) are the deficient gene
dons (Achilles tendons and elbow regions) and in products, respectively. The other genetically identi-
the CNS, where it is associated with ataxia, spastic- fied forms (CLN3, CLN5, CLN6, and CLN8) are
ity, accelerated atherosclerosis, and impaired intel- marked by deficiencies of structural transmem-
lect. The disease generally becomes manifest in brane proteins, perhaps of lysosomal location; the
Table 10.1. Current Classification of the Neuronal Ceroid Lipofuscinoses (CLN)
CLINICAL FORM / EPON Y M GENE CHROMOSOME GENE PRODUC T U LT R A S T R U C T U R E PROTEINS

OF L IP OPIGME N T S ACCRUED
Infantile CLN1/PPT1 1p32 Lysosomal palmitoyl-protein GROD SAPs

CLN Santavuori-Haltia thioesterase 1 (PPT1)
Late-infantile CLN CLN2/TPP1 CLN2: 11p15 Lysosomal tripeptidyl peptidase CP SCMAS
Jansky- Bielschowsky CLN1 1 (TPP1)
Juvenile CLN CLN3, CLN1 CLN3: 16p12 Transmembranous CLN3 RP, CP, FP SCMAS
Spielmeyer- Sjögren-Vogt CLN9, CLN10 protein (battenin) in lysosomes
Adult CLN: CLN4, CLN1 CLN4: Unknown Granular, CP, FP SCMAS
Kufs (autosomal-recessive) CLN5, CLN6 unknown20q13.33 Cysteine string protein alpha Granular SAPs
Parry (autosomal-dominant) DNAJC5
Finnish variant CLN CLN5 13q-22 Soluble CLN5 protein in RP, CP, FP SCMAS
lysosomes
Early-juvenile Indian/Czech CLN6 15q21-23 Transmembranous CLN6 RP, CP, FP SCMAS
Roma variant CLN protein in ER
Lake-Cavanagh
Late-infantile Turkish CLN7/MFSD8 4q28.1-2 Transmembranous CLN7 RP, CP, FP SCMAS
variant CLN protein in lysosomes
“Northern epilepsy” CLN8 8p23 Transmembranous CLN8 protein Granular, CP, FP SCMAS
of ER and ER-Golgi complexes
Juvenile CLN CLN9 Unknown Unknown Granular, CP, FP SCMAS
Congenital + juvenile CLN CLN10/CTSD 11p15.5 Cathepsin D in lysosomes Granular SAPs
RP, rectilinear profiles; CP, curvilinear profiles; FP, fingerprint profiles; ER, endoplasmic reticulum; GROD, granulo-osmiophilic deposits; SAPs, sphingolipid activator proteins; SCMAS, subunit C of mitochondrial
ATP synthase.
CLN3 protein has been named battenin. For in vivo phosphatase. They are PAS-positive and are stained
and prenatal diagnoses, biochemical activities of by Luxol fast blue (Fig. 10.6C). Varying in degree,
PPT1 and TPP1 may be measured and are severely the lipopigments may also contain the subunit C of
reduced or absent in CLN1 and CLN2, respectively. mitochondrial ATP synthase and sphingolipid acti-
CLN9 is a putative juvenile form, but without a vator proteins that are demonstrable by immunohis-
disease-specific gene or protein known. The gene tochemistry. Immunohistochemical absence of the
for CLN4, an adult-onset phenotype, is also not yet genetically deficient tripeptidyl peptidase (TPP)
known. However, several adult CLN patients have enzyme protein in late-infantile CLN/CLN2 has
been found to have autosomal recessive mutation been documented.
in genes associated with childhood onset (CLN1, As the lipopigments in CLN show different
CLN5, and CLN6). Recently, mutations in a new ultrastructural patterns, conventional diagnosis of
gene have been identified in a few families with individual CLN forms may be achieved by electron
adult autosomal dominant CLN, also named Parry microscopic examination of circulating lympho-
disease (Table 10.1). cytes in which, among numerous other cell types
CLN are uniformly fatal disorders, the late-infantile (skin biopsies, appendectomy specimens, muscle
form resulting in death during the second decade of biopsies), lipopigments accrue. A granular pat-
life. Patients with juvenile CLN may survive to the tern may be seen in infantile CLN (Fig. 10.6E);
third or even fourth decade of life. Patients who have curvilinear bodies are a hallmark of late-infantile
adult CLN usually succumb within less than 10 years CLN (Fig. 10.6F); fingerprint profiles within
after onset. In affected children, the clinical tetrad membrane-bound lysosomal vacuoles are indica-
of visual disturbance (ending in blindness owing to tive of juvenile CLN (Fig. 10.6G); and genetic
retinal degeneration), ataxia, seizures, and demen- late-infantile variants show a granular matrix and fin-
tia may be encountered in each form, although with gerprint profiles within the circulating lymphocytes.
a different onset of first symptoms and sequence of In adult CLN, lymphocytes have not been found
subsequent clinical findings. The ocular fundi show affected by lipopigment formation. Apart from gran-
thinning of the degenerating retina and brownish pig- ular material, fingerprint profiles have been identi-
mentation. However, visual disturbances or blindness fied in neuronal lipopigments (Fig. 10.6H) and
are not a clinical component of the adult form and the curvilinear/rectilinear lipopigment profiles within
electroretinogram is largely normal. skeletal muscle fibers in Kufs disease. Prenatal elec-
Lesions in CLN involve predominantly the cortex tron microscopy may reveal granular lipopigments
(cerebral and cerebellar), resulting in almost com- in the infantile type and lamellar inclusions in juve-
plete depletion of nerve cells in the infantile form at nile CLN within mural cells of chorionic vessels,
autopsy, lesser depletion in the late-infantile form, whereas late-infantile CLN is prenatally marked by
and some neuronal depletion in the juvenile form, curvilinear bodies within amniotic fluid cells.
while there relatively little neuronal loss in the adult
form. Macroscopically, there is variable brain atro- 3. PEROXISOMAL
phy, which correlates with onset and duration of the
disease. It is particularly severe in the infantile and
DISORDERS
late infantile forms (Fig. 10.6A), whereas the juvenile Peroxisomes are intracellular organelles with a
CLN cortex may display a brownish hue. Secondary single membrane and a granular matrix by electron
loss of axons and myelin, shrinkage of the white mat- microscopy. Initially identified as “microbodies”
ter, and dilatation of the ventricles and the subarach- by electron microscopy, peroxisomes contain cata-
noid space are also common. lase, and their ability to cleave hydrogen peroxide
Two microscopic features define CLN: (1) loss via the enzymatic activity of catalase allowed their
of nerve cells followed by cellular and fibrillar initial localization and is the basis for their name.
astrocytosis and proliferation of macrophages and They are involved in a number of metabolic path-
(2) the intracellular, especially intraneuronal, accu- ways, including the initial pathway for breakdown
mulation of lipopigments. This may lead to enlarge- of very-long-chain fatty acids (VLCFAs), and the
ment of nerve cell perikarya (Fig. 10.6C, D) and catabolism of several organic acids (phytanic acid,
proximal segments, albeit usually not to the degree glutaric acid, pipecolic acid). Defects in the biogen-
as seen in the gangliosidoses. The lipopigments esis of the entire organelle may lead to deficiencies
are autofluorescent (Fig. 10.6B) and rich in acid of all of the enzymatic functions of the peroxisome
A B
C D
E F
G H
FIGURE 10.6 Neuronal ceroid lipofuscinosis. (A) Gross appearance, severe atrophy of the cerebral and of the
cerebellar cortex. (B) Cerebellar cortex, presence of autofluorescent pigment in the Purkinje cells (H&E) seen by
fluorescence microscopy. (C) Intraneuronal accumulation of Luxol fast blue positive pigment. (D) Semi-thin section
showing intraneuronal accumulation of ceroid lipofuscin (toluidine blue). (E–H) Ultrastructural appearance of the
ceroid lipofuscin pigment: Granular osmiophilic deposits in infantile CNL (E); curvilinear profiles in late-infantile
CNL (F); fingerprint profiles in juvenile NCL (G); fingerprint profiles in granular matrix in adult CNL (H).

(Zellweger disease, neonatal Refsum disease, and which is located in the peroxisome and is involved
neonatal adrenoleukodystrophy); involvement of in transporting VLCFA into the peroxisome for
a single gene product results in the deficiency of a catabolism. In the absence of functional ABCD1,
single enzymatic function of the peroxisome. VLCFAs accumulate in the blood and brain.
Accumulation is also evident in the adrenal and may
lead to functional hypoadrenalism.
3.1. Zellweger Syndrome In the classic juvenile form, young males often
(cerebrohepatorenal syndrome) present with behavioral problems or adrenal insuffi-
Zellweger syndrome is an autosomal recessive sys- ciency (Addison disease). The adrenal insufficiency
temic syndrome caused by mutations in any of at often includes hyperpigmentation of the skin.
least eight genes involved in the biogenesis of the The disorder is rapidly progressive; initial demy-
peroxisome. The eight genes identified so far have elination is detected by MRI in the occipital lobes
all been named “peroxins,” or peroxisome biogen- (Fig. 10.7B) but progresses to eventually involve the
esis factors, and mutations in peroxins 1, 3, 5, 10, entire cerebral hemispheres. Demyelination in the
13, 14, 19, 26 (PEX1–PEX26) have all been iden- CNS is the predominant neuropathological finding
tified in Zellweger disease. Patients are symptom- and is extensive and symmetrical. Midline struc-
atic at birth, with dysmorphic features and severe tures (corpus callosum, fornix) and the optic nerves
hypotonia (“floppy baby”), and often have cataracts, and tracts are severely affected (Fig. 10.7A), and at
retinitis pigmentosa, deafness, hepatomegaly, small late stages, the demyelination may be accompanied
renal cysts, pulmonary hypoplasia, and cerebral mal- by axonal loss and cavitary leukomalacia with sec-
formations. Death usually occurs before the age of ondary degeneration of the descending pathways.
6 months. Myelin stains show the complete absence of myelin
Electron microscopy of cells from patients with in the areas of chronic involvement, and the older
Zellweger syndrome has demonstrated an absence central portion of the demyelinated lesion shows
of peroxisomes, usually identified by special tech- severe fibrillary gliosis. Scattered macrophages con-
niques that localize catalase in the peroxisome of tain myelin degradation material, which stains with
control patients. Absence of peroxisomal function is neutral lipid stains and is PAS-positive. In chronic
identified by elevated serum levels of VLCFA, pipe- lesions, macrophage infiltration is intense and is
colic acid, and phytanic acid. accompanied by a marked inflammatory infiltrate
The neuropathological findings in patients (Fig. 10.7C).
with Zellweger syndrome are principally those The pathology in peripheral nerve is predomi-
of a neuronal migration disorder. The cortex may nantly a demyelinating neuropathy, with thin myelin
show polymicrogyria, pachygyria, or subcorti- sheaths and segmental demyelination on teased
cal neuronal heterotopias, all findings that are fibers. By electron microscopy, membrane-bound
associated with abnormalities of neuronal migra- cleft-like intracytoplasmic inclusions are seen, usu-
tion. Closely related, but less severe, disorders ally in cells of the adrenal cortex, interstitial cells of
are neonatal adrenoleukodystrophy and infan- the testis, and Schwann cells.
tile Refsum disease. These disorders share the By electron microscopy, storage material forms
early onset and cerebral malformation findings of cleft-like inclusions composed of two lamellae that
Zellweger disease but are less severe phenotypes measure 2.5 to 3.5 nm in thickness and are separated
with longer survival. Neonatal adrenoleukodys- by a clear space measuring 4 to 10 nm (Fig. 10.7D).
trophy also has the inflammatory demyelination of These inclusions are sometimes associated with lipid
adrenoleukodystrophy. droplets. They are most readily identified in cells of
the adrenal cortex but may also be found in macro-
phages in the CNS, in Schwann cells in peripheral
3.2. Adrenoleukodystrophy (and nerves, and in interstitial cells of the testis.
adrenomyeloneuropathy) Adrenomyeloneuropathy is the adult form of the
Adrenoleukodystrophy is an X-linked recessive disease and occurs in the same families with adreno-
leukodystrophy with a defect in the catabolism leukodystrophy. These patients present with clumsi-
of VLCFA. The affected gene (ABCD1), located ness and ataxia, which results from involvement of the
on chromosome Xq28, encodes a member of the long tracts of the spinal cord and peripheral nerve. It
ATP-binding cassette, subfamily D, member 1, may affect either hemizygous males or heterozygous
A B
FIGURE 10.7 Adrenoleukodystrophy. (A) Coronal section of the cerebral hemispheres showing symmetrical

severe demyelination (Loyez). (B) Massive demyelination sparing the U fibers in the right occipital lobe (Loyez).
(C) White matter with severe myelin loss, macrophages, reactive astrocytosis, and perivascular inflammatory
infiltrate (H&E). (D) Electron microscopy showing characteristic inclusions in a macrophage of the CNS.
females in families with ABCD1 gene mutations. abnormalities, nystagmus, ichthyosis, skeletal
Adrenal insufficiency is also common and may be deformities, and a cardiomyopathy that can lead to
associated with slowly progressive spastic paraplegia. arrhythmias, cardiac failure, and early death. The dis-
ease makes its appearance in late childhood, adoles-
cence, or early adult life, and, untreated, progresses
3.3. Refsum disease (phytanic acid gradually, though with occasional remissions.
oxidase deficiency) The biochemical abnormality is a marked
Refsum disease is an autosomal recessive disease increase in the serum levels of phytanic acid, a
caused by a mutation in the gene (PHYH, chromo- branched 20-carbon fatty acid. Accumulation of
some 10p13) encoding the peroxisomal enzyme, phytanic acid is due to the deficiency of phytanoyl
phytanoyl-CoA hydroxylase (phytanic acid oxi- CoA hydroxylase, the enzyme responsible for the
dase). The disease is characterized by progressive first step in the catabolism of phytanic acid via
distal motor and sensory impairment, ataxia of alpha-oxidation within the peroxisome.
trunk and limb movements, blindness (from pig- The peripheral nervous system shows a severe
mentary degeneration of the retina), and deafness demyelinating neuropathy. The nerves (including
of sensorineural type. Additional clinical manifesta- the spinal nerve roots) are considerably enlarged as
tions, of varying degrees, include anosmia, pupillary compared with normal. Microscopically, there are

prominent concentrically arranged Schwann cells The condition is characterized by the presence of
interspersed with collagen fibers, creating a strik- symmetrical spongy necrotizing lesions that affect
ing onion bulb pattern. There is also an increase of both the gray and the white matter; the lesions are
perineurial and interstitial connective tissue. Axons, predominantly located near midline structures.
myelinated and unmyelinated, are decreased in Basal ganglia (especially the putamen), thala-
numbers. In the CNS, cerebellar system degenera- mus (Fig. 10.8A), substantia nigra, subthalamic
tion is often present, with neuronal loss in the infe- nucleus, tegmentum of the midbrain (Fig. 10.8B),
rior olivary nucleus and dentate nucleus and loss of inferior olives, and posterior columns of the spi-
fibers in the cerebellar peduncles. Posterior column nal cord may be involved. The relative sparing of
degeneration and loss of neurons in the gracile and the neurons, the presence of gliosis, and especially
cuneate nuclei also have been observed. the endothelial proliferation (Fig. 10.8C) closely
resemble the lesions of Wernicke encephalopathy
(see Chapter 9). Sponginess and demyelination are
4. MITOCHONDRIAL DISEASES subsequently replaced by cystic cavitation, necrosis,
(MITOCHONDRIAL ENCEPHA - and cortical pseudolaminar destruction. Sensory
LOMYELOMYOPATHIES) neuropathy is seldom recognized. Ultrastructural
studies show alterations of mitochondria, but only
The mitochondrial encephalomyelomyopathies are
in a few cases. The same abnormalities may or may
a group of clinically heterogeneous disorders with
not be present in skeletal muscle.
multiorgan involvement caused by dysfunction of
Recent data have demonstrated extensive
the mitochondrial respiratory chain. Most of them
genetic heterogeneity of the disease, which may
involve muscle, of which the morphological and the
be related to mutations of mitochondrial genes,
biochemical analysis often allow the diagnosis (see
nuclear autosomal genes, and an X-linked gene
Chapter 12). But abnormalities are not always pres-
(pyruvate dehydrogenase complex, subunit E1α,
ent in skeletal muscle, especially when the CNS is
deficiency). Among the nuclear autosomal genes,
predominantly involved.
there are abnormalities of the nuclear genes of com-
Mitochondria contain their own DNA which
plex I, II, and IV (mutations of assembly genes of
encodes 13 polypeptides, including subunits of
cytochrome C oxidase, such as SURF1). Among
the respiratory chain (complexes I, III, IV, V) and
the mitochondrial-encoded genes are genes cod-
also 22 tRNAs and 2 rRNAs. The remainder of the
ing for ATPase 6 and tRNA (Lys). Enzyme defects
mitochondrial proteins is encoded by nuclear genes.
have been demonstrated in muscle biopsy material
Mitochondrial disorders may thus be caused by
in a low percentage of cases and fewer in the brain.
mutations either in the mitochondrial or the nuclear
Congenital lactic acidosis may likewise cause necro-
genome; defects of intergenomic signaling may
tizing lesions in the hemispheric white matter.
also interfere. There are two main types of mtDNA
mutations: those that affect mitochondrial protein
synthesis in toto and those that affect protein-coding
genes. Disorders related to mtDNA mutations are
4.2. Mitochondrial encephalopathy with
sporadic or due to maternal transmission. Mendelian
lactic acidosis and stroke (MELAS)
transmission characterizes nuclear DNA mutations MELAS is defined by the association of mito-
and defects of intergenomic signaling. chondrial encephalomyopathy, lactic acidosis, and
Histologically most of the mitochondrial enceph- stroke-like episodes. Other CNS signs include
alomyelomyopathies are characterized by sponginess dementia, seizures, and deafness. Pathologically,
affecting gray and white matter, capillary prolifera- infarcts are present in the cerebral cortex and
tion, and some degree of neuronal loss and gliosis. subcortical white matter, often located in the
Some of the diseases may overlap. parieto-occipital lobes, the cerebellum, and rarely
in the brainstem. The spinal cord may be involved.
Calcifications of basal ganglia are common. Enlarged
4.1. Leigh disease (subacute necrotizing mitochondria, present in pericytes, smooth muscle
encephalopathy, infantile) cells, and endothelial cells of the terminal arterioles,
Leigh disease is seen most often in early childhood, have been considered responsible for the recurrence
but variants with late onset have been described. of transient cerebral ischemia. Ragged-red fibers
A B
FIGURE 10.8 Leigh disease. (A) Necrosis of the walls of the third ventricle and of the basal ganglia. Note that
the mammillary bodies are spared (Loyez). (B) Periaqueductal necrosis (Loyez). (C) Microscopic appearance
of necrosis, macrophage reaction, capillary proliferation, and relative neuronal sparing.
(RRFs) (Fig. 12.15A) are usually abundant in mus- spinal cord lesions resembling Friedreich ataxia,
cle. MELAS was first associated with a point muta- and degeneration of the substantia nigra, cerebel-
tion in the tRNA Leu (UUR) (3243 A-G) gene but also lar cortex, inferior olivary nucleus, locus coeruleus,
with mutations in complexes I and IV (Cox III). It is gracile and cuneate nuclei, and the pontine tegmen-
usually maternally transmitted. tum. Many RRFs are found in muscle. MERRF was
first associated with point mutations in the tRNA
Lys gene (8344 A-G; 8356 T-C), and deficiency in
4.3. Myoclonic epilepsy with ragged complexes I, III, and IV (Cox II) have been reported
red fibers (MERRF) subsequently. It is usually maternally transmitted.
MERRF (or Fukuhara disease) is defined by the
association of myoclonic epilepsy with RRFs. Other
signs include dementia, cerebellar ataxia, and deaf-
4.4. Kearns-Sayre syndrome
ness. Pathologically, the central and peripheral ner- Kearns-Sayre syndrome is defined as progressive
vous systems and skeletal muscle are involved. The external ophthalmoplegia and pigmentary reti-
topographical distribution of lesions is reminiscent nopathy with onset before 20 years of age. Cardiac
of neuronal system degeneration: degeneration conduction block is important for prognosis. The
of the dentatorubral and pallidoluysian system, disease progresses slowly and patients often develop

more severe multisystem involvement. In the CNS, microscopy or stained with PAS. Glia may also have
its pathological hallmarks are spongy or vacuolar excess glycogen content. Acid maltase deficiency is
myelinopathy of the brainstem and cerebellum with unique among the glycogen storage diseases; due
neuronal loss. The lesions may extend to the cerebral to the role of the enzyme in the lysosomal deg-
white matter with mineralization of basal ganglia radation of glycogen, its deficiency results in the
and thalamus. Skeletal muscle nearly always dis- intralysosomal storage of glycogen. The glycogen is
plays RRFs (see Chapter 12). Large-scale deletions surrounded by a lysosomal membrane on electron
of mtDNA are present in Kearns-Sayre syndrome microscopy (Fig. 12.16C) and is associated with
(“common deletion of 4,977bp”). Most cases are acid phosphatase in routine histological sections.
sporadic. The disease often presents as a “floppy” infant and is
rapidly progressive, with death by the age of 1 year.
4.5. Alpers syndrome (mitochondrial
DNA depletion syndrome 4A)
5.2. Lafora disease and adult
Alpers syndrome is an autosomal recessive disorder polyglucosan body disease
characterized by progressive neurological deterio-
ration, seizures, cortical blindness, and liver failure Lafora disease is an autosomal recessive disorder
(progressive neuronal degeneration of childhood characterized by progressive myoclonic seizures.
with liver disease). The disease is caused by muta- It is caused either by mutations of the laforin gene
tions in the gene encoding mitochondrial DNA (EPM2A, chromosome 6q24.3) or by mutations of
polymerase gamma (POLG), a nuclear gene located the malin gene (NHLRC1, chromosome 6q22.3).
on chromosome 15q.26.1. Survival is not usually The laforin gene encodes a protein phosphatase that
beyond 3 years of age. The hepatic involvement is hydrolyzes phosphorylated tyrosine, serine, or thre-
initially a fatty change and midzonal necrosis, but onine residues; laforin also plays a role in glycogen
it often progresses rapidly to nodular cirrhosis. metabolism. The malin gene encodes a single subunit
The neuropathology shows spongy changes in less E3 ubiquitin ligase. Both genetic defects result in an
affected areas of the brain, but in severely affected abnormality of carbohydrate metabolism that causes
areas, there is widespread neuronal loss and exten- an accumulation of polyglucosan bodies, the Lafora
sive gliosis. Although the changes are diffusely bodies (Fig. 1.17), in a number of cell types. The
distributed, they tend to be the most severe in the onset of the disease is usually during childhood, and
occipital visual cortex. there is a progressive degeneration of the nervous
system, along with progressive myoclonic epilepsy.
In adults, storage of glucose polymer inclu-
5. METABOLIC DISORDERS sions (polyglucosan bodies) has been described
OF GLYCOGEN AND OTHER in the axons of the central and peripheral nervous
CARBOHYDRATES system, in astrocytic processes, and in some of the
viscera, associated with progressive involvement of
central and peripheral motor neurons, sensory dis-
5.1. Glycogenoses turbances, sphincter disturbances, and dementia.
The glycogenoses are glycogen storage diseases This form of “adult polyglucosan body disease” can
that result in the intracellular accumulation of gly- be distinguished from the nonspecific presence of
cogen. Some, such as McArdle disease and Forbes corpora amylacea—which may be numerous in the
disease, involve chiefly the skeletal musculature elderly—by the distribution of the inclusions in
(see Chapter 12); the CNS is affected only excep- the cortex (Fig. 10.9B) and, in peripheral nerves, in
tionally. Pompe disease (or glycogen storage dis- the axons (Fig. 10.9D, E), and by the presence of a
ease II), which is caused by acid maltase deficiency diffuse or focal myelin pallor in the cerebral white
(acid alpha-1,4-glucosidase deficiency), however, matter (Fig. 10.9A, C). Reduced glycogen branching
may involve the nervous system. The neurons of enzyme activity has been found in adult polygluco-
the anterior horns, of some brainstem nuclei, of the san body disease, and the disease may represent a
cerebellum, and, to a lesser extent, of the cortex may form of glucose storage disorder IV (amylopectino-
be vacuolated and swollen and may show excessive sis, or Andersen disease). Most patients, however,
storage of glycogen when examined by electron have no family history.
A
C D
FIGURE 10.9 Adult polyglucosan body disease. (A) Presence of multiple foci of myelin pallor in the cerebral
white matter (Loyez). (B) Cerebral cortex with numerous polyglucosan bodies present in the neuropil (PAS).
(C) Hemispheric white matter with accumulation of polyglucosan bodies, especially in the perivascular regions
(Cresyl violet–Luxol fast blue). (D, E) Peripheral nerve biopsy with intra-axonal inclusion stained with tri-
chrome (D) and with PAS after teasing (E).

6. ENZYME DEFICIENCIES cerebellar atrophy is common and includes almost
total loss of Purkinje cells and granule cells, as well
WITHOUT INTRACELLULAR as glial proliferation.
STORAGE Axonal swellings are also seen in the peripheral
In addition to enzyme deficiencies that lead to intra- nerves and in the nerve fascicles of the dental pulp,
cellular accumulation of a metabolic product (“stor- the skin, the conjunctiva, and the perirectal plex-
age diseases”), some metabolic disorders are due to uses, thus permitting the diagnosis to be made with
a deficiency of the activity of a cytoplasmic enzyme biopsies. By electron microscopy, the axonal swell-
without storage or elevation of intracellular metabo- ings are composed of tubulomembranous material,
lites. In this section are included neuroaxonal dys- in contrast to other axonal swellings (Fig. 10.10B).
trophies, the disorders of DNA repair, and defects in
heme biosynthesis (porphyrias). 6.1. 2 . NEUROAXONAL DYSTROPHY
WITH IRON ACCUMUL ATION TYPE
6.1. Neuroaxonal dystrophies I (H AL L ERVORDEN- SPATZ DISEASE)
6.1.1. INFANTILE NEUROAXONAL Hallervorden-Spatz disease is an autosomal recessive

DYSTROPHY (SEITELBERGER DISEASE disorder that results from a mutation in the panto-
AND SCHINDLER DISEASE) thenate kinase gene, PANK2, located on chromo-
some 20p13. Onset is in the first or second decade
Infantile neuroaxonal dystrophy is a recessive auto- with a typical survival of 15 to 20 years, although
somal disorder of infancy characterized by axonal adult cases have been reported. Progressive rigidity
enlargement with a dystrophic appearance (axonal is accompanied by involuntary movements involv-
dystrophy). The disease affects only the nervous sys- ing the limbs, face, and tongue; mental deterioration
tem and has a wide distribution of spheroid bodies and pigmentary retinitis occur later. MRI enables
throughout the nervous system, which correspond antemortem diagnosis of the disease, showing iron
to the axonal dilatations. The classic form of the dis- deposition in the globus pallidus and pars reticulata
ease, Seitelberger disease, is characterized by mental of substantia nigra. Gross examination of the brain
retardation, paralysis, and epilepsy and is caused by shows orange-yellow discoloration of the globus
mutations in the PLA2G6 gene (located on chromo- pallidus and substantia nigra and iron deposition in
some 22q13.1), a phospholipase (type A2 group 6). the basal ganglia, which results from intracytoplas-
A similar form of infantile neuroaxonal dystro- mic accumulation of iron pigment in neurons, astro-
phy, Schindler disease, results from a deficiency of cytes, and macrophages, or free in the parenchyma,
N-acetyl-alpha-D-galactosaminidase (NAGA, chro- surrounding the blood vessels. Neuronal loss and
mosome 22q13.2). NAGA is a lysosomal enzyme gliosis are marked in the globus pallidus and incon-
that cleaves acetylgalactosaminyl moieties from stant in the cerebral cortex. The red nucleus and the
complex carbohydrates. subthalamus may also be involved. Axonal spheroids
On gross examination in infantile neuroax- are abundant in the globus pallidus and substantia
onal dystrophy, the globus pallidus may be nigra. Ultrastructurally, the spheroids consist of
orange-yellow and the white matter has a chalky packed membranes, dense bodies, tubules, and
appearance (Fig. 10.10A). The ventricles may be mitochondria.
dilated, and there is frequently cerebellar atrophy.
Microscopic studies have shown the presence of
dystrophic axons, which have given the disease 6.2. Disorders associated with
its name and which consist of rounded structures, defective DNA repair
measuring 10 to 20 μm. These axonal “spheroids”
6.2. 1 . XERODERMA PIGMENTOSUM
are argentophilic and weakly eosinophilic and stain
strongly with PAS stain. They are especially numer- Xeroderma pigmentosum is a genetically hetero-
ous in the gray matter of the spinal cord and the geneous autosomal recessive disorder that is char-
medulla and are present in lesser numbers in the acterized by exaggerated sensitivity of the skin and
cerebellum, the pontine nuclei, the white matter of eyes to ultraviolet radiation and a greatly increased
the spinal cord, the medulla, and the pons; they are susceptibility to sun-induced malignant epithelial
rare in the cerebral hemispheres. Severe and diffuse neoplasms. Neurological abnormalities occur in
A B
FIGURE 10.10 Neuroaxonal dystrophy. (A) Orange-yellow discoloration of the globus pallidus. (B) Electron

microscopy of a swollen axon containing tubulomembranous material.
18% of patients; among these, the most frequent (with mutations in ERCC5) include some families
abnormality (in 80%) is intellectual impairment, initially described as having Cockayne syndrome.
which is often progressive. In a smaller proportion Similar to XP, the genes involved in Cockayne syn-
of patients, there is evidence of involvement of drome are involved in the repair of DNA following
peripheral neuropathy: absence of stretch reflexes, ultraviolet radiation, but there is no association with
ataxia, muscular wasting, and distal sensory impair- an increased incidence of malignancies.
ment. Examination of peripheral nerves shows Classic Cockayne syndrome, with a gene locus
both demyelination and axonal degeneration with on chromosome 5q12.1 (ERCC8), is associated
endoneurial and perineurial fibrosis. The molecular with dwarfism, microcephaly, retinitis pigmentosa,
basis for the disease is a lack of normal mechanisms deafness, and peripheral nerve involvement. The
to protect or repair ultraviolet-induced damage to brain is atrophic, especially the cerebellum and
DNA. The disease may be caused by mutations brainstem. The demyelination, which is often sub-
in any of several genes involved in the nucleotide cortical, is a “tigroid” demyelination. Calcifications
excision repair mechanism. Group A patients have are present in the basal ganglia and in the dentate
mutations in the XPA gene (located on chromo- nuclei. A demyelinating peripheral neuropathy
some 9q22.33); group B patients have mutations can be demonstrated electrophysiologically and
in the ERCC3 gene (located on chromosome pathologically.
2q14.3); and group C patients, the most common
form, have mutations in the XPC gene, involved
in the detection of DNA damage, a first step in 6.2.3 . ATAXIA- TEL ANGIECTASIA
nucleotide excision and repair. Additional groups Ataxia-telangiectasia (AT) (Louis-Bar disease) is
of patients (D through G) have recognized muta- a rare autosomal recessive disorder that combines
tions; all affect genes involved in DNA nucleotide progressive neurological symptoms, including cer-
excision and repair. ebellar ataxia, and extrapyramidal and oculomotor
disturbances with telangiectatic vascular prolifera-
tion in the skin and conjunctiva, and defects in the
6.2.2. COCKAYNE SYNDROME
immune system (involving both B-cell and T-cell
Cockayne syndrome is a very rare autosomal reces- function). Patients with AT are prone to neoplastic
sive disorder with mental retardation and photosen- diseases, particularly non-Hodgkin lymphomas and
sitivity. There are multiple genes that can give rise carcinoma of the stomach. It is caused by a defect in
to the Cockayne syndrome. ERCC8 and ERCC6 DNA repair, and AT cells are abnormally sensitive to
are the genes affected in Cockayne syndrome types ionizing radiation.
A and B, respectively. Overlap syndromes between The gene, ATM, is located on chromo-
mild forms of xeroderma pigmentosa (XP) and some 11q22.3 and encodes a protein in the
Cockayne syndrome have been recognized; XP phosphatidyl-inositol-3 kinase family, a member of
group B (with mutations in ERCC3) and group G the group of proteins that respond to DNA damage

by phosphorylating the substrates involved in DNA These nuclei are large, pale, and multilobulated and
repair. present the picture of Alzheimer type II glia. Large
Neuropathological examination shows a con- cells of macrophage/microglial origin with eccentric
stant and usually diffuse atrophy of the cerebellar nuclei, Opalski cells, are also found scattered in the
cortex. It involves predominantly the Purkinje cells basal ganglia (Fig. 10.11B–D). Microscopic copper
and the granule cells and may be accompanied by deposits are found at the periphery of astrocytes but
neuronal cell loss in the dentate nuclei and the infe- are difficult to visualize. The disorder is also accom-
rior olives. Nerve cell loss in the anterior horns and panied by cirrhosis of the liver with elevated copper
degeneration of the posterior columns are common, levels and Kayser-Fleischer rings (copper-colored
especially in longstanding cases. In the spinal root rings at the periphery of the cornea). Mitochondrial
ganglia, neurons are small, the number of satellite dysfunction has been demonstrated in the liver but
cells is reduced, and the residual satellite cells may not in the brain.
show marked nuclear abnormalities, as do the nuclei Low serum levels of ceruloplasmin are a diagnos-
of Schwann cells in peripheral nerves. tic feature of Wilson disease but are secondary to the
decreased fixation of copper on apoceruloplasmin.
The ceruloplasmin gene, located on chromosome 3,
6.3. Porphyrias is not affected in Wilson disease. In contrast, in cases
Porphyrias are a group of disorders of heme biosyn- of hereditary ceruloplasmin deficiency linked to a
thesis. Acute intermittent porphyria is a neurological mutation of the ceruloplasmin gene, the major mor-
disorder characterized by acute psychotic episodes phological feature is the deposition of iron in the
and acute-onset peripheral neuropathy. The disor- basal ganglia, particularly the putamen, thalamus,
der is due to a deficiency of porphobilinogen deami- and dentate nuclei.
nase (hydroxymethylbilane synthase; HMBS gene),
and the onset of symptoms is abrupt, typically with
gastrointestinal symptoms and neuropathy; the
7.2. Menkes disease (kinky
patients are healthy between the episodes. In the
hair disease)
peripheral nervous system, there is an axonopathy; Menkes disease (kinky hair disease or trichopoliodys-
in the CNS, neuronal chromatolysis in the anterior trophy) is an X-linked disorder of copper metabolism.
horn cells and in the motor nucleus of the vagus may The disease is due to mutations of a gene (Xq21.1)
be associated with cerebellar lesions. that encodes the copper-transporting ATPase 7A.
There are low levels of copper and ceruloplasmin in
the blood. The disease causes abnormalities in the hair
7. DISORDERS OF COPPER and neuropsychiatric manifestations. Pathologically
METABOLISM there are changes in the hemispheric myelin (tempo-
ral lobes) and lesions in the cerebellar cortex (gran-
7.1. Wilson disease ule and Purkinje cells) and in the blood vessel walls
Wilson disease (hepatolenticular degeneration) is an (thickening and splitting of elastic fibers).
autosomal recessive disorder of copper metabolism
with accumulation of copper in the liver and brain 8. DISORDERS OF AMINO
and prominent hepatic and neurological symptoms.
It is due to mutations of the Wilson gene (ATP7B
ACID METABOLISM
gene, chromosome 13q14.3). The protein product These disorders are the cause of many syndromes of
of ATP7B is a plasma membrane cation-transporting mental retardation in childhood and may be associ-
P-type ATPase with six copper-binding domains. ated with a number of neurological manifestations.
Characteristic brain lesions are found in the Most of the disorders of amino acid metabolism are
basal ganglia. These culminate, in advanced autosomal recessive disorders and are characterized
stages, in necrosis of the putamen with cavitation pathologically by a prominent spongiosis or cavita-
(Fig. 10.11A), whereas the globus pallidus, the thal- tion of the white matter with accompanying gliosis.
amus, and the cerebral cortex are involved to a lesser Different mechanisms are involved in the pathogen-
extent. Less severe lesions consist of a spongy state, esis of the neurological disorders, as amino acids
with glial changes that involve the astrocytic nuclei. have a role in neurotransmission, protein synthesis,
A B
C D
FIGURE 10.11 Wilson disease. (A) Bilateral necrosis of the putamen. (B–D) Opalski cells with eccentric
nucleus and granular cytoplasm (B: H&E; C: Bodian–Luxol stain; D: immunolabeling with CD68 macrophage
marker).
lipid metabolism, and mitochondrial function. 6 months of life, with death occurring by 18 months
A direct toxic effect may be induced by abnormal of age. The abnormality is exclusively in the CNS
accumulation of byproducts. The diagnosis is usu- and consists of a spongy degeneration creating an
ally made by identification of elevated amino acids increased volume of the brain with a soft, gelatinous
or their byproducts in serum or urine. consistency. The spongiosis often involves the sub-
cortical white matter of the cerebral hemispheres
and cerebellum (Fig. 10.12A) with intramyelinic
8.1. Canavan disease (aspartoacylase edema (Fig. 10.12B). Proliferation of Alzheimer
deficiency, spongy degeneration of the type II astrocytes is common, and the severity of
CNS, or spongy leukodystrophy) demyelination usually parallels that of the spongio-
Canavan disease is an autosomal recessive leukodys- sis. Macrophages are infrequent.
trophy caused by mutations of the gene encoding
the enzyme aspartoacylase (ASPA; gene locus 17
p13.2). Aspartoacylase is the enzyme that cleaves
8.2. Phenylketonuria
N-acetylaspartate into aspartate and acetate, and its Phenylketonuria (PKU), the most common ami-
absence leads to elevated levels of N-acetylaspartate. noaciduria, is due to absence of phenylalanine
Missense point mutations involving the APSA gene hydroxylase, which is encoded by the PAH gene
are the most common, but deletions have also been on chromosome 12q23.2 and which hydroxylates
detected. phenylalanine to tyrosine. Elevated levels of phe-
The symptoms include mental deterioration nylalanine result in retardation in neural develop-
and megalencephaly. The onset is usually in the first ment, and there is a relative deficiency of tyrosine,

A catabolized by an alpha-keto acid dehydrogenase spe-
cific for branched-chain amino acids, and mutations
in the individual subunits of the complex are caus-
ative of the disorder. The disease may be identified
by the presence of sotolone in the urine, which has
a characteristic odor that has been likened to maple
syrup. Plasma concentrations of branched-chain
amino acids are increased, with a particularly ele-
vated level of leucine. The disorder is characterized
by spongy lesions in the white matter resembling
those of Canavan disease without evidence of myelin
breakdown.
8.4. Homocystinuria
Homocystinuria is an autosomal recessive disor-
der characterized by ocular abnormalities (lentis
ectopia and myopia), mental retardation, and a pro-
pensity for thromboembolic events. The disorder is
B due to mutations of the cystathionine β-synthase
gene (located on chromosome 21q22.3); the gene
product is the enzyme of the same name, which
normally couples homocysteine to serine to form
cystathionine. The disease may cause alterations in
blood vessel walls, with fibrosis of the intima, degen-
eration of the elastic fibers, and thromboses. Foci of
cerebral necrosis of vascular origin are often found,
and although the onset is typically in the first or
second decade of life, it may also present in young
adulthood.
FIGURE 10.12 Spongy degeneration of the CNS
(Canavan disease). (A) Spongiosis of the cerebellar 8.5. Hartnup disease
white matter (Loyez). (B) Microscopic appearance of
intramyelinic edema (H&E). Hartnup disease is due to an abnormality in tryp-
tophan metabolism and produces a picture that
resembles pellagra, with clinical features of derma-
which becomes a dietary essential amino acid. The titis, dementia, and diarrhea. The neuropathological
neuropathological findings are variable but include features include cortical atrophy and neuronal loss,
microcephaly, spongiosis of the white matter, atro- especially in the occipital cortex and cerebellum.
phic neurons with poorly developed dendritic trees, The gene (SLC6A19) is located on chromosome
and pallor of the myelin of the hemispheric and 5p15.33 and encodes the amino acid transporter
cerebellar white matter, optic tracts, and fornices, protein that transports neutral amino acids across
resembling a leukodystrophy. the apical membrane in the kidney and gastrointes-
tinal tract.
8.3. Maple syrup urine disease
(branched-chain ketoaciduria) 8.6. Hyperglycinemia
Maple syrup urine disease is a neonatal disorder Hyperglycinemia arises in two forms. In the ketotic
caused by mutations of enzymes involved in the form of hyperglycinemia, the disease is caused by
catabolism of the branched-chain amino acids, leu- a defect in the catabolism of propionic acid. The
cine, isoleucine, and valine. These amino acids are deficiency of propionyl-CoA carboxylase results in
elevation of glycine and propionic acid, with epi- In the typical clinical form, the onset of symp-
sodes of lethargy, vomiting, and leukopenia, and a toms is usually with seizures and megalencephaly
progressive developmental retardation. The nonke- in the early infantile period. Death usually occurs
totic form of hyperglycinemia is due to a defect of within 10 years of the age of onset. On gross
the mitochondrial glycine cleavage enzyme system examination, the white matter is softened and
and leads to an encephalopathy in the newborn friable, and the abnormality is especially promi-
characterized by hypotonia, lethargy, and seizures. nent in the frontal lobes. There is massive demy-
Agenesis of the corpus callosum and gyral malfor- elination involving the cerebral hemispheres
mations are associated with vacuolation of the white (Fig. 10.13A), cerebellum, and, to a lesser degree,
matter and loss of myelin. the brainstem and spinal cord. A unique histologi-
cal feature that sets Alexander disease apart from
other leukodystrophies is a prominent accumu-
8.7. Urea-cycle disorders lation of Rosenthal fibers. Rosenthal fibers are
Urea-cycle disorders are genetic disorders in the densely eosinophilic astrocytic processes, which
conversion of ammonia to urea; a block in this by electron microscopy are filled with glial inter-
detoxification pathway is associated with hyper- mediate filaments and electron-dense structures
ammonemia and its complications. The most composed of alpha-B crystallin (Fig. 10.13C).
common deficiency is that of ornithine carbamoyl- In Alexander disease, Rosenthal fibers are
transferase which is an X-linked disorder is. Other particularly numerous around blood vessels
forms include arginase deficiency, arginosuccinic (Fig. 10.13B), adjacent to the ventricular walls,
aciduria, citrullinemia, and carbamoylphosphate and in the subpial zone.
synthetase deficiency. Alzheimer type II astro-
cytes, related to hyperammonemia, are frequent; in
severe cases the cerebral cortex and the deep gray
matter may be involved.
9.2. Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease is an X-linked
recessive leukodystrophy caused by muta-
9. DISORDERS OF tions in the proteolipid protein-1 gene (PLP1).
STRUCTURAL PROTEINS Proteolipid protein-1 is a structural protein of
CNS myelin, and point mutations, deletions, and
Unlike the hereditary metabolic disorders described gene duplications in PLP1 have all been described
thus far, some inherited diseases are caused by in Pelizaeus-Merzbacher disease. In the classic
genetic mutations of genes encoding structural infantile form, infants have rotary movements of
proteins. Since they play no known role in cell the head and eyes and develop spasticity of the
metabolism, their classification as “metabolic” dis- limbs, cerebellar ataxia, and parkinsonian symp-
eases could be questioned. However, they share the toms during childhood. Death usually occurs in
genetic inheritance and clinical progression of other late adolescence. As in other leukodystrophies,
metabolic diseases and were classified with the other the disease is characterized by the loss of myelin
inherited metabolic diseases prior to the identifica- in the white matter. Due to the sparing of a few
tion of the genes involved. small islands of normal myelin, often in a peri-
vascular distribution, the “striped” appearance of
perivascular myelin sparing has been known as
9.1. Alexander disease a “tigroid leukodystrophy” (Fig. 10.14A , C, D).
Alexander disease is an autosomal recessive mega- The cerebral and cerebellar white matter appears
lencephalic leukodystrophy caused by mutations of atrophic. Axons are relatively preserved, and there
the glial fibrillary acidic protein (GFAP) gene. GFAP is a severe gliosis. The abnormalities of myelin are
is the intermediate filament protein of glia, with limited to the CNS; the peripheral nervous sys-
individual subunits assembled into 10-nm interme- tem is usually spared, and visceral involvement is
diate filaments. Point mutations are typically found absent.
and may be recessively inherited or occur as de novo While the usual form of the disease presents in
mutations. the first 3 months of life, a connatal form (congenital

A B
FIGURE 10.13 Alexander disease. (A) The massive demyelination of the cerebral hemispheres is less obvious
as the numerous Rosenthal fibers are stained by the Loyez method. (B) Hemispheric white matter with numer-
ous Rosenthal fibers especially dense around a blood vessel (H&E). (C) Electron microscopy of Rosenthal
fibers, which appear as electron-dense masses in pericapillary astrocytic processes.
form of Seitelberger) is characterized by a nearly Demyelination is diff use, ill defined, and often
complete absence of CNS myelin (Fig. 10.14B) and irregular (Fig. 10.15); it tends to predominate
severe symptoms in infancy. in the frontal lobes, which accounts for the fre-
quency of psychiatric disorders. Axonal involve-
ment is frequent. Macrophage reaction is discrete
10. ORTHOCHROMATIC and there is no inflammation.
In a subset of young patients, an autosomal reces-
LEUKODYSTROPHIES sive orthochromatic leukodystrophy is known as leu-
The orthochromatic leukodystrophies are a het- koencephalopathy with vanishing white matter (or
erogeneous group of rare disorders characterized childhood ataxia with central hypomyelination). It is
by abnormalities largely limited to the white mat- characterized by a cavitary orthochromatic leukoen-
ter of the brain. Some of the disorders are infantile, cephalopathy with increased oligodendrocyte den-
with presentation before the age of 5, and often sity. It is caused by mutations in any of the five genes
with a rapidly progressive course. Other disor- encoding the subunits of the translation initiation
ders present in adults and have a slower evolution. factor, EIF2B: EIF2B1, E1F2B2, E1F2B3, E1F2B4,
They represent the most frequent leukodystro- or E1F2B5 (with gene loci of chromosome 12q24.1,
phies in adults. The lesions involve the CNS only. 14q24.3, 1p34.1, 2p23.3, and 3q27.1, respectively).
A B
C D
FIGURE 10.14 Pelizaeus-Merzbacher disease. (A) Typical infantile form of Pelizaeus-Merzbacher tigroid leu-

kodystrophy (Loyez; courtesy of Professor Jean Lapresle). (B) Massive congenital form of Seitelberger (Loyez).
(C, D) Microscopic appearance with relative preservation of the myelin around blood vessels (C: Luxol fast
blue–Cresyl violet; D: Loyez).
FIGURE 10.15 Simple diffuse orthochromatic FIGURE 10.16 Cavitating orthochromatic leuko-

leukodystrophy (Loyez). dystrophy (Loyez).

In a few adult cases of orthochromatic leuko- forms presenting as highly destructive white matter
dystrophy, sporadic or familial, the macrophages lesions (Fig. 10.16) with increased density and “clus-
and glial cells contain a brown, autofluorescent and tering” of oligodendrocytes have been described in
PAS-positive pigment (pigmentary orthochromatic children and in adults. Overlaps between cavitary and
leukodystrophy of Van Bogaert and Nyssen). Cavitary pigmentary forms have been observed occasionally.
11
Congenital Malformations and Perinatal
Diseases
F É R ÉC HT É E NC HA-R A ZAV I , R EB EC C A F O L K ER TH , B RIA N N. H A RD ING , H A RRY V. VINTERS,
A N D J E FFR E Y A. GOL D EN
1. GENERAL multifactorial basis. Understanding the underly-

ing pathogenesis for any congenital anomaly of the
CONSIDERATIONS central nervous system (CNS) is of importance for
Congenital anomalies are deviations from nor- genetic counseling of parents and siblings of affected
mal form and/or structure, present at birth. infants.
Malformations are developmental failures due to a Over the past decade significant progress has
primary disruption of normal embryological devel- been made in understanding the molecular/genetic
opment, which can be genetic or environmental in basis of many congenital anomalies, and with that
origin or, most commonly, multifactorial, resulting has come a greater appreciation for the complexity
from complex interactions between genes and the of brain development. Neural tube closure defects
environment. In contrast, a disruption represents the (e.g., myelomeningoceles and anencephaly) have
perturbation or abrogation of the normal develop- largely eluded molecular characterization. However,
mental process; examples of this include a vascular extensive and ongoing studies have clearly impli-
accident resulting in porencephaly or hydranen- cated a multifactorial pathogenesis for these dis-
cephaly or the well-known consequences of in utero orders involving the planar-cell-polarity signaling
infection (e.g., cytomegalovirus). These too can be pathway, along with adequate maternal nutrition,
environmental, genetic, or multifactorial. Finally, folate intake in particular.
deformations exist when external forces alter but Another example of this complexity has come
do not disrupt normal development. An example through the greater elucidation of the pathogenesis
of this would be the arthrogryposis that frequently of holoprosencephaly. This complex malformation
accompanies oligohydramnios. Once again, defor- can arise in the setting of a mutation in a single gene,
mations can occur on a genetic, environmental, or in the presence of multiple genetic alterations, due
• 257
to gross chromosomal alterations (e.g., trisomy 13), NTDs are widely believed to result from a complex
or on a multifactorial basis. Further confusing the interaction between genetics and environmental
evaluation, a mutation in a known causative gene for influences, since the risk of recurrence among cou-
holoprosencephaly, such as SHH, does not always ples who have had an affected offspring is increased
correlate with this specific brain anomaly and can over that of the general population. Preconceptional
seen in individuals with a normal brain, even in the multivitamin and folate supplementation reduces
same family with an individual with the same muta- the recurrence risk for women with one affected
tion but exhibiting holoprosencephaly, further sup- child and also appears to reduce the overall inci-
porting the complex genetic, or multifactorial, basis dence in all women. Successful screening programs
of most congenital anomalies. using a panel of maternal serum markers, along with
A clear understanding of normal brain devel- a follow-up ultrasound or MRI examination for pos-
opment is critical for the evaluation of congenital itive cases, identify the majority of cases with a high
anomalies, as the effect of an exogenous factor on degree of sensitivity and specificity. NTDs may be
the brain is dependent upon the development tim- isolated malformations or found in association with
ing of the exposure. For example, exposure of the other malformations as part of a syndrome, the lat-
fetus to alcohol in the first trimester can result ter primarily being occipital encephaloceles associ-
in microcephaly and other disorders, whereas ated with a variety of Mendelian disorders such as
exposure in the second or third trimester usually the Meckel-Grüber syndrome (a ciliopathy) and the
results in a normal brain structure but functional Walker-Warburg syndrome (a congenital disorder of
perturbation. glycosylation).
2. CONGENITAL 2.1. 1 . CRANIAL NTDS

MALFORMATIONS Exencephaly and anencephaly are characterized by
the absence of the calvarium, abnormalities of the
2.1. Neurulation failure skull base, and variable disruption of the intracranial
The transformation of the neural plate into the neu- neuroepithelium. The commonly involved sphenoid
ral tube begins around the end of the third gesta- bone often results in shallow orbits, causing protru-
tional week and is complete by the end of the fourth sion of the eyes (Fig. 11.1).
gestational week. Failure of this process results in Anencephaly is the most common form of
neural tube closure defects (NTDs). NTDs are the cranial NTD. In this condition there is variable
most frequent CNS malformations, with an inci- loss (destruction) of the forebrain, diencephalon,
dence of 1 to 2 per 1,000 live births, although there and rostral brainstem, which are replaced by an
is wide geographical variability; for example, the irregular web of neurovascular tissue that includes
incidences in Ireland and Punjab, India, are reported ependyma-like epithelium and choroid plexus
to reach 8 per 1,000 live births. As mentioned above, (“area cerebrovasculosa”).
A B
FIGURE 11.1 Anencephaly.
A B
FIGURE 11.2 Exencephaly (A) associated with craniorachischisis (B).
Exencephaly (Fig. 11.2) is a very rare related 2.1.2 . SPINAL NTDS

condition in which the cerebral hemispheres,
Spinal NTDs have a complex and often interchange-
although disorganized and rudimentary, are usually
ably used nomenclature (Fig. 11.4). Generic terms
present. Experimental studies suggest the neural
such as spina bifida have been used to describe all
tissue, growing outside the confines of the skull and
forms, and this has been further subdivided by some
thus resulting in the disorganization, is protected
to be either open (“aperta”) or closed (“occulta”).
from the amniotic fluid, likely by the meninges.
It is perhaps more accurate to use the descriptive
Destruction of the neural tissue occurs when the
terminology of spinal or vertebral dysraphism if only
neuroepithelial tissue is in contact with the amni-
the vertebral body is involved but not either the spi-
otic fluid, eventuating in the area cerebrovasculosa.
nal cord or the meninges, meningocele when only the
Involvement of the cranial contents along with
meninges are involved with a vertebral anomaly, and
the upper or entire spinal cord is referred to as
myelomeningocele when there is involvement of all
craniorachischisis.
three—the vertebral bodies, the meninges, and the
Encephalocele (or meningoencephalocele) is
spinal cord.
the herniation of cerebral tissue and/or menin-
Defining the location in addition to the type
ges (meningocele if involving the meninges only)
is also important, the lumbosacral region being
through a calvarium defect of variable size. In 80% of
involved most commonly. Iniencephaly is a related
cases the bone defect occurs in the occipital region
disorder where the cervical posterior vertebral
and is associated with skin and hair abnormalities
arches are foreshortened and fused, resulting in a
(Fig. 11.3). The neural tissue within the encepha-
fixed extension and shortening of the neck, usu-
locele is usually disorganized, occasionally showing
ally and often associated with abnormalities of
polymicrogyria, and frequently showing evidence of
the brainstem. Similar to that described for the
ischemic injury.
cranial region above, when the defect is open to
A B
FIGURE 11.3 Occipital meningoencephalocele.
Chapter 11 Congenital Malformations and Perinatal Diseases • 259

Skin Neural groove
Spinal apophysis Skin

Spinal canal
Spinal cord
Subarachnoid space
Meninges
Vertebral body
Normal Spina bifida aperta
Skin
Meninges Meninges
Skin Spinal cord
Spinal cord
Meningocele Myelomeningocele
Dermal sinus Skin

Closure defect of
Skin
posterior vertebral
Meninges arch
Meninges
Spinal cord
Spinal cord
Congenital dermal sinus Spina bifida occulta
FIGURE 11.4 Spinal neural tube closure defects.
the amniotic fluid there is destruction of the neu- of posterior fossa anomalies. They include a low-set
roepithelium, with resulting neurovascular tissue tentorium and small posterior fossa, lengthening of
referred to as area myelovasculosa or medullovas- the cerebral peduncles, a Z-shaped deviation of the
culosa. If covered by meninges but involving the medulla oblongata, and cerebellar hypoplasia with
neural placode, the developing spinal cord is vari- downward displacement of the cerebellar vermis
ably disorganized but recognizable, although the through an enlarged foramen magnum (dorsally
dorsal aspect will be splayed open. The spinal cord overlying the cervical spinal cord) (Fig. 11.6). This
adjacent to the defect, where the neural tube has complex association, called the Chiari type II (or
closed, and in cases where the neuroepithelium is Arnold-Chiari) malformation, is further character-
not involved, may show syringomyelia (Fig. 11.5), ized by hydrocephalus, sometimes with a polygyric
hydromyelia, diplomyelia, or diastematomyelia pattern of the cerebral convolutions and subependy-
(partial duplication). A related condition is the mal heterotopia at birth. Of considerable interest,
presence of a congenital dermal sinus; a commu- the recent advancements in the repair of lumbosa-
nication persists between the skin surface and the cral myelomeningoceles in utero (fetal surgery) have
subarachnoid space, which can be complicated by resulted in the elimination of the cerebral compo-
recurrent meningitis. nents of the Chiari II malformation in most cases,
Lumbosacral meningomyeloceles are nearly suggesting it is a secondary deformation rather than
always associated with a characteristic constellation a true malformation.
2.2. Disorders of development of the
prosencephalon
The most rostral subdivision of the neural tube
is known as the prosencephalon. Bilaterally sym-
metrical outgrowths from the prosencephalon give
rise to the telencephalic vesicles in the fifth week
of gestation. These paired structures will become
the cerebral hemispheres and the basal ganglia. The
caudal-medial part of the prosencephalon, which
FIGURE 11.5 Syringomyelia, with expansion of the
remains as a single entity, becomes the diencepha-
central canal and compression of the posterior horn
lon (future thalamus) and also gives rise to the optic
and column (Loyez stain for myelin).
A C
B D
FIGURE 11.6 Arnold-Chiari malformation. (A) Dorsolumbar meningomyelocele (courtesy Dr. J.C.

Larroche). (B) Dorsal view of the posterior fossa showing cerebellar engagement and Z-shaped deviation of the
medulla oblongata (courtesy Dr. J.C. Larroche). (C) Coronal section of the cerebral hemispheres and midbrain
showing bilateral ventricular dilatation; sagittal section of the brainstem and cerebellum showing cerebellar
tonsil herniation and Z-shaped deviation of the medulla oblongata. (D) Sagittal section of the brainstem and
cerebellum showing cerebellar tonsil herniation and Z-shaped deviation of the medulla oblongata (Loyez stain).

vesicles. The most rostral aspect of the neural tube
becomes the lamina terminalis, where the cerebral
hemispheres meet as corpus callosum fibers decus-
sate around the 12th week of gestation. The cerebral
hemispheres and the olfactory placodes derive from
the telencephalic vesicles. In man, the olfactory vesi-
cles regress at about 10 weeks and form the olfactory
bulbs, but they persist in many other vertebrates.
2.2.1. HOLOPROSENCEPHALIES
Failure of the two telencephalic vesicles to grow out
from the prosencephalon results in a spectrum of
FIGURE 11.7 Alobar holoprosencephaly.
malformations called holoprosencephalies, which are
classically associated with ocular and midline facial
abnormalities, such as cyclopia, cebocephaly, eth- convolutions may be aberrant and pachygyric.
mocephaly (nose with single nostril), facial median The olfactory bulbs and hypophysis are usually
cleft due to the absence of the premaxilla, and hypo- absent (arrhinencephaly). The brainstem and the
or hypertelorism. cerebellum may also be affected (mesencephalo/
The holoprosencephalies are now recognized as rhombencephalosynapsis).
signaling defects from the ventral or dorsal midline. • Semilobar holoprosencephalies have interhemi-
The genetic basis is associated most frequently with spheric fissures only in the parieto-occipital
a mutation in one of several pathways essential for regions, contrasting with continuous cortical
normal midline signaling. In addition, holoprosen- gyri bridging over the midline in frontal regions
cephaly may accompany trisomy 13 and much less (Fig. 11.8). The prosencephalic monoventricle is
commonly trisomy 18 as well as other chromo- frontal, divided posteriorly into two temporal and
somal aberrations. Prenatal ultrasound may detect occipital horns. There may be no, partial, or com-
the malformation as soon as 12 weeks’ gestation plete fusion of the diencephalic structures and the
and fetal MRI possibly even earlier. The holopros- basal ganglia. Again, the olfactory bulbs and tracts
encephaly spectrum ranges from complete absence are absent.
of the prosencephalon, to minimal abnormality • Lobar holoprosencephaly is characterized by
(isolated absence of the olfactory bulbs and tracts), two well-developed hemispheres connected by
with numerous transitional forms. Not all of these an orbital frontal bridge of cortical convolu-
midline conditions are necessarily based on the tion. The callosum is again absent or occasion-
same pathogenesis—for example, absence of the ally hypoplastic, and the septum pellucidum is
olfactory bulbs and tracks may be in this spectrum absent.
or arise via a distinct pathogenesis, namely failed • Middle interhemispheric variant of holoprosen-
induction or outgrowth. cephaly is characterized by a variable-sized nodule
of heterotopic gray matter extending across the
• Aprosencephaly and the related atelencephaly dorsal midline and often protruding into or even
are extremely rare conditions characterized by obliterating the ventricles. The corpus callosum
a rudimentary prosencephalon and extreme is absent from the regions where the heterotopic
micrencephaly. gray matter resides and the cerebral cortex is con-
• Alobar holoprosencephaly (Fig. 11.7) consists tinuous across the midline. Ventral structures are
of an undivided holospheric cerebrum, or pros- usually preserved, including the olfactory bulbs
encephalic monoventricle, which may open and tracts.
posteriorly into a dorsal sac-like structure. The • Arrhinencephaly, the least severe form of the
thalamic and other diencephalic nuclei are most holoprosencephalies, consists of isolated absence
often totally or partly fused, with a narrow or of olfactory bulbs and tracts and of the straight
absent third ventricle. The corpus callosum and sulci along the orbital frontal cortical surface
septum pellucidum are absent. The cerebral (Fig. 11.9).
A C
B D
FIGURE 11.8 Semilobar holoprosencephaly. (A) Basal view. (B) Dorsal view.(C) Coronal section.

(D) Microscopic appearance.
Histological findings in holoprosencephalic brains 2.2.2 . OTHER ABNORMAL ITIES OF

differ from case to case. However, hypoplastic deep MID L INE STRUCTURES
nuclei and cytoarchitectonic abnormalities with
2.2.2.1. Agenesis of the corpus callosum This
subependymal heterotopias are frequently reported.
is a relatively common malformation that may be
isolated or associated with other brain or systemic
anomalies. It may occur sporadically or as part of
chromosome aberration syndrome such as trisomy
18 and 8. Familial cases have been also reported.
Some are incidental findings at autopsy in adults
with no neurological or developmental difficulties.
The corpus callosum develops rostrocaudally from
the crossing of telencephalic commissural axons
between the 10th and 20th weeks of gestation; thus,
this abnormality can be seen even in early prenatal
ultrasonograms.
In complete agenesis, the medial surface of the
hemispheres shows secondary abnormalities, char-
acterized by an aberrant callosal artery and replace-
ment of the normal cingulate gyrus by perpendicular
(“radiating”) gyri and sulci. On coronal sections,
in addition to the absence of a crossing tract, the
FIGURE 11.9 Arhinencephaly. corners of the lateral ventricles show a vertical

A B
FIGURE 11.10 Agenesis of corpus callosum. (A) Interhemispheric view. (B) Coronal section.
(“batwing” or “staghorn”) orientation (Fig. 11.10). obliterated toward term but persist postnatally in a
The ventricular roof is membranous and may bulge minority of individuals.
into the interhemispheric fissure. In most cases the Agenesis of the septum pellucidum results in a
misdirected callosal fibers form an aberrant antero- pseudo-monoventricle, usually associated with reti-
posterior tract along the dorsal-medial margin of nal dysplasia, hypothalamo-hypophyseal anomalies,
the ventricle and are known as Probst’s bundle. and endocrine dysfunctions. Many of these cases
Partial agenesis of the corpus callosum is clas- are now recognized as a Mendelian disorder related
sically posterior, so that there is a variably present to mutations in one of several genes. In hydroce-
rostrum, genu, and anterior body of the corpus cal- phalic brains, the destruction of one or both leaves
losum (Fig. 11.11). The cingulate gyrus is present of the septum may also lead to a similar appearance;
only to the extent that the corpus callosum is also however, the retinal dysplasia and hypothalamic/
formed. hypophyseal defects are not present in these cases
Whether total or partial, callosal agenesis may be (Fig. 11.13).
accompanied by lipomatous tissue, vascular abnor-
malities, or calcifications along the dorsal midline
at the site normally inhabited by the absent fibers. 2.3. Malformations of the cortical plate
Disorders of normal cortical cell genesis, migration,
2.2.2.2. Anomalies of septum pellucidum and maturation lead to a spectrum of cytoarchitec-
Cavum septi pellucidi (rostral) and cavum septi vergae tonic abnormalities, leading to external gyral abnor-
(caudal) are seen in fetuses as developmentally nor- malities (agyria/pachygyria or polymicrogyria) or
mal midline cavities lying between the two leaves to more subtle lesions, such as heterotopic neurons
of the septum (Fig. 11.12). They tend to become in the white matter.
FIGURE 11.11 Partial agenesis of the corpus FIGURE 11.12 Cavum septi pellucidi.

callosum.
within the centrum semiovale, separated from the
normal-looking cortex by a band of white matter
composed of numerous small nodules of gray matter
that frequently coalesce into irregular larger nodules
(Fig. 11.14A). Histologically, heterotopias reveal
well-differentiated, randomly oriented, and focally
clustered nerve cells, including pyramidal cells, form-
ing bands or aggregates (Fig. 11.14B). The overlying
cortex usually has a normal hexalaminar organization.
The syndrome is most commonly linked to muta-
tions in DCX on chromosome Xq22.3-Xq23. The gene
encodes a signaling protein, doublecortin. To date, all
cases are in females; male patients in the same family
FIGURE 11.13 Septal rupture. have lissencephaly. However, this condition may also
be seen in males and in sporadic cases. At least some of
2.3.1 DISORDERS OF BRAIN SIZE these are associated with a LIS1 mutation.
Proliferation of neural progenitor cells along the 2.3.2.2. Periventricular nodular heterotopia
lumen of the neural tube (nascent ventricles) is criti- Minute (microscopic) heterotopias, consisting of
cal for the generation of normal numbers of neurons small clusters of neurons in the subcortical white
in the CNS. Perturbations of this process alone result matter, are occasional findings in otherwise normal
in reduced numbers of neurons in the brain and brains. In the cerebellum, heterotopias are more
subsequently a small brain, primary microcephaly. frequent, and are mainly found in the central white
Primary microcephaly may have a normal-appearing matter of the hemispheres (Fig. 11.15). Their sig-
gyral pattern or a simplified gyral pattern. While nificance is unknown, since they are found in nor-
most cases do not have a known etiology, the genetic mal fetuses, as well as in chromosome aberrations,
basis of a subset of cases has been elucidated and in including trisomy 18 and genetic disorders.
most cases is the result of mutations in centrosomal Periventricular nodular heterotopia consists of
proteins required for normal cell division. small clusters of neurons adjacent to the ventricle
and frequently protruding into the ventricle. Single
or several periventricular heterotopias may occasion-
2.3.2. NEURONAL HETEROTOPIA
ally be found in an otherwise normal brain. When
2.3.2.1. Laminar, subcortical band heteroto- periventricular nodular heterotopias are numerous,
pia This condition consists of bilateral, often sym- essentially lining the walls of the lateral ventricles,
metrical bands of gray matter, of variable thickness, the condition is almost always genetic in origin. In
A B
FIGURE 11.14 Laminar subcortical heterotopia. (A) Heterotopic tissue separated from the normal cortex by
a layer of normally myelinated white matter (Luxol fast blue/Cresyl violet). (B) Nerve cells in the heterotopic
gray matter are arranged in irregular aggregates of normal-looking pyramidal cells (Luxol fast blue).

Females, who carry one copy of the mutant gene and
one normal copy, have a subset of neuroblasts that are
able to migrate normally to the cortex. The random
inactivation of the normal allele, then, results in a sub-
population of neurons with the mutant allele that are
unable to migrate and thus remain in the ventricular
region. Males carrying the mutant gene (i.e., only
one X chromosome) have major migrational failure,
which most commonly results in prenatal lethal-
ity. There are, however, rare occurrences of nodu-
lar heterotopia in males who are germline mosaics,
a mechanism also responsible for phenotypically
normal mothers of affected daughters. Isolated peri-
FIGURE 11.15 Cerebellar heterotopia. ventricular heterotopia may be found on neuroim-
ages obtained in patients with intellectual disability
these cases the heterotopias appear as discrete or and epilepsy, or incidentally in normal subjects. The
confluent, well-defined nodules (2 mm to more mechanistic relationship of heterotopia to intellectual
than 10 mm) beneath the ependymal lining and disability or epilepsy remains uncertain.
again protruding into the ventricle, giving a lumpy
appearance to the normally smooth ventricular sur- 2.3. 3 . POLYMICROGYRIA
face (Fig. 11.16). The trigones and occipital horns of Polymicrogyria refers to a cortical malformation
the lateral ventricles are the most commonly affected characterized by an excessive folding and irregular
regions. Histologically, nodules consist of islands fusion of adjacent gyri with a thin cortical ribbon.
of mature nerve cells resembling cortical neurons, The leptomeninges covering the polymicrogyric
sometimes with a concentric arrangement as well as cortex can be abnormally vascularized and may con-
interneurons and glia. Nodular heterotopia may be tain ectopic (i.e., displaced and disorganized) neuro-
an isolated finding or may complicate other cerebral glial tissue (Fig. 11.17).
malformations, such as hydrocephalus, microceph- Polymicrogyria may be seen in a variety of con-
aly, and agenesis of the corpus callosum, cerebellar ditions. There are now well-defined Mendelian dis-
hypoplasia, polymicrogyria, agyria, pachygyria, and orders that include polymicrogyria, some in specific
cortical dysplasia. patterns, for example perisylvian, bilateral frontal,
Periventricular nodular heterotopias represent a bilateral frontal-parietal, and others. Polymicrogyria
failure of migration of immature neuroblasts from the may also be found in patients with complete triploi-
ventricular zone, due, in some cases, to a mutation in dies, in association with primary metabolic disorder
the Filamin A (Filamin-1) gene on the X chromosome. such as Zellweger syndrome, and in patients with
congenital disorders of glycosylation. Mutations in
FIGURE 11.16 Subependymal/periventricular
heterotopia. Section of frontal lobe showing multiple
nodules of gray matter above the caudate nucleus. FIGURE 11.17 Micropolygyria.
FGFR3, which give rise to thanatophoric dysplasia, growth factor receptor gene (FGFR) leading also
are also associated with polymicrogyria. Finally, to skeletal growth plate disruption (Fig. 11.18).
polymicrogyria may result from disruptions of cere- “Four-layered polymicrogyria” refers to that
bral cortical development in a narrow window of described by Bielschowsky in 1915, characterized
time from approximately 16 to 17 gestational weeks by a superficial acellular molecular layer that infolds
through approximately 23 to 24 gestational weeks. and fuses to produce a microsulcus; a second cel-
Examples of these disruptions resulting in polymi- lular layer comprising neuronal types normally
crogyria include the margins of porencephaly and belonging to cortical laminae II and III; a third layer
hydranencephaly (see below). Congenital cyto- devoid of neurons, containing mostly glial cells;
megalovirus infection is also well known to cause and a fourth layer contiguous with normal layer
polymicrogyria, likely on a disruptive basis. Thus, VI of the adjacent cortex (Fig. 11.19). This micro-
the pathogenesis of polymicrogyria is likely to be scopic appearance, along with the fact that it may
multifactorial. be focal, bordering porencephalic defects, suggests
At the microscopic level, polymicrogyria may be that four-layered polymicrogyria may be a sequela
heterogeneous, chaotic (called unlayered), or with of laminar necrosis of layers IV and V due to early
a “four-layered” organization. Both forms can be ischemic, toxic, or infectious injury (see below).
seen in the same brains, for example in association Focal polymicrogyria may also be found in
with abnormal temporal lobe sulcation in thana- Chiari II malformations and in encephaloceles, as
tophoric dysplasia, a mutation in the fibroblast well as in fetal alcohol syndrome.
A B
FIGURE 11.18 Thanatophoric dysplasia. (A) Basal view. (B) Temporal sulcus. (C) Cytoarchitectonic

abnormalities.

sparsely cellular layer with numerous myelinated
1
2 Cortex fibers, and a deep, highly cellular layer of disorga-
3
4
nized neurons (Fig. 11.21). The remnant periven-
tricular white matter may contain single or grouped
White matter heterotopic neurons. The four-layer pattern is seen
with mutations in both LIS1 and XLIS, the most
common causes of lissencephaly. Mutations in ARX
FIGURE 11.19 Cortical changes in polymicrogyria. result in a three-layer lissencephaly. A two-layer lis-
(After Crome L, Stern J. Pathology of mental retarda- sencephaly has been identified but with no asso-
tion, 2nd ed. Baltimore: Williams & Wilkins, 1972) ciated specific genetic mutations. The pathology
associated with other lissencephaly genes is less
well characterized. Anomalies of the inferior olivary
2.3.4. LISSENCEPHALY nuclei, cerebellum, and corticospinal tracts are vari-
The term means “smooth brain” and refers to ably present.
the macroscopic appearance of few or no sulci, Mutations in LIS1 are the most common
although the major fissures (interhemispheric and cause of lissencephaly. The autosomal dominant
Sylvian) are intact. The term is used interchange- Miller-Dieker syndrome includes lissencephaly and
ably with agyria, but when localized to smaller characteristic facial features. This syndrome is due
regions of the brain, the term pachygyria is preferred. to a deletion of the short arm of chromosome 17,
Hemi-lissencephaly (involving only one cerebral involving 17p13, which includes LIS1 but also 14-3-
hemisphere) may be seen in some children/infants 3ε (also called YWHAE), which functionally inter-
with intractable epilepsy. acts with LIS1 to disrupt cell migration. Isolated
mutations in LIS1 give rise to lissencephaly but
2.3.4.1. Type I lissencephaly Classic, or type I, without the full Miller-Dieker syndrome.
lissencephaly is characterized by a markedly thick- In X-linked lissencephaly, the gene XLIS encodes
ened cortex overlying a reduced volume of white the protein doublecortin (DCX), also important in
matter (Fig. 11.20). Ventricular enlargement is also the normal migration of neuroblasts. XLIS muta-
frequent. These macroscopic features, especially the tions in the female result in subcortical band hetero-
altered white/gray ratio, are easily seen on fetal or topia as described above. Males exhibit four-layer
postnatal MRI. Histologically, the thickened gray lissencephaly, particularly severe in the frontal lobes.
matter displays an abnormal horizontal lamination,
with most cases showing a four-layer cortex in a 2.3.4.2. Type II lissencephaly Type II (LISII)
vaguely “inside-out” pattern: the most superficial or “cobblestone” lissencephaly (Fig. 11.22A , B) is
layer is an acellular molecular layer, followed by a a distinct cytoarchitectonic disorder characterized
highly cellular zone of large pyramidal neurons, a by the population of the arachnoid space by numer-
ous clusters of ectopic neurons and glial cells along
with disrupted meninges. The obliteration of the
subarachnoid space by the infiltration of neural glial
tissue is also believed to impair cerebrospinal fluid
dynamics, leading to the commonly associated early
hydrocephalus, which may be severe and is detect-
able by ultrasound as early as 16 weeks’ gestation.
LISII has no recognizable pattern of lamination.
Instead, the superficial disorganized band of neu-
rons, glia, and vascular connective tissue (menin-
ges) overlies a band of neurons likely representing
the remnant of the cortical plate. These bands are
separated by an ill-defined line thought to represent
the early embryonic pial surface (Fig. 11.22C). The
pathogenesis of this type of lissencephaly is due
to the over-migration of neurons and glia through
FIGURE 11.20 Agyria/pachygyria (Loyez stain). a defective pial-glia limitans. The underlying
1 Normal cortex
2
3
Cortex
4
White matter
FIGURE 11.21 Cortical changes in agyria/pachygyria. (After Crome L, Stern J. Pathology of mental retarda-
tion, 2nd ed. Baltimore: Williams & Wilkins, 1972)
molecular defect in all known cases is a disruption PROTEIN, and LARGE, are all known to be gly-
in O-glycosylation, primarily affecting dystrogly- cosyltransferases. Mutations in one of these genes
can. The known genes, including POMT1, POMT2, have been found in 32% to 50% of patients. Newly
POMGNT1, FUKUTIN, FUKUTIN-RELATED identified genes are under study (see Chapter 12).
A B
FIGURE 11.22 Type II lissencephaly. External appearance of cerebral hemispheres: cobblestone (A). Coronal

section (B) and whole mount histological preparation (Cresyl violet stain) (C) showing ventricular enlargement,
cortical plate malformation, and characteristic cortical malformation with neuroglial ectopia into the arachnoid
space leading to obliteration of the arachnoid space.

In addition to the cerebral hemisphere defect, (Fig. 11.23A), with increased numbers of branch-
involvement of the brainstem and cerebellum is also ing and arbors of dendritic processes, as revealed
extremely common. by Bielschowsky stain (dysmorphic neurons), and
This class of disorders represents a continuum balloon cells (Fig. 11.23C), which have abundant,
with brain, ocular, and muscular involvement, the glassy cytoplasm and an astrocyte-like morphol-
most severe called Walker-Warburg syndrome and ogy (i.e., they resemble gemistocytic astrocytes)
also including the muscle-eye-brain diseases and but show variable GFAP positivity and are there-
Fukuyama muscular and cerebral dystrophy. The fore sometimes called “uncommitted/undifferen-
Walker-Warburg syndrome (OMIM#236670), tiated cells.” “Balloon cells” may also show two or
also known under the HARD+/-E acronym more nuclei, or a partly reduplicated nucleus with
(hydrocephalus, agyria, retinal dysplasia, enceph- a nuclear “bridge,” as well as variably prominent
alocele), is characterized by major neurologi- eosinophilic nuclear inclusions.
cal deficit, visual and muscular impairment, and Abnormal nerve cells in areas of FCD show cyto-
a rapidly fatal outcome. Less severe examples skeletal changes, such as coarse intracytoplasmic
within the same spectrum, with subtle eye abnor- fibrillary inclusions, which stain with antibodies to
malities, less significant neurological deficit, and high- and medium-molecular-weight (phosphory-
a milder muscular dystrophy, include muscle-eye lated) neurofilaments, to microtubule-associated
brain disease, first described in the Finnish popu- protein (MAP), as well as weakly to ubiquitin.
lation (OMIM#253280) and in Fukuyama mus- Although these inclusions are reminiscent of the
cular and cerebral dystrophy, common in Japan neurofibrillary tangles seen in Alzheimer disease
(OMIM#253800). (and can be readily identified with silver impregna-
tion techniques), they do not stain with antibodies
to paired helical filaments (PHFs). Ultrastructural
2.3.5. LOCALIZED OR FOCAL
examination fails to show PHFs; instead, the cyto-
MALFORMATIONS
plasm contains skeins of interwoven filaments.
2.3.5.1. Focal cortical dysplasia Focal corti- In addition, dysplastic cortical cells are positive
cal dysplasia (FCD) is localized or multifocal or with antibodies to immature MAPs (MAP1B, 2C);
even multilobar cortical malformation, frequently this may reflect an increased plasticity and remod-
found in surgical corticectomy or hemispherectomy eling of dendrites in these cells. Dysplastic cells
specimens removed from infants and children with also stain with antibodies to the embryonal form
intractable epilepsy, including infantile spasms. The of the cell adhesion molecule N-CAM (E-NCAM)
younger the child/infant from whom a specimen and to developmental neurofilaments nestin and
originates, the greater the likelihood that it will rep- internexin, supporting maturational failure. Balloon
resent severe FCD. FCD may involve any lobe, but cells in FCD stain with anti-GFAP antibody, in keep-
most frequently it affects the frontal and temporal ing with electron microscopic evidence of interme-
lobes. Macroscopic examination of the resected diate cytoplasmic filaments. In addition, some cells
specimen is often unremarkable, although a smooth contain neuronal markers and even dual labeling has
cortex lacking sulci, thickening of the gyri, and blur- been elicited, thus reflecting an intermediate glial
ring of the gray–white matter border have been and neuronal differentiation. Accordingly, the pro-
reported. liferation index of these cells is low.
Histological findings include anarchic, hyper- An extreme form of neuronal migration abnor-
cellular cortex with disruption of the normal mality is represented by the rare epileptogenic
lamination and neuronal polarity; persistence or malformation of hemimeganencephaly (HME),
disruption of the columnar alignment of nerve in which a malformed cerebral hemisphere is
cells; and heterotopic nerve cells in the molecu- markedly enlarged compared to the more “nor-
lar layer and increased numbers of neurons in the mal” hemisphere. Neuropathological findings in
underlying juxtacortical white matter (Fig. 11.23B). resected HME specimens are extremely variable;
The following cytological abnormalities have been some show features of severe FCD, though many
described: bizarre, cytomegalic nerve cells reaching cases lack the balloon cell change described above,
the size of Betz cells, often with cytoplasmic fibril- despite pronounced neuronal disorganization and
lar inclusions resembling those seen in the neuro- abnormal polarity. Some HME specimens show
fibrillary tangles of Alzheimer disease (see below) hemi-lissencephaly (see above).
A B
C D
FIGURE 11.23 Focal cortical dysplasia. (A) Dysplastic neurons in focal cortical dysplasia. The neurons are
enlarged and show apparent thickening of the nuclear membrane. They are irregularly orientated within the
cortex (Cresyl violet stain). (B)Aggregates of balloon cells in the white matter underlying an area of focal cortical
dysplasia (LFB/Nissl). (C)Balloon cells in the cortex in a region of focal cortical dysplasia (H&E). (D) An area
of cortical dysplasia with marked gliosis as seen on GFAP immunostaining.
Additional histological features reported in FCD and no family history of tuberous sclerosis, and the
include subpial layers of myelinated axons, reactive onset of epilepsy tends to occur at an older age than
gliosis (Fig. 11.23D), subpial fibrillary (“Chaslin”) in tuberous sclerosis. In addition, the tubers in tuber-
gliosis (a nonspecific abnormality found in resec- ous sclerosis tend to be multiple and distributed
tion specimens from corticectomy for epilepsy, throughout the cerebral hemispheres and are macro-
regardless of etiology), loss of axons, and increased scopically recognizable, whereas the lesions in FCD
numbers of corpora amylacea. Low-grade tumors are more often solitary. Microscopic examination of
(pilocytic and fibrillary astrocytomas, dysembryo- tubers shows a paucicellular cortex with bizarre nerve
plastic neuroepithelial tumor (DNT), ganglioglio- cells but with relatively more atypical glial cells at the
mas) and meningioangiomatosis have been reported corticomedullary junction. A peculiar “wheat-sheaf”
adjacent to cortical malformations. Less commonly arrangement of astrocytes in the subpial region is
reported features are inflammatory, degenerative, or typical of tubers. However, differentiation from FCD
destructive lesions (infarcts, cysts, encephalomala- is not always possible on histology alone, and genetic
cia). Hippocampal sclerosis and Rasmussen enceph- analysis should be carried out when there is uncer-
alitis may occur in combination with FCD, although tainty. The two genes (TSC1 and TSC2) in which
the latter usually occurs as a sporadic abnormality. mutations/deletions occur to cause tuberous sclero-
FCD has overlapping features with the cortical sis can be analyzed, although such genetic analysis
tubers associated with tuberous sclerosis. However, is unfortunately available in relatively few centers.
the following characteristics should help distinguish Although antibodies to the respective gene products
between the two disorders: patients with FCD show (hamartin and tuberin) are widely available, staining
no systemic or cutaneous stigmata of tuberous sclero- of a suspected tuber or FCD specimen with these
sis, absence of subependymal lesions or calcifications, reagents is not of value in differentiating the two types

of lesions. Several studies have also been able to dis- 2.3.5.2. Mild malformations of cortical
tinguish these two entities based on the activation of development Mild cortical malformations are
S6 kinase in the mTOR pathway. not visualized either by imaging or naked-eye
A recent consensus classification system of FCD examination. The spectrum of histological fea-
has been proposed but not universally adopted. It tures includes the presence of unipolar or bipo-
distinguishes isolated forms (FCD types I and II) lar nerve cells in the subpial layer; an excess of
from those associated with another principal lesion nerve cells in the molecular layer, either singly or
(FCD type III) (Table 11.1). FCD type I is a malfor- in nodules; an indistinct boundary between lami-
mation presenting with abnormal cortical layering, nae I and II; protrusion of nerve tissue into the
either compromising radial migration and matura- pia; persistence of columnar alignment of cortical
tion of neurons (FCD type Ia) or the six-layered nerve cells in some cases; and increased numbers
tangential composition of the cortex (FCD type Ib), of heterotopic neurons in the white matter. Such
the combination of both variants being classified as malformations have also been associated with
FCD type Ic. FCD type II is a malformation present- epilepsy.
ing with disrupted cortical lamination and specific
cytological abnormalities. These allow differentiat-
ing FCD type IIa, containing dysmorphic neurons 2.4. Disorders of hindbrain
without balloon cells, from FCD type IIb, containing development
dysmorphic neurons and balloon cells. FCD type III
2.4. 1 . MAL F ORMATIONS OF THE
refers to cortical lamination abnormalities associ-
CER EBEL L UM
ated with a principal lesion, usually adjacent to or
affecting the same area/lobe. Four variants should be A broad range of anomalies affect the cerebellum,
distinguished: FCD type IIIa, associated with hip- ranging from gross structural defects to those that
pocampal sclerosis; FCD type IIIb, associated with are only found microscopically. Furthermore, the
tumors; FCD type IIIc, associated with vascular mal- malformations may affect primarily the vermis, parts
formation; and FCD type IIId, associated with any of the vermis, the lateral hemispheres, or the vermis
other principal lesion acquired during early life. and lateral hemispheres.
Table 11.1. Classification System of Focal Cortical Dysplasia (FCD) Proposed by the

International League Against Epilepsy
FCD type FCD with abnormal radial FCD with abnormal FCD with abnormal radial and
I (isolated) cortical lamination tangential cortical tangential cortical lamination
(FCD type Ia) lamination (FCD type Ic)
(FCD type Ib)
FCD type II FCD with dysmorphic neurons FCD with dysmorphic neurons and
(isolated) (FCD type IIa) balloon cells (FCD type IIb)
FCD type III Cortical lamination Cortical lamination Cortical Cortical
(associated abnormalities in the abnormalities lamination lamination
with principal temporal lobe associated adjacent to a glial or abnormalities abnormalities
lesion) with hippocampal sclerosis glioneuronal tumor adjacent adjacent to
(FCD type IIIa) (FCD type IIIb) to vascular any other
malformation lesion acquired
(FCD type IIIc) during early life
(e.g., trauma,
ischemic injury,
encephalitis)
(FCD type IIId)
From Blümcke et al. Epilepsia 2011;52:158–174.
2.4.1.1. Dandy-Walker malformation The depending on the other CNS and extra-CNS find-
Dandy-Walker malformation (Fig. 11.24) consists ings. All of them are associated with mutations in a
of an anteriorly rotated, incompletely formed cer- cilia-related gene, thus characterizing Joubert syn-
ebellum giving rise to a cyst-like dilation of the fourth drome as one of the ciliopathies. Mutations in at least
ventricle (i.e., no true cyst is present). The tentorium 18 different cilia proteins have been associated with
is superiorly inserted, giving rise to an enlarged pos- this syndrome.
terior fossa. The vermis may be absent or hypoplastic;
when hypoplastic it is primarily the inferior vermis 2.4.1.3. Chiari malformations In the late 1800s
that is affected. Microscopic sections of the inferior Chiari described a series of what he referred to as
vermis and contiguous posterior membrane around cerebellar herniation anomalies. The Chiari II mal-
the foramen of Magendie reveal an atretic cerebel- formation, as described above, consists of the cer-
lum. The lateral hemispheres of the cerebellum may ebellar vermis being displaced below the foramen
be normal or show variable degrees of hypoplasia. magnum and overlying the lower medulla and dorsal
Malformations of the brainstem and supratentorial spinal cord. The Chiari I malformation involves the
structures are variably present with the Dandy-Walker cerebellar tonsils, as opposed to the vermis, which
syndrome, thus requiring complete analysis of the extend below the foramen magnum (by definition
brain, as the finding of additional anomalies is associ- more than 1.5 cm inferior). While brain herniation
ated with a poor prognosis. While the pathogenesis of can lead to displacement and ultimately necrosis of
the Dandy-Walker malformation has been enigmatic, the cerebellar tonsils, the advent of modern imaging
recent studies have identified ZIC1; ZIC4 mutations techniques has shown that displacement of the ton-
in a subset of patients. Approximately 15% of patients sils can be seen even in patients with no symptoms, as
with Walker-Warburg syndrome are also reported to well as in patients with headaches and/or long-tract
have Dandy-Walker malformations, although the cere- signs. The displaced tonsils may show dysplasia, and
bellum in these patients shows much more severe dys- syringomyelia, hydromyelia, syringobulbia, and/or
plasia, including loss of folia in the lateral hemispheres. hydrobulbia may coexist. Chiari III malformations
are quite rare and represent the herniation or inclu-
2.4.1.2. Joubert syndrome Joubert syndrome sion of posterior fossa elements, mainly the cerebel-
includes a characteristic cerebellar vermis hypo- lum, in an occipital encephalocele.
plasia along with a deep ventral midline cleft in the
pons. The cerebellar peduncles are also elongated, 2.4.1.4. Rhombencephalosynapsis In rhomb-
which in the horizontal plane gives rise to the “molar encephalosynapsis, the vermis is replaced by medially
tooth” appearance of the hindbrain. situated (fused) cerebellar hemispheres containing
While originally believed to be a single entity, a dentate nucleus crossing the midline. The fourth
Joubert syndrome is now recognized as part of a broad ventricle is obtruded. The malformation may extend
range of disorders, which fall into a variety of subtypes rostrally to the mesencephalon and in such cases may
A B
FIGURE 11.24 Dandy-Walker syndrome, with agenesis of the vermis and cyst-like dilation of the fourth
ventricle. (A) Posterior view. (B) Sagittal section of brainstem and cerebellum.

impinge on the aqueduct of Sylvius with secondary
obstructive hydrocephalus. In these cases the colliculi
may be indistinct. Rhombencephalosynapsis can be
found in association with holoprosencephaly but is
much more commonly found as an isolated defect.
2.4.1.5. Posterior fossa arachnoid cyst

Arachnoid cysts may arise in the posterior fossa like
they do at other intracranial sites. When in the mid-
line, these true cysts may compress and displace the
cerebellar vermis and cause hydrocephalus. They can
be difficult to distinguish from a Dandy-Walker mal-
formation; however, the presence of a compressed
fourth ventricle is more in keeping with a retrocerebel-
lar arachnoid cyst, while expansion of the fourth ven-
tricle is the hallmark of Dandy-Walker malformation.
FIGURE 11.25 Aqueduct atresia.
2.4.2. ABNORMALITIES OF THE

AQUEDUCT OF SYLVIUS deep nuclear elements) and white matter at the same
time, manifested clinically as “hypoxic-ischemic
Isolated aqueductal stenosis, in which there is nar-
encephalopathy.” However, their distinct neuro-
rowing or forking of the lumen, with otherwise no
pathological patterns will be discussed separately.
histological changes of the aqueduct, is rare. It has
Disruptive lesions are reported in association with
been reported in males with hydrocephalus, pyra-
a variety of situations causing altered in utero hemo-
midal tracts abnormalities (absence or severe hypo-
dynamics, including trauma, gas intoxication, drug
plasia of the medullary pyramids), and abducted
abuse, and twin gestations.
thumbs. This constellation of findings is known as
X-linked hydrocephalus or MASA syndrome and is
associated with mutations in L1-CAM. 3.1. Lesions of developing gray matter
In atresia, the aqueduct of Sylvius shows an Exogenous processes disrupting the normal
abnormal shape (forking) or may be entirely lack- sequence of neuronal migration and cortical dif-
ing, replaced by a few rosettes. Atresia of the aque- ferentiation (encephaloclastic processes) usually
duct may be posthemorrhagic or found in fetal act after mid-gestation. They lead to a spectrum of
disruption syndromes, including intrauterine strokes cortical abnormalities, ranging from disturbed cyto-
(Fig. 11.25). Occlusion of the aqueduct, which may architecture, often at the margins of cysts (poren-
be infectious, neoplastic, or hemorrhagic, can result cephalies), to loss of cortical plate segments (“basket
in triventricular hydrocephalus. In such cases, the brain”), to complete absence of supratentorial brain
lumen of the aqueduct is of normal size (or dilated) tissue (hydranencephaly). Lesser degrees of insult
but occluded by necrotic tissue, inflammatory debris, may have effects on selective neuronal populations.
or hemorrhage. The ependymal layer of the aque- Finally, disruptions of germinal matrix and deep
duct, as well as elsewhere in the ventricular system, is nuclei of the diencephalon and brainstem have dis-
disrupted and replaced by reactive gliosis and sidero- tinctive features. The vast majority of disruptions
phages. At later stages the aqueduct may be occluded have in common some element(s) of decreased per-
by a glial plug or covered over by a glial septum. fusion (ischemia) and low oxygen tension (hypoxia),
phenomena that tend to occur together (hence the
3. DISRUPTIONS OF commonly used term “hypoxia-ischemia”).
DEVELOPING BRAIN
3.1. 1 . ENCEPHAL OCL ASTIC L ESIONS
The foregoing sections have considered primarily
OF DEVEL OPING NEOCORTEX
abnormalities of development related to genetic or
environmental influences on early organogenesis. 3.1.1.1. Porencephaly Porencephaly refers to
Disruptions often affect both gray (i.e., cortical and any defect extending from the brain surface toward
including trauma, attempted abortion, toxoplas-
mosis, rubella, cytomegalovirus, or herpes virus
(TORCH) infection, and household gas intoxication,
have been correlated with hydranencephaly, although
most antecedent events are unknown. The extent of
destruction dictates the clinical picture, which typi-
cally includes spasticity, severe seizures, and vegeta-
tive signs; mortality in infancy is high. Since the areas
involved are often in the distribution of the carotid
arteries, the inferior temporal and occipital lobes tend
to be preserved, with polymicrogyria at the interface.
The basal ganglia are variably affected, but the thala-
mus and descending tracts are always atrophic. Head
FIGURE 11.26 Porencephaly. enlargement develops in longer-surviving infants as
a result of scarring of the aqueduct leading to hydro-
the ventricle. Usually these are in the region of the cephalus. Hydranencephaly has been reported in a
Sylvian fissure (Fig. 11.26). They may be bilateral, familial form due to a distinctive proliferative vascu-
sometimes denominated “schizencephaly.” The lopathy (Fowler’s hydrancephaly).
margins are smooth and have anomalous gyral
architecture, either polymicrogyria or gyri radiat- 3.1.1.3. “Basket brain” “Basket brain” is con-
ing outwardly from the lips of the defect. The poly- sidered intermediate between porencephaly and
microgyria found at the margins in some cases is hydranencephaly. The cingulate gyri and medial
thought to be due to incomplete ischemia in the hemispheric structures are preserved (correspond-
tissue lying near the defect. ing to the “handle” of the basket) while the lateral
Porencephalies lack significant glial scarring. parietal and frontal lobes are cystic bilaterally.
These features are consistent with an intrauterine
insult occurring after neuroblast migration and 3.1.1.4. Multicystic encephalomalacia Multi-
prior to gyration. The basal ganglia, cerebellum, and cystic encephalomalacia (also known as multicystic
brainstem are not affected, although the thalamus leukoencephalopathy) differs from porencephaly
and descending white matter tracts may be second- and hydranencephaly by the presence of innumer-
arily atrophic. Clinical manifestations are related to able cysts separated by glial septa, involving the
the area of involvement and may include hemipare- cortex and white matter in all lobes (Fig. 11.27).
sis, blindness, and seizures. Microscopic evidence of resolved infarction and
hemorrhage, including macrophages and hemo-
3.1.1.2. Hydranencephaly Hydranencephaly siderin, can be seen accompanying the marked
(“bubble brain”) refers to the residua of intrauter- gliosis and suggests an insult in the perinatal
ine massive hemispheric necrosis. Various insults, period (i.e., late gestation to early infancy). As
A B
FIGURE 11.27 Multicystic encephalomalacia in a case of neonatal carbon monoxide intoxication. (A) Gross

appearance. (B) Loyez stain.

with porencephaly and hydranencephaly, associated than are neurons in upper layers, giving rise to lami-
events have included maternal suicide attempts, nar necrosis, a layer of destruction within the corti-
infection, and parturition-related complications cal ribbon. The pattern of vulnerability depends on
such as cord prolapse. In surviving infants, severe the developmental stage; for example, Sommer’s
cognitive and motor deficits along with epilepsy are sector of the hippocampus is vulnerable in the term
common. baby, while the subiculum is susceptible in the pre-
mature. Coexistence of neuronal necrosis in predict-
3.1.1.5. Ischemic strokes Perinatal ischemic able patterns, as in pontosubicular necrosis, may be
strokes, usually arising in the territory of the middle seen and may be highly associated with white matter
cerebral artery, can be seen, often in the setting of necrosis (discussed below).
congenital heart disease, for example, or other con-
ditions requiring extracorporeal membrane oxygen-
3.1. 2 . ENCEPHAL OCL ASTIC L ESIONS
ation. Theses strokes are similar to those occurring
OF DEVEL OPING BASAL GANGL IA AND
in adults in terms of their histological evolution.
THAL AMUS
3.1.1.6. Selective neuronal necrosis The pre- In both term and premature infants, thalamic and
mature infant has a somewhat different profile of basal ganglionic neurons may undergo necrosis,
neuronal vulnerability to hypoxia-ischemia than resulting in mineralization (or ferrugination) of
that of the full-term baby, believed to be due to varia- individual cells. In babies surviving a year or more,
tions in patterns of cerebral blood flow. For example, damage to the thalamus and basal ganglia may lead
the parasagittal regions, which are the border zones to disturbed architecture known as status marmora-
between anterior and middle cerebral artery territo- tus (or “état marbré”), in which aberrant myelina-
ries, are especially susceptible to hypoxia-ischemia. tion of disoriented axons and glial processes leads to
Injury in these areas gives rise to “basket brain” or a marbled gross appearance.
lesser degrees of porencephaly, as described above. Clinical features accompanying status marmo-
The depths of sulci are end-arterial regions, so that ratus classically include static (non-progressive)
neurons there are susceptible to hypoxia-ischemia, bilateral choreoathetosis, motor and intellectual
leading to ulegyria, a mushroom-like appearance retardation, spastic diplegia, and sometimes epi-
of sulcal atrophy with preservation of gyral crests lepsy; the inexact term “cerebral palsy” has been
(Fig. 11.28). For unclear reasons, neurons within applied to many such affected individuals.
the deeper cortical layers are more prone to injury
3.1. 3 . L ESIONS OF THE GANGL IONIC
EM INENCE (GERMINAL MATRIX)
The periventricular gray matter in utero is composed
of immature cells (neuroblasts and glial progenitors),
proliferation and migration of which peaks between
the 18th and 26th gestational week. Because the
vessels of this region are remodeling actively during
this time and therefore have incompletely formed
basal lamina and loosely interdigitated glial end-feet,
they are particularly vulnerable to any alterations in
hemodynamics.
Not surprisingly, then, periventricular hemor-
rhages represent a common lesion in prematurely
delivered babies, who are typically respiratorily
compromised and hemodynamically labile. Large
periventricular hemorrhages can result in extensive
destruction of precursor cells as well as adjacent
FIGURE 11.28 Ulegyria. Loyez stain showing mature structures, such as the caudate and internal
atrophy of gyral sulci with relative preservation of capsule, and can interrupt the overlying ventricu-
gyral crests. lar (ependymal) surface, leading to intraventricular
hemorrhage and hydrocephalus. In surviving infants,
macrophages resorb the hemorrhage, resulting in
periventricular cysts. Hemosiderosis, gliosis, and
rosette-like remnants of ependymal cells may remain.
In non-cavitating healed lesions, mineralization of cell
bodies and processes may persist as markers of injury.
Hemorrhages of the choroid plexus, although not
examples of lesions of the ganglionic eminence, are
mentioned here as they can have the same sequelae
(i.e., hydrocephalus) as intraventricular hemor-
rhages arising from the germinal matrix.
Coexistence of deep (germinal matrix) and sur-
face (cortical plate) disruptions is common in the
porencephalies, described above. Likewise, some FIGURE 11.29 Periventricular leukomalacia.
forms of perisylvian polymicrogyria are thought
to reflect a combination of disruption of the local
glia limitans and cortical plate together with inter- PVL is defined as circumscribed regions of tis-
ruption of precursor migration, leading to complex sue loss, measuring 0.2 to 1.0 cm, usually occurring
cortical dysplasia and deep gray matter heterotopia. within 1.5 cm of the lateral ventricular wall in the
hemispheric white matter. Generally, these are ante-
rior to the frontal horns, lateral to the atria, or along
3.2. Lesions of developing white matter the occipital horns (Fig. 11.29). Within 3 to 8 hours
In the human, white matter development lags of the initiating event, shrinkage of glial cell nuclei is
behind gray matter development, such that the vul- accompanied by vacuolization, eosinophilia, and axon
nerable period for the former is the final trimester beading or swelling. Astroglial and capillary promi-
through the first year of life—that is, the period of nence develops by 12 hours postinjury, followed by
myelinogenesis. The most severe form of perinatal microglial proliferation progressing to macrophage
white matter damage is periventricular leukomalacia infiltrates over the next few days. Mineralization of
(PVL) (Fig. 11.29), in which cystic degeneration of disrupted axons and necrotic glial cells and processes
necrotic deep white matter is thought to be the con- at the periphery of the lesion, with associated gliosis,
sequence of ischemia, with or without reperfusion, occurs within days to weeks. If large enough, the area
and cytokine release potentiated by infection. The will cavitate as macrophages clear the necrotic debris.
vulnerability of the hemispheric white matter is due Because oligodendroglia are among the irreversibly
in part to the above-mentioned anatomical “water- damaged elements, myelination is disrupted, appear-
sheds” at the depths of sulci, extending into the ing as increased T2-weighted signal on MR imaging
periventricular regions, coupled in very premature in vivo and as pallor on myelin-stained autopsy brain
infants with frequently significant hemodynamic sections. If severe, the white matter volume is macro-
and respiratory compromise. scopically reduced and is marked by hydrocephalus
Perinatal telencephalic leukoencephalopathy is ex vacuo and thinning of the corpus callosum and
the mildest, and possibly earliest, manifestation of descending tracts.
hypoxia-ischemia in the hemispheric white matter. The clinical manifestations of perinatal white mat-
It is characterized neuropathologically by the occur- ter injury tend to be more pronounced in preterm
rence of prominent, often hypertrophic astrocytes, babies and include spastic diplegia or quadriplegia
“acutely damaged glia” (pyknotic nuclei), capillary (“cerebral palsy”). On MR scanning, cystic cavities
cell proliferation, and perivascular “globules,” which may be obvious, along with evidence of delayed or
may mineralize. The term white matter gliosis is used permanently deficient myelination as determined
interchangeably and refers to the diffuse prolifera- by signal characteristics. In children followed by MR
tion of GFAP-positive cells accompanying myelin over time, early cavitations may be replaced by glial
pallor on LFB stain. Perinatal telencephalic leukoen- scars with adjacent white matter hypomyelination
cephalopathy may be seen alone or in conjunction and hydrocephalus ex vacuo, suggesting a capacity
with the focal lesions of frank PVL. for remodeling in some lesions.

12
Pathology of Skeletal Muscle
H A R T G. W. LI DOV, UM B ER TO D E G I R O L A MI , A N TH O NY A . A MATO , A ND RO MA IN G H ERA RD I
1. GENERAL 2. BIOPSY OF SKELETAL

CONSIDERATIONS MUSCLE
Neuromuscular pathology must always be evaluated in
a multispecialty context; clinical features (age of onset, 2.1. Site of the biopsy
pattern of involvement, course, family history, concur- It is important to biopsy a muscle that is affected but
rent medical problems), electrophysiological studies not so severely that a biopsy will only reveal nondi-
(electromyography [EMG] and nerve conduction agnostic end-stage changes. Thus, we advise biopsy
studies), laboratory results (e.g., creatine kinase levels, of a muscle that has a Medical Research Council
presence of a monoclonal gammopathy), and in some (MRC) grade of around a 4/5. Occasionally, when
instances neuroimaging, provide information that per- there is only mild weakness (e.g., only in hip girdle,
mits the formulation of most likely clinical diagnostic which is not typically biopsied), the choice of mus-
hypotheses preceding the biopsy. cle to biopsy can be aided by doing an EMG on one
The objective of the biopsy is then to confirm, side of the body and then to biopsy a muscle that
extend, or perhaps disprove these initial hypoth- was abnormal on EMG on the contralateral limb.
eses. Determining the need for a muscle or nerve Alternatively, skeletal muscle MRI scans can be used
biopsy, ensuring its performance, and formulating to guide the choice of muscle to be biopsied. It is
the interpretation can best be accomplished as a important not to biopsy sites of prior EMG needle
collaborative effort between the neurologist and examination, where a focal necrotic inflammatory
neuropathologist. reaction might give misleading information.
278 •
2.2. Techniques 2.2.2 . MUSCL E ENZYME
HISTOCHEMISTRY
2.2.1. CHOICE OF TECHNIQUE
Assessment of muscle pathology largely relies on
The choice of appropriate techniques in the evalua- histoenzymatic reactions aimed at detecting endoge-
tion of a nerve or muscle biopsy is made in the con- nous enzymatic activities of muscle fibers that convert
text of the clinical setting. Biopsies are performed soluble artificial substrates into insoluble precipi-
in circumstances ranging from known systemic tates. Particular methods employ specific substrates
disease, which may or may not manifest with neu- to demonstrate specific enzymes, such as myosin
romuscular deficit (e.g., vasculitis, sarcoidosis), to ATPase, COX, many of the lysosomal enzymes, and
primary neuromuscular disorders. Unfortunately, the enzymes of the glycolytic pathway. These meth-
the clinical manifestations frequently do not per- ods require frozen unfixed tissue sections in which
mit such a clear-cut distinction prior to the biopsy, the native enzymatic activities are preserved.
and indeed the goal of the biopsy is to discriminate In muscle pathology, this study has several
between these possibilities. objectives.
• At one end of the spectrum, the diagnosis may be 2.2.2.1. To analyze the different fiber types
obtained satisfactorily with “routine” histopatho- One of the defining characteristics of type 1 or
logical techniques performed on formalin-fixed, slow-twitch muscle fibers and type 2 or fast-twitch
paraffin-embedded tissue, which is adequate for fibers is that the myosin ATPase in these two iso-
the study of interstitial lesions, such as inflamma- forms with different pH optima. Advantage can be
tion and vasculitis. taken of this difference by pre-incubating tissue at
• At the other extreme, precise analysis of morphol- pH 4.3 or 9.4, respectively, and as a result, the histo-
ogy, immunocytochemical expression of specific chemical reaction selectively demonstrates type 1 or
proteins, and even ultrastructural study may be type 2 fibers. The ATPase activity of type 1 fibers is
necessary for the diagnosis of a specific neuro- weak at alkaline pH (9.4) but strong at pH 4.3; thus,
muscular disease. the type 1 fibers appear pale at pH 9.4 and dark at
4.3, and the reverse is true of type 2 fibers. This dis-
Therefore, in cases of suspected neuromuscular tinction can be further refined by carrying out the
disease, it is proper to begin the muscle biopsy ATPase reaction at pH 4.6, which permits differen-
evaluation by studying precisely oriented frozen tiation of type 2A and type 2B fibers (Table 12.1 and
cross-sections of muscle stained with H&E, the Fig. 12.1). A small percentage of fibers appear dark
modified Gomori trichrome stain, PAS, and oil (i.e., strongly reactive at both acid and basic pH), and
red O, as well as a battery of muscle enzyme histo- these are designated 2C fibers. They are interpreted
chemical reactions, including NADH, cytochrome as fetal/pathological fibers, since this pattern of lack
C oxidase (COX), and ATPase at acid and alkaline of pH sensitivity appears to be a normal feature of
pHs. The study can be complemented by (1) immu-
nocytochemistry for specific structural proteins or
immunological markers, (2) Congo red stain for Table 12.1. Enzyme Histochemical
suspected cases of amyloidosis, (3) stains for myo- Characteristics of the Different Types of
phosphorylase and phosphofructokinase in cases of Muscle Fibers
myoglobinuria or suspected glycogenosis, (4) acid
phosphatase in cases of vacuolar myopathy, and ENZ YME 1 2A 2B
(5) electron microscopy, which is essential for the RE AC TIONS
identification of certain structural abnormalities. It
is also the rule to keep frozen tissue for possible bio- NADH-TR +++ ++ +
chemical studies, particularly in metabolic diseases, ATPase 9.4 + +++ +++
or for the molecular diagnosis of hereditary disease ATPase 4.6 +++ 0 +
(Western blot, Southern blot PCR, mitochondrial ATPase 4.3 +++ 0 0
DNA analysis).
Chapter 12 Pathology of Skeletal Muscle • 279

on frozen sections and, for the identification of some
proteins, on paraffin sections. They may be used for
the following purposes:
2.2.3.1. To identify the different fiber types

Imunohistochemistry for fast myosin, which is
expressed in type 2 fibers, alpha actinin, which is
expressed in type 1 fibers, or using an antibody to
slow myosin is an excellent means for fiber typing on
paraffin sections; it representing a useful alternative
when frozen tissue is not available.
2.2.3.2. To reveal muscle regeneration The

FIGURE 12.1 Frozen section of a normal muscle NCAM isoform CD56/Leu19 is a marker of human
with ATPase reaction at 4.6: mosaic pattern of the satellite cells that are mononucleated muscle precur-
different fiber types.
sor cells, which normally reside beneath the basal
lamina of muscle fibers. They account for more than
fibers expressing yet a different isoform that may be 10% of myonuclei in young people and about 2% to
re-expressed during regeneration. 3% in adults. Postnatal muscle growth and regenera-
Type 1 fibers, which are rich in oxidative enzymes, tion result from activation, proliferation, and fusion
stain strongly by NADH tetrazolium reductase of satellite cells into muscle fibers. Increased expres-
(NADH-TR) and succinic dehydrogenase (SDH), sion of NCAM by muscle fibers is useful to assess
whereas type 2 fibers are relatively weakly stained. muscle regeneration following injury.
One caveat in this fiber type differentiation is that
there is an apparent “concentration” of organelles in 2.2.3.3 To detect structural protein deficits in
atrophic fibers, and a tendency for all small atrophic muscular dystrophies (see Section 6.1)
fibers to stain darkly with oxidative reactions.
2.2.2.2. To demonstrate subcellular phenom- 2.2.3.4 To identify specific immunopatholog-

ena The acid phosphatase reaction reveals increased ical reactions in inflammatory myopathies (see
lysosomal activity. Mitochondria are reactive for Section 9)
NADH-TR, SDH, and COX, whereas the T-tubule
system and other membranous organelles are only 2.3. Normal appearance on frozen
reactive for NADH-TR. section
2.2.2.3. To detect or specify certain struc- Much information is gained from the initial his-
tural abnormalities NADH-TR beautifully reveals tological examination of the overall architecture
structural anomalies associated with focal mito- of the muscle biopsy. In cross-section, the muscle
chondrial loss or dysorganized mitochondrial distri- fibers are polygonally shaped, with little interven-
bution as in target fibers, cores, lobulated fibers, or ing space between them, and fairly uniform in size.
“moth-eaten” fibers. Neuromuscular spindles are recognized as round
structures (about 50 to 100 μm in diameter) con-
2.2.2.4. To demonstrate specific enzymatic taining rounded intrafusal fibers and contained by
defects Staining for myophosphorylase and phos- a connective tissue capsule. The nuclei of muscle
phofructokinase can demonstrate deficiency in fibers are predominantly located next to the sub-
McArdle disease and Tarui disease, respectively. sarcolemma, although even in specimens without
any apparent neuromuscular disease, as many as 3%
to 5% of fibers may have more centrally located or
internalized nuclei. Endomysial connective tissue
2.2.3. IMMUNOHISTOCHEMISTRY
normally consists of thin, delicate, almost impercep-
Immunohistochemical reactions are now used rou- tible septa between the fibers and around the capil-
tinely in muscle pathology. They can be performed lary network. The perifascicular connective tissue,
or perimysium, contains small arteries, arterioles, diameter is abnormal even in infants). There may
veins, and nerve twigs but in the adult is normally be normally increased variability in fiber size and
devoid of adipocytes. The fascia or epimysium, situ- shape near tendinous insertions (sites that should
ated at the periphery of several fascicles, contains be avoided in biopsy) and certain muscles such as
neurovascular bundles and fatty tissue. the extraocular muscle, diaphragm, and paraspinal
A motor unit (i.e., a single motoneuron and its muscles, but fiber type grouping is never a normal
innervated myocytes) comprises solely muscle phenomenon.
fibers of a single histochemical type. Normally, the
muscle fibers belonging to a given motor unit are
not adjacent but are spatially dispersed in a muscle 3. BASIC REACTIONS
fascicle over a distance of several millimeters. On
histoenzymatic reactions that type the fibers, the 3.1. Changes in muscle fibers
muscle appears as a mosaic (checkerboard) of the Before considering the spectrum of pathological
two fiber types (Fig. 12.1). Adjacent fibers may be change in muscle fibers, one must be cognizant
of the same histochemical type but are not neces- of the histological artifacts that may occur and
sarily part of the same motor unit. In the adult, the avoid interpreting these as significant alterations.
numbers of type 1, 2A, and 2B fibers are roughly Foremost of these is “freeze artifact,” or the forma-
comparable in the muscles that are usually studied tion of spaces due to intramyocyte crystal ice for-
(i.e., type 1, 30% to 40%; type 2A, 20% to 30%; type mation, which is the result of improper freezing
2B, 40% to 50%; type 2C, 1% to 2%). The percent- of the muscle tissue. Tissue fixed in formaldehyde
ages of each fiber type will vary based on the muscle destined for paraffin-embedding and not appropri-
studied, but also according to sex, age (Table 12.2), ately stretched with a muscle biopsy clamp or other
and physical state, making it necessary to com- device can become distorted during fixation and is
pare the results with normative data from closely rarely properly oriented. Paraffin sections, under
matched controls. these circumstances, commonly show contraction
The appearance of normal muscle just described artifacts that preclude fine morphological analysis
applies only to adults; in infants and very young of muscle fibers. Paraffin sections are run routinely
children, the muscle fibers are rounded and take to assess the status of vessels, infectious/inflam-
on a polygonal cross-sectional shape only later matory changes, and the presence of neoplastic
in development (age 3 to 6). Furthermore, as the infiltrates.
mean fiber diameter is a function of age, analysis
of muscle biopsies in infants and children requires
comparison to normal values for age. Nevertheless, 3.1.1 . VARIATIONS IN SIZE
variability of fiber diameter is not a function of age, AND SHAPE
and the distribution of fiber types across a biopsy is The first parameters evaluated are the uniformity
not age dependent (i.e., excessive variation in fiber of muscle fiber size (diameter) and shape. Fibers
should be relatively uniform in size, although the
mean diameter increases up to ages of years. If a
Table 12.2. Mean Diameters of Muscle considerable population of small or larger fibers
Fibers According to Age is present, the condition is described as “exces-
sive variation in fiber size.” So-called “small angu-
AGE DIA ME T ER (μ M) lated fibers” (i.e., smaller-than-normal fibers
having a roughly triangular shape) are never nor-
Newborn 12 mal. “Hypercontracted fibers” (see Fig. 12.11B
1 year 16 later in the chapter) are characterized by a dis-
10 years 40 tinctly round cross-sectional appearance in a
background of somewhat smaller polygonal fibers,
Adult female 30–70 and moderate hyperchromasia. They can occur in
Adult male 40–80 biopsies with no other evidence of neuromuscular
disease and are particularly frequent in muscular
After Brooke and Engel, 1969. dystrophies.

A B
FIGURE 12.2 Variation in size and shape of the muscle fibers. (A) Small angulated fibers contrasting with
hypertrophic fibers with centronucleation. (B) Hypertrophic, split muscle fiber with central nuclei in muscular
dystrophy.
3.1.2. ATROPHY AND HYPERTROPHY pathological process; when they involve both fiber
types, they may represent early stages of denervation.
Hypertrophy consists of an increase in the size of the
Atrophy may select a particular fiber type. Type
muscle fibers, often associated with loss of their usual
1 atrophy (Fig. 12.3) is usually seen in adults with
polygonal outline. Some observers have reported
myotonic dystrophy and also in some childhood
that physiological hypertrophy of type 2 fibers may
congenital myopathies, perhaps due to developmen-
be seen in athletes, but definitive data on the biopsy
tal arrest. Type 2 atrophy is very frequent (mainly
appearance of muscle changes in response to training
involves type 2B fibers) and is seen in a variety of
are lacking. In pathological skeletal muscle, hypertro-
conditions, including immobilization, chronic
phied fibers are a compensatory change and are often
debilitating disorders, and steroid treatment.
accompanied by structural changes such as internal-
ized nuclei and split fibers (Fig. 12.2).
Atrophic fibers may be rounded in myopathic pro- 3.1. 3 . PREDOMINANCE OR DEF ICIENCY
cesses. They may be angulated, as a result of fiber split- OF A F IBER TYPE
ting in type 2 fiber atrophy, or in neurogenic processes
in adults. In the end stages of atrophy, the atrophic The prevalence of type 1 and type 2, or more
fibers form “nuclear bags” (i.e., clusters of sarcolem- precisely type 2A and 2B, depends on the specific
mal nuclei within shrunken muscle cells largely muscle biopsied. For the most frequently biopsied
devoid of myofibrillary material) (see Fig. 12.7C later
in the chapter). In the late stage of a severe myopathic
or neurogenic process, the muscle can be severely
damaged and is referred to as “end stage.” It is largely
replaced by fibroadipose connective tissue with few
remaining atrophic fibers, and it is often impossible to
infer the etiological basis of the initial insult.
It is important to determine the distribution of
the atrophic fibers; they may occur randomly or be
grouped together in clusters. Fascicular or group
atrophy, a hallmark of denervation, consists of aggre-
gates of atrophic fibers that occupy part of a fascicle.
This process differs from perifascicular atrophy, as
seen in dermatomyositis, in which atrophic fibers
line the edges of the fascicles, and where the tran- FIGURE 12.3 Type 1 predominance and
sition to atrophy is gradual. Randomly scattered type 1 atrophy in a case of congenital myopathy
atrophic fibers are less characteristic of a specific (NADH-TR).
sites, the deltoid, quadriceps, biceps, and gastroc- show a homogenization and glassy appearance of
nemius muscle, an abnormal predominance of fiber the cytoplasm and poor staining. In longitudinal sec-
type is recognized when the proportion of fibers tions, there is pallor and loss of cross-striations. There
exceeds 55% type 1 or 80% type 2 fibers. Type is also loss of staining with PAS and NADH-TR.
1 fiber predominance can be seen in congenital Over time, fibers become vacuolated and eventu-
myopathies (Fig. 12.3). Cases of “central hypoto- ally are invaded by inflammatory cells extending
nia” often show aberrations of fiber-type propor- across the basement membrane (Fig. 12.4A). Later,
tions in the absence of overt denervation. Type 2B admixtures of macrophages, T-lymphocytes (pre-
deficiency, sometimes total, and/or the presence dominantly T8), and regenerating myoblasts arising
of type 2C fibers may be seen in certain myopathic from neighboring muscle fibers may be seen within
processes. the muscle tube. This stage ends with the migration
of inflammatory cells toward the adjacent blood
vessels. In some conditions, muscle fiber necrosis
3.1.4. STRUCTURAL ANOMALIES OF is segmental; this phenomenon is best seen in lon-
MUSCLE FIBERS
gitudinal sections (Fig. 12.4B). Centromyocytic
3.1.4.1. Nuclear anomalies Central displace- necrosis, presenting as a collection of inflammatory
ment of the nuclei, “internalized nuclei,” is consid- cell invasion of nonnecrotic fibers, is said to be char-
ered abnormal when present in over 3% to 5% of the acteristic of polymyositis.
fibers (Fig. 12.2).
The biological basis of this phenomenon is not 3.1.4.4. Basophilic fibers These fibers corre-
clear; it is a marker of fibers that have regenerated spond to regenerating muscle fibers, rich in RNA.
or are in the process of regeneration. Relatively On H&E preparations the fibers have a basophilic
unremarkable-appearing nuclei may be internal- cytoplasm, express NCAM, may be either weakly
ized in hypertrophic fibers, possibly representing striated or nonstriated, and possess vesicular nuclei
a preliminary stage in the process of fiber splitting. with prominent nucleoli. Regeneration may result
In certain diseases, notably myotonic dystrophy, on in complete restitution of the muscle fiber or leave
longitudinal sections of muscle, nuclei can be seen sequelae such as variation in the shape and size of
to aggregate closer together and line up in chains; fibers. Regenerative lesions are either scattered ran-
these are referred to as “nuclear chains.” Nemaline domly or occur in small clusters.
rod myopathy.
3.1.4.5. Target fibers These may be detected
3.1.4.2. Split fibers These are especially seen in standard preparations (see Fig. 12.7B later in
in hypertrophic fibers. In cross-section, splitting the chapter) but are particularly well seen with
presents as a fissure originating from the surface NADH-TR. True target fibers are particularly but
of a muscle fiber. This fissure may be branched or not exclusively seen in type 1 fibers. They are com-
contain a capillary (Fig. 12.2). It may become more posed of three concentric zones: a central pale zone,
ill defined in the center of the fiber or extend to which lacks oxidative enzyme activity; a dark, annu-
another edge of the fiber. Multiple splits may lead to lar intermediate zone, which is rich in oxidative
grouping of angulated muscle fibers of the same his- enzymes; and a normal peripheral zone. They are
tochemical type, a phenomenon sometimes termed often found in denervation. A “targetoid” fiber is
myopathic grouping. The mechanism of splitting is one in which the intermediate zone is absent and is
not settled. Its significance is doubtful at myotendi- considerably less specific.
nous junctions.
3.1.4.6. Moth-eaten fibers These are recog-
3.1.4.3. Necrotizing changes Fiber necrosis or nized in oxidative enzyme preparations. They pres-
degeneration (terms used interchangeably, albeit ent as ill-defined zones of enzyme loss, resulting in
perhaps imprecisely) is the hallmark of dystro- a disorganized aspect of the intermyofibrillary net-
phic, inflammatory, or toxic myopathic processes. work. They are not specific and are seen in a wide
Conversely, the presence of necrotic fibers should range of conditions, including inflammatory myopa-
cast doubt on a diagnosis of a neurogenic process, thies, malignant hyperpyrexia, or denervation.
although it may be seen in the late stages of neuro- Lobulated or trabeculated fibers are also best
genic atrophy. In H&E preparations, necrotic fibers appreciated with NADH-TR. Individual fibers

A B
C D
FIGURE 12.4 Structural anomalies of muscle fibers. (A) A necrotic fiber is invaded by inflammatory cells.
(B) Central myocyte necrosis is shown on longitudinal section. (C) Rimmed vacuole. (D) Whorled fibers or
“coiled fiber” with central disorganization of the myofilaments.
have a lobulated appearance such that there are may be seen in myotonic dystrophy and other dys-
many small zones of enzyme loss encircled by trophies and myotonic disorders.
darker zones within fibers. Certain dystrophies
are associated with many lobulated fibers (e.g., 3.1.4.8. Vacuoles Clear intramyocytic spaces of
LGMD2A), but this is a nonspecific myopathic variable size and location are seen with H&E, modi-
feature. We see these also in paraspinal muscle fied Gomori trichrome, and other stains and have
biopsies in patients with axial myopathies (neck variable pathological significance best determined
extensor myopathy, bent spine syndrome),
facio-scapulo-humeral muscular dystrophy, and
other dystrophies.
3.1.4.7. Inclusions and other uncommon

findings and lateral sarcoplasmic masses Striated
annulets (Ringbinden, or ring fibers) are formed by
myofibrils that are normal in structure but abnor-
mally arranged so as to be perpendicular to the
muscle fiber axis as seen on cross-section. Lateral
sarcoplasmic masses present as delicately granulated
nonstriated clear areas that are filled with oxidative
enzymes and are situated between the sarcolemmal
membrane and a central myofibrillary zone of nor-
mal appearance (Fig. 12.5). These two abnormalities FIGURE 12.5 Lateral sarcoplasmic masses.
after a battery of special stains, and sometimes only in nonmitochondrial disorders. Conversely, their
after electron microscopy. They occur in the follow- absence in a given biopsy specimen does not exclude
ing conditions: the diagnosis of a mitochondrial cytopathy.
• Nonlysosomal storage diseases (e.g., glycogen in 3.1.4.10. Tubular aggregates Presenting as

McArdle disease; lipids in carnitine deficiency) well-limited zones that are usually subsarcolem-
• Lysosomal storage diseases, which are recog- mal and stain blue with H&E and red with Gomori
nized by the acid phosphatase reaction and by trichrome, tubular aggregates affect mainly type 2
identification of the stored material (e.g., glycogen fibers. They are strongly positive with NADH-TR
in Pompe disease; autofluorescent lipopigment in but are SDH negative. By electron microscopy,
ceroid lipofuscinosis) their appearance is that of aggregates of tubules
• Autophagic vacuoles with lysosomal arranged in an organ-pipe pattern. These structures
hyperactivity, revealed by the acid phosphatase are not specific but are often encountered in dys-
reaction (e.g., chloroquine myopathy) kalemic paralysis and represent the chief histologi-
• Rimmed vacuoles (Fig. 12.4C), as seen in inclu- cal skeletal muscle anomaly seen in the myalgia/
sion body myositis, where their outer border is cramps syndrome associated with tubular aggre-
granular and basophilic on H&E and reddish with gate myopathy.
the modified Gomori trichrome stain; by electron
microscopy they are seen to consist of membra-
nous debris and intermediate filaments 3.2. Interstitial changes
• Vacuoles produced by dilatation of the internal Some of the changes seen in the interstitial tissue
membrane systems, as in periodic paralysis; may have diagnostic significance and establish the
microvacuoles produced by dilatation of the etiology of the process with certainty (e.g., sarcoid-
T-transverse tubular system and seen amid osis and polyarteritis nodosa, and amyloidosis).
healthy regions of the sarcoplasm next to recent Increased endomysial connective tissue or “endo-
zones of segmental necrosis; accumulation of sar- mysial fibrosis” is less specific but suggests muscular
cotubular material identified at the ultrastructural dystrophy. In end-stage muscle of whatever cause,
level, in sarcotubular myopathy there is infiltration and replacement of muscle by
• Vacuoles resulting from the disappearance of adipose tissue.
myofibrils, as in dermatomyositis and critically ill Discrete inflammatory cellular infiltrates may
patient myopathy, in which the content may have be seen in a variety of conditions: to some extent in
a reticulated honeycomb appearance. muscular dystrophies such as dystrophinopathies
and dysferlinopathies, in rhabdomyolysis (in the
3.1.4.9. Ragged red fibers These subsarcolem- setting of a toxic or metabolic myopathy), and in
mal and/or intermyofibrillary aggregates are the inflammatory myopathies, such as dermatomyosi-
hallmark of mitochondrial myopathy. They appear tis, polymyositis, and inclusion body myositis. The
reddish with Gomori trichrome (see Fig. 12.15A topography and also the cellular composition of
later in the chapter), hence the name, and bluish the inflammatory infiltrates are important clues to
with H&E. These aggregates, which are essentially establish an etiological basis.
formed by abnormal mitochondria, are filled with
oxidative enzymes and therefore stain strongly with
the NADH-TR and SDH reactions. Ragged red 4. NEUROGENIC ATROPHY
fibers that are SDH positive (ragged blue fibers) Two broad diagnostic categories of neuromuscular
but COX negative are indicative of an underlying disease are recognizable on muscle biopsy: neuro-
mutation in the mitochondrial DNA or in nuclear genic and myopathic processes (Table 12.3). These
genes that encode mitochondrial respiratory chain major subdivisions denote fundamental differences
subunits. Ultrastructurally, they are associated with in the pathogenesis of the neuromuscular disor-
accumulation of abnormal mitochondria, glycogen, der: (1) diseases characterized by denervation and
and lipids. Although strongly indicative of mito- subsequent atrophy of the fiber or (2) myopathies
chondrial myopathy when found before the age where the primarily insult involves constituents of
of 60 years, scattered ragged red fibers may also be the muscle fiber itself, resulting in structural abnor-
found in the muscle tissue of elderly individuals malities and potential destruction of the cell.

Table 12.3. Characteristic Myopathic myosin immunocytochemistry and show a marked
and Neurogenic Processes: Differential increase of oxidative enzyme activity. At a later stage,
Histological Features the atrophied fibers may be grouped in small nests
and, later, in islands, giving the picture of fascicular
M Y O PAT H I C NEUROGENIC atrophy (Fig. 12.6). In the absence of reinnervation,
PROCESSES PROCESSES the atrophied fibers form nuclear bags (Fig. 12.7C).
Considerable variation Nests of atrophic fibers

in the fiber size 4.1. 2 . GROUPING OF F IBERS
OF THE SAME HISTOCHEMICAL
Rounded fibers Angular fibers
TYP E (TYPE GROUPING)
Increase in the number Pseudomultiplication
of nuclei of the nuclei due to The denervated muscle fibers may recover up to
cytoplasmic atrophy their normal size when reinnervated by collateral
Internalized nuclei – sprouting from unaffected motor axons. As the his-
tochemical fiber type is believed to depend on the
Necrotic and –
innervating motoneuron, with reinnervation the
basophilic fibers
fiber type may change. When the sprouting axons
Cytoplasmic Target fibers reinnervate atrophic fibers in the vicinity of unaf-
alterations in fected fibers of the same motor unit, this results in
contractile proteins patches of contiguous fibers of the same enzyme
Conspicuous Minimal interstitial histochemical type. Repeated cycles of this process
interstitial fibrosis fibrosis result in the progressive pathological enlargement
Inflammatory cellular No inflammatory cellular of motor units, composed of a single fiber type, and
infiltrates infiltrates gradually the formation of giant motor units (also
recognized neurophysiologically). As a result, there
is progressive disappearance of the normal check-
In denervating diseases, the site of injury may erboard appearance of the muscle fibers. In ATPase
be the innervating motor neuron cell body in the stain, the appearance is that of large, contiguous
spinal cord (or brainstem), the axon in the anterior fields of fibers of the same histochemical type and
root, peripheral nerve, or the intramuscular termi- involving both fiber types; this is called “fiber type
nal nerve twigs, or the neuromuscular motor end grouping” (Fig. 12.6) and is virtually pathogno-
plate. Pathological examination of the muscle alone monic of denervation (Fig. 12.7A). Fibers at this
ordinarily cannot determine the precise locus; cor- stage may be of uniform normal diameter, but often
relative clinical and neurophysiological data are enough the fibers in the group are of variable size and
required. larger than normal. As the disease progresses, when
a newly innervating axon that had incorporated
the atrophic fibers in its motor unit also becomes
4.1. General features damaged, this results in atrophy of the type 1 or
type 2 muscle fibers that were clustered together,
4.1.1. DENERVATION ATROPHY
a phenomenon referred to as “group atrophy.” The
For reasons that are not entirely clear, denervation phenomenon is apparent on H&E (Fig. 12.7D) and
of skeletal muscle fibers results in a progressive on histochemical preparations. Pseudo-groupings
reduction in the size of the fiber and loss of contrac- of myopathic nature may occur when multiple fiber
tile proteins, but with preservation of the integrity of splits are present. It is not firmly established what
the cell membrane and intracellular organelles. The the definitive number of contiguous fibers should
first detectable change is a reduction in the caliber of be to be certain that one is dealing with genuine
the cell and an alteration in its cross-sectional con- type grouping, but the presence of fibers of a given
tour, which loses its polygonal shape and becomes fiber type, surrounded by nearest neighbors all of
triangular (“angulated”). Small angulated fibers scat- the same fiber type (so-called “enclosed fibers”),
tered throughout the biopsy may be apparent only may be used as a rough guide, particularly when
with close examination; they are of both type 1 and the phenomenon is observed in both fiber types.
type 2 fibers as assessed by ATPase reactions or fast It is important to consider the proportion of fiber
1 2A 2B 1 1 2A 2B 1 2A
1 2 3
1 2A 1 2B
4 5 6
FIGURE 12.6 Mechanisms of denervation.
A B
C D
FIGURE 12.7 Neurogenic atrophy; morphologic appearance. (A) Type grouping (ATPase at pH.4.6).

(B) Simple angular atrophy and target fibers. (C) Atrophic fibers forming “nuclear bags” (i.e., clusters of nuclei
within muscle cells largely devoid of myofibrillary material). (D) Fascicular atrophy.

types and the relative size. Clearly, if one fiber type 4.3. Acute and chronic neurogenic
markedly predominates, it is inevitable that some processes
examples of enclosed fibers of that type will be
found. The histological findings described give some sense
of the tempo of the process such that a sense of the
stage of the disease can sometimes be inferred.
4.1.3. TARGET FIBERS
Target fibers are very common in denervation. • The hallmark of acute denervation is angulated,
Their presence is typically ascribed to attempts at random muscle fiber atrophy.
reinnervation. They are best visualized in oxidative • With time, the denervated atrophic fibers may
enzyme preparations, as in NADH-TR. In paraf- be reinnervated and may regain their former size,
fin sections they may, however, also be recognized but ATPase histochemistry will reveal fiber type
with H&E (Fig. 12.7B) and especially with Gomori grouping, which implies a further evolution of the
trichrome. process.
• In the late stages of the disease, the neuron
responsible for reinnervated fibers may become
4.2. Neurogenic atrophy in infants affected, resulting in group atrophy.
In infantile spinomuscular atrophy (Werdnig- • In slowly evolving denervation, or in prolonged
Hoffmann disease; SMA1), muscle biopsy dem- chronic denervation, in addition to typically neu-
onstrates numerous hypotrophic type 1 and type 2 rogenic changes, muscle fiber hypertrophy, with
fibers with rounded (not angulated) outlines. This excessive numbers of central nuclei, split fibers,
form of atrophy is associated with groups of hyper- and interstitial fibrosis (“pseudomyopathic”
trophic fibers, predominantly of type 1 (Fig. 12.8). changes), may be found, including scattered
There may be relatively little capacity to reinnervate perivascular mononuclear cellular infiltrates of
denervated muscle fibers in these patients, and as a necrotic fibers.
result, fiber type grouping is seldom seen. We often
do not see muscle biopsies in SMA1 infants anymore
as genetic testing is widely available. 5. NEUROMUSCULAR
In the juvenile form of the disease (Kugelberg- TRANSMISSION DEFECTS
Welander disease; SMA3), more typical findings of
These diseases present clinically with a myasthenic
denervation are the rule.
syndrome characterized by weakness and fatigabil-
ity that may be generalized but may be most obvious
in extraocular and eyelid muscles. The basic mecha-
nism of injury is dysfunction of the neuromuscu-
lar junction resulting in impaired neuromuscular
transmission.
The diseases may be separated into acquired,
autoimmune myasthenic syndromes, including
myasthenia gravis (MG) and Lambert-Eaton syn-
drome, and congenital myasthenic syndromes.
5.1. Myasthenia gravis

MG is due to an antibody-mediated autoimmune
response to nicotinic acetylcholine receptors
(AChR) or less often to muscle-specific tyrosine
FIGURE 12.8 Neurogenic atrophy in an infant kinase (MuSK) localized on the postsynaptic part of
with Werdnig-Hoffmann disease (SMA1). Numerous the neuromuscular junction. MG may be associated
hypotrophic fibers with rounded outlines are associ- with other autoimmune disorders. Thymus hyper-
ated with groups of hypertrophic fibers (Masson plasia is found in 70% of patients with MG and thy-
trichrome). momas are found in 15% to 20%.
The diagnosis is usually obtained by clinical myasthenic syndromes include mutations in AchR
examination, electrophysiological examination subunits genes that increase (fast channel syn-
showing the characteristic decremental EMG drome) or decrease (slow channel syndrome) the
response to successive nerve firings, pharmacologi- synaptic response to Ach, and a myasthenic syn-
cal tests, particularly the prostigmine test, and detec- drome caused by mutations in the genes that encode
tion of AchR or MuSK autoantibodies in serum. for plectin, rapsyn, muscle-specific kinase (MuSK),
Muscle biopsy is generally not necessary, except Dok-7, agrin, or voltage-gated sodium channel of
in seronegative cases to eliminate other diseases with skeletal muscle (Nav1.4) or SCN4A.
similar clinical presentation, namely mitochondrial In some congenital myasthenic syndromes, a spe-
cytopathies. Lymphocytic infiltrates (lymphor- cific diagnosis can be made by simple histological or
rhages) and mild, nonspecific alterations of the mus- EMG study, but in others, muscle biopsy of an inter-
cular fibers such as type 2 atrophy may be seen but are costal muscle is required, allowing in vitro electro-
uncommon. Ultrastructural study of the neuromus- physiology, immunocytochemistry, ultrastructural,
cular junction shows widening of the synaptic cleft and immunoelectron microscopy. If these tests point
and simplification of the postsynaptic membrane to a specific defect, then molecular genetic analysis
with atrophy and flattening of the postsynaptic folds. becomes feasible and allows for a precise diagnosis.
5.2. Lambert-Eaton syndrome 6. GENETICALLY

The Lambert-Eaton syndrome, another acquired
DETERMINED DISEASES OF
autoimmune disorder, typically presents as a para- SKELETAL MUSCLE
neoplastic syndrome in association with a small The diseases affecting primarily the skeletal muscle
cell carcinoma of the lung. Patients develop anti- may be acquired (toxic or inflammatory) or geneti-
bodies against voltage-gated calcium channels on cally determined. The latter group may be classified
the presynaptic nerve terminal in neuromuscular into three main categories: (1) muscular dystro-
junctions (see Chapter 9). Muscle biopsy is not phies, which are progressive myopathies typically
contributory. characterized by conspicuous degeneration and
regeneration (exception: myotonic muscular dys-
trophies, which are fundamentally entirely separate
5.3. Congenital myasthenic syndromes categories); (2) congenital myopathies, which typi-
The congenital myasthenic syndromes represent cally have a very early onset, tend to have a nonpro-
a heterogeneous group of disorders due to genetic gressive or very slowly progressive course, and show
abnormalities of the proteins of the neuromuscular distinctive pathological alterations, allowing a spe-
junction. Given the large number of these proteins, cific morphological diagnosis; and (3) metabolic
increasing numbers of new mutations will likely be myopathies, including mainly glycogen, lipid stor-
discovered in the future. age, and mitochondrial cytopathies.
These conditions affect mainly children but may A classification taking into account the specific
also occur in adults. Clinical and electrophysiological molecular defects responsible for the myopathy is
symptoms are those of myasthenia, but serological emerging. Such defects may involve structural pro-
tests for AchR and MuSK autantibodies are negative. teins or less often enzymes. In the future, with a
According to the site of the defect one may dis- greater understanding of the underlying pathobiol-
tinguish presynaptic, synaptic, or postsynaptic con- ogy of the genetically determined muscular diseases,
genital myasthenic syndromes. A number of entities the distinctions between muscular dystrophies, con-
have been described thus far. genital myopathies, and perhaps some metabolic
Presynaptic congenital myasthenic syndrome myopathies might prove arbitrary.
includes a paucity of synaptic vesicles and reduced
quantal release caused by mutations in choline
acetyltransferase (CHAT) and endplate choline 6.1. Muscular dystrophies
acetyltransferase deficiency (congenital myas- The muscular dystrophies are classically a group
thenic syndromes with episodic apnea) caused by of genetically determined myopathies marked
mutations in ColQ gene. Postsynaptic congenital clinically by chronic and progressive weakness and

FIGURE 12.9 Diagram of the cytoskeletal proteins involved in the pathogenesis of muscular dystrophies
(modified from Dalkilic & Kunkel, 2003).
markedly elevated serum creatinine kinase levels. This complex is also increasingly recognized to trans-
The past few decades have witnessed a revolution duce survival signals. The respective roles of the
in the understanding of the genetic and molecular “structuropathies” and of the “signalopathies” associ-
basis of the muscular dystrophies. ated with disruption of the complex are not yet clear.
Central to our understanding are a group of The current and evolving classification schemes
disorders that have been shown to be the result of the muscular dystrophies reflect the progress in
of mutations in the genes encoding functionally the understanding of the genetic and molecular
related cytoskeletal proteins of the muscle fiber. biology of the disease while taking into account the
These form a link between cytoskeletal actin and collected body of knowledge regarding the mode of
the extracellular matrix (Fig. 12.9) and include genetic transmission (X-linked, autosomal domi-
extracellular matrix proteins (merosin, collagen VI), nant/recessive) and the clinical aspects of the illness.
transmembrane- and membrane-associated proteins
(dystrophin, sarcoglycans, dystroglycans, caveolin-3,
α5- and α7-integrins, dysferlin), intracellular pro- Emery Dreifuss MD
LGMD1B
teases (calpain-3), cytoplasmic proteins associated
Emerin
with organelles and sarcomere (titin, telethonin,
myotilin, and fukutin and related enzymes), and
LaminA/C
nuclear membrane proteins (lamin A/C, emerin)
(Fig. 12.10). It seems likely that this complex of
cytoskeletal proteins stabilizes the muscle fiber Nucleus
plasma membrane (the sarcolemma) against the
mechanical stress of repeated cycles of contraction
and relaxation. The absence of dystrophin or of other FIGURE 12.10 Diagram of the nuclear proteins
components of this mechanical link robs the muscle involved in the pathogenesis of muscular dystrophies
of this protective effect and results in clinical disease. (modified from Dalkilic & Kunkel, 2003).
6.1.1. X-LINKED MUSCULAR age 2, the biopsy will show rounded fibers and small
DYSTROPHIES numbers of degenerating and regenerating fibers.
Endomysial fibrosis is subtle if present, and fatty
6.1.1.1. Duchenne muscular dystrophy
infiltration of the endomysium is not seen.
Duchenne muscular dystrophy (DMD) is the
When biopsy is performed at the end of the age
paradigmatic muscular dystrophy as well as being
spectrum, or at autopsy, it may show abnormalities
the foundation for many of the recent advances in
largely consisting of fat and abundant fibrosis with
the understanding of these diseases. The gene that
only scattered surviving muscle fibers (Fig. 12.11F).
is mutated in the disease is the DMD gene, a large
In the latter stages of the disease, with extensive loss
gene (about 2700 kb) that encodes the 427 kD mus-
of muscle, the creatine kinase level is often lower
cle cytoskeletal protein, dystrophin. This is now the
than at any time in the antecedent years.
largest gene identified in the human genome. DMD
The absence of dystrophin demonstrated either
is inherited as an X-linked recessive (i.e., involv-
directly, by immunohistochemistry or Western blot,
ing males and transmitted by females). However,
or implicitly by genetic analysis is now the defining
about one third of DMD cases result from sponta-
feature of this disorder. Immunocytochemistry that
neous mutations. Females are carriers and gener-
normally demonstrates dystrophin in its characteris-
ally asymptomatic. Manifesting carriers presumably
tic subsarcolemmal distribution usually shows a total
reflect skewed inactivation of the X chromosome
absence of expression in DMD, contrasting with nor-
carrying the intact copy of the DMD gene.
mal expression of spectrin used as control of mem-
The myopathy is of early onset in the muscles of
brane integrity. A weak expression may be found
the pelvic limb-girdle and presents a pseudohyper-
with monoclonal antibodies to the N-terminus or to
trophic appearance most obviously in the calves,
the rod domain but never with antibodies to the C
but seen elsewhere as well. Creatine kinase levels are
terminus (Fig. 12.11C, D), allowing distinction with
characteristically markedly increased, to the range of
Becker dystrophy (see below). Manifesting female
more than 10,000 IU. Dystrophin is present in cardiac
carriers may show a mosaic of dystrophin-positive
muscle and cardiac dysfunction may be a feature. The
and -negative fibers. Western blotting on muscle
course is rapid, leading to death in young adulthood.
homogenates identifies a marked decrease in dystro-
Muscle biopsies are less commonly performed
phin size or amount in patients with DMD.
nowadays as genetic testing has become the screen-
Genetic testing has now become standard to
ing tool of choice as it is non-invasive. Nevertheless,
directly identify mutations in the DMD gene. The
biopsies are done at times and may be useful those
genetic information can also be used for carrier
too young with genetic test results and severity of
identification and for prenatal diagnosis in subse-
muscle involvement such that it is difficult to pre-
quent at-risk pregnancies.
dict prognosis (e.g., Duchenne or Becker muscular
dystrophy). The appearance of the muscle biopsy 6.1.1.2. Becker muscular dystrophy While
may differ dramatically depending on the age of DMD is produced by mutations that result in the
the patient at the time of biopsy. In the moderately nearly absolute loss of dystrophin, Becker muscular
affected boy biopsied in late childhood, the skeletal dystrophy (BMD) results from mutations associ-
muscle shows striking variation in fiber size, with ated with preservation of some dystrophin, albeit
atrophic fibers mixed with rounded hypertrophic abnormal either in amount (underexpression) or
fibers, centronucleation, swollen fibers with opaque molecular size (either truncated proteins or, in rare
sarcoplasm, so-called “hypercontracted fibers,” foci instances, larger-than-normal dystrophin), which
of small basophilic fibers, myophagocytosis, and nonetheless does not function normally.
scattered inflammatory infiltrates. Also distinctive Clinically, this type of myopathy is similar to
is a progressive increase in endomysial connective DMD, but its onset occurs later and its course is
tissue (Fig. 12.11A , B). As muscle degeneration pro- longer and has a considerably wider variation in
ceeds, there is gradual infiltration of the muscle by severity. Patients with severe forms of BMD may
adipose tissue. Poor enzyme histochemical fiber dif- be hardly better off than those with DMD, whereas
ferentiation is often seen in ATPase reactions. those with mild cases may be able to walk until late
The appearance at either end of the natural his- in life. Those with more mild forms, identified only
tory of the disease is a variation on this basic pattern. by molecular testing, may have nothing more than
At an early stage of the disease, typically at about cramps and an elevated serum creatine kinase level.

A B
C D
E F
FIGURE 12.11 Duchenne muscular dystrophy: morphologic appearance. (A) Necrotic fibers with myo-

phagocytosis and foci of small basophilic fibers, variation in fiber size, with atrophic fibers mixed with rounded
hypertrophic fibers and centronucleation. (B) “Hypercontracted fiber” and increased endomysial connective
tissue. (C) Total absence of expression of dystrophin at immunocytochemistry using an antibody to the C
terminus, compared to a normal control (D). (E) Immunocytochemistry for α-sarcoglycan shows partial loss
of expression. (F) Morphologic appearance of the muscle at a late stage of the disease: only scattered surviving
muscle fibers are present within fibrosis and ingrowth of adipocytes.
In keeping with this, the appearance on muscle in BMD may reveal by irregularity in labeling inten-
biopsy is variable, with qualitatively the same fea- sity both between fibers and in the same fiber. It is
tures seen in DMD, but in some instances with much important to use antibodies to different regions of
less severe findings. Dystrophin immunochemistry the dystrophin molecule to avoid false-negative
results. It is prudent to confirm these observations Onset of LGMD is most often in the second
by Western blotting and genetic studies particularly or third decade of life but may range from child-
if immunostaining is normal. hood to late adulthood. Patients usually present
with weakness of the pelvic/hip-girdle muscles and
6.1.1.3. X-linked Emery-Dreifuss muscu- shoulder-girdle muscles. There may be scapular
lar dystrophy Emery-Dreifuss muscular dystrophy winging, calf hypertrophy, or calf atrophy depend-
(EDMD) is the less common X-linked muscular dys- ing on the subtype of LGMD. Additionally, some
trophy. Prominent features that distinguish it clini- forms of LGMD are associated with early cardiac or
cally from DMD are the later age of onset, prominent ventilatory muscle involvement. The creatine kinase
contractures, and cardiac involvement. The early level may range from the upper limit of normal to
muscle contractures characteristically involve elbows, several hundred times normal.
Achilles tendons, neck extensors, and scapulohume- Muscle biopsies of only slightly affected muscles
roperoneal muscles. Disturbances in cardiac con- may reveal only irregularities in fiber size and a mild
duction often lead to death by the fifth decade. The excess of fibers with internalized nuclei. Weaker
muscle biopsy shows dystrophic changes but is not muscles demonstrate more evidence of muscle
otherwise distinctive. It may show atrophy of type 1 degeneration, along with progressive rounding of
fibers and considerable endomysial fibrosis. The diag- fibers, increasing variation in fiber diameter, cen-
nostic study is immunocytochemistry for emerin, a tronucleation, muscle fiber degeneration and regen-
nuclear protein that is mutated in this disease. Emerin eration, and fatty replacement. Mild inflammatory
is a membrane-spanning component of the molecu- infiltrates may be seen. Hypertrophic fibers subse-
lar skeleton that supports the nuclear membrane quently show splitting and various other cytoplas-
(Fig. 12.10). It is expressed in all cells. Absent immu- mic changes that include whorled fibers, moth-eaten
nocytochemical expression of emerin can be assessed fibers, and lobulated fibers. Endomysial fibrosis
in muscle as in other tissues, such as skin. develops.
There are actually at least five genetically distinct Molecular genetics revolutionized the under-
forms of EDMD. Emerin mutations are the most standing of these diseases. They are now classified
common cause of X-linked EDMD, although muta- according to their pattern of inheritance, autosomal
tions in FHL1 may also be associated with a similar dominant and recessive, and chromosomal locus or
phenotype, which is X-linked as well. Mutations in linkage. The standard nomenclature assigns the pre-
FHL1 are also the cause of X-linked scapulopero- fix LGMD followed by 1 (autosomal dominant) or 2
neal myopathy/dystrophy. (autosomal recessive), followed by a letter (A, B, C,
Mutations in lamin A/C are the most common etc.). For many of the LGMDs, the mutated gene and
cause of autosomal dominant EDMD (also known as abnormal or absent protein have been identified, and
LGMD1B). Mutations in this gene are also a common they may be termed according to the deficient pro-
cause of hereditary cardiomyopathy. Autosomal domi- tein (sarcoglycanopathies, dysferlinopathies, caveo-
nant EDMD can occur less commonly with mutations linopathy, myotilinopathy) (Table 12.4). For these
involving nesprin-1, nesprin-2, and TMEM43. proteins, specific antibodies have become available
commercially, allowing immunocytochemical diag-
nosis of a number of LGMDs. Sarcoglycans, as well
6.1.2. AUTOSOMAL DYSTROPHIES as dysferlin (LGMD 2B), normally have a sarcolem-
6.1.2.1. Limb-girdle muscular dystrophies mal distribution identical to that of dystrophin and
Limb-girdle muscular dystrophies (LGMDs) form are absent in the homozygous forms. Because they
a heterogeneous group of myopathies of autosomal normally form a complex of dystrophin-associated
recessive or, less commonly, autosomal dominant proteins, sarcoglycan and dystroglycan expression
inheritance. These autosomal dystrophies have may be altered secondary to the loss of one of the
clinical and myopathological features overlapping other members of the complex (Fig. 12.11E). Loss
with, if not similar to, DMD or BMD, except that of any one sarcoglycan may produce variable sec-
they may occur in females. In referral-based clinical ondary loss of other sarcoglycans, although they
populations, fukutin-related protein (FKRP) defi- do not appear to have similar secondary effects on
ciency (LGMD2I), calpainopathies (LGMD2A), either dystrophin or dystroglycans. Thus, confir-
and anoctaminpathies (LGMD2L) appear to be the mation of a specific defect by molecular genetics
most common LGMDs. remains mandatory.

Table 12.4. Classifications and Characteristic of Limb-Girdle Muscle Dystrophies
SUBT YPE GENE PRODUC T GENE C H A R A C T E R I S T I C F E AT U R E

LOCALIZ ATION
Limb-girdle dystrophies: Autosomal dominant

1A Myotilin 5q31 Nasal dysarthric speech; features of
myofibrillar myopathy on biopsy
1B Lamin A/C 1q21 Dilated cardiomyopathy, conduction defects
1C Caveolin-3 3p25 Childhood onset, cramps,
rippling muscle disease
1D DNAJB6 6q23 features of myofibrillar myopathy on biopsy
1E Desmin 7q7-9 Cardiomyopathy; features of myofibrillar
myopathy on biopsy
Limb-girdle dystrophies: Autosomal recessive
2A Calpain-3 15q15 Scapular winging, may have contractures
and facial weakness late
2B Dysferlin 2p12 Proximal or distal weakness

2C Gamma-sarcoglycan 13q12 Scapular winging, calf hypertrophy,
possible dilated cardiomyopathy
2D Alpha-sarcoglycan 17q21 Scapular winging, calf hypertrophy,
2E Beta-sarcoglycan 4q12 Scapular winging, calf hypertrophy,
2F Delta-sarcoglycan 5q33 Scapular winging, calf hypertrophy,
2G Telethonin 17q11-12 Anterior distal weakness, rimmed vacuoles
2H TRIM32 9q31-q34.1 Slowly progressive
2I Fukutin-related protein 19q13.3 Calf hypertrophy, dilated cardiomyopathy,
respiratory failure
2J Titin 2q31 Rimmed vacuoles; rarely other features of
myofibrillar myopathy on biopsy
2K POMT1 9q31 More commonly presents as
Walker-Warburg syndrome
2L Anoctamin 5 11p14.3 Quadriceps weakness; early gastrocnemius
weakness and atrophy mimicking
dysferlinopathy (Miyoshi type 1)
2M Fukutin 9q31-33 More commonly presents as the congenital
Fukuyama muscular dystrophy
2N POMT2 14q24 More commonly presents as
Walker-Warburg syndrome
2O POMGnT1 1p32 More commonly presents as
muscle-eye-brain disease
2P Alpha-dystroglycan 2p
6.1.2.2. Distal myopathies/muscular dystro- staining sometimes demonstrates accumulation of
phies The distal myopathies/muscular dystrophies desmin and other proteins in myofibrillar myopathy
are notable for their preferential early involvement and large deposits of myosin heavy chain in the sub-
of distal muscle weakness, in contrast to proximal sarcolemmal region of type 1 muscle fibers in Laing
weakness with most other myopathies. The major myopathy. Dysferlin deficiency and sometimes amy-
distal myopathies are summarized below. loid deposits around blood vessels and muscle fibers
rarely may be seen in Miyoshi myopathy.
• Nonaka distal myopathy (also known as autosomal
recessive hereditary inclusion body myopathy) and 6.1.2.3. Congenital muscular dystrophies
Miyoshi myopathy (a phenotype of dysferlinopathy) Congenital muscular dystrophy is one of the dis-
are distinguished by autosomal recessive inheri- eases in the differential diagnosis of the hypotonic
tance and onset in the late teens or twenties. infant but may also present with muscular contrac-
Nonaka myopathy is associated with progressive tions and joint deformities. Congenital muscular
anterior tibial weakness, whereas Miyoshi myopa- dystrophies may be subdivided into those that are
thy preferentially affects the calf muscles at onset. merosin (laminin 2) negative, those that are merosin
• Laing distal myopathy is a dominantly inherited positive, and those associated with CNS malforma-
disorder associated with progressive footdrop; tions. The latter two are genetically heterogeneous.
it is distinguished by onset in childhood or early Merosin-negative congenital muscular dystrophy or
adult life, rigidity of cervical paraspinal muscles, MDC1A is typically associated with contractures, cre-
and cardiomyopathy. atine kinase elevation to more than 10 times normal,
• Welander, Udd, and Markesbery-Griggs distal diffuse MRI changes in the cerebral white matter, and
myopathies are all late-onset, dominantly inherited dystrophic features at muscle biopsy, with increased
disorders of the distal limb muscles, usually begin- endomysial connective tissue, degenerating and
ning after age 40 years. Welander, which appears regenerating fibers, and frequently inflammatory infil-
to be more common in Scandinavians, prefer- trates. Merosin immunocytochemistry shows absence
entially involves the wrist and finger extensors, of the normal expression of the α2 subunit of laminin
whereas the others are associated with anterior (merosin) in the basement membrane. It can also be
tibial weakness leading to progressive footdrop. demonstated on skin biopsies. It seems likely that a
• The myofibrillar myopathies are a clinically and partial merosin-deficient state may have a milder clini-
genetically heterogeneous group of disorders that cal course than total absence of the protein.
can be associated with prominent distal weakness; Merosin-positive congenital muscular dystro-
they can be inherited in an autosomal dominant phy: A heterogeneous group of patients with dys-
or recessive pattern. Of note, Markesbery-Griggs trophic muscle biopsies in the neonatal period show
myopathy (caused by mutations in ZASP), apparently normal immunolabeling for merosin.
LGMD1A (caused by mutations in myotilin), Secondary alpha-dystroglycanopathies: A third
LGMD1D (caused by DNAJB6 mutations), class of congenital muscular dystrophy consists of
LGMD1E (caused by titin mutations) are sub- the cases associated with overt malformations of the
types of myofibrillar myopathy. Titinopathies also CNS. In this category are Fukuyama congenital mus-
can sometimes look like a MFM on biopsy. cular dystrophy, which is caused by mutation in fuku-
tin and involves predominantly Japanese patients;
The serum creatine kinase level is markedly MDC1B caused by mutations in fukutin-related
elevated in Miyoshi myopathy and only slightly protein (FKRP); muscle-eye-brain disease, typically
increased in the other conditions. EMGs are myo- caused by mutations in O-mannose beta-1,2-N-ace
pathic. In the myofibrillar myopathies, myotonic or tylglucosaminyltransferase (POMGNT1); and the
pseudomyotonic discharges are common. Walker-Warburg syndrome, in which there is genetic
Muscle biopsy shows nonspecific dystrophic fea- heterogeneity with mutations having been demon-
tures and, with the exception of Miyoshi and Laing strated in the O-mannosyltransferase 1 (POMT1)
myopathies, often shows rimmed vacuoles. The gene, the O-mannosyltransferase 2 (POMT2) gene,
myofibrillar myopathies are associated with the accu- the fukutin gene, and the FKRP gene.
mulation of dense inclusions, as well as amorphous A unifying hypothesis is that the multiple lesions
material best seen on Gomori trichrome, and myo- in these diseases may all result from the failure to
fibrillar disruption on electron microscopy. Immune correctly glycosyslate components of the membrane

cytoskeleton, specifically α-dystroglycan, or the and hypomethylation of the region that leads to
extracellular matrix, with consequent deleterious the permissive overexpression of the DUX4 gene.
effects on both muscle and the developing brain. In both FSHD1 and FSHD2 the permissive poly-
A fourth group of congenital muscular dystrophies morphism introduces a polyadenylation signal that
is collagenopathies (Ullrich/Bethlem myopathies). results in an aberrant, toxic DUX4 transcript.
Both disorders share a uniform combination of laxity
in some joins with contracture in others. Ullrich myop- 6.1.2.5. Oculopharyngeal dystrophy This is an
athy is a relatively severe autosomal recessive disorder uncommon muscular dystrophy, usually autosomal
with onset in young infants and children. Bethlem dominant, characterized by the late-life appearance
myopathy is a milder autosomal dominant disease with of external ophthalmoplegia with severe dyspha-
onset in the first or second decade. Both conditions gia. Discrete limb-girdle involvement may be pres-
are connected to the three genes that encode collagen ent. Muscle biopsy demonstrates rare “rimmed
6: COL6A1, COL6A2, and COL6A3. However, dem- vacuoles,” intranuclear inclusions, and occasion-
onstration of collagen 6 deficiency by immunohisto- ally type 1 fiber predominance. Necrotic fibers are
chemistry may require concurrent double labeling. not typical; ragged red fibers are occasionally seen.
Ultrastuctural studies show intranuclear tubulofila-
6.1.2.4. Facio-scapulo-humeral muscular dys- mentous inclusions measuring 8 μm in diameter, not
trophy Facio-scapulo-humeral muscular dystrophy found in the cytoplasm.
(FSHD) usually begins in adolescence and is typi- The genetic defect in this disease has been
cally slowly progressive. It predominantly involves shown to be an expanded trinucleotide repeat in
the face, the scapular girdle (with the notable excep- the poly(A) binding protein nuclear 1 (PABPN 1).
tion of the deltoid muscle), and the perihumeral Although immunocytochemistry has shown
musculature. Peroneal involvement is frequent. PABPN 1 to be present in the intranuclear inclu-
Muscle biopsies reveal nonspecific dystrophic fea- sions, the confirmatory diagnostic study is identifi-
tures along with whorled fibers, moth-eaten fibers, cation of the expanded GCG repeat.
and, especially, lobulated fibers (well seen with the
NADH-TR reaction in the shape of irregularities in
6.1. 3 . MYOTONIC DYSTROPHY AND
the intermyofibrillary network) and a pseudomyositic
NON DYSTROPHIC MYOTONIAS
appearance due to the presence of inflammatory cel-
lular mononuclear infiltrates. Considerable histologi- Myotonic dystrophies are classified among muscular
cal differences are seen from one muscle to the next. dystrophies for historical reasons. The pathogenesis
Endomysial fibrosis, of variable intensity, is frequent. of dystrophic myotonias and related myotonic dis-
FSHD is inherited in an autosomal domi- orders is complex and heterogeneous (Table 12.5).
nant pattern, but penetrance can be quite variable.
Approximately 97% of cases (so-called FSHD1) are 6.1.3.1. Dystrophic myotonias Myotonic dys-
associated with deletions of tandem 3.3-kb D4Z4 trophy, DM1, or Steinert disease is seen in young
repeats at 4q35. The deletion reduces the number of subjects. It includes characteristic facial involvement
repeats to a fragment of less than 35 kb in most patients. with distal limb amyotrophy, myotonia, and systemic
Within these repeats lies the DUX4 gene, which is not manifestations. The latter include frontoparietal
normally expressed. In FSHD1 the deletion in the baldness, posterior cataracts, endocrine disturbances
setting of a specific polymorphism results in hypo- dominated by genital hypoplasia, and cardiac involve-
methylation of the region and toxic expression of the ment. Neonatal myotonic dystrophy affects children
DUX4 gene. Recently it has been found that patients who have inherited the genetic anomaly from their
with the FSHD clinical phenotype but without the mother and is manifested by severe hypotonia with
classic deletions in D4Z4 (FSHD2) have mutations in facial, oropharyngeal, and respiratory involvement.
SMCHD1 (structural maintenance of chromosomes Histological lesions vary greatly in different patients
flexible hinge domain containing 1 gene) on chromo- and in different muscles. Characteristic anomalies
some 18. The mutation leads to reduced D4Z4 hypo- include selective atrophy of type 1 fibers and a consid-
methylation and overexpression of DUX4. Recently it erable increase in internalized nuclei. Some of the atro-
has been found that those patients with FSHD clini- phied fibers may be reduced to simple nuclear bags
cal phenotype but without the classic deletions in or have the appearance of pseudoneurogenic angu-
D4Z4 (FSHD2) also have the same polymorphism lar fibers. Sarcolemmal nuclei show, in longitudinal
Table 12.5. Characteristic Genetic, Clinical, and Pathological Features of
Channel-Disease Myotonia
DISE ASE G E N E N A M E GENE PRODUCT CLINICAL PATHOLOGY

EPONYM LOCUS FUNCTIONAL FEATURES
CHANGE
Myotonia congenita CLCN1 Chloride channel 1 Recessive, childhood Muscle

myotonia hypertrophy
Becker 7q35 Loss of function onset, transient weakness Mild hypertrophy
Thomsen Same Gain of function Dominant, second Myofibrillar
(as above) decade onset disarray
Loss of 2B fibers
Potassium-aggravated SCN4A Sodium channel Dominant, variable onset
myotonia 17q23 α-subunit No weakness
Gain of function
Paramyotonia SCN4A Sodium channel Dominant, childhood
congenita 17q23 α-subunit onset
Gain of function Cold-induced stiffness,
weakness, Paramyotonia
Hypokalemic periodic CACNL1A3 Calcium channel Dominant, second Vacuoles
Paralysis type 1 decade onset
Episodic weakness
triggered by
Hypokalemic periodic SCN4 Sodium channel carbohydrates or exercise, Vacuoles
Paralysis type 2 A17q23 α-subunit no myotonia, improved
by potassium
Hyperkalemic periodic 11q13-14 Loss of function Dominant, childhood Vacuoles

paralysis SCN4 Sodium channel onset or tubular
A17q23 α-subunit Episodic weakness, aggregates
Loss of function triggered by rest after
exercise, myotonia
may occur
section, an arrangement in chains at various depths Another dystrophic myotonia (DM2), also called
of the sarcoplasm. The presence of striated annulets PROMM (proximal myotonic myopathy), was
(ringbinden) and of numerous lateral sarcoplasmic recently identified. DM2 is caused by a DNA expan-
masses is common. Endomysial fibrosis and evidence sion mutation consisting of a CCTG repeat in intron 1
of degeneration and regeneration are modest. of the ZNF9 gene located at chromosome 3q13.3-q24.
The mutation in myotonic dystrophy is the Myotonia may be less prominent than in DM1. Muscle
unstable expansion of a CTG repeat that is in the 3‘ biopsy reveals muscle fibers with numerous internal-
untranslated region of the “DM protein kinase” gene ized nuclei as well as nuclear clumps. Unlike DM1,
(DMPK gene) on chromosome 19, although alter- type 1 atrophy and Ringbaden are not often seen.
native explanations of the effect of the CTG expan- The DNA expansions in DM1 and DM2 lead to
sion are possible. a toxic gain of function of the mutant mRNA. In

both disorders, the mutant RNA appears to form modified Gomori trichrome stain and reactive with
intranuclear inclusions composed of aberrant RNA. NADH, so the distinction from “ragged red fibers”
These RNA inclusions sequester RNA binding pro- and mitochondrial myopathy is important. The tubu-
teins that are essential for proper splicing of a variety lar aggregates do not exhibit cytochrome oxidase or
of other pre-messenger RNAs. This results in abnor- succinic dehydrogenase activity, which are specific for
mal transcription of multiple proteins in a variety mitochondria, and ultrastructually are quite different.
of tissues/organ systems and explains the systemic The genetic mutation is not known, but the clinical
manifestations associated with DM1 and DM2. similarities of the periodic paralyses make it tempting
to speculate that an ion channel may be involved.
6.1.3.2. Nondystrophic hereditary myotonias
The nondystrophic hereditary myotonias include
myotonia congenita and paramyotonia congenita. 6.2. Congenital myopathies
Autosomal dominant myotonia congenita, also known In general, the clinical course of patients with “con-
as Thomsen disease, is associated with considerable genital myopathies” differs from that of those with
myotonia and generalized muscular hypertrophy pre- muscular dystrophies in that the tempo of the disease
senting in childhood. The autosomal recessive variant is either nonprogressive or very slowly progressive.
is known as Becker disease (not to be confused with Nevertheless, this distinction is imprecise. Many are
BMD) and is more frequently associated with proxi- first manifest as neonatal hypotonias, whereas others
mal weakness. Paramyotonia congenita is inherited in are first detected in the neonatal period or later and
an autosomal dominant fashion and typically presents result in retarded motor development and/or muscle
in early childhood. Unlike the myotonic dystrophies weakness of variable distribution. There is frequent
and myotonia congenita, in which muscle stiffness association with skeletal dysmorphism, reflecting
(myotonia) improves with repetitive activity, the myo- the early and even prenatal muscular dysfunction.
tonia paradoxically worsens with repetitive activity in Muscle enzyme levels are below normal as a conse-
paramyotonia congenita, thus the name. Additionally, quence of low muscle mass. All modes of inheritance
some patients with paramyotonia congenita have peri- are found among the congenital myopathies; indeed,
odic paralysis and develop fixed weakness. most show several patterns of inheritance, and this
Serum creatine kinase levels are usually mildly is often of prognostic significance. The congenital
elevated in myotonia congenita and paramyoto- myopathies are, for the most part, characterized by
nia congenita. EMG reveals myotonic discharges. specific structural anomalies in the muscle fiber.
Muscle biopsies may demonstrate nonspecific Advances in understanding the underlying molecu-
myopathic features but are not diagnostic or use- lar basis are leading to more precise classification.
ful. Myotonia congenita is caused by mutations in
the chloride channel (CLCN1), while paramyoto-
6.2. 1 . CONGENITAL MYOPATHIES WITH
nia congenita is caused by mutations in the muscle
STR UCTURAL ANOMAL IES
sodium alpha subunit 4 (SCNA4).
6.2.1.1. Nemaline myopathy Nemaline myopa-
6.1.3.3. Related disorders Related classes of dis- thy is a heterogeneous group of disorders character-
ease are hyperkalemic periodic paralysis and hypo- ized by the presence of intracytoplasmic rodlets that
kalemic periodic paralysis. The former may exhibit are visible by light microscopy (reddish on modified
myotonia as it is often allelic with paramyotonia con- Gomori trichrome, most often within hypotrophic
genita. Both are dominantly inherited. Both may have type 1 fibers) (Fig. 12.12). By electron microscopy,
mutations in a sodium channel subunit, but hypoka- they are seen as electron-dense structures, measuring
lemic periodic paralysis is more often associated with 1 to 3 μm in length and 0.3 μm in diameter, anchor-
mutation in a calcium channel. Both diseases show ing thin (actin) filaments, and in the neighborhood of
gradually increasing vacuolation, which ultrastructur- or in continuity with Z discs. The number of affected
ally are expansions of the T-tubule system and sarco- fibers is highly variable and is not correlated with the
plasmic reticulum. Tubular aggregates may be seen clinical severity of the disease. Type 1 fibers often pre-
and are related to the sarcoplasmic reticulum. dominate. Both dominant and recessive forms, vari-
There are also rare myopathies characterized by ants with infantile (most severe), childhood (most
cramps and prominent tubular aggregates. At the common), and adult onset, have been described.
light microscopic level, the aggregates are red with the Nemaline myopathy is associated with genetic defects
sections. Frequently observed are predominance and
a selective hypotrophy of type 1 fibers. In the domi-
nant adult form, the type 1 fibers remain smaller than
normal for age, while the type 2 fibers are normal or
even hypertrophic (Fig. 12.13). Either type 1 or both
fiber types have a central cluster of nuclei mixed with
a core of granular debris and in longitudinal sections
may have central chains of nuclei.
6.2.1.3. Central core disease This myopathy

usually has autosomal dominant inheritance and
results from mutations of the RYR1 gene on chro-
mosome 19 encoding for the ryanodine receptor,
FIGURE 12.12 Nemaline myopathy. Presence of which is involved in calcium homeostasis. Other
intracytoplasmic rodlets that appear reddish on modi- forms have been associated with myosin heavy-chain
fied Gomori trichrome. mutations. This form of myopathy is character-
ized by the presence of areas devoid of mitochon-
of thin filament-associated molecules including drial oxidative and phosphorylase activity within
tropomyosin, nebulin, actin, and troponin T. type 1 fibers (Fig. 12.14). These zones, which are
Nemaline rods can also occur as a secondary phe- rounded in cross-section, correspond to cylindrical
nomenon, in other myopathies (dystrophies, inflam-
matory, mitochondrial), and even as an acquired
response to tenotomy, neoplasia, and weightless-
ness. It seems likely that they are a secondary phe-
nomenon, or “final common pathway,” reflecting
many aberrations in muscular contractile function.
6.2.1.2. Centronuclear or myotubular myopa-

thy Centronuclear myopathy, as the name implies, is
characterized by the presence of a centrally placed
nucleus in a majority of abnormally small fibers.
This appearance gives an “immature” look to the
fibers and has led to the suggestion that it repre-
sents a developmental arrest of muscle fibers at an
early fetal stage (myotubular stage), but there is no FIGURE 12.13 Centronuclear myopathy. Atrophy
persuasive evidence to support this concept. At least and centronucleation of type 1 fibers, whereas type 2
three forms of the disease are recognized: a severe fibers are normal (fast myosin).
X-linked infantile form, a milder childhood form
that seems to occur both in autosomal dominant and
recessive forms, and a mild adult form that is domi-
nantly inherited. The severe infantile X-linked form
appears to be caused by mutations in myotubularin, a
tyrosine phosphorylase. Some of the later-onset vari-
ants have been associated with mutations in dynamin
2 (MYF6), a muscle-specific transcription factor.
Oculomotor palsies are frequent. Typically, a large
number of central sarcolemmal nuclei present in 50%
to 90% of fibers are associated with excessive oxida-
tive enzyme activity—with loss of ATPase activity—
in the central myocytic zones. The intermyofibrillary
network often has a radial appearance well seen
in NADH histochemistry and semi-thin plastic FIGURE 12.14 Central core disease (NADH-TR).

axes extending throughout the length of the fiber. Ultrastructually, the aggregates can have dense cores
Ultrastructurally they show streaming, disruption, as well as a filamentous clear halo.
and sometimes disorganization of the contractile The condition is genetically heterogeneous; many
apparatus and Z bands. There is a strong predomi- mutations in cytoskeletal protein genes have been iden-
nance of type 1 fibers, and biopsies are sometimes tified, including desmin, ZASP, myotilin, αB-crystallin,
described as “uniform type 1.” The central core BAG3, filamin C, FHL1, DNAJB6, and titin.
resembles that seen in target fibers in reinnervation,
but the latter involves both muscle fiber types. A few
isolated, angular, atrophic fibers may also be seen. 6.4. Metabolic myopathies
Central core disease may be associated with an 6.4. 1 . MITOCHONDRIAL MYOPATHIES
increased incidence of the potentially fatal malig-
nant hyperthermia reaction in response to certain Primary mitochondrial disorders constitute a
general anesthetics. RYR1 mutations may also pres- group of systemic conditions that are highly vari-
ent as a late-onset axial myopathy (bent spine syn- able from the clinical standpoint and related to
drome or neck extensor myopathy). mitochondrial enzyme deficits (see Chapter 10).
Other congenital “core myopathies” include Mitochondrial myopathy may be an organ-specific
conditions referred to descriptively as multicore, manifestation of what is more appropriately referred
minicore, or even multiminicore myopathy, some of to as a mitochondrial cytopathy. Mitochondrial
which have been shown to be associated with muta- cytopathies may result from mutations of the mito-
tions of either RYR1, as central core disease, or a chondrial DNA or more commonly nuclear DNA.
selenoprotein encoding gene. Mitochondrial DNA is a 16.5kb DNA encoding for
22 transfer RNA, 2 ribosomal RNA, and 13 mRNA
for respiratory chain proteins. The other 67 poly-
6.2.2. CONGENITAL FIBER TYPE peptides implicated in the mitochondrial respiratory
DISPROPORTION chain are encoded by the nuclear DNA. Many cases
appear to be sporadic, but autosomal (dominant or
This myopathy was originally identified because of the
recessive) Mendelian transmission and especially
distinctive histological appearance of small (hypotro-
non-Mendelian maternal transmission by the mito-
phic), excessively numerous type 1 fibers (fiber type
chondrial genome are sometimes present. So-called
disproportion) and a benign prognosis. However, this
maternal inheritance is only a feature of mutations
appearance is far from specific, since it may be seen
of mitochondrial DNA.
in other congenital myopathies and in myotonic dys-
Among a wide range of clinical manifestations,
trophy type 1 (DM1). Thus, the nosologic identity
external ophthalmoplegia, heart conduction block,
of this condition is uncertain, although the diagnosis
short stature, deafness, diabetes, and epilepsy are
can be made on morphologic grounds. Thus, these
particularly suggestive of mitochondrial cytopathy.
may represent a heterogeneous collection of disor-
Detection of these diseases is mainly based on an
ders with a common morphologic phenotype.
elevated lactate/pyruvate ratio in blood and cere-
brospinal fluid and muscle biopsy, and confirmed by
biochemical and genetic testing.
6.3. Myofibrillar myopathies These disorders are inconstantly associated with
These progressive and devastating diseases are histo- intramyocytic accumulation of abnormal mitochon-
pathologically characterized by pathological protein dria, which are detectable by light microscopy, par-
aggregates and degenerative changes of myofibrils. ticularly in the modified Gomori trichrome stain, as
Some cases are likely to be identical to what has been “ragged red fibers” (Fig. 12.15A). The presence of
described as “desmin myopathy,” “cytoplasmic body ragged red fibers in a muscle biopsy is a major diag-
myopathy,” “spheroid body myopathy,” or “protein nostic feature, but it is neither specific nor invariable.
storage myopathies.” It may manifest with proxi- The number of ragged red fibers is highly variable
mal or distal muscle weakness as well as ventilatory within a biopsy sample and from one muscle to
muscle weakness or cardiopathy. Muscle biopsy is another. The same subsarcolemmal accumulations are
mainly characterized by intracytoplasmic granu- seen with NADH histochemistry, although SDH and
lofilamentous protein accumulations including COX are more specific for demonstrating mitochon-
desmin, myotilin, dystrophin, and other proteins. dria. Histoenzymatic demonstration of cytochrome
A C
FIGURE 12.15 Mitochondrial cytopathies. (A) Ragged red fiber (Gomori trichrome). (B) COX-negative

fiber. (C) “Parking-lot” type of paracrystalline inclusion in electron microscopy.
C oxidase (COX; complex IV of the mitochondrial The oculocraniosomatic syndrome (ophthalmople-

respiratory chain) deficiency is extremely useful to gia plus, Kearns-Sayre syndrome)
assess mitochondrial dysfunction. In most patients MERRF (myoclonus epilepsy with ragged red
with mitochondrial DNA mutations, COX reaction fibers)
shows a pattern of reactivity in which selected, ran- MELAS (mitochondrial myopathy, encephalopathy,
domly distributed fibers are totally COX negative lactic acidosis, and stroke-like episodes)
(Fig. 12.15B). Concomitant with mitochondrial dis- MNGIE syndrome (mitochondrial myopathy, neu-
ease and altered glycogen and lipid metabolism, there rogastrointestinal encephalomyopathy)
may be accumulations of lipids and/or glycogen. Leigh’s disease or subacute necrotizing
Electron microscopy may show mitochondria with encephalomyelopathy
structural abnormalities such as cristae that are con- Leber’s hereditary optic neuropathy, in which mus-
centrically arranged or honeycombed or that contain cle biopsy is typically normal
paracrystalline inclusions (Fig. 12.15C).
Molecular studies of the mitochondrial genetic Acquired mitochondrial myopathy may occur
material and biochemical studies of the mito- in patients treated with zidovudine (AZT), an anti-
chondrial electron transport chain enzymes can viral nucleoside analog interfering with mtDNA
be performed on either muscle biopsy samples or replication.
lymphocytes. Clinicopathological correlations are
complemented by the fact that the same biochemi-
cal deficit may be responsible for a highly variable 6.4.2 . L IPID MYOPATHIES
clinical picture. Conversely, identical clinical mani- 6.4.2.1. Carnitine deficiency Three main forms
festations may be caused by different enzyme abnor- are known.
malities. Deletions of mitochondrial DNA are often
seen in Kearns-Sayre syndrome. • Muscle carnitine deficiency causes a limb-girdle
While a general biochemical classification con- myopathy presenting in the second decade of life.
tinues to evolve, there is a practical advantage in Muscle biopsy reveals vacuolar myopathy. Lipid
referring to a few distinct clinical forms (Table 12.6): storage presents as droplets stained with Sudan

Table 12.6. Selected Mitochondrial Myopathic Syndromes
SYNDROME GENE TICS C L I N I C A L F E AT U R E S PAT H O L O G Y
Kearns-Sayre Single large mtDNA Progressive external Variation in muscle

deletion most ophthalmoplegia fiber size
common mutation Pigmentary degeneration of retina Ragged red fibers
type (80%) identical Heart block; mitochondrial common
in Pearson syndrome myopathy COX negative fibers
& progressive external
Weakness: proximal, symmetrical
ophthalmoplegia
Mitochondrial mtDNA point Encephalopathy, seizures, Ragged red
Encephalomyopathy mutations hemiplegia fibers: COX negative
Lactic acidosis Pigmentary retinopathy fibers
Stroke (MELAS) Myopathy, exercise intolerance Basal ganglia
Proximal symmetrical weakness calcification
Cerebral focal
necrosis
Myoclonic mtDNA point Late adolescence onset, myoclonus Ragged red fibers,
Epilepsy mutations Polyneuropathy, myopathy COX negative
Ragged red fibers Hearing loss, optic atrophy
(MERRF)
black. This storage is localized in type 1 fibers and in the skeletal muscle, the leukocytes, and cultured
is accompanied by mitochondrial abnormalities. fibroblasts.
Muscle carnitine levels are low, but serum levels In terms of evaluating muscle biopsies, the Oil
are normal. red O stain is rather fickle and is better at demon-
• Systemic carnitine deficiency may become strating significantly increased lipid content than
evident early in life in the form of acute meta- decreased content. Examination of plastic sections
bolic episodes, in the course of which the is an underutilized and considerably more reliable
myopathy may be detected only as a secondary reflection of lipid content.
phenomenon.
• Secondary partial carnitine deficiency may be
associated with cachexia, liver pathology, chronic
6.4. 3 . GLYCOGENOSES
hemodialysis, or another form of myopathy,
especially mitochondrial myopathy. Carnitine In these conditions, striking aggregates of glycogen
deficiency, and the consequent lipid storage accumulate within the muscle fiber and are demon-
myopathy, may also be drug induced, secondary strable in PAS-stained sections, which should be
to valproate anticonvulsant therapy. confirmed with ultrastructural and biochemical
studies. The presence of granular glycogen that is
infiltrated into the contractile apparatus may be
6.4.2.2. Carnitine palmityl transferase defi- used as a rough guide to increased glycogen. From
ciency This disorder is manifested from early child- the morphological viewpoint, it is important to
hood by episodes of cramps with myoglobinuria, differentiate muscle glycogenoses according to the
occurring after prolonged effort. Hyperlipidemia site of glycogen accumulation: mainly lysosomal
may be present. Between these episodes of rhab- (i.e., type II or Pompe disease) or cytoplasmic
domyolysis, muscle biopsy is usually normal. Lipid (types III, IV, V, and VII). A further distinction is
storage, which is detected in less than one third the presence of abnormal fibrillary glycogen (poly-
of the cases, is less evident than in carnitine defi- glucosan) in type IV and phosphofructokinase
ciency. The enzyme deficit may be demonstrated deficiency.
6.4.3.1. Pompe disease (Type II, acid malt- diagnosis can be confirmed by biochemical assay.
ase deficiency) and Danon disease (LAMP-2) It is important to recognize Pompe disease as now
Acid maltase deficiency can present in early infancy there is enzyme replacement therapy available for
(classic infantile Pompe) to late adult life. The clas- treatment.
sic infantile form is usually fatal within 2 years due Danon disease, associated with lysosomal-
to cardiopulmonary involvement. Late-onset acid associated membrane protein 2 (LAMP-2) mutation,
maltase is frequently associated with a limb-girdle presents with the same clinical and pathological mani-
pattern of weakness (thus it can be mistaken for festations as Pompe disease but without maltase acid
DMD, BMD, or one of the LGMDs). Respiratory deficiency.
muscles are also frequently involved and may be
more severely affected than limb muscles. 6.4.3.2. Forbes disease (Type III, deficit of
Muscle biopsies reveal a vacuolar myopathy the debranching enzyme amylo-1,6 glucosidase)
(Fig. 12.16A). The vacuoles involve a highly vari- Characterized by the accumulation of dextrin,
able proportion of muscle fibers, usually of type Forbes disease is usually evidenced in childhood by
1. They may be small and scanty and readily stain nonmyopathic manifestations.
with acid phosphatase owing to the lysosomal origin
of the vacuoles. They contain PAS-positive inclu- 6.4.3.3. McArdle disease (Type V, myophos-
sions (Fig. 12.16B) that are digested by amylase. phorylase deficiency) This is usually recognized
Electron microscopy (Fig. 12.16C) demonstrates in the adult because of painful cramps, which are
that the abnormal storage often extends beyond sometimes associated with myoglobinuria and
the lysosomes to invade the cytosol. Biopsies in occur during short and intense bouts of physical
late-onset cases may be relatively normal and show exertion. The cramp, which is electrically silent, is
nonspecific myopathic features or even neurogenic followed by a “second-wind” phenomenon that is
atrophy, probably due to abnormal accumulation of characteristic as the effort is being made. The curve
glycogen that also occurs in anterior horn cells. The of hyperlactacidemia, normally obtained in effort, is
A C
FIGURE 12.16 Pompe disease; large empty-looking vacuoles on H&E (A) are strongly stained by PAS (B).
Electron microscopy shows lysosomal storage (Courtesy of Pr. M. Baudrimont) (C).

flat. Muscle biopsy inconstantly shows subsarcolem- which present or are accentuated by physical exer-
mal vacuoles with PAS-positive contents. The diag- tion and may be accompanied by cramps. These
nosis is made in enzyme histochemical preparations include the glycogenoses, some of the lipidoses,
(i.e., by the negativity of the phosphorylase reaction and the toxic and endocrine myopathies. In prac-
and biochemical assay). The histochemical reaction tice, the muscle biopsy in these predominantly
is unusual in that the product is not stable and needs myalgic syndromes is often disappointing and
to be examined immediately and is best done with a shows only nonspecific changes, such as moder-
parallel control. ate atrophy of type 2 fibers. Such is often the case
in rheumatic fibromyalgia. The entity myopathy
6.4.3.4. Tarui disease (Type VII, phospho- with tubular aggregates is characterized by painful
fructokinase deficiency) The clinical picture is sim- intolerance on muscular exertion and presents in
ilar to that of McArdle disease and is associated with adulthood; tubular aggregates are found in type 2
moderate hemolytic anemia. Phosphorylase activity fibers. The term myoadenylate deaminase deficiency
is normal. The diagnosis is made either biochemi- is included here for completeness as it continues
cally or on the basis of enzyme histochemistry. to be raised in differential diagnoses, although its
nosologic status is in doubt. Deficiency of this
6.4.3.5. Other glycogenosis disorders (rare) enzyme is common in the general asymptomatic
Among these, a group of disorders characterized population or may be seen in well-characterized
by the accumulation of glucose polymers (poly- myopathies, such as polymyositis, muscular dys-
glucosan bodies) is recognized; they include type trophy, or with denervation.
IV glycogenosis, Lafora disease, and polyglucosan
myopathy (see Chapter 10).
6.4. 6 . MAL IGNANT HYPERPYREXIA
6.4.4. ENDOCRINE MYOPATHIES SYN DROME
Although muscle weakness is often observed in vari- This hereditary disease, transmitted as an autoso-
ous endocrine disorders, the corresponding histo- mal disease, is manifested in the course of general
logical changes usually show little specificity. anesthesia with halothane and/or succinylcholine
as a severe general syndrome that includes hyperpy-
6.4.4.1. Steroid myopathy Steroid myopathy is rexia and rhabdomyolysis. Although as mentioned
seen mostly in Cushing disease or as a result of pro- above it is sometimes associated with a well-defined
longed corticosteroid therapy. An acute form may myopathy, such as central core disease or a myotonic
occur in status asthmaticus when treatment with syndrome, in most cases muscle biopsy performed
curare and high doses of hydrocortisone is neces- during the latent phase is normal or shows only
sary. Steroid myopathy is manifest by type 2 muscle minor nonspecific abnormalities.
atrophy, especially type 2B. Lipid and/or glycogen
storage, as well as vacuolar myopathy, may also be
seen. 7. TOXIC MYOPATHIES
6.4.4.2. Thyroid myopathy In hyperthyroid- In the wide variety of drug-related and chemical toxic
ism, the muscle biopsy is ordinarily unremarkable. myopathies, both the clinical manifestations and
The muscle biopsies of patients with thyrotoxic histological appearances are highly variable. The pic-
periodic paralysis, seen mainly in Japan, show the ture may be that of a rhabdomyolysis, of a subacute
picture of dyskalemic vacuolar myopathy. In hypo- necrotizing myopathy, of a hypokalemic myopathy,
thyroidism, abnormalities in the muscle biopsy are or of a painless proximal myopathy, or it may show
more frequent; these include myopathic changes, various functional manifestations such as a myalgia/
type 2 fiber atrophy, glycogen storage, and baso- cramp syndrome or myotonia, both of which may
philic accumulations in the connective tissue. be induced by serum triglyceride-reducing drugs
(statins) (Table 12.7). Necrotizing autoimmune
myopathy (see Section 9.2.3), a recently delineated
6.4.5. MYALGIAS/CRAMPS SYNDROMES
entity, may be an autoimmune process that can be
A large number of well-recognized muscle disorders precipitated by drugs and thus an immune-mediated
may be manifest primarily as painful myopathies, toxic myopathy.
Table 12.7. Conditions Associated with 8. RHABDOMYOLYSIS
Toxic Myopathies
This is characterized by concomitant necrosis of
Rhabdomyolysis a large number of muscle fibers, followed by their
Alcohol presumably synchronous regeneration (“blue mus-
cle fibers”). The inflammation is often remarkably
Heroin
discrete. Postnecrotic intramyocytic calcifications
Amphetamines are encountered in rare instances. Rhabdomyolysis
Methadone may follow a traumatic or ischemic cause such as
Barbiturates crushing, excessive exercise, or compression within
Amphotericin B an anatomical compartment, particularly in the set-
Carbon monoxide ting of acute intoxication, generally due to alcohol
or psychotropic drugs. It may also be found in con-
Subacute necrotizing myopathy
junction with a metabolic myopathy (such as a gly-
Alcohol cogenosis of the McArdle or Tarui type, a deficiency
Fibric acid derivatives of carnitine palmityltransferase, malignant hyper-
Epsilon-aminocaproic acid pyrexia, or a potassium, phosphorus, or magnesium
Emetine deficiency), a hemoglobinopathy (such as drepano-
Azidothymidine (AZT) cytosis), or an inflammatory muscle disease (such as
a viral myositis).
Statins
Hypokalemic myopathy
Diuretics 9. INFLAMMATORY
Laxatives MYOPATHIES
Licorice These acquired myopathies are characterized by
Inflammatory myopathy muscle fiber inflammation, usually associated with
D-penicillamine destruction of the myocytes. They may be divided
into two groups according to whether the causative
Cimetidine
agent is a known infectious agent or whether the
Procainamide inflammatory process is believed to be an autoim-
Vacuolar myopathy with lysosomal hyperactivity mune phenomenon.
Colchieine Amiodarone
Chloroquine 9.1. Inflammatory myopathies caused by
Perhexiline maleate microorganisms
Type 2 fiber atrophy 9.1.1 . VIRAL MYOSITIS
Corticosteroids The most frequent acute myositis disorders are due
to (1) an influenza virus, which may cause acute
Chloroquine neuromyopathy gives rise to a benign myositis or severe rhabdomyolysis, and
most characteristic picture. Progressive proximal (2) an enterovirus, which in particular may be
muscle weakness is associated with vacuolar myop- responsible for Bornholm disease or epidemic myal-
athy, seen on muscle biopsy. The vacuoles often gia (Coxsackie B).
predominate in type 1 fibers, are partially filled In the setting of HIV infection, muscle involve-
by PAS-positive material, and are strongly reac- ment can be classified in four groups:
tive for acid phosphatase, indicating a lysosomal
origin (autophagic vacuoles). Lysosomal overac- • HIV-associated myopathy may be the presenting
tivity may also be seen in the absence of vacuoles. manifestation of the infection and is similar to
Electron microscopy of muscle and nerve shows seronegative polymyositis. HIV antigens may be
the presence of membranous whorlings, myelin detected in endomysial and perivascular macro-
figures, and curvilinear inclusions, the latter per- phages, and muscle fibers strongly express MHC
sisting many years after cessation of treatment. class 1 molecules.

• AZT myopathy is a toxic mitochondrial myopathy Toxoplasma cysts may be detected in muscle
frequently associated with an inflammatory com- biopsies of severely immunocompromised patients.
ponent. This condition is associated with myal- They reflect systemic reactivation of the parasite
gias that improve rapidly after AZT withdrawal. encysted in brain, retina, myocardium, and skeletal
Muscle biopsy typically shows AZT fibers (ragged muscle (Fig. 12.18).
red fibers with marked shrinkage of myofibrils)
and COX-negative fibers.
9.1. 4 . F UNGAL MYOSITIS
• Muscle involvement linked to immunodeficiency,
including pyomyositis, toxoplasmic polymyositis, Instances of fungal myositis are rare.
and primary muscle lymphoma
• A variety of other conditions, including
HIV-cachectic myopathy, acquired nemaline 9.2. Idiopathic inflammatory
myopathy, and recurrent myoglobinuria. myopathies
These subacute or chronic diseases, which involve
9.1.2. BACTERIAL MYOSITIS both adults and children, have been the subject of
evolving classification schemes. Dermatomyositis,
Bacterial myositis may be a complication of a skin polymyositis, inclusion-body myositis, autoimmune
injury (muscle abscess or gas gangrene caused by a necrotizing myopathy, and overlap myositis are the
clostridium) or part of a pyomyositis. The latter con- most common forms.
dition, which is seen in severely debilitated patients
in intensive care units and is also observed in tropi-
cal countries (tropical pyomyositis), may present as 9.2. 1 . DERMATOMYOSITIS
a spontaneous, acute suppurative infection culmi- In dermatomyositis, proximal muscular weakness,
nating in the formation of abscesses in one or several often painful and of acute or subacute onset, is typi-
skeletal muscle groups. It is caused by strict anaero- cally associated with cutaneous signs dominated by
bic organisms. erythema of the face and the extremities, resulting
in a purplish-blue discoloration of the eyelids and
periungual hyperemia. Dysphagia, arthralgia, con-
9.1.3. PARASITIC MYOSITIS
stitutional symptoms, and elevated levels of serum
The most frequent parasitic myositis is trichinosis, muscle enzymes are frequent. Dermatomyositis
which is secondary to the ingestion of meat infested is associated with visceral cancer in 15% of adult
with Trichinella spiralis. The latter may be diagnosed patients; therefore, cases occurring in adulthood,
in muscle biopsy when encysted larvae are demon- especially in the elderly, should be considered as
strated (Fig. 12.17). a possible paraneoplastic manifestation and must
FIGURE 12.17 Muscular trichinosis. Encysted larva FIGURE 12.18 Muscular toxoplasmosis.

in a muscle cell. Toxoplasma cyst in a muscle cell.
trigger a search for occult tumor. In children, der- contrast with dermatomyositis, it is not associated
matomyositis is often accompanied by a systemic with capillary loss, perifascicular atrophy, or other
vasculitis. It may be difficult or impossible to dis- ischemic changes. Inflammatory infiltrates are
tinguish from systemic lupus erythematosus with mainly composed of CD8+ T cells (Fig. 12.20B)
muscle involvement. and are found in endomysium, where they ini-
Muscle biopsy is the definitive diagnostic test. tially surround individual healthy-appearing
Myopathological features are most characteristic muscle fibers, then attack and invade them focally,
and reflect primary involvement of the micro- together with macrophages, tunnel the center of
circulation mediated by humoral processes with the fiber, and, finally, destroy it (Fig. 12.20A).
secondary ischemic changes of muscle fibers. Muscle cells die from perforin-mediated necrosis.
Myofiber alterations include (1) progressive These autoinvasive T cells have been demonstrated
atrophy of marginal layers of myofibers (perifas- to exhibit selective gene rearrangements of their
cicular atrophy) (Fig. 12.19A) that is preceded by T-cell receptors. It is likely that the accumulated
local re-expression of type 1 interferon-inducible cytotoxic CD8+ T-cells that use their TCR to rec-
proteins, including MHC class 1 (Fig. 12.19B); ognize peptide antigens presented by MHC class 1
(2) punched-out vacuoles within perifascicular molecules at the surface of muscle fibers have been
fibers (Fig. 12.19C); and (3) microinfarcts con- subjected to antigen-driven expansion, these T-cell
sisting of foci of contiguous necrotic or regener- clones being specific of as yet unknown muscle
ating fibers (Fig. 12.19D). Microvascular changes autoantigens. Widespread and strong MHC class 1
include (1) overexpression of type 1 inducible re-expression by muscle fibers constitutes a major
proteins in small blood vessels; (2) early capillary immunopathological feature of polymyositis (Fig.
deposition of the complement C5b-9 membra- 12.20C). It is associated with re-expression of the
nolytic attack complex (MAC); (3) subsequent nonclassical MHC antigen HLA-G. MHC class 1
destruction of endothelial cells (free basement expression may be detected even in the absence
membranes) with focal loss of capillaries predom- of endomysial inflammatory cells, as observed in
inating in perifascicular areas; and (4) endothelial patients with inactive polymyositis following ther-
hyperplasia with tubuloreticular inclusions (that apy. The possibility of an association with a con-
are known to be inducible by type 1 interferons). nective tissue disease is raised when the disease
Inflammatory infiltrates include (1) septal peri- is associated with perivascular lymphocytic infil-
vascular infiltrates (without fibrinoid necrosis) trates (Fig. 12.20D).
(Fig. 12.19E) and endomysial infiltrates predomi-
nating in perifascicular areas; (2) a mixture of
9.2.3 . IMMUNE- MEDIATED
mononuclear cells including CD4+ plasmacytoid
NEC ROTIZING MYOPATHY
dendritic cells, B-cells, CD8+ T-cells, and macro-
phages (Fig. 12.19F); and (3) no CD8+ lympho- This is an underappreciated form of autoim-
cytic invasion of non-necrotic myofibers. mune myopathy. Most cases present with acute
proximal-greater-than-distal weakness with mark-
edly elevated serum creatine kinase levels and myo-
9.2.2. POLYMYOSITIS
pathic EMGs and clinically resemble polymyositis.
Polymyositis is a syndrome of diverse causes that However, muscle biopsies demonstrate scattered
may occur separately or in association with other necrotic and regenerating fibers without much in
connective tissue diseases or retroviral infections the way of inflammatory cell infiltrate (aside from
(see above). It manifests by symmetrical muscle myophagocytosis of necrotic fibers). The sarco-
weakness of subacute or chronic onset in adulthood, lemma of non-necrotic muscle fibers may stain for
with, or more often without, myalgia. There are no MHC class 1 and membrane attack complex. The
skin changes. Focal onset may occasionally occur. mechanism of muscle destruction is unclear but pre-
Creatine kinase levels are usually increased and sumed to be autoimmune. Some cases are associated
EMG is consistent with myositis. Since polymyo- with myositis-specific antibodies (e.g., anti-signal
sitis has no unique clinical features, its diagnosis is recognition particle [SRP]). Some cases seem to be
one of exclusion. triggered by statin use. Unlike classic toxic myopa-
Polymyositis is a CD8+ T-cell-mediated and thy caused by statin use, some patients continue to
MHC class 1-restricted autoimmune myopathy. In have severe and progressive muscle weakness and

A B
C D
E F
FIGURE 12.19 Dermatomyositis. (A) Perifascicular atrophy. (B) Expression of MHC class 1 antigens by

the peripheral myofibers. (C) Ischemic “punched-out” lesion due to focal myosin loss. (D) Microinfarct.
(E) Perivascular septal inflammatory infiltrate. (F) Immunocytochemistry for CD4 showing predominant CD4
lymphocytes within the inflammatory infiltrate.
increased creatine kinase levels months after stop- 9.2. 4 . OVERL AP MYOSITIS
ping the statin medication and have a biopsy reveal-
ing active necrosis. Recently, antibodies targeting Although there are clinical and histopathological
the HMG-CoA-reductase have been identified in differences between the subsets of myositis, histo-
many of these cases. The necrotizing myopathies are pathological features may be scarce or unspecific
often difficult to treat and require aggressive immu- or sometimes overlap. Dermatomyositis, polymyo-
nosuppressive therapy. sitis, and autoimmune necrotizing myopathies may
A B
C D
FIGURE 12.20 Polymyositis. (A) Inflammation in the endomysium surrounding individual muscle fibers,

some of which appear vacuolized and invaded by inflammatory cells. (B) Immunocytochemistry for CD8 show-
ing predominant CD8 cytotoxic lymphocytes within the inflammatory infiltrate. (C) Immunocytochemistry
for MHC class 1 showing widespread expression by muscle fibers. (D) Lymphocytic vasculitis in a case of
polymyositis associated with lupus.
be associated with connective tissue diseases or kinase levels are normal or slightly elevated.
myositis-specific autoantibodies (overlap myosi- Approximately two-thirds of patients have antibod-
tis), which may confer subtle additional pathologi- ies directed against an cytosolic 5’-nucleotidase IA
cal features. As an example autoimmune myositis (cN-IA). EMG shows a mixture of large and small
with anti-RNA synthetase (mainly JO1 antibody) motor unit potentials owing to the chronicity of the
often presents with perifascicular predominance of disease process by the time patients usually come
necrotic and inflammatory alterations. in for evaluation. Progression is slow and relentless,
and patients often do not respond to immunosup-
pressive treatment. Re-evaluation of muscle biopsy
for possible signs of inclusion body myositis should
9.2.5. INCLUSION BODY MYOSITIS
be performed in patients with presumed polymyosi-
This sporadic disease mainly affects men over tis resistant to steroids.
50 years old. Onset is insidious and painless and is Typical muscle biopsy findings are required for
typically reported as an increasing difficulty with the diagnosis. They may not be observed at the first
everyday tasks requiring proximal or distal limb biopsy and should be sought in additional muscle
muscles. Early involvement of quadriceps muscles, biopsies. The characteristic myopathological pic-
remarkable involvement of distal limb muscles, ture includes the coexistence of a variable number
mainly deep finger flexors and foot extensors, that of rimmed vacuoles in atrophic muscle fibers some-
is often asymmetric are typically present. Creatine times associated with eosinophilic inclusions and

a multifocal inflammatory process composed of granulomatous polymyositis, has a similar histological
CD8+ T-cells with heterogeneous myofiber expres- picture but is unassociated with any extramuscular
sion of MHC class 1 molecules. An oligoclonal pat- clinical or histological evidence of sarcoidosis.
tern of the TCR gene and of plasma cells has been
observed.
9.2. 7 . NODUL AR F OCAL MYOSITIS
Importantly, in about one third of cases, any
give muscle biopsy may lack the canonical fea- Nodular focal myositis may be seen in various con-
tures of IBM (i.e., rimmed vacuoles, amyloid, or nective tissue diseases but is especially frequent in
other inclusions on LM or EM. Therefore, the longstanding rheumatoid arthritis. It is character-
clinical exam is paramount in making the diag- ized by the interstitial infiltration of lymphocytes
nosis. Some have noted accumulation of many and plasma cells, forming compact nodules mea-
Alzheimer-associated proteins by immunohisto- suring 1 to 2 mm in diameter, situated near a small
chemistry. Whether or not the accumulated pro- artery or arteriole but without invasion of the ves-
teins provide autoantigens is unclear. One of most sel wall. There may or may not be changes in the
common inclusions reported is TDP-43, similar to adjacent muscle fibers. An identical picture known
what is evident in neurons in hereditary neurode- as lymphorrhages is sometimes seen in myasthenia
generative disorders (see Chapter 8). In addition, gravis.
mitochondrial abnormalities (ragged red fibers,
COX-negative fibers, secondary mtDNA muta-
tions) are appreciated. On electron microscopy, 9.2. 8 . EOSINOPHIL IC MYOSITIS AND
cytoplasmic and intranuclear 15- to 21-nm tubulo- FASCIITIS
filaments may be appreciated
Eosinophilic myositis is defined by the presence
9.2.5.1. Hereditary inclusion body myopathy of inflammatory cellular infiltrates containing
(H-IBM) A heterogeneous group of patients with eosinophils in the muscle and can be associated
hereditary myopathies have muscle biopsy findings with degenerative lesions of the muscle fibers.
that are similar to inclusion body myositis, includ- In addition to parasitic diseases of muscle and to
ing rimmed vacuoles and immunocytochemical and systemic vasculitis (especially the Churg-Strauss
ultrastructural findings, although they lack promi- syndrome), the main causes include the hypereo-
nent inflammation. sinophilic syndrome, a rare multisystem disorder
The clinical features, pattern of weakness, in which muscle involvement includes the picture
and age of onset differ from inclusion body myo- of eosinophilic polymyositis and eosinophilic
sitis. There are both autosomal dominant and fasciitis.
recessive forms of H-IBM. Autosomal reces- Eosinophilic fasciitis (or Shulman syndrome)
sive H-IBM (also known as Nonaka myopa- is characterized by a subcutaneous indura-
thy) is caused by mutations in the GNE gene tion that spares the face and fingers stiffening of
(UDP-N-acetylglucosamine 2-epimerase) on the joints, and a raised blood eosinophil count.
chromosome 9p12-p11. Sclero-inflammatory lesions predominate in the fas-
Autosomal dominant inclusion body myopa- cia but may extend into the dermis or muscle. In the
thy, Paget disease, and premature frontotemporal tissues, eosinophilia is often well circumscribed or
dementia (IBMPFD) is caused by mutations in the absent. The lymphocyte and plasma cell infiltrates
valosin-containing protein gene on chromosome are essentially perivascular.
9p13.3-p12.
9.2. 9 . MACROPHAGIC MYOFASCIITIS
9.2.6. SARCOIDOSIS
Macrophagic myofasciitis is a recently recog-
Interstitial epithelioid and giant cell granulomas may nized entity defined by stereotyped deltoid
be seen in the muscle of patients with sarcoidosis, muscle biopsy findings that include perimuscu-
particularly at postmortem examination, irrespective lar infiltration by large macrophages with a finely
of clinical manifestations referable to muscle involve- granular PAS-positive content, a lymphocytic
ment. A possibly related condition, referred to as infiltrate, and inconspicuous muscle fiber damage
(Fig. 12.21). It mainly manifests at adulthood sclerosing segmental polymyositis, inflammatory
by chronic fatigue and diff use myalgias, form- pseudomotor (focal) myositis, and proliferative
ing a syndrome that meets the criteria for the myositis.
so-called chronic fatigue syndrome. Macrophages
contain intracytoplasmic osmiophilic crystalline
9.2.1 1 . VASCUL ITIS INVOLVING
inclusions composed of aluminum and similar
SKEL ETAL MUSCL E
to aluminum hydroxide, a Th2 immunostimula-
tory compound frequently used as a vaccine adju- In the systemic vasculitides (see the discussion in
vant. Macrophagic myofasciitis is now recognized Chapter 13), nerve and muscle biopsy may estab-
as a lesion secondary to long-term local persis- lish the diagnosis (Fig. 12.22). The lesions in skel-
tence of vaccine-derived aluminum hydroxide in etal muscle consist of small inflammatory cellular
muscle. infiltrates adjacent to the involved blood vessels,
nonspecific type 2 atrophy, or evidence of denerva-
tion atrophy related to concomitant peripheral nerve
9.2.10. LOCALIZED MYOSITIS
involvement. Focal infarction of muscle is sometimes
Noninfectious myositis localized to a portion of seen involving part of a fascicle. The affected muscle
the muscle, to one particular muscle, or to one fibers have lost their tinctorial affinity and at the
muscle group essentially includes orbital myositis,
A B
C D
FIGURE 12.21 Macrophagic myofasciitis. (A) Perimuscular interstitial infiltration by large macrophages

with a basophilic cytoplasm. (B) Higher magnification shows the finely granular cytoplasmic content of the
macrophages. (C) Immunocytochemistry for CD68 clearly shows the perifascicular infiltration of the muscle
by macrophages. (D) Immunocytochemistry for T-lymphocytes shows the presence of lymphocytes within the
infiltrate.

FIGURE 12.22 Polyarteritis nodosa. FIGURE 12.23 Cholesterol emboli: occlusion of a
small muscular arteriole by a cholesterol crystal.
periphery inflammatory cells may be seen, including 9.2. 1 2 . CHOL ESTEROL EMBOL I
acute inflammatory cells.
Within the framework of ischemic myopathies may
be included cholesterol emboli, which are often the
source of systemic manifestations due to micro-
infarction of multiple organs. Cholesterol crystals
migrate from aortic atheromatous plaques and
occlude small arteries (Fig. 12.23), especially those
of lower-limb muscles, following which they may be
surrounded by reactive changes and inflammatory
cell infiltrates including macrophages.
13
Pathology of Peripheral Nerve
J E A N -M I C HE L VALLAT, D O U G L A S C . A N TH O N Y, A N D U MB ERTO D E G IRO LA MI
1. PERIPHERAL NERVE lowest yield of useful information is in biopsies from

patients with chronic, slowly progressive, diffuse,
BIOPSY symmetrical, axonal peripheral neuropathies. Since
multiple specialized techniques can be used to eval-
1.1. Indications for a Peripheral uate peripheral neuropathies, it is often best to con-
Nerve Biopsy vey to the pathologist and laboratory the indications
With advances in clinical, electrophysiological, for the biopsy and the specific clinical questions that
and molecular diagnostics, the frequency of nerve are being addressed. This allows the most efficient
biopsies in patients with peripheral neuropathy and targeted handling of the biopsy specimen.
has decreased. However, nerve biopsy leads to a
change in diagnosis and management in up to 60%
of patients with peripheral neuropathy, depend- 1.2. Site of the biopsy
ing on the expertise of the laboratory handling the By and large, a peripheral nerve biopsy is taken from
biopsy and the selection of patients. In general, the a purely sensory nerve of sufficient caliber to yield
laboratory should be capable of performing routine meaningful information. The choice in practice is
histology, frozen-section histology, plastic embed- limited to two nerves in the lower limb: the sural
ding and preparation of semi-thin sections, and nerve (a branch of the common fibular nerve) and
electron microscopy, with expertise in the inter- the superficial peroneal nerve (a branch of the lat-
pretation of nerve biopsies. The highest diagnos- eral popliteal nerve). There is extensive information
tic yield is in the patient population with focal (or on the normal fiber composition in these sites, and
asymmetrical) neuropathies, demyelinating neurop- these nerves in the leg are particularly advantageous
athies, or small-fiber neuropathies. In contrast, the as a site of biopsy in patients with distal distribution
• 313
of neuropathic symptoms. The superficial peroneal 1.3. 1 . ROUTINE HISTOL OGY
nerve is sometimes chosen, especially in the absence
Fixation in 10% formaldehyde and paraffin embed-
of sensory involvement, because the underlying
ding is commonly employed and enables the study
peroneus brevis muscle may also be sampled with
of abnormalities of interstitial tissue, including an
a single surgical incision. When there is selective
evaluation of blood vessels, the infiltration of inflam-
involvement of the limb girdle, it is at times possible
matory cells, and the presence of deposits of sub-
to perform a biopsy of a sensory superficial branch of
stances such as amyloid. The stains most commonly
the crural nerve; when the neuropathy is restricted
employed for paraffin sections include H&E, elastic
to the upper limbs, a sensory superficial branch of
tissue stains, Masson trichrome, silver impregna-
the radial nerve of the forearm may be biopsied.
tion for reticulin, myelin stains combined with silver
Skin biopsies are also being used more at this
impregnations for myelin and axons, and Congo red
time for analysis of small-fiber peripheral neuropa-
for amyloid deposits. Routine paraffin-embedded
thies. These biopsies have an advantage of being
tissue is also optimal for immunohistochemistry,
less invasive and can provide information on both
should it be necessary to localize particular antigens
myelinated and unmyelinated fibers. Skin biopsies
in the diagnostic evaluation.
intended for evaluation of peripheral neuropathies,
however, do require special processing and must
be handled with specialized laboratory procedures, 1.3. 2 . PL ASTIC EMBEDDING
separate from skin biopsies for dermatological dis-
orders. Muscle biopsies may be performed to assess Plastic embedding following immediate fixation in
nerve terminals but are used much less often and 2.5% buffered glutaraldehyde allows for semi-thin
provide restricted information. (1 μm thick) transverse and longitudinal sections,
Following a nerve biopsy, there is an area of which is the method of choice to examine the fine
numbness in the distribution of the sensory nerve. structural details of both myelinated and unmy-
For the sural nerve, the numbness is localized to elinated fibers (Fig. 13.1A–C). The semi-thin sec-
the region of the heel. Rare complications include tions allow the examination of greater detail due
allergic reaction to anesthetic agents, operative site to non-overlapping structures and allow quantita-
infection, and post-biopsy dysesthesias that may last tive assessment of axonal density, myelin thickness,
several months. and subcellular structures that cannot be visual-
ized with routine histology. Plastic embedding also
allows detailed ultrastructural evaluation, when
1.3. Methods necessary, by electron microscopy (Fig. 13.1D–F).
Alerting the laboratory that a nerve biopsy is being In some cases, immuno-electron microscopy may
performed is optimal and allows preparation for the be performed to identify specific proteins at the
handling that is required. Immediately after removal, ultrastructural level.
the biopsy specimen must be processed using spe-
cial methods so that a number of special studies can
1.3. 3 . DISSOCIATION OF F IBERS
be carried out. These often include routine histol-
(NE RVE TEASING)
ogy, electron microscopy, and teased-fiber prepa-
rations; tissue may also be set aside and frozen for This technique consists of the separation of single
frozen sections and chemical analyses. Perhaps the myelinated fibers (around 1 cm long), after alde-
most complicated part of handling a nerve biopsy hyde fixation and osmication, by teasing them apart
is maintaining it as a straight segment. The nerve with fine needles under visualization with a dissect-
is best analyzed by cross-sections and longitudinal ing microscope. Light microscopic examination of
sections (or teased fibers). However, due to the nat- the teased fibers clearly shows the relative positions
ural elasticity of nerve, it tends to recoil after biopsy, of nodes of Ranvier and is very helpful in discrimi-
creating difficulties in assessing either the cross or nating between lesions characteristic of demyelin-
longitudinal planes, unless it has been fixed as a lin- ation versus axonal degeneration. This is due to the
ear segment. A number of methods are available to differences in the length and thickness of myelin
maintain the linear arrangement of the fibers, but sheaths along the long axis of the fibers, as visualized
they require that the nerve be positioned properly in the longitudinal plane (Fig. 13.2). Because the
prior to fixation. preparation of individual teased nerve fibers is very
A D
B E
C F
FIGURE 13.1 Normal morphological appearance of peripheral nerve: semi-thin transverse section (A,B);

semi-thin longitudinal section with Renaut body (C); ultrastructural appearance at low magnification (D); at
higher magnification showing myelin sheath with Schmidt-Lanterman incisure (E); at high magnification show-
ing periodicity of myelin layers (F).
Chapter 13 Pathology of Peripheral Nerve • 315

Nerve cell
body
Nucleus
Axon
Internode
Node of
Ranvier
Schwann cell
Nucleus
Motor end plate
Muscle
Normal Wallerian Segmental Axonal
degeneration demyelination degeneration
FIGURE 13.2 Diagram showing the primary types of pathological findings in peripheral neuropathies. Note
that the axon remains intact during segmental demyelination.
time-consuming, the technique is often reserved for investment in equipment. Ordinarily, such tech-
evaluation of a specific differential diagnosis. niques cannot be justified; they tend to be reserved
for research purposes or when dealing with a very
specific differential diagnosis. Instead, a trained
1.3.4. FROZEN SECTIONS FOR observer can often give a reliable opinion as to the
I MMUNOFLUORESCENCE AND/OR
density of myelinated fibers, an estimate of the
CHEMICAL ANALYSIS
degree of loss of large or small fibers, and the pres-
Direct immunofluorescence studies can be carried ence and severity of demyelinating and/or axonal
out using specific antibodies to identify abnormal lesions, without the expense and delay that is added
deposits of immunoglobulins in endoneurium or in by quantitative assessment. When morphometric
myelinated fibers. Various markers can be employed to analyses are indicated, they can be performed in
identify different types of inflammatory cells (T- and cross-sections or longitudinal sections.
B-lymphocytes, and macrophages) as well as amyloid In the longitudinal plane, morphometric analysis
deposits. Frozen tissue is also useful when testing for quantifies the internodal distances on single nerve
metabolic or chemical disorders, both because direct fibers using statistical computer-assisted methods
chemical analysis of tissue can be performed and (mean +/- SD). This is usually represented as a plot
because storage materials, which may be removed dur- of internodal distances against the mean diameter of
ing routine aldehyde fixation and dehydration, may be the fibers for a number of myelinated fibers.
detected histochemically in frozen sections. Morphometric analysis of cross-sections of the
nerve may be carried out either after photography
or directly by image analysis. Analysis of myelinated
1.3.5. MOLECULAR ANALYSIS
fibers may be performed on either plastic-embedded
DNA can be extracted from either paraffin-embedded sections or by electron microscopy; however, mor-
or frozen tissue. This allows for the molecular classi- phometry of unmyelinated fibers requires electron
fication of archival material. Alternatively, molecular microscopy.
tests are now available on whole blood samples from In young adults, the average axonal density is
patients with suspected hereditary forms of periph- 7,000 to 10,000 fibers/mm2 of endoneurial area.
eral neuropathy. There are marked age-dependent differences, and
the number of fibers decreases progressively with
age. The diameter of myelinated fibers ranges from
1.3.6. QUANTITATIVE AND
2 to 12 μm in a bimodal distribution, with peaks
MORPHOMETRIC ANALYSES
at 3 to 6 μm and 9 to 12 μm. There are more small
From a practical standpoint, morphometric stud- myelinated fibers than large myelinated fibers. The
ies are time-consuming and require a substantial relationships between the size of the axon and the
number of myelin lamellae can only be established bodies (Fig. 13.1C) occur at multiple sites through-
with electron microscopic examination; it is a nearly out the peripheral nervous system, including at sites
linear relationship. In addition, the g ratio (ratio of of potential entrapment, such as in the median nerve
axonal diameter to fiber diameter) is commonly at the wrist and the ulnar nerve at the elbow. Absent
used to evaluate the severity of the demyelinating in the fetus, they increase in number with age. They
lesions and may be measured on semi-thin sections are made up of cells showing perineurial differen-
of high quality. tiation. Their precise function is not known, but a
The electron microscopic examination of unmy- cushioning effect has been speculated.
elinated fibers is time-consuming and costly and is
not carried out on a routine basis. It also requires
special expertise to reliably identify unmyelinated 2.2. Axons (and nerve fibers)
fibers. The diameter of these myelinated axons The ratio of myelinated to unmyelinated axons and
ranges from 0.2 to 2.5 μm in a unimodal distribution, the diameter of the axons vary considerably from
with a peak at 1.4 to 1.6 μm. The density of unmy- nerve to nerve, depending on the number of sen-
elinated fibers ranges from 20,000 to 35,000/mm2. sory/autonomic fibers of various modalities and the
The ratio of unmyelinated fibers to myelinated ones number of motor axons within a given nerve. In this
is about 4 to 1. Other parameters may also be quan- regard, the most extensive body of quantitative data
tified, such as the thickness of the perineurium and is from the sural nerve, and as mentioned above,
the extent of proliferation of endoneurial connective unmyelinated nerve fibers are about four times as
tissue. numerous as myelinated nerve fibers (Fig. 13.1D).
Axonal diameters may be estimated across the short
axis of the axon, or as the calculated diameter of
2. NORMAL ANATOMY a circle of equal area to the cross-sectional area of
the axon. The axonal diameter does not include the
2.1. Connective tissue sheaths of myelin layers surrounding the axon. Nerve-fiber
peripheral nerve diameters are calculated across the short axis of
The nerve fibers of peripheral nerve trunks are com- the entire fiber (including the myelin layer), and
partmentalized in bundles or fascicles, separated the nerve-fiber diameter is, therefore, necessarily
by organized connective tissue sheaths. Individual greater than the axonal diameter. The g ratio (ratio
myelinated and unmyelinated nerve fibers are of axonal diameter to fiber diameter) is on the order
embedded in a meshwork of delicate connective of 0.5 to 0.7.
tissue, the endoneurium. Bundles of nerve fibers
within each fascicle are held together by multiple
2.2.1 . MYEL IN SHEATHS
concentric layers of specialized cells that form the
perineurium (perineurial cells). The vascular bundles In myelinated fibers, the myelin sheath extends as
that travel along with peripheral nerves and give segments from one end of the axon to the other,
rise to their vascular supply lie within layers of con- from just beyond the neuronal cell body to just
densed fibro-adipose connective tissue, which sur- before the axon terminal. Myelin is produced by,
rounds one or multiple fascicles. This condensed and situated within, Schwann cells, which line up
fibro-adipose tissue is known as the epineurium. along the axon. The myelin sheath is not a continu-
During dissection or biopsy, the epineurium adheres ous structure throughout the length of the axon but
to the group of fascicles as the nerve is dissected is interrupted at regular intervals along its length.
from adjacent looser connective tissue. The space between two adjacent Schwann cells
Within each fascicle is the endoneurial compart- is referred to as a node of Ranvier. The stretch of
ment (or endoneurium), which contains the myelin- myelin between one node of Ranvier and the next
ated and unmyelinated fibers, their Schwann cells is referred to as an internode; in myelinated axons,
and collagen fibers, capillaries, mast cells, fibro- the internode represents the segment of an axon
blasts, and Renaut bodies. Endoneurial capillaries myelinated by a single Schwann cell. The length of
have tight junctions, as do those in the brain and an internode is fairly constant along the axon and
spinal cord, thus forming an effective blood–nerve is proportional to the diameter of the axon. The
barrier analogous to the blood–brain barrier. Renaut Remak cell has many similarities to the Schwann

cell but surrounds unmyelinated axons and does not axolemma as those of myelinated fibers; they are,
produce myelin. As mentioned, each internode of a however, smaller in diameter and lack the repeti-
myelinated axon is supported by a single Schwann tive layers of myelin lipid membranes. Also unlike
cell, whereas several unmyelinated axons are within myelinated fibers, the multiple unmyelinated axons
the purview of one Remak cell. The myelin sheath that are usually enclosed by a single Remak cell are
is made up of very regular concentric lamellae with closely packed and separated from each other by a
a 12- to 17-nm periodicity, forming major dense thin layer of cytoplasm.
lines separated by electron-lucent zones in which
one or two inter-period lines can be observed
(Fig. 13.1E, F). Discontinuity in the compaction 3. GENERAL REACTIONS
of the lamellae is seen at the Schmidt-Lanterman OF PERIPHERAL NERVE TO
incisures (Fig. 13.1E), where the major dense lines DISEASE
open, allowing invaginations of Schwann cell cyto- The general reaction of peripheral nerve to injury
plasm to penetrate between them. can be separated into two prototypes: those that
involve primarily the axon and those that preferen-
tially involve the myelin sheath; combinations of the
2.2.2. MYELINATED AXONS
two are common.
Myelinated axons vary in diameter between 3 and
12 μm. They are surrounded by a 7- to 8-nm-thick
membrane, the axolemma, which communicates 3.1. Primary axonal degeneration
directly with the internal mesaxon. The axolemma There are four principal types of axonal degenera-
has the same ultrastructural characteristics as the tion (Fig. 13.2). By and large, all forms ultimately
cytoplasmic membranes of Schwann cells; it is lined result in denervation of muscle fibers when the pro-
by a basal lamina that passes from one Schwann cess affects motor axons.
cell to the next without interruption at the nodes
of Ranvier. The axoplasm contains longitudinally
oriented mitochondria, smooth endoplasmic retic- 3.1. 1 . TYPES OF AXONAL DEGENERATION
ulum, multivesicular bodies, neurofilaments, and 3.1.1.1. Wallerian degeneration Wallerian
microtubules. Neurofilaments have a mean diameter degeneration is the response of the distal part of
of 10 nm, whereas microtubules contain a central an axon to the physical transection of the nerve
lumen and have an external diameter of approxi- (Fig. 13.3). In the early stages, it is characterized
mately 25 nm. morphologically by breakdown of the axon and its
myelin sheath. A reparative stage begins shortly after
2.2.3. SCHWANN CELLS transection and consists of proliferation of Schwann
cells within the tube formed by the original Schwann
Schwann cells can be distinguished from endoneu- cell basal lamina. The Schwann cell groups are
rial fibroblasts by the presence of a basement mem- arranged as a linear tube and constitute a band that
brane. Their elongated nuclei are found roughly may be seen in cross-section by electron microscopy;
equidistant from two adjacent nodes of Ranvier. The it is called a band of Büngner. Regeneration occurs
cytoplasm, between the inner lamella of the myelin through the sprouting of axons from the proximal
sheath and the axon, and between the outermost stump of the sectioned nerve; it begins almost at once
myelin lamella and the cell membrane, is sparse. after axotomy but progresses slowly (1 to 3 mm per
Located mainly around the nucleus, the cytoplasm day). These sprouts, usually two to five per sectioned
contains endoplasmic reticulum, a Golgi apparatus, axon, may enter the bands of Büngner. This process
mitochondria, sometimes a centriole, and complex results in the morphologic appearance of clusters of
multilamellar lipid membranous granules (π gran- small, thinly myelinated groupings of regenerating
ules, or granules of Reich). fibers (see Fig. 13.6 later in the chapter).
3.1.1.2 Dying-back neuropathy (progres-

2.2.4. UNMYELINATED FIBERS
sive distal axonopathy) This type of axonal
The axons of unmyelinated fibers have a simi- injury is characteristic of a group of neuropathies
lar ultrastructural appearance of axoplasm and whose fairly symmetrical subacute or chronic
Nerve Nerve
cell body Nucleus of Schwann cell
ending
Axon Myelin sheath Basement membrane Schwann cell
Node of Ranvier
AXONAL TRANSECTION
Degeneration of myelin and axonal components in distal portion
Macrophage removing myelin

and axonal debris
outing of proximal
Macrophages
portion of the axon Proliferation of Schwann cells
Remyelination of axonal sprout
Complete regeneration of nerve fiber
FIGURE 13.3 The main stages of Wallerian degeneration and regeneration of a myelinated fiber. (Redrawn
and modified from Bradley WG. Disorders of peripheral nerves. Oxford: Blackwell, 1974.)
degeneration first affects the most distal portions understood. Some have viewed it as a “biochemical
of axons, followed by progressively more proxi- transection” that progressively involves more proxi-
mal degeneration of the axon. The longest and mal segments of the axon, owing to the morpho-
largest fibers are usually the first to be involved logic similarities with Wallerian degeneration. There
(size-dependent vulnerability). The central axonal is some evidence to support that the dying-back
extensions from sensory neurons undergo degen- process is related to particular abnormalities of fast
eration concomitant with that of their peripheral axonal transport. The neuropathological picture
extensions; degeneration of the posterior columns, is characterized by a reduction in the number of
for example, thus starts from the upper end of the myelinated fibers, with evidence of regeneration,
spinal cord. For some time, the conduction veloc- including axonal sprouting.
ity remains near normal, owing to a retention of a
significant proportion of normal fibers. But as the 3.1.1.3. Neuronopathy Neuronopathy is a cat-
disease progresses, conduction velocities drop in egory of axonal neuropathy wherein the primary
later stages of the disease. abnormality is thought to be within the neuronal cell
The pathogenesis of this commonly observed body, with a more or less synchronous injury along
phenomenon in nerve biopsy samples is still poorly the entire length of the axon. Because the neuron

degenerates in neuronopathies, axonal regeneration is expressed by a loss of the circular outline of the
is impossible. Neuronopathies, as is true of neuro- fiber and by a reduction of average axonal diame-
nal degenerations in the neocortex, characteristi- ter. In prolonged insults, secondary demyelination
cally are slowly progressive and sequentially involve may occur and be sufficiently severe to mimic a
selective populations of neurons. primary chronic demyelinating process. Axonal
Sensory neurons are more often affected than atrophy in the elderly has been documented in
motor neurons in neuronopathic toxic injuries Charcot-Marie-Tooth disease, in uremic neu-
(e.g., pyridoxine intoxication, paraneoplastic ropathy, in diabetic neuropathy, in neuropathy
neuropathy). The reasons for this predilection associated with myeloma, and in various toxic
of sensory systems are not known but have been neuropathies. Axonal swelling resulting from focal
postulated to be related to the lack of vascular or multifocal accumulation of neurofilaments and
barrier in dorsal root ganglia, thereby permitting other organelles is characteristic of hereditary neu-
direct access of toxins or paraneoplastic antibod- ropathies (e.g., hereditary giant axonal neuropa-
ies to the ganglion cells. Furthermore, preferential thy) (Fig. 13.4A) and of toxic neuropathies (e.g.,
involvement of populations of the neurons within hexane neuropathy) (Fig. 13.4B).
dorsal root ganglia is well recognized, as occurs
in neuropathies that selectively involve either the
3.1. 2 . MORPHOL OGIC APPEARANCES
small neurons (e.g., Fabry disease) or the large
OF ACUTE/CHRONIC AXONAL
neurons (e.g., sensory paraneoplastic neuropathy,
DEGENERATION AND AXONAL
Friedreich ataxia, abetalipoproteinemia). Another
REG ENERATION IN PERIPHERAL
proposed mechanism of cell injury theorizes the
NEUROPATHIES
uptake of noxious substances in the free sensory
terminals, which are devoid of the blood–nerve These vary depending on the course of the disease,
barrier, thereby allowing for their access to the the interval between biopsy and the onset of the
perikaryon through retrograde axonal transport disease, and the site of the nerve sample along the
(“suicide transport”). length of the fiber.
In the early stages of an axonal neuropathy, axo-
3.1.1.4. Abnormalities of axonal caliber nal degeneration may be seen by light microscopy
Axonal caliber is related to, among other things, as ovoids, axonal fragments surrounded by disin-
the number of neurofilaments and neurotubules tegrating myelin (Fig. 13.5). This form of degen-
contained in the axon. In human pathology, axo- eration is sometimes difficult to distinguish from
nal atrophy chiefly affects the large fibers, per- crush artifact. It is best appreciated by electron
haps because they are richest in neurofilaments microscopy (Fig. 13.5C) and in teased-nerve prepa-
(caliber-dependent vulnerability). Axonal atrophy rations (Fig. 13.5D). In addition, teasing permits
A B
FIGURE 13.4 Axonal swellings on peripheral nerve biopsy. (A) Light microscopy in a case of hereditary
giant axonal neuropathy with multiple distended axons. (B) Electron microscopy in a case of hexane neuropa-
thy: accumulation of neurofilaments.
A B
C D
FIGURE 13.5 Acute axonal degeneration, showing the morphological appearance on routine H&E light
microscopy (A), on semi-thin sections by light microscopy (B), at the ultrastructural level by electron micros-
copy (C), and on teased-fiber preparations (D). In the longitudinal plane, there are rows of ovoid lipid-filled
vacuoles, while in the transverse plane, there is a loss of distinction of the axoplasm with myelin debris.
identification of the earliest lesions, which consist sprouts with regularly spaced internodes, but which
of myelin retraction on either side of the node of are too short for the diameter of the fiber.
Ranvier, followed by myelin irregularity and frag- In the chronic or late stages of axonal degenera-
mentation in each internodal segment. Phagocytosis tion, the principal morphologic features include a
of degenerating nerve fiber fragments by Schwann loss of myelinated axons and an increase in endo-
cells, and by circulating mononuclear phagocytes, neurial connective tissue (Fig. 13.7). The pres-
is seen to better advantage in longitudinal sections ence of regenerating clusters is good presumptive
and by electron microscopy (Fig. 13.5C). Early axo- evidence that the underlying pathological process
nal sprouting may also be seen. The earliest changes is due to axonal degeneration. Teased-nerve-fiber
that attend axonal degeneration are best detected preparations may demonstrate different stages of
by electron microscopy as disruption of the myelin degeneration and regeneration, indicating an ongo-
sheath, associated with abnormalities within the ing process.
axon, including clustering and swelling of organ-
elles. Axonal regeneration is first identifiable by light
microscopy when the sprouting axonal extensions
3.2. Primary segmental demyelination
are myelinated and form clusters of small, closely This is a process whereby the primary site of injury
packed fibers, which are well seen in semi-thin is the myelin sheath. When a motor axon is affected,
cross-sections (regeneration fascicles) (Fig. 13.6). since the axon remains intact, denervation atrophy
Teasing may also demonstrate myelinated axonal of muscle does not occur.

A B
FIGURE 13.6 Clusters of small-caliber, closely packed fibers, typical of “regeneration fascicles,” in semi-thin
cross-sections (A) and by electron microscopy (B). The band of Büngner is evident only by electron microscopy,
where it is evident that the basal lamina surrounds the entire group of small axons.
A B
C D
FIGURE 13.7 Severe chronic axonal neuropathy. Axonal loss, resulting from the cumulative effects of chronic
axonal degeneration, is seen on transverse (A) and longitudinal sections (B) (Bodian silver axonal impregnation
combined with Luxol fast blue myelin stain in paraffin sections) and on semi-thin section (C). Ultrastructural
examination shows severe loss of myelinated fibers in a case of autosomal recessive CMT2 (D).
3.2.1. ACUTE SEGMENTAL cells, which form small, intercalated internodes. In
DEMYELINATION AND REMYELINATION teased-nerve preparations, the characteristic appear-
ance of a fiber that has undergone remyelination
Primary involvement of the myelin sheaths or the
after segmental demyelination consists of inter-
Schwann cells causes segmental demyelination
nodes of unequal size, in which the remyelinated
(i.e., myelin destruction, with relative sparing of the
internodes are shorter than normal and have a thin-
axon, occurring one internodal segment at a time).
ner myelin sheath than that of the adjoining, unaf-
This process diffusely and randomly involves the
fected internodes (Fig. 13.8). In semi-thin sections
myelin of individual internodes along the length
and when the cross-section traverses a remyelinated
of many fibers within a fascicle, affecting some in
internode, these fibers appear to be hypomyelinated
sequence while skipping others. The process begins
(i.e., the myelin sheaths are disproportionately thin
near the node of Ranvier. Subsequently, Schwann
compared to the axon diameter Fig. 13.9A).
cells and mononuclear phagocytes participate in
the phagocytosis of degenerated myelin fragments.
3.2.2 . OTHER MYEL IN L ESIONS
Widening of the nodes of Ranvier and denuded
stretches of demyelinated internodes affecting most During myelination and with remyelination, one
fibers within a nerve, over the course of time, causes may observe incomplete compaction of the out-
a reduction in the speed of nerve conduction and ermost myelin lamellae at the ultrastructural level
conduction blocks. Myelin loss involving only very (Fig. 13.9B). In this situation, the spacing between
short segments of the fiber (i.e., less than 15-μm the lamellae is abnormally wide. In pathological
stretches) may be followed by remyelination initi- circumstances, this widening of myelin lamellae
ated by the surviving Schwann cell responsible for may stem from abnormalities and genetically deter-
the affected internode. When the extent of myelin mined mutations of certain proteins in compact
internodal loss is greater than 15 μm, remyelination myelin, such as myelin protein zero (P0). This phe-
is achieved by selected, newly proliferated Schwann nomenon may also be observed in neuropathies
Basement membrane of Schwann cell

Plasma membrane
Node of Ranvier
Nucleus
Myelin sheath Axon

FOCAL DISSEMINATED DESTRUCTION OF MYELIN SHEATH
Removal of myelin debris by macrophages
Remyelination of involved internodal segments (shorter)
FIGURE 13.8 The main stages of segmental demyelination and remyelination of a myelinated peripheral
nerve fiber. (Redrawn and modified from Bradley WG. Disorders of peripheral nerves. Oxford: Blackwell, 1974.)

A B
FIGURE 13.9 Ultrastructural appearance of demyelination/remyelination. At low magnification, numerous

fibers are nonmyelinated or hypomyelinated (A), reflecting demyelination and the process of early remyelin-
ation. Uncompacted myelin is also a feature of the early stages of remyelination (B).
due to monoclonal gammopathy (often of immuno- of the axon (Fig. 13.11A–C). When the process is
globulin M [IgM] type with anti-myelin associated severe, the Schwann cell processes form multiple
glycoprotein [MAG] or anti-glycolipid activity). concentric layers (Fig. 13.11C) around a majority
Hypo-and hypermyelination, the presence of of axons and are referred to as “onion bulbs.” There
abnormally thin or abnormally thick myelin sheaths, is also an increase of collagen in the endoneurium,
are seen in genetically determined neuropathies. which often has a loose, sometimes metachromatic
Hypermyelination is an excess of myelin lamellae appearance. The early stages of onion bulb forma-
relative to the diameter of the axon, often production may be demonstrable only by electron micros-
ing redundant, abnormally folded loops of myelin. copy (Fig. 13.11D).
These lesions, referred to as tomacula, affect a por-
tion of one internode and are characteristic of cer-
tain genetically determined entrapment peripheral 3.3. Lesions that are both axonal and
neuropathies. Tomacula are occasionally seen in demyelinating
conditions other than hereditary pressure-sensitive In chronic peripheral neuropathies, a purely axonal
neuropathy, such as sporadic chronic neuropathy in or demyelinating neuropathy is seldom encoun-
childhood, neuropathy associated with alcoholism, tered. Instead, one form of injury is often the
and benign monoclonal gammopathy. In the major- predominant type. Thus, in a chronic axonal neu-
ity of families, the disorder is inherited as an autoso- ropathy, there is a severe depletion of axons and
mal dominant trait, and affected individuals have a mild stages of demyelination and remyelination.
deletion of a large portion of chromosome 17p11.2. Similarly, in a chronic demyelinating neuropathy,
In the congenital hypomyelinating neuropathies, onion bulb formation may be extensive and a degree
myelin is abnormally thin for the patient’s age. of axonal loss may also be present. These patho-
logical findings correlate with the electrophysi-
ological studies on the patient. Early stages of an
3.2.3. SCHWANN CELL PROLIFERATION
axonal peripheral neuropathy may show decreased
AND ONION BULB FORMATION
amplitude on nerve conduction studies, while the
Repeated episodes of segmental demyelination and conduction velocity is relatively spared. However,
remyelination culminate in Schwann cell abnor- later in axonal neuropathies, the conduction veloc-
malities (Fig. 13.10). Onion bulb formation is a ity may also be decreased, reflecting an element of
process characterized by an exuberant proliferation secondary demyelination. Similarly, demyelinat-
of Schwann cells and of basement membrane depos- ing neuropathies often show a slowing of conduc-
its arranged concentrically around an intact axon, tion velocity as an early finding, and only in later
which may be completely denuded of myelin or may stages, when there is substantial axonal loss, is there
have a thin myelin sheath relative to the diameter a change in the amplitude on nerve conduction
FIGURE 13.10 Diagram of the process of formation of an onion bulb.
studies. In general, the more severe pathological nerve lesions, but precise pathogenesis of the ill-
abnormality, whether on nerve conduction studies ness is incompletely understood. Nerve biopsy is
or peripheral nerve biopsy, is usually presumed to only rarely needed to establish the diagnosis of GBS,
be the primary event and may be described as “axo- although in a few severe cases, in the presence of
nal neuropathy with secondary demyelination,” for electrically silent nerves, histological examination
example. of biopsy specimens can determine the type and
extent of lesions. Biopsy may also identify the very
rare, purely axonal forms of GBS (acute motor axo-
4. INFLAMMATORY nal neuropathy or acute motor and sensory axonal
POLYNEUROPATHIES neuropathy) and assess the relative extent of demy-
elinating and axonal lesions.
4.1. Immunopathological disorders of In the acute phases of the disease, lesions typi-
unknown cause cally consist of disseminated foci of segmental
demyelination that predominate in the perivenu-
4.1.1. GUILLAIN-BARRÉ SYNDROME OR
lar locations and are associated with endoneurial
ACUTE INFLAMMATORY DEMYELINATING
edema and mononuclear cellular inflammatory
POLYNEUROPATHY
infiltrates. A characteristic feature is revealed by
Guillain-Barré syndrome (GBS) can be the pri- electron microscopy: macrophages cross the basal
mary manifestation of a neurological illness or may lamina and displace the Schwann cell cytoplasm;
occur in the setting of systemic disorders, including their processes surround the myelin sheaths and
infections (for example, by the cytomegalovirus, the insert themselves between the outer myelin lamellae
Epstein-Barr virus, mycoplasma, hepatitis viruses, (Fig. 13.12). The myelin sheaths are thus progres-
HIV), vaccinations, surgery, pregnancy, immuno- sively destroyed so that macrophages are in contact
suppression, and cancer. Immune-mediated nerve with the axon. Perhaps independent of this process,
damage is believed to be the cause of the peripheral myelin sheaths undergo vesicular degeneration.

A B
C D
FIGURE 13.11 Onion bulbs. Microscopic appearance in hypertrophic neuropathy (A), created by the pres-
ence of many onion bulbs. Onion bulbs on semi-thin section (B), with multiple layers of Schwann cell processes
surrounding many of the axons. Ultrastructural appearance: proliferation of Schwann cells and of basement
membrane concentrically around an intact axon (C); early stage of onion bulb with a few layers of concentrically
arranged Schwann cell processes surround a thinly myelinated axon (D).
Axonal degeneration is also sometimes seen in

teased-nerve preparations.
Autopsy studies have shown that the inflamma-
tory lesions tend to predominate in the proximal
regions of the peripheral nervous system. For this
reason, sural nerve biopsies may be less informative
than those from more proximal locations within the
peripheral nervous system. The inflammatory infil-
trate in GBS is composed of macrophages and espe-
cially of T-lymphocytes, in which the T4/T8 ratio is
identical to that seen in the blood.
4.1. 2 . SUBACUTE/CHRONIC
INFL AMMATORY DEMYEL INATING
POLYRADICUL ONEUROPATHY
As with GBS, the lesions in chronic inflammatory
FIGURE 13.12 Guillain-Barré syndrome.
demyelinating polyradiculoneuropathy (CIDP)
A tongue-like macrophage extension inserts itself
vary considerable in severity. The demyelination is
between the outer myelin lamellae.
segmental and irregular and tends to predominate in HB) (Fig. 13.13B), sometimes collected in large
the nerve roots. Inflammatory infiltrates are usually aggregates (globi). The bacilli are abundant, espe-
minimal or absent. Light microscopic examination cially in the cytoplasm of Remak cells. On ultra-
of Epon-embedded nerve sections shows some loss structural examination, bacilli predominate in
of myelinated fibers. Some of the remaining axons macrophages and Schwann cells but may also be
are totally devoid of myelin, while others are sur- seen in axons and in the cytoplasm of endothelial
rounded by a thin sheath of myelin, probably indica- cells. Individual bacteria or groups of organisms
tive of remyelination. The process of segmental are surrounded by a clear electron-lucent halo (Fig.
demyelination and remyelination is well shown with 13.13C). In a number of cases, there is a marked
teased-fiber preparations. Ongoing demyelination proliferation of neutrophils, as is the case in the
is best shown on electron microscopic examina- paucibacillary forms of the disease.
tion. Onion bulbs formations are striking both in
plastic sections and by electron microscopy as the 4.2.1.2. Paucibacillary (tuberculoid) leprosy
characteristic concentric whorling of Schwann cell In this form of leprosy, bacilli are either completely
cytoplasm with skeins of basal membrane surround- absent on light microscopic examination or extremely
ing normally myelinated or thinly myelinated axons. rare. Granulomatous infiltrates predominate and con-
Regenerating clusters, indicative of concomitant sist of T-lymphocytes with some B-cells, plasma cells,
axonal involvement, and interpreted as secondary to Langhans giant cells, and histiocytes (Fig. 13.14). In
chronicity, are also seen. There is often also signifi- some cases, necrosis may occur, producing abscesses.
cant involvement of unmyelinated fibers. Marked distortion of the walls of capillaries and
small vessels is also found. Axons, Schwann cells, and
myelin are lost, and there is fibrosis of the perineu-
4.1.3. SARCOIDOSIS
rium and endoneurium; the nerves adjacent to the
Sarcoidosis is a T-cell-mediated inflammatory foci of granulomatous inflammation undergo nodular
response to unknown antigenic stimulation. There thickenings and become abnormally firm.
is a wide range of clinical and pathological mani-
festations of the disease as it affects the peripheral 4.2.1.3. Intermediate forms of leprosy The
nervous system. Non caseating granulomas with nerve lesions in these patients are characterized by
giant cells may be seen in the nerves, chiefly in the varying amounts of inflammatory infiltrates and
epineurium. Inflammatory infiltrates invade the leprosy bacilli. Organisms are often in a state of dis-
endoneurium, following connective tissue septa integration and can be demonstrated ultrastructur-
and blood vessels; a necrotizing vasculitis occurs in ally in the cytoplasm of Schwann cells as well as in
some cases. Multifocal heterogeneous axonal loss is macrophages.
the rule; demyelination is rare.
4.2.2 . AIDS
4.2. Neuropathies due to infections Several types of involvement of peripheral nerve
have been described in patients with AIDS. Apart
4.2.1. LEPROSY
from toxic iatrogenic peripheral neuropathy, which
A wide variety of peripheral neuropathies and is increasingly frequent, a number of HIV-associated
peripheral nerve lesions are found in all forms of peripheral neuropathies can be related directly to
leprosy. HIV infection, although none of these appears to
be the direct result of viral attack. However, in situ
4.2.1.1. Multibacillary (lepromatous) leprosy hybridization and immunocytochemical meth-
There is nearly always a widespread involvement of ods have detected viral antigen in mononuclear
cutaneous sensory nerves even in patients with no endoneurial cells.
clinical signs of neuropathy, and most cases show Inflammatory polyradiculoneuropathies (GBS
signs of modest inflammation with a widespread or CIDP) have been observed mainly in the early
infiltration of the endoneurium, perineurium, stages of the disease. HIV-related inflammatory
and epineurium by numerous macrophages (Fig. polyneuropathies are more frequently associated
13.13A). The cytoplasm of these macrophages is with pleocytosis in the cerebrospinal fluid than are
filled with Mycobacterium leprae (Hansen bacilli, GBS or CIDP in the absence of HIV infection.

A B
FIGURE 13.13 Multibacillary (lepromatous) leprosy. Infiltration of the endoneurium by numerous macro-

phages (A). The cytoplasm of these macrophages is filled with lepra bacilli, well demonstrated on Ziehl-Nielsen
stain for acid-fast bacilli (B). Ultrastructural examination shows a group of bacteria surrounded by an
electron-lucent halo (C).
A B
FIGURE 13.14 Paucibacillary (tuberculoid) leprosy. Granulomatous inflammatory infiltration of the

endoneurium with Langhans-type giant cells (A). On transverse section, note inflammation and fibrosis of the
perineurium and endoneurium (B).
Distal painful sensory neuropathies have been
described in the late stages of HIV and are attributed
to involvement of the dorsal root ganglia with apop-
tosis of neurons. The cause of the neuronal apopto-
sis is unknown. In addition, necrotizing vasculitis
identical to that seen in polyarteritis nodosa may be
found in some cases of multiple mononeuropathy in
HIV infection.
A subset of HIV-infected patients develops per-
sistent CD8 hyperlymphocytosis and a Sjögren-like
syndrome associated with multivisceral CD8T-cell
infiltration, known as the diffuse infiltrative lympho-
cytosis syndrome. Nerve biopsy has shown marked
angiocentric CD8 infiltrates without mural necro- FIGURE 13.15 Tick-bite neuropathy, perivascular
sis and abundant expression of HIV p24 protein in mononuclear cell infiltrate.
macrophages.
Some patients with AIDS develop peripheral defines the entity of necrotizing vasculitis. When
neuropathy induced by cytomegalovirus, and a par- vasculitis involves the peripheral nervous system,
ticularly dreaded complication is a painful menin- it usually involves the blood vessels of the epineu-
gomyeloradiculitis that affects the lumbosacral rium. Parenchymatous lesions secondary to vascular
regions. The characteristic viral inclusions are seen involvement usually take the shape of a predomi-
on light microscopic examination, highlighted by nantly axonal type of degeneration. Infarction of a
immunocytochemistry; by electron microscopy, peripheral nerve is rare. In fact, the usual appear-
viral particles are present in Schwann cells, macro- ances are those of rarefaction of nerve fibers, due
phages, endothelial cells, and fibroblasts. to multiple foci of hypoperfusion situated more
proximally. The lesions are typically heterogeneous
4.2.3. BORRELIOSIS OR from one fascicle to the next and/or within the same
LYME DISEASE (TICK-BITE fascicle (centro-fascicular or eccentric depopu-
MENI NGORADICULONEURITIS) lation). The clinical picture most suggestive of a
vasculitis-induced neuropathy is that of a multiple
Signs of acute axonal involvement are found in mononeuritis, sometimes also called “mononeuritis
peripheral nerve biopsies in the meningoradiculo- multiplex”; a polyneuropathy may also be seen.
neuritic or secondary stage of Lyme disease. There Two types of vasculitis are most commonly asso-
may also be a prominent lymphocytic and plasmo- ciated with nerve and/or muscle disease: polyarteri-
cytic reaction around blood vessels in the endoneu- tis nodosa and hypersensitivity microvasculitis.
rium (Fig. 13.15), perineurium, and epineurium.
The inflammatory-cell infiltrates have been found
to be mainly of B-lymphocytes. No demyelinating 4.3.1 . POLYARTERITIS NODOSA
lesions or dissociation of myelin lamellae by inflam- (SY STEMIC VASCUL ITIS AF F ECTING
matory cells as seen in GBS have been seen. Vessel MID DL E- CAL IBER ARTERIOL ES)
walls are free of fibrinoid necrosis or inflammatory The classical lesions of polyarteritis nodosa involve
infiltrates. Borrelia burgdorferi has yet to be detected the arteries of small- and middle-caliber and arteri-
in nerve lesions. oles (70 to 200 μm). The vasculitis is characterized
by medial fibrinoid necrosis, polymorphonuclear
panarterial cellular inflammatory infiltrates, and
4.3. Vasculitic neuropathies vascular thrombosis. It is typical to find lesions of
The term vasculitis is used to describe an inflamma- different ages. Hepatitis B surface antigen is often
tory disorder of the vascular system characterized detectable.
by lesions consisting of a cellular inflammatory infil- The Churg-Strauss syndrome, or allergic angiitis
trate involving the walls of blood vessels. The pres- with granulomatosis, is a variant of systemic vascu-
ence of an associated fibrinoid necrosis of the wall litis affecting middle-caliber arterioles and occurs

in asthmatic patients, who often have received pro- numbers of chronic inflammatory cells in the
longed treatment with corticosteroids. The vascular endoneurial or epineurial compartments, angio-
lesions are similar to those of polyarteritis nodosa centric or otherwise, must be regarded as patho-
but differ by the great abundance of eosinophils in logical, although this finding may be associated
the cellular infiltrates, by the frequency with which with a number of disorders. This is the picture
both veins and capillaries are involved, by the less that may be seen in collagen vascular diseases,
frequent presence of fibrinoid necrosis, and by the such as rheumatoid arthritis, systemic lupus ery-
presence of extravascular granulomas in some cases. thematosus, Sjögren disease, or scleroderma, or
Patients with rheumatoid arthritis may have with carcinoma, especially when muscle lesions of
peripheral nerve lesions that are identical to those the same type are also present.
seen in polyarteritis nodosa but also involve the
microcirculation and are often especially rich in
plasma cells. Less often, a necrotizing panarteritis
5. NEUROPATHIES
may occur in other collagen diseases (e.g., systemic ASSOCIATED WITH
lupus erythematosus, Sjögren syndrome). A distinc- HEMATOLOGICAL
tive necrotizing or non-necrotizing granulomatous DISEASES AND
angiitis involving large- and middle-caliber blood
vessels is seen in patients with Wegener granuloma- NEOPLASMS
tosis and other granulomatous angiitides; in these
conditions, characteristic lesions may be seen in 5.1. Paraneoplastic neuropathies
muscle and nerve biopsies. Patients with carcinoma or lymphoma may develop
a diffuse peripheral neuropathy at the time of diag-
nosis, before diagnosis, or months or even years
4.3.2. MICROVASCULITIS (VASCULITIS
later, that is the result of a circulating paraneoplastic
AFFECTING BLOOD VESSELS LESS THAN
immunoglobulin. In cases of paraneoplastic sen-
70 μM IN DIAMETER)
sorimotor peripheral neuropathy, axonal lesions
Peripheral nerve microvasculitis, which affects involving fibers of all kinds may be observed on
mainly the postcapillary venules but also the arte- nerve biopsy; sometimes perivascular lymphocytic
rioles, capillaries, and small veins, is characteristic infiltrations are seen. Typical chronic inflammatory
of hypersensitivity angiitides. It may follow various demyelinating polyradiculoneuropathy may also be
antigenic exposures, such as a drug, a heterologous observed.
protein (Zeek angiitis), an infectious agent like The paraneoplastic sensory neuropathy origi-
hepatitis B virus, or a neoplastic antigen. It may also nally described by Denny-Brown is characterized
supervene in the course of a systemic disease. The by extensive loss of neurons in the spinal sensory
lesions are usually all of the same age. Two types are ganglia, with secondary degeneration of their axons
recognized, probably caused by distinct pathogenic in the posterior spinal nerve roots and posterior col-
mechanisms: umns of the spinal cord. Lymphocytic infiltrations,
indicating a prominent inflammatory component of
• In leukocytoclastic vasculitis, various degrees the disorder, have been found in peripheral nerves
of vessel wall necrosis are associated with a cel- in some cases, and the presence of anti-Hu antibod-
lular infiltrate composed of more or less altered ies in blood has a high specificity for paraneoplastic
polymorphonuclear neutrophils. This lesion is sensory neuropathy (see Chapter 9).
typically seen in skin biopsies but may be demon-
strable on nerve or muscle biopsies on occasion.
• Lymphocytic microvasculitis is a non-necrotizing 5.2. Neuropathies associated with
vasculitis characterized by an infiltration of the malignant lymphomas
vessel walls by mononuclear cells. Lesions of Patients with non-Hodgkin malignant lymphomas
this type are not infrequent in peripheral nerve may develop a distal sensorimotor peripheral neu-
biopsies in a variety of clinical setting; their role ropathy. In such cases, malignant B- or T-cell pro-
in the pathogenesis of associated nerve lesions is liferation may be demonstrated in nerve biopsies
uncertain. Nevertheless, the presence of sizable by immunolabeling of the infiltrates on paraffin
or frozen sections using specific antibodies. The IgM deposits may be identified along the myelin
patchy distribution of the lesions in this condition sheaths. It has been estimated that approximately
should be borne in mind, underscoring the fact that 50% of all the patients with IgM monoclonal gam-
a negative biopsy does not rule out the possibility of mopathy and peripheral neuropathy have monoclo-
lymphomatous infiltrates in the nerve. Widespread nal IgM antibodies that bind to MAG. In some of
polyradiculoneuropathies have also been seen the 50% of the patients who do not have IgM that
in cases of non-Hodgkin malignant lymphomas, binds MAG, the IgM reacts as an antibody to glyco-
described under the term of “neurolymphomato- proteins other than MAG or to glycolipids; in other
sis.” It is not yet clear whether the heavy and diffuse patients, no peripheral nerve antigen toward which
cell infiltration of the peripheral nervous system is the IgM might be directed has been identified.
due to inflammatory mechanisms or lymphomatous Nerve biopsy is ordinarily not needed in patients
infiltration, as few of these biopsies have been stud- with the POEMS (polyneuropathy, organomegaly,
ied in detail. endocrinopathy, M-protein, and skin abnormalities)
syndrome (also called Crow-Fukase syndrome).
This disorder is characterized by a complex of
5.3. Monoclonal gammopathies findings in patients with a plasma cell dyscrasia or
myeloma, with findings that include peripheral
5.3.1. GENERAL CONSIDERATIONS
neuropathy, organomegaly (hepatosplenomegaly,
Involvement of peripheral nerve is frequent in lymphadenopathy), endocrinopathy (which can
patients with monoclonal gammopathies; it may be multiple), M-protein (IgG), and skin changes
result from different mechanisms. Patients with the (thickening, hyperpigmentation, hypertrichosis).
osteosclerotic form of myeloma with monoclonal
IgG are at greatly increased risk for the develop-
5.3.2 . SPECIF IC CHANGES IN
ment of peripheral neuropathy in comparison with
PATIENTS WITH MONOCL ONAL
those with multiple (osteolytic) myeloma. In some
GAMMOPATHY- ASSOCIATED PERIPHERAL
studies, neuropathological examination of nerves in
NEU ROPATHY
myeloma-associated neuropathy, both with light and
electron microscopy, has shown both distal axonal 5.3.2.1. Widening of myelin lamellae This
degeneration and demyelination and remyelination. lesion consists of 23-nm spacing between the sepa-
Perivascular collections of lymphocytes (endoneu- rated leaflets of the intermediate line, which contains
rial and/or perineurial) have been observed. an electronlucent material. The ultrastructural integ-
An anti-MAG (myelin associated glycoprotein) rity of the dense lines remains unchanged. These
monoclonal IgM has been implicated as causative, widened lamellae are associated with dilatation of
but the diagnosis may require nerve biopsy for immu- the outer mesaxon and are mainly located on the
nohistochemical confirmation. By direct immuno- outer part of the sheath (Fig. 13.16). In some fibers,
fluorescence and immunoperoxidase techniques, the widening is restricted to the outermost lamellae,
labeled antibodies to the respective monoclonal and careful examination is required to notice it. Such
A B
FIGURE 13.16 Widening of peripheral myelin lamellae in a case of monoclonal gammopathy of undeter-

mined significance (MGUS) (A) and in a case of IgA monoclonal gammopathy (B).

features are indicative of a dysglobulinemia and, in a
patient with peripheral neuropathy of unknown ori-
gin, should prompt the search for a monoclonal peak
with laboratory testing.
Widening of myelin lamellae is observed in
Waldenström macroglobulinemia and in monoclo-
nal gammopathy of unknown significance (MGUS)
(Fig. 13.16A). In very few patients with IgA (Fig.
13.16B) or IgG monoclonal gammopathies and
polyneuropathy, identical widening of the myelin
lamellae have been described. This abnormal wid-
ening has also been seen rarely in the absence of a
dysglobulinemia.
5.3.2.2. Uncompacted myelin lamellae Myelin

lamellae can be found not to be normally flattened FIGURE 13.17 Myeloma neuropathy:
and joined together but separated from each other electron-dense endoneural deposit of IgG.
(Fig. 13.9B); they may also be seen as stacks of
Schwann cell cytoplasm. This unusual alteration of
myelin is encountered in the POEMS syndrome, distinct categories, depending on the particular
although it is not specific to any one disease and has immunoglobulin or combination that is present.
also been observed in cases of acute and CIDP. They can be isolated monoclonal (type 1) as found
in paraproteinemia (around 25% of cases), mixed
5.3.2.3. Endoneurial deposits In a few cases, including a monoclonal component (type 2, around
amyloid deposits have been observed in the course 25% of cases), or polyclonal (type 3, around 50%
of peripheral neuropathy associated with either of cases). Cryoglobulins may occur idiopathically
multiple myeloma or Waldenström macroglobu- (essential cryoglobulinemia) or secondary to a spe-
linemia. Finding 7- to 8-nm-in-diameter filaments cific predisposing disease. Cryoglobulins are said to
in various planes on ultrastructural examination be symptomatic in less than one third of cases.
is particularly informative. In these instances, the The clinical manifestations of cryoglobulinemia
amyloid is derived from kappa and lambda light include purpura, weakness, arthralgia or arthritis,
chains. fever, glomerulonephritis, Raynaud phenomenon,
The presence and specificity of immunoglobulin and neurological involvement, which can present
deposits can be established only by ultrastructural as peripheral neuropathy, vasculitic encephalopa-
and immunopathological investigations. Minute thy, or both. The specific type of cryoglobulinemia
deposits may not be detectable on light microscopic needs to be determined: if type 1, anti-nerve activity
examination using any of the current immunopath- (anti-glycolipids and anti-MAG) should be sought;
ological techniques. The ultrastructural appearance a few cases have been observed of IgM cryoglobu-
of these deposits is quite variable, and they may be linemia (type 1) with anti-MAG activity. On both
observed as fingerprints, fibrils, granules, or micro- electrophysiological and histological grounds, the
tubules or with no defined structure (Fig. 13.17). neuropathy appears to be demyelinating, just like
Such deposits are not specific for any monoclonal neuropathies induced by an IgM paraproteinemia
dysglobulinemia, and they have been described with anti-MAG activity. If the cryoglobulin is of
in MGUS (IgM or IgG or IgA), myeloma, and type 2 or 3, axonal lesions are often associated with
Waldenström macroglobulinemia. widespread vasculitis affecting medium and small
epineurial vessels and, more rarely, endoneurial ves-
sels. In such cases, the presence of axonal lesions
5.4. Cryoglobulinemias in a nerve biopsy requires the careful examination
Cryoglobulins are circulating immunoglobulins that of several serial sections of the nerve fragment, as
precipitate when cooled to 4°C in the laboratory deposits or vasculitis tend to be multifocal or nodu-
and redissolve when warmed to body temperature lar. The relationship between vasculitis and circulat-
(37°C). Cryoglobulinemias are classified into three ing cryoglobulins is not clear, as globulin deposits in
vessel walls have not been observed in such cases. peripheral neuropathy clinically after 25 years of
A necrotizing vasculitis is observed in 22% of diabetes, and nearly 100% have conduction abnor-
patients infected with hepatitis C virus suffering malities electrophysiologically. Several distinct
from peripheral neuropathy associated with a mixed clinicopathological patterns of diabetes-related
cryoglobulinemia peripheral nerve abnormalities have been recog-
nized. The most common peripheral neuropathy is a
symmetrical neuropathy that involves distal sensory
5.5. Direct invasion of nerve by and motor nerves. Another manifestation of dia-
neoplasm betic neuropathy is dysfunction of the autonomic
Nerve invasion by malignant cells is demonstrated nervous system; this affects 20% to 40% of diabetics,
not infrequently in the course of autopsy studies of nearly always in association with a distal sensorimo-
individuals with disseminated disease (Fig. 13.18). tor neuropathy. Some patients, especially elderly
Patients may or may not have clinical manifestations, adults with a long history of diabetes, develop a
but when they do, the peripheral neuropathy pres- peripheral neuropathy that manifests as a disorder
ents as a painful mononeuropathy or radiculopathy. of a single individual peripheral or cranial (such as
Peripheral nerve biopsy is rarely necessary under oculomotor nerve) nerve (mononeuropathy) or of
these circumstances, but when clinically indicated, several individual nerves in an asymmetrical distri-
it may reveal the nature of the malignant tumor. bution (multiple mononeuropathy or mononeu-
ropathy multiplex).
In patients with distal symmetrical sensorimo-
6. METABOLIC tor neuropathy, the predominant pathological find-
AND NUTRITIONAL ing is an axonal neuropathy. As with other chronic
NEUROPATHIES axonal neuropathies, there is often some segmen-
tal demyelination. There is a relative loss of small
Functional and structural changes in peripheral myelinated fibers and of unmyelinated fibers, but
nerve develop in response to various metabolic large fibers are also affected. Endoneurial arteri-
alterations, either from endogenous disorders or oles show thickening, hyalinization (Fig. 13.19A)
from exogenous agents. The most common of these and intense periodic acid-Schiff (PAS) positivity
processes are discussed here. in their walls and extensive reduplication of the
basement membrane (Fig. 13.19B). Whether the
lesions are due to ischemia or metabolic derange-
6.1. Diabetes
ment is unclear.
The prevalence of peripheral neuropathy in patients The pathogenesis of mononeuropathies in
with diabetes mellitus depends on the duration of adult-onset diabetes is thought to involve vascu-
the disease. Up to 50% of diabetic patients develop lar insufficiency, creating ischemic injury of the
peripheral nerve.
CIDP may occur in diabetic patients, although
a higher incidence than expected by chance is still
debated; in some atypical cases, nerve biopsy may
help confirm the diagnosis and direct immunomod-
ulatory treatment.
Cases of lumbosacral radiculopathy may also
show signs suggestive of ischemic injury from micro-
vasculitis without fibrinoid necrosis. In a minority
of patients, extensive epineurial perivascular inflam-
matory infiltrates are present in the peripheral ner-
vous system.
6.2. Other metabolic neuropathies

FIGURE 13.18 Invasion of nerve by neoplastic cells As many as 65% of patients with renal failure will
in a case of chronic lymphocytic leukemia. be found to have clinical evidence of peripheral

A B
FIGURE 13.19 Diabetic neuropathy. Loss of small myelinated fibers on semi-thin section (A).
Microangiopathy with marked reduplication of the basement membrane (B).
neuropathy before the initiation of dialysis treat- of axons that extends into adjacent anterior and
ment (uremic neuropathy). This is typically a distal, posterior roots as well as into mixed sensorimotor
symmetrical neuropathy that may be asymptomatic nerves.
or may be associated with muscle cramps, distal dys-
esthesias, and diminished deep tendon reflexes. In
these patients, axonal degeneration is the primary 7.2. Accidental and industrial exposures
event, with fiber loss. Occasionally there is second- Among the heavy metals and the organophosphates,
ary demyelination. Regeneration and recovery are arsenic, thallium, alkyl mercury, and tri-ortho-cresyl
common after dialysis. phosphate have been incriminated.
Peripheral neuropathy can also develop in
patients with chronic liver disease, chronic respi-
ratory insufficiency, and thyroid dysfunction. 7.2. 1 . ARSENIC
Thiamine deficiency is characterized by axonal This metallic element has been known for centuries
neuropathy, a clinical condition termed neuropathic to be highly toxic and has frequently been used with
beriberi. Axonal neuropathies also occur with defi- homicidal or suicidal intent. Apart from encepha-
ciencies of vitamins B12 (cobalamin) and B6. lopathy, a mixed sensory and motor neuropathy is
a well-known and often disabling sequela of both
7. TOXIC NEUROPATHIES acute and chronic arsenic intoxication. The charac-
teristic neuropathological feature of this neuropa-
Peripheral neuropathies can occur after exposure to thy is an axonopathy in the most distal parts of the
industrial or environmental chemicals, biological longest nerves. The larger fibers are more severely
toxins, or therapeutic drugs. Prominent among the affected than the small ones.
environmental chemicals are heavy metals, includ-
ing lead and arsenic. In addition, many organic com-
pounds are neurotoxic. 7.2. 2 . L EAD
Lead poisoning in adults occurs most often as a
7.1. Diphtheria toxin result of occupational exposure; in children, it usu-
ally ensues from ingestion of dust and fragments of
Peripheral nerve involvement in diphtheria results the lead-containing paint that formerly was exten-
from the effects of the diphtheria exotoxin and sively used in households. Lead intoxication induces
begins with paresthesias and weakness; early loss of a peripheral neuropathy in adults, while in children
proprioception and vibratory sensation is common. encephalopathy is the more common clinical mani-
The earliest changes are seen in the sensory ganglia, festation. Despite the numerous clinical descriptions
where the incomplete blood–nerve barrier allows of lead-induced polyneuropathy, very little is known
entry of the toxin. There is selective demyelination about its neuropathological features in humans; the
most commonly observed lesion is axonal degenera- associated with treatment with amphophilic cat-
tion rather than segmental demyelination. ions; these include amiodarone and chloroquine.
Amiodarone neuropathy is a subacute polyneuropa-
thy, whereas chloroquine causes a neuromyopathy.
7.2.3. ORGANOPHOSPHORUS The diagnosis may be apparent from semi-thin sec-
COMPOUNDS tions, based on the presence of numerous dense
The organophosphorus compounds have been cytoplasmic inclusions in the Schwann cells and
extensively used in industry and agriculture as endothelial cells. Electron microscopic study can
insecticides, modifiers of plastics, petroleum addi- demonstrate polymorphic lysosomal inclusions,
tives, lubricants, antioxidants, and flame retardants. some of which have a paracrystalline or a multilamel-
A biological effect of many of them is to phosphory- lar reticular appearance (Fig. 13.20). The accumu-
late acetylcholine-esterase (AChE), which leads to lated lipids include gangliosides and phospholipids.
irreversible inhibition of the function of this enzyme Many other commonly used drugs may cause
and consequently severe symptoms of excessive peripheral neuropathy, which is predominately
cholinergic activity within a day or less of acute axonal. These include vincristine, cisplatinum, the
exposure to the compound. Death from respiratory nitrofurantoin compounds, metronidazole, isonia-
paralysis can occur during this acute phase of the zid, disulfiram, almitrine, and pyridoxine.
intoxication; if the patient survives this phase, recov-
ery ensues and there are no delayed effects. Some 8. TRAUMATIC
organophosphorus compounds, however, also have
the effect of inducing a delayed polyneuropathy that
NEUROPATHIES
is not due to inhibition of AChE but correlates with Peripheral nerves are commonly injured in the
inhibition of another esterase, neurotoxic esterase course of trauma. Lacerations result from cutting
(NTE). The onset of symptoms is delayed from the injuries and can complicate fractures when a sharp
exposure, and the peripheral nervous system shows fragment of bone lacerates the nerve. Avulsions of
an axonal neuropathy with axonal degeneration. nerve may occur when tension is applied to a periph-
eral nerve, often as the result of a force applied to one
of the limbs. The direct severance of nerves is associ-
7.2.4. HEXANE AND RELATED ated with hemorrhage, and there is transection of the
COMPOUNDS connective tissue planes. Regeneration of peripheral
nerve axons does occur, albeit slowly. Regrowth
The six-carbon compounds n-hexane and
may be complicated by discontinuity between the
methyl-n-butyl ketone (MBK), used as indus-
proximal and distal portions of the nerve sheath as
trial solvents, produce striking toxic effects on the
peripheral nervous system. The ensuing polyneu-
ropathy, which involves the distal parts of both
sensory and motor nerves, is characterized by focal
swelling of axons to some two to three times their
normal diameter (Fig. 13.4B). The myelin sheaths
surrounding these swollen axonal segments are
thinned, and there is retraction of myelin at the
nodes of Ranvier, with some segmental demyelin-
ation. Electron microscopy of the axonal swellings
demonstrates that they contain accumulations of
10-nm neurofilaments, and the axon distal to the
swellings undergoes axonal degeneration.
7.3. Complications of therapeutic

agents
Drug-induced neuropathies with prevailing or FIGURE 13.20 Amiodarone neuropathy, multiple
notable segmental demyelination include those lipid inclusions in Schwann cells.

well as by the misalignment of individual fascicles. perspective, in many cases, the mode of inheritance
Axons, even in the absence of correctly positioned and clinical and electrophysiological data may
distal segments, may continue to grow, resulting in be sufficient to identify the causative mutations.
a mass of tangled axonal processes known as a trau- Nevertheless, at present, screening of the 40 most
matic neuroma (or amputation neuroma). Within commonly affected genes is costly. Pathological
this mass, small bundles of axons appear randomly analysis of the nerve lesions may narrow the search
oriented; each, however, is surrounded by organized of specific genes when the differential diagnosis
layers containing Schwann cells, fibroblasts, and is broad.
perineurial cells.
Compression neuropathy (entrapment neuropa-
thy) occurs when a peripheral nerve is compressed, 9.1. Hereditary motor and sensory
often within a restricted anatomical compartment. neuropathies (HSM)
Carpal tunnel syndrome, the most common entrap-
9.1. 1 . TYPE I (HSM I);
ment neuropathy, results from compression of the
CHARCOT- MARIE- TOOTH DISEASE,
median nerve at the level of the wrist within the
HYPERTROPHIC F ORM; CMT 1
compartment delimited by the transverse carpal
ligament. Additional compression neuropathies The most common hereditary peripheral neuropa-
include involvement of the ulnar nerve at the level thy is Charcot-Marie-Tooth (CMT) disease, hyper-
of the elbow, the peroneal nerve at the level of the trophic form (HMSN I, or CMT 1), which usually
knee, and the radial nerve in the upper arm, as seen presents in childhood or early adulthood. Patients
after sleeping with the arm improperly positioned may be asymptomatic, but when they present, it is
(“Saturday night palsy”). Another form of com- often with symptoms such as distal muscle weak-
pression neuropathy is found in the foot, affecting ness, atrophy of the calf (peroneal muscular atro-
the interdigital nerve at intermetatarsal sites. This phy), or secondary orthopedic problems of the
problem, which occurs more often in women than foot (such as pes cavus). The disorder is autosomal
in men, leads to foot pain (metatarsalgia). The his- dominant, and although it is slowly progressive, the
tological findings of the lesion (Morton neuroma) disability of sensorimotor deficits and associated
include evidence of chronic compressive injury. orthopedic problems are usually limited in severity
and a normal lifespan is typical.
9. HEREDITARY CMT1 is a demyelinating neuropathy, both by
nerve neurophysiological conduction velocity and
NEUROPATHIES by pathological criteria. Histological examination
Peripheral neuropathy is a clinical manifestation of shows the consequences of repetitive demyelination
many hereditary neurological syndromes where the and remyelination, with multiple onion bulbs, some-
course of the disease is typically progressive and what more pronounced in distal than in proximal
often disabling. Classification schemes of hereditary nerves. The axon is often present in the center of the
diseases affecting mostly or exclusively the periph- onion bulb, and the myelin sheath is usually thin or
eral nervous system are based upon whether the dis- absent. In some biopsies, nearly every axon is sur-
ease predominantly affects the motor and sensory rounded by an onion bulb. The redundant layers of
modalities (hereditary motor and sensory neuropa- hyperplastic Schwann cells surrounding individual
thies, HMSN group) or predominantly the sensory axons may be associated with enlargement of individ-
and autonomic modalities (hereditary sensory and ual peripheral nerves that are sometimes individually
autonomic neuropathies, HSAN group). Other palpable, which has led to the term “hypertrophic”
hereditary diseases that may also have symptoms of neuropathy. In the longitudinal plane, individual seg-
peripheral neuropathy as an additional component ments of the axon may show evidence of segmental
of a broader neurological and systemic illness will be demyelination. These findings support the view that
discussed in Chapter 10. Classification is here often the primary cause is disruption of the maintenance
based of the nature of the metabolic defect, such as of myelin, and these forms are primarily demyelin-
diseases of lipid metabolism. ating neuropathies pathologically and electrophysi-
Recent advances in molecular genetics have greatly ologically. In the later stages of the disease, axonal
enhanced the understanding of Charcot-Marie-Tooth loss also occurs, involving the most distal portions of
disease and related neuropathies. From the clinical axons. Autopsy studies of affected individuals have
shown degeneration of the posterior columns of the Autosomal recessive cases are much less fre-
spinal cord as well. quent in Western countries. MTMR2, MTMR13
The disease is genetically heterogeneous, and (CMT4B), and Frabin mutations (CMT4H) induce
subgroups of dominant forms have been identified as severe demyelinating lesions associated with numer-
types IA, IB, or IC. In about 75% of CMT1 pedigrees ous outfoldings of myelin sheaths.
(known as HMSN IA or CMT1A), there is a dupli-
cation of a large region of chromosome 17p11.2-p12
9.1.2 . TYPE II (HSM II);
resulting in “segmental trisomy” of the duplicated
CHA RCOT- MARIE- TOOTH DISEASE,
region that includes the myelin protein, PMP22.
AXO NAL F ORM; CMT2
A separate genetic locus in some CMT1 families
is located on chromosome 1 and involves myelin Hsm II or CMT2 is an axonal form of autosomal
protein zero (MPZ). This disease has an identical dominant CMT disease that presents with signs
clinical and pathological phenotype: demyelinating and symptoms similar to those of CMT1, although
lesions and onion bulbs (HMSN IB or CMT 1B). nerve enlargement is not seen and the disease pres-
Electron microscopic examination may also detect ents at a slightly later age. This form is less common
characteristic anomalies of myelin compaction, than CMT1 and is recognized electrophysiologi-
which are quite specific as MPZ is the main protein cally by conduction velocities in the normal range
of myelin compaction. Some multifocal thicken- (more than 38 m/s). Loss of myelinated axons is
ings of the myelin sheaths may also be encountered. the predominant finding on nerve biopsy (Fig.
Some pedigrees have a genetic locus on the X chro- 13.7D). Segmental demyelination of internodes is
mosome with X-linked inheritance and mutations infrequent, and onion bulbs are not present. These
in the gene for the gap junction protein beta-1, also findings indicate that the site of primary cellular dys-
known as connexin-32. Several of these proteins are function is the axon or neuron.
integral membrane proteins of myelin or involved in CMT2 is also heterogeneous genetically, and
myelin compaction (Fig. 13.21). each locus has been identified as a specific subtype.
CX32 PMP22 MPZ PRX MBP
Extracellular
Intracellular
Extracellular
Intracellular
Extracellular
FIGURE 13.21 Diagram of peripheral nerve myelin and proteins affected in hereditary demyelinating neurop-
athies. Peripheral myelin protein 22 (PMP22) is the gene that is duplicated in CMT1A and deleted in hereditary
neuropathy with liability to pressure palsies. Myelin protein 0 (MPZ) is the gene affected in CMT 1B. Connexin
32 is affected in the X-linked form of CMT (CMT X), and periaxin (PRX) in CMT3. Myelin basic protein
(MBP) is a major component of myelin located in the major dense line of myelin; no hereditary neuropathies
involving MBP are known.

In some dominant families (designated CMT2A maintenance of myelin. The genes identified thus far
or HMSN IIA), two separate genetic loci have in Déjerine-Sottas disease include peripheral myelin
been identified at 1p36.2: CMT2A1 (only one protein-22 (PMP22), myelin protein zero (MPZ),
family described) is caused by mutations in the early growth response 2 gene (EGR2), and periaxin
KIF1B gene, which encodes a molecular motor of (PRX).
the kinesin superfamily, and CMT2A2 is caused Congenital hypomyelinating neuropathy is a term
by mutations in the mitofusin 2 (MFN2) gene. that has been used to designate a diffuse symmetrical
CMT2A2 accounts for 20% to 30% of dominant polyneuropathy that is evident at birth or becomes
forms of CMT2. In nerve biopsies of CMT2A2 manifest shortly thereafter. It is characterized patho-
cases, there are significant and unusual alterations logically by nearly complete absence of myelin in
of intra-axonal mitochondria, which are well appre- the presence of normal axons and is closely related
ciated on longitudinal sections. The organelles are clinically to Déjerine-Sottas disease. Patients with
abnormally focally aggregated, are round instead of this disease are sometimes referred to as having
tubular, have irregularities in their external and inter- congenital Déjerine-Sottas disease (HMSN III) or
nal membranes, and show disruption of the cristae. congenital hypomyelinating neuropathy (CMT 4E).
Additional less common loci have been identified in Mutations thus far have been identified in EGR2 and
CMT2 families, namely RAB7 (CMT2B), TRPV4 myelin protein zero (MPZ).
(CMT2C), and neurofilament light chain in NFL
(CMT2E). In recessive cases, several other genes
9.1. 4 . TOMACUL OUS NEUROPATHY
have been identified: lamin A/C (autosomal reces-
(HE REDITARY NEUROPATHY WITH
sive: AR-CMT2B1), and MED25 (AR-CMT2B2).
LIABIL ITY TO PRESSURE PAL SIES)
Tomaculous neuropathy is transmitted as an autoso-
9.1.3. TYPE III (HSM III);
mal dominant trait and is characterized by recurrent
DÉJERINE-SOTTAS DISEASE; CMT 3
attacks of mononeuropathy, single or multiple, that
Déjerine-Sottas disease (HMSN III, CMT3) is a characteristically are brought on by pressure, such as
progressive, autosomal recessive disorder beginning that affecting the ulnar nerve when the elbow rests
in early childhood, usually before the age of 2, mani- on a table for an extended period, or by traction or
fested by delay in the developmental milestones, stretching. There is generally some recovery (which
such as the acquisition of motor skills. At present may require weeks or months), although with
this entity is debated by some authors, as in clini- repeated attacks some permanent sensory or motor
cal practice it may be difficult to differentiate such dysfunction may remain.
patients from those with CMT1 and patients with Examination of peripheral nerve biopsies shows
congenital hypomyelinating neuropathy. either focal enlargements of the myelin sheath
On physical examination, enlarged peripheral involving entire internodal segments or confined
nerves can be detected by inspection and palpa- to the paranodal regions (Fig. 13.22A , B). These
tion. The deep tendon reflexes are depressed or enlargements create a fusiform enlargement,
absent, and nerve conduction velocity is markedly or sausage-like appearance, in the longitudinal
slowed. plane referred to as tomacula (from Latin tomacu-
Morphologically, the size of individual periph- lum = sausage). Morphometric examinations have
eral nerve fascicles is increased, often dramatically, shown decreased numbers of large myelinated fibers
with abundant onion bulb formation as well as seg- with relatively normal numbers of smaller myelin-
mental demyelination. There is usually evidence of ated fibers and scattered small onion bulb struc-
axonal loss, and the remaining axons are often of tures. The tomaculous swellings, when examined
diminished caliber. These findings are most severe in by electron microscopy, have been shown to be
the distal portions of the peripheral nervous system; made up of greatly thickened and abnormally folded
however, autopsy studies have shown that similar myelin sheaths (Fig. 13.22C); axons enclosed by
findings may be present in spinal roots. these abnormal myelin structures often appear con-
Families have been identified with mutations of tracted. The disorder is usually caused by deletion
different genes, but in each pedigree, the mutation of the peripheral myelin protein 22 (PMP22) or a
has involved genes involved in the formation and whole segment of chromosome 17p11.2 that spans
A B
FIGURE 13.22 Tomaculous neuropathy: scattered focal swellings of individual myelin sheaths with a

sausage-like appearance in the longitudinal plane, seen on teased-fiber preparations (A, B). By electron micros-
copy, the swellings are made up of greatly thickened and abnormally folded myelin sheaths (C).
the PMP22 gene. This is the same region of chromo- and intellectual deterioration. Most affected individ-
some 17 that is duplicated in CMT 1A. uals have an unusual appearance of the hair, variously
described as “frizzy” or less acceptably “kinky.”
The distinctive neuropathological feature of this
9.1.5. NEUROPATHY ASSOCIATED WITH disorder is the presence of greatly enlarged axons, 20 to
HEREDITARY ATAXIA
50 μm in diameter (Fig. 13.4A). Overlying the enlarged
A neuropathy with clinicopathological features portion of the axon, the myelin sheath is either greatly
closely resembling those in HMSN I and II is reg- thinned or absent, and electron microscopy shows
ularly found in the most frequently encountered that the enlarged portions of the axons are filled with
form of genetically determined progressive ataxia, masses of densely packed intermediate filaments,
Friedreich ataxia. This topic is covered in Chapter 8. 9 nm in diameter, frequently arranged in whorl-like
patterns. In addition to the changes in the peripheral
nerves, there are striking abnormalities in the central
9.1.6. GIANT AXONAL NEUROPATHY nervous system, including enlarged axons (spheroids)
Giant axonal neuropathy is characterized by greatly and amorphous masses of glial fibrillary protein in the
enlarged axons in the central and peripheral nervous form of Rosenthal fibers. Aggregates of intermediate
systems and a gradually progressive sensorimotor filaments also occur in fibroblasts and glia, and the
neuropathy beginning in early childhood. A pattern accumulation of aggregates of intermediate filaments
of autosomal recessive inheritance occurs in most occurs in cultures of fibroblasts from patients.
affected pedigrees. The disease becomes manifest The gene responsible for giant axonal neuropa-
generally as an awkwardness of gait with a tendency thy, GAN, is located on chromosome 16q24.1 and
to fall. Increasing motor instability ensues, associated encodes gigaxonin, a protein thought to have a role
with sensory loss that affects mainly deep sensibility in cytoskeletal organization.
and proprioception, with less involvement of sensa-
tions for light touch, pain, and temperature. The dis-
9.1.7 . INFANTIL E NEUROAXONAL
ease progresses gradually but relentlessly, and clinical
DYS TROPHY
manifestations of dysfunction of the central nervous
system become evident in the form of nystagmus, Infantile neuroaxonal dystrophy, or Schindler dis-
visual impairment with optic atrophy, dysarthria, ease, is an autosomal recessive disorder characterized

by a relentlessly progressive global deterioration of fibers of all calibers in peripheral nerve. The gene is
cerebral function, beginning during early infancy the SPTLC1 gene, located on chromosome 9q22; it
after a normal neonatal period and leading to death encodes serine palmitoyltransferase, an important
in childhood. Weakness is profound, associated enzyme in sphingolipid synthesis
with hypotonia and muscular wasting, and there is
an exaggeration of muscle-stretch reflexes. The out-
9.2. 2 . HSAN TYPE II
standing neuropathological finding is the presence
of enlarged axons (spheroids) at all levels of the cen- Autosomal recessive inheritance is the main distin-
tral nervous system (see Chapter 10) and frequently guishing feature of this variety of HSAN, and the
on nerve biopsies, although they are less frequent predominant clinical feature is impairment of pain
than in the brain. The enlarged axons are filled with perception, resulting in painless injuries (insensitiv-
tubulovesicular or membranous arrays, displacing ity to pain), often beginning in childhood. Nerve
the cytoplasm and distending the axonal diameter. biopsy studies show widespread loss of myelin-
The disorder is caused by mutations in the NAGA ated fibers of all sizes; unmyelinated fibers are only
gene and deficiency of the encoded protein and slightly decreased. A striking vacuolation of the
enzyme activity, alpha-N-acetylgalactosaminidase. cytoplasm of endoneurial fibroblasts has also been
reported. Mutations in the HSN2 gene, an isoform
of the WNK1 gene, and in the FAM134B gene have
9.2. Hereditary sensory and autonomic been detected and are subclassified as HSAN 2A
neuropathies (HSAN) and HSAN 2B, respectively.
The hereditary sensory and autonomic neuropa-
thies mainly affect sensation, with relative sparing
9.2. 3 . HSAN TYPE III (FAMIL IAL
of motor strength, and are accompanied by vary-
DYSAUTONOMIA; RIL EY- DAY
ing degrees of autonomic nervous system dysfunc-
SYN DROME)
tion. The most widely accepted classification of
these hereditary neuropathies combines them in HSAN type III is characterized by severe autonomic
an overall category of hereditary sensory and auto- nervous system dysfunction present at birth, as evi-
nomic neuropathies (HSAN) and divides this into denced by absent lacrimation and abnormal reac-
several subtypes based on inheritance and the clini- tions to anxiety (lability of blood pressure, salivation,
cal manifestations: HSAN type I (predominantly excessive sweating, and erythematous blotching of
sensory, autosomal dominant), HSAN type II the skin). The syndrome is inherited as an autoso-
(predominantly sensory, autosomal recessive), and mal recessive trait and tends to occur in children of
HSAN type III (predominantly autonomic, autoso- Ashkenazi Jewish parentage. Integral components of
mal recessive). Other types, including various types the syndrome include early-appearing lack of pain
of congenital indifference to pain, have also been perception and lack of fungiform papillae in the
described. tongue. Sural-nerve biopsy shows a great decrease
in the numbers of unmyelinated fibers and of large
and small myelinated fibers. Teased fibers show
9.2.1. HSAN TYPE I (FAMILIAL
some with shortening of the internodal length but
ULCEROMUTILATING ACROPATHY OF
no segmental demyelination or remyelination and
THÉVENARD, DOMINANT)
no onion bulb structures. Autopsy studies have
HSAN type I is characterized by dominant inheri- reported shrinkage and neuronal loss in dorsal root
tance and very slow progression. Painless injuries ganglia, sympathetic ganglia, and the intermedio-
to the feet, with ulcerations of the skin and damage lateral cell column of the spinal cord, suggesting
to joints, are typical. Dysfunction of the autonomic that the primary abnormality is in neurons of the
nervous system is not prominent. Neuropathological autonomic and spinal sensory ganglia, and that the
examination has shown extensive loss of neurons in changes seen in peripheral nerve specimens are sec-
spinal sensory ganglia, with secondary axonal loss ondary to the axonal degeneration that results from
in the posterior roots and posterior columns of the neuronal death.
spinal cord, and preservation of motor neurons and The gene for familial dysautonomia is located
anterior roots. There also is severe loss of myelinated on chromosome 9q31.3 and encodes an inhibitor
of kappa light polypeptide gene enhancer in B cells,
a kinase-complex associated protein known as
IKBKAP. The role of this gene product in the nervous
system is not fully understood. More than 99.5% of
the alleles in families with the mutation share a com-
mon ancestral haplotype, supporting that the ethnic
basis of the disease is due to a founder effect.
9.2.4. ADDITIONAL TYPES OF HSAN

Some cases of hereditary sensory neuropathy, with
or without autonomic dysfunction, have been iden-
tified and are recognized rare variants of HSAN.
FIGURE 13.23 Interstitial amyloid deposit in
They differ from one another in the details of their
peripheral nerve (Congo red).
clinical expression as well as in the pattern of neu-
ropathological changes, and a number of genetic
causes have been identified. fibrils by electron microscopy. Parenchymatous
involvement is essentially axonal and typically
affects mainly small myelinated and unmyelinated
9.3. Amyloid neuropathies fibers. In the most common form of familial amyloid
Peripheral neuropathy may occur due to deposition neuropathy (TTR-related), the amyloid fibrils are
of amyloid in peripheral nerve, and there are two composed of transthyretin and can be demonstrated
major categories of amyloid neuropathies: familial in tissue by immunoperoxidase methods.
amyloid polyneuropathies and sporadic amyloidosis.
9.3.2 . ACQUIRED AMYL OID
9.3.1. FAMILIAL AMYLOID NEU ROPATHIES
POLYNEUROPATHIES Acquired amyloidosis may occur in association
The familial amyloid neuropathies are character- with immunocyte (B-cell) dyscrasias (“primary
ized predominantly by the deposition of amyloid amyloidosis”) or as reactive systemic amyloido-
within the peripheral nervous system, with symp- sis (“secondary amyloidosis”). The amyloid in the
toms that may be restricted to those of peripheral immunocyte dyscrasias is of AL type (composed
neuropathy. Most kindreds exhibit mutations of the of fragments of immunoglobulin light chains, most
transthyretin (TTR) gene, located on chromosome often lambda chains), while the amyloid deposits in
18q11.2-q12.1. More than 20 forms of mutant TTR reactive systemic amyloidosis is of AA type (com-
have been identified. Rarer forms of amyloid neurop- posed of a fragment of the serum protein, serum
athy are characterized by the deposition of different amyloid-associated protein). The amyloid depos-
amyloid-forming proteins: a variant of apolipopro- its, whether familial TTR-derived, AL type, or AA
tein A1 in familial amyloid polyneuropathy, type III, type, are often discrete and may be demonstrated
and a mutant form of gelsolin in the Finnish form of by immunohistochemical techniques. They must be
familial amyloid polyneuropathy, type IV. Clinically, distinguished from abnormal globulin deposits that
these are sensory-motor and autonomic polyneurop- do not have the features of amyloid. AL amyloido-
athies with predominant deficiency of temperature sis may also infiltrate the skeletal musculature and
and pain sensation, as in the TTR-related familial the transverse carpal ligament (flexor retinaculum),
amyloid neuropathies, but there is corneal clouding causing the carpal tunnel syndrome.
in some of these types in addition to the neuropathy.
In all cases, the pathological amyloid lesions
are acellular deposits situated in the endoneurium
9.4. Porphyria
and in blood vessel walls, stained by Congo red Polyneuropathy of acute or subacute evolution
(Fig. 13.23), birefringent by polarized light, and is characteristic of three varieties of dominantly
composed of characteristic nonbranching 7-nm inherited disorders of heme metabolism: acute

A B
FIGURE 13.24 Metachromatic leukodystrophy: presence of metachromatic material (appearing red on

toluidine blue stain) in macrophages in the peripheral nerve (A). By electron microscopy this material has a
characteristic “tuffstone” appearance (B).
intermittent porphyria, variegate porphyria, and disorders in which the central or peripheral nervous
hereditary coproporphyria. The polyneuropa- system may be involved, among many other organs.
thy may be asymmetrical and tends to involve In many cases, nerve biopsy may show diagnostic
motor fibers more than sensory fibers. The neuro- deposits or intracellular inclusions of abnormal lipid
logical aspects are the same in all three varieties of (Fig. 13.24 and Table13.1). Most of these diseases
porphyria. may be now diagnosed by molecular testing. The
The primary axonal neuropathy associated with neuropathological aspects of these diseases, includ-
all forms of the disease has a distribution that sug- ing the changes in peripheral nerves, are described
gests a dying-back axonopathy, an impression in detail in Chapter10.
confirmed by electrophysiological observations.
Unmyelinated axons are affected as well as large and
small myelinated fibers. In severe cases of longstand-
ing neuropathy, secondary changes in the spinal Table 13.1. Neuropathies in Disorders of
cord and sensory ganglia (central chromatolysis; Lipid Metabolism
ascending degeneration in the posterior columns) Lipid disorders with prominent involvement of
are regularly encountered, as is atrophy of dener- the peripheral nervous system
vated musculature. The relationship of the disor-
• Refsum disease
der of heme metabolism to the development of the
lesions in the nervous system is still unknown. • Bassen-Kornzweig disease or
abeta-lipoproteinemia
• Tangier disease
9.5. Disorders of lipid metabolism Lipid disorders with predominant involvement
A number of the systemic disorders of lipid metabo- of the central nervous system
lism may present with prominent involvement of the • Metachromatic leukodystrophy
nervous system. In some of these diseases, such as • Adrenoleukodystrophy
Refsum disease, Bassen-Kornzweig syndrome, or
• Krabbe disease
Tangier disease, peripheral nerve involvement may
be the presenting sign. In other conditions, par- • Niemann-Pick disease
ticularly in the leukodystrophies (metachromatic • Neuronal ceroid lipofuscinosis
leukodystrophy, adrenoleukodystrophy, or Krabbe Lipid disorders with predominant systemic
disease) or in Niemann-Pick disease, involvement involvement
of the brain is usually the predominant feature. • Fabry disease
Other conditions, such as Fabry disease or cere- • Cerebrotendinous xanthomatosis
brotendinous xanthomatosis, present as systemic
14
Diseases of the Pituitary Gland
VÂ N I A NOS É AND E . TES S A H ED L EY- W H YTE
1. GENERAL adenohypophyseal cells. Molecular pathology tech-

niques, such as molecular genetics, have character-
CONSIDERATIONS ized transcription factors and genes important in the
The pituitary is the endocrine gland that controls the development of the anterior pituitary.
release or inhibition of hormones from the hypo-
thalamus and the peripheral endocrine glands. It has 2. THE NORMAL
two major components, anterior and posterior.
The anterior pituitary is composed of epithelial
PITUITARY
cells with secretory granules containing trophic hor- The adenohypophysis and the neurohypophysis
mones. It is controlled by hypothalamic hormones form the human pituitary gland. The adenohypoph-
that stimulate or inhibit the release of the anterior ysis develops from an evagination of the primitive
pituitary hormones (Table 14.1). The posterior stomateal ectoderm, Rathke’s pouch. The neurohy-
pituitary is composed of axons arising from nerve pophysis originates from the infundibular process
cells in the supraoptic and paraventricular nuclei of of the diencephalon. The pituitary can be recog-
the hypothalamus, and glial cells. nized by the third month of fetal development, and
The first approach to pituitary pathology is to the hormone-producing cells of the anterior gland
appreciate the close association of the clinical and can be recognized as early as 5 weeks of gestation
laboratory information with the histopathologi- (Table 14.2). The adult gland weighs 400 to 600 mg
cal findings. Routine histology and immunohisto- and is located in the sella turcica.
chemistry, hormonal immunohistochemistry, and The anterior pituitary constitutes approximately
electron microscopy usually enable one to clas- 70% to 80% of the pituitary gland and is composed of
sify the normal pituitary cells and their neoplasms the pars distalis, pars intermedia, and pars tuberalis. It
and to identify tumors not composed primarily of can also be roughly subdivided into a central mucoid
• 343
Table 14.1. Major Hypothalamic Hormones and Their Effect on Anterior Pituitary
Hormones
H Y P O T H A L A M I C S T I M U L AT O R Y H O R M O N E S P I T U I TA R Y H O R M O N E S
Corticotrophin-releasing hormone (CRH) Adrenocorticotrophic hormone

released from paraventricular neurons, supraoptic (ACTH): basophilic/corticotrophs. ACTH
and arcuate nuclei, and limbic system is a product of propiomelanocortin (POMC).
Melanocyte-stimulating hormone (MSH): alternate
product of POMC gene.
Endorphins: also products of POMC genes.
Growth hormone-releasing hormone (GHRH) Growth hormone(GH): acidophilic/somatotrophs
Gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH) and follicle-stimulating
mostly released from preoptic neurons hormone (FSH): Gonadotrophs
Thyrotropin-releasing hormone (TRH) released Thyroid-stimulating hormone (TSH): Thyrotrophs
from anterior hypothalamic area
Prolactin-releasing factors(include serotonin, Prolactin (PRL): Lactotrophs
acetylcholine, opiates, and estrogens)
H Y POT H A L A MIC INHIBITORY HORMONES
Somatostatin (GIH) Inhibits the release of GH

Prolactin-inhibiting factors (PIF, includes Inhibit the release of PRL
dopamine)
wedge and lateral acidophilic wings (Fig.14.1). The staining reveals that acidophil cells are concentrated
so-called intermediate lobe, vestigial in humans, is in the lateral wings, basophilic cells are concentrated
composed of gland-like spaces, which are remnants in the mucoid center, and chromophobe cells are dif-
of Rathke’s cleft, intermixed with ACTH-secreting fusely spread in a horizontal section across the pitu-
cells. The anterior pituitary cells are arranged in cords itary (Fig. 14.2A). The sustentacular-like cells in the
surrounded by a rich network of capillaries. The ante- adenohypophysis, stellate cells, are distinct from the
rior pituitary cells are characterized by their tinctorial epithelial cells and stain for S-100 protein and GFAP.
properties in H&E-stained preparations, by immu- The anterior pituitary produces and releases six
noreactivity indicating their function and by their hormones that are under the control of different
ultrastructural features. The distribution of the vari- stimulatory and inhibitory hypothalamic releasing
ous cell types is uneven (Table 14.2). Routine H&E factors (Table 14.2).
Table 14.2 . Cells of the Anterior Pituitary, Identification of Cell Types in Fetal

Development, Cell Percentages in Adults and Location
CELL T YPES W E E K S O F G E S TAT I O N C E L L % I N A D U LT S L O C AT I O N
Corticotroph-ACTH 5 weeks 10-20 Mucoid edge

Somatotroph-GH 8 weeks 40-50 Lateral wings
Alpha-subunits 9 weeks variable Diffuse throughout
Thyrotroph-TSH 12 weeks 5 Ant. mucoid edge
Gonadotroph-FSH/LH 12 weeks 10 Diffuse throughout
Lactotroph-PRL 12 weeks 10-30 Lateral wings
A B
FIGURE 14.1 Normal pituitary with anterior, posterior, and intermediate lobes, in horizontal section.
(A) Whole-mount section demonstrating the anterior, intermediate, and posterior lobes of the pituitary. The
section reveals the normal distribution of the GH-producing cells in the lateral lobes of the anterior pituitary.
(B) A high-power picture with detail of normal GH-producing cells (immunohistochemistry for GH).
The posterior pituitary constitutes 20% to 3. LESIONS OF THE

30% of the gland and is composed of the infun-
dibulum or median eminence, the infundibular
PITUITARY GLAND
stem or pituitary stalk, and the posterior lobe of Lesions of the pituitary consist of a wide variety of
the pituitary gland (neurohypophysis). The neu- distinct conditions (Table 14.3).
rohypophysis is part of a neurosecretory unit and The signs and symptoms of pituitary lesions are
stores oxytocin and vasopressin hormones asso- due to (1) hormonal hyperfunction, (2) hormonal
ciated with the carrier protein, neurophysin. The hypofunction, and/or (3) compression of sur-
neurohypophysis is composed of nerve fibers, rounding structures.
axon terminals, and pituicytes, a glial cell of the Hyperfunction is due to excess secretion of
posterior lobe. trophic hormones. The most common cause is a
A B
POSTERIOR POSTERIOR
PITUITARY PITUITARY
GH GH
GH GH PRL PRL
GH-PRL GH-PRL
PRL ACTH PRL NULL NULL
FSH/LH ACTH FSH/LH
FSH/LH FSH/LH TSH NULL TSH
FSH/LH
FSH/LH
ANTERIOR TSH
ANTERIOR TSH
PITUITARY PITUITARY
Proportion of adenoma types:

Proportion of normal cells:
GH 50% TSH 5% GH 20% FSH/LH 10%
PRL 10-30% FSH/LH 10% PRL 30% TSH 1%
ACTH 10-30% GH-PRL 5% NULL 20%
ACTH 10% OTHERS 4%
FIGURE 14.2 (A) Drawing of cell type distribution in anterior pituitary in horizontal section. Note the dis-
tribution and proportion of GH-producing cells as illustrated in Figure 14.1. (B) Distribution of pituitary adeno-
mas in horizontal section. The principal locations of subtypes of pituitary adenomas correspond to the location
and distribution of the cells in the normal pituitary, as seen in (A).
Chapter 14 Diseases of the Pituitary Gland • 345

Table 14.3 . Lesions of the Pituitary and Sellar Region
Benign Neoplasms
Pituitary adenoma Neurilemomma
Atypical pituitary adenoma Paraganglioma
Meningioma Glomangioma
Craniopharyngioma Hemangioma
Granular cell tumor Hemangioblastoma
Gangliocytoma Myxoma
Ganglioglioma Fibrous dysplasia of bone
Ganglioneuroma Histiocytosis X
Glioma Giant cell tumor of bone
Paraganglioma Schwannoma
Osteoma Teratoma
Chondroma
Inflammatory disorders
Xanthomatous hypophysitis Giant cell granuloma
Lymphocytic hypophysitis Granulomatous hypophysitis
Vascular lesions
Pituitary infarction Aneurysm; Vascular malformation
Pituitary apoplexy
Cysts/malformations
Rathke’s cleft cyst Mucocele
Arachnoid cyst Dermoid cyst
Epidermoid cyst Hamartoma
Choristoma Congenital malformations
Malignant neoplasms
Pituitary carcinoma Metastatic carcinoma
Chordoma Metastatic carcinoma to pituitary adenoma
Germ cell tumors Leukemia
Hemangiopericytoma Metastatic lymphoma
Post irradiation sarcoma Plasmacytoma
Osteosarcoma Fibrosarcoma
Hemangiosarcoma Melanoma
Malignant histiocytosis Malignant peripheral nerve sheath tumor
Chondrosarcoma
Infectious diseases
Bacterial abscess Syphilis
Tuberculosis Cysticercosis
Fungal abscess Hydatid cyst
Systemic diseases
Hemosiderosis/hemochromatosis Amyloidosis
Mucopolysaccharidoses Sarcoidosis
Physical injury
Trauma Radionecrosis
Empty sella syndrome
Primary Secondary
functional adenoma, less frequently hyperplasia and diabetes insipidus, due to abnormal antidiuretic
rarely pituitary carcinomas. Non-pituitary tumors and hormone secretion. Alterations in the secretion of
hypothalamic diseases are rare causes of hyperpituita- the other posterior pituitary hormone, oxytocin,
rism. The clinical syndromes match with the hormone rarely cause a significant clinical syndrome.
produced by the lesion. The most common syn- The expanding mass effects of an adenoma can
dromes are gigantism/acromegaly due to the overpro- lead to sellar expansion, bone erosion, and disrup-
duction of growth hormone (GH), Cushing disease tion of the diaphragma sellae. Due to its location
or pituitary-dependent hypercortisolism due to the adjacent to the visual pathways, the expanding mass
overproduction of adrenocorticotrophic hormone, within the pituitary can cause compression of the
galactorrhea and ovulatory disturbances in hyperpro- optic chiasm with bitemporal hemianopsia. Patients
lactinemia in women and decreased libido and erectile with pituitary adenoma may develop increased
dysfunction in men, and hyperthyroidism or hypo- intracranial pressure, headaches, seizures, obstruc-
thyroidism in patients with pituitary-dependent TSH tive hydrocephalus, and cranial nerve palsies.
excess. Overproduction of gonadotrophic hormones
rarely causes well-defined clinical signs.
Hypofunction is caused by deficiency of trophic
4. HYPERPITUITARISM,
hormones due to lesions within the sella turcica PITUITARY ADENOMAS,
with destruction of the hormone-producing cells AND HYPERPLASIA
(Table14.4). The most common cause is a pituitary
Functional pituitary adenomas are the most common
adenoma; a less common one is inflammatory dis-
cause of hyperpituitarism. They represent 10% to
eases. The loss of the hormone-producing cells, and
20% of intracranial neoplasms in neurosurgical series.
consequent absence of the trophic hormones, leads
Incidental adenomas are found in up to 25% of autop-
to hypopituitarism, with thyroid, gonadal, and adre-
sies. Pituitary adenomas are benign, usually mono-
nal dysfunction. Patients may also show signs of iso-
clonal, well-circumscribed neoplasms, surrounded
lated anterior pituitary hormone deficiency such as
by a reticulin pseudocapsule. These tumors are found
hypothyroidism or hypogonadism.
primarily in women, in all age groups, but mostly
The most commonly observed clinical syndrome
between the third and sixth decades of life, while
associated with injury to the neurohypophysis is
childhood pituitary adenomas are extremely rare.
The clinicopathological classifications of pitu-
Table 14.4 . Major Causes of
itary adenomas are based on multiple factors,
Hypopituitarism
including histology and immunohistochemistry
Pituitary Diseases (Table 14.5), ultrastructure (Table14.6), endocrine
activity (Table 14.7), imaging data, and operative
Pituitary adenomas and carcinomas
findings (Table 14.8).
Pituitary surgery and radiation While the great majority of pituitary adenomas
Autoimmune diseases and hypophysitis will remain benign, a few show invasive behavior
Infiltrative and metabolic lesions and very rarely do they become malignant. The pat-
Pituitary infarction and apoplexy tern of growth can be expansive, grossly invasive, or,
Sheehan syndrome rarely, metastatic (Table 14.8). The location of the
adenomas within the pituitary has a basically similar
Genetic diseases
distribution to that of the normal anterior pituitary
Empty sella syndrome cells (Fig. 14.2B).
Pituitary cysts
Hypothalamic diseases
4.1. Peptide-hormone-producing
Mass effect: benign and malignant tumors adenomas:
Radiation for CNS and nasopharyngeal
malignancies 4.1.1 . PROL ACTIN (PRL ) CEL L ADENOMA
(PR OL ACTINOMA)
Infiltrative lesions
Trauma with fracture of skull base Most prolactinomas are composed of diffuse uni-
Infections formly round chromophobic cells by routine histo-
logical staining, with a paucity of secretory granules,

Table 14.5. Pituitary Adenomas and Immunohistochemical Findings
I M M U N O H I S T O C H E M I C A L C L A S S I F I C AT I O N O F A D E N O H Y P O P H Y S E A L T U M O R S
ADENOMA T YPE P R I N C I PA L I M M U N O R E A C T I V I T Y SECONDARY IMMUNORE AC TIVIT Y
Somatotrophic GH PRL, α-SU, TSH, FSH, LH

Lactotrophic PRL α-SU
Combined features GH and PRL α-SU, TSH
Corticotrophic ACTH LH, α-SU
Thyrotrophic TSH α-SU, GH, PRL
Gonadotrophic FSH/LH/αSU PRL, GH, ACTH
Plurihormonal Plurihormonal
Null cell Hormone immunonegative
WHO Histological Typing of Endocrine Tumors, 2004.
Table 14.6. Ultrastructural Classification of Adenohypophyseal

Tumors
TUMOR T YPE VA R I A N T
GH cell adenoma Densely granulated

Sparsely granulated
PRL cell adenoma Densely granulated
Sparsely granulated
Adenomas with GH and PRL cell Mixed GH and PRL cell adenoma
differentiation Mammosomatotroph cell adenoma
Acidophil stem cell adenoma
ACTH cell adenoma Densely granulated
Crooke cell variant
Sparsely granulated
TSH cell adenoma
FSH–LH cell adenoma Male type
Female type
Null cell adenoma Non-oncocytic
Oncocytic
Other adenomas Silent “corticotroph” subtype 1
Silent “corticotroph” subtype 2
Silent adenoma subtype 3
Plurimorphous adenomas (e.g.,
GH-PRL-TSH, PRL-ACTH, etc.)
Unclassified
WHO Histological Typing of Endocrine Tumors, 2004.
Table 14.7. Functional Classification of Table 14.8. Imaging and Surgical
Adenohypophyseal Tumors Classification of Adenohypophyseal
Tumors Based on Location, Size, and
Endocrine hyperfunction Growth Pattern
Acromegaly/gigantism, elevated GH levels
Hyperprolactinemia and sequelae Location
Cushing syndrome, elevated ACTH and Intrasellar
cortisol levels Extrasellar(extension into surrounding
Hyperthyroidism with inappropriate secretion structures: suprasellar, nasopharynx, sphenoid
of TSH sinus, cavernous sinus, etc.)
Significantly elevated FSH/LH and/or Ectopic
alpha-subunit levels Size
Multiple hormonal overproduction Microadenoma
Clinically nonfunctioning Macroadenoma
Functional status undetermined Growth Pattern
Endocrine hyperfunction due to ectopic sources Expansive
Clinical acromegaly secondary to ectopic GRH Grossly invasive to dura, bone, nerves, or brain
overproduction Metastatic (craniospinal or systemic)
Cushing syndrome secondary to ectopic CRH
overproduction
PRL-secreting tumors in males are usually
WHO Histological Typing of Endocrine Tumors, 2004. macroadenomas, while in females they are micro-
adenomas. Dopamine-agonist therapy produces
involution, atrophy, tumor growth arrest, and micro-
and are PAS negative. Prolactinomas are composed calcifications in prolactinomas.
of a homogeneous population of small cells with PRL-secreting tumors have to be differentiated
no pleomorphism (Fig.14.3A) and tend to contain from other lesions producing prolactinemia, such
microcalcifications and psammoma bodies. The as by interference of dopamine release by com-
PRL immunoreactivity in the sparsely granulated pression of the pituitary stalk. The serum level of
tumors is paranuclear in the region of the Golgi PRL in patients with stalk compression is usually
apparatus. The rarer densely granulated PRL cell less than 300 IU/microl, whereas in those with a
adenoma shows diffuse cytoplasmic prolactin posi- prolactin-secreting tumor it is usually above 1,000
tivity (Fig.14.3B). IU/microl.
A B
FIGURE 14.3 Prolactinoma. This adenoma is composed of sheets of uniform small cells with a densely stain-
ing nucleus and little cytoplasm (A). The tumor cells stain uniformly for prolactin (B).

4.1.2. GH CELL ADENOMAS differing prognoses. Immunohistochemistry for GH
shows a variable expression. If the tumor is sparsely
Clinical or immunohistochemical evidence of GH
granulated, the immunoexpression of GH is weak;
production occurs in around 30% of pituitary ade-
if the tumor is densely granulated, there is strong
nomas, including GH-only pituitary adenomas, GH
immunoreactivity.
and PRL pituitary adenomas, and plurihormonal
pituitary adenomas producing GH. These adeno-
4.1.2.2. Mixed GH cell/PRL cell adenoma
mas are the major cause of acromegaly/gigantism
Patients with acromegaly can also have evidence of
(Table 14.9).
hyperprolactinemia, due to the production of both
hormones (Fig.14.4). The mixed GH cell/PRL cell
4.1.2.1. GH-only pituitary adenomas
adenomas contain two different cell types, well char-
GH-producing tumors have a diffuse homogeneous
acterized by both their distinctive ultrastructural
cell population of round to oval cells. The majority
appearances and immunohistochemistry. These
of the cells in these tumors are acidophilic by rou-
lesions are not aggressive.
tine H&E staining. Because the GH molecule lacks a
carbohydrate component, PAS stains are uniformly
4.1.2.3. Mammosomatotrophic cell adenoma
negative. These tumors also have two different
This rare tumor is characterized by dual immu-
keratin patterns that correlate with the presence or
nopositivity and by a monomorphous cell popu-
absence of the alpha subunit and are associated with
lation. Unlike in mixed bicellular tumors, these
cells by electron microscopy exhibit both lac-
Table 14.9. Causes of Acromegaly/ totroph and somatotroph differentiation in the
Gigantism same cell.
Excess GH secretion 4.1.2.4. Acidophil stem cell adenoma These

Pituitary origin (around 98%) rare adenomas are clinically nonfunctioning or
GH cell adenoma (about 60%) may simulate prolactinoma because of stalk com-
pression. Acromegaly with elevation of GH is very
Mixed GH cell and PRL cell adenoma (about
unusual. These tumors are thought to represent
20%)
stem cells of the acidophilic line. By routine H&E
Mammosomatotroph cell adenoma (about 10%) stains, they are chromophobic, and the cells have
Plurihormonal adenoma a vacuolated cytoplasm. Both GH and PRL are
GH cell carcinoma detected in the same cell by immunohistochem-
MEN1 with GH cell adenoma istry and by electron microscopy; the tumor cells
McCune-Albright syndrome with adenoma show features intermediate between those of GH
and PRL cells.
Ectopic sphenoid or parapharyngeal sinus
pituitary adenoma
Extrapituitary origin 4.1. 3 . PL URIHORMONAL ADENOMA
Pancreatic islet cell tumor These adenomas are characterized by the produc-
Excess GHRH secretion tion of multiple hormones. They produce not only
Central ectopic (<1%) GH but also PRL, one or more of the glycoprotein
Hypothalamic hamartoma, choristoma, hormones, and the alpha subunit of the glycoprotein
ganglioneuroma hormones. The plurihormonal adenomas may be
functioning, partially functioning, or silent. One or
Peripheral ectopic (1%)
more cell types as detected by electron microscopy
Bronchial carcinoid, pancreatic islet cell can form these tumors. The monomorphous type is
tumor, small cell lung cancer, adrenal composed of one cell type that can produce multiple
adenoma, medullary thyroid carcinoma, hormones. The plurimorphous type is composed of
pheochromocytoma at least two cell types, each with distinct immuno-
Excess growth factor activity histochemical and electron microscopic character-
Acromegaloidism istics. Some of these last may represent a collision
tumor.
A B
FIGURE 14.4 Mixed GH-producing adenoma. This patient had acromegaly. The tumor is composed of
uniform small cells with only a small amount of cytoplasm (A). Most of the tumor cells stain positively for both
human GH (B) and PRL (C).
4.1.4. ACTH-PRODUCING ADENOMAS presence of ACTH or other propiomelanocortic

derivatives demonstrated by immunohistochemistry
A large number of lesions underlie the overproduction
(Fig.14.5). These adenomas have teardrop-shaped
of ACTH. The most common is ACTH-dependent
neurosecretory granules with variable electron den-
Cushing syndrome from a basophilic ACTH-producing
sity and cytokeratin accumulation in the perinuclear
pituitary adenoma with adrenal cortical hyperplasia
region, simulating the Crook’s hyaline change of nor-
(Table 14.10). ACTH-independent Cushing disease is
mal corticotrophs. Diffuse Crook’s hyalinization of
less frequent.
ACTH adenomas is rare and associated with larger
neoplasms-macroadenomas with invasion.
4.1.4.1. Corticotroph cell adenomas These
represent approximately 20% of the pituitary ade-
nomas, and they occur more often in women than 4.1.4.2. Silent corticotroph adenoma These
men. Most corticotroph cell adenomas are micro- are macroadenomas that are endocrinologically
adenomas and arise in the central mucoid wedge nonfunctioning but immunoreactive for ACTH.
of the anterior pituitary, where most of the normal Most likely, these neoplasms elaborate abnormal
ACTH-producing cells are located. Posteriorly endocrinologically inactive products or they fail to
located adenomas are uncommon; they are thought release the hormone. Some patients have a mildly
to derive from intermediate lobe corticotrophs and elevated serum ACTH level. Silent corticotroph
are usually silent. ACTH-producing macroadeno- adenomas are composed of basophilic to chromo-
mas are rare and often invasive. At microscopy, the phobic cells, with immunoreactivity to ACTH or
tumors are monotonous, composed of cells with other POMC derivatives, similar to the usual corti-
basophilic and PAS-positive cytoplasm, and the cotroph cell adenoma.

Table 14.10. Causes of Cushing to demonstrate immunoreactivity for these hor-
syndrome mones (Fig.14.6). Gonadotroph adenomas exhibit
ultrastructural diversity. These tumors are believed
ACTH-dependent Cushing syndrome to be nonfunctional because of a failure to appropri-
Cushing disease—Pituitary adenoma/ ately combine the alpha and beta subunits of the gly-
carcinoma coprotein hormones to make the active hormone.
Ectopic ACTH syndrome Most of the gonadotroph adenomas become
Ectopic CRH syndrome evident because of mass effect on the surround-
ing structures. Some tumors are diagnosed in the
elderly after a long history of hypogonadism. These
ACTH-independent Cushing syndrome macroadenomas less frequently invade surrounding
Adrenal adenoma structures and recur less often than the other mac-
Adrenal carcinoma roadenoma subtypes (Table 14.11).
Micronodular hyperplasia
Macronodular hyperplasia 4.1. 6 . THYROTROPH CEL L ADENOMA
Primary pigmented nodular adrenocortical
TSH-producing tumors are rare, often invasive
disease
macroadenomas, which can present with either
Pseudo-Cushing syndrome hyperthyroidism or hypothyroidism. They repre-
Major depressive disorder sent approximately 1% of pituitary adenomas. The
Alcoholism majority of these tumors have polygonal cells that
are chromophobe by routine H&E stains and faintly
PAS positive. Immunohistochemistry shows the
4.1.5. GONADOTROPH CELL ADENOMA tumor cells to be positive for both beta-TSH and the
alpha subunit of the glycoprotein hormones. Most
The normal FSH/LH cells are basophilic and PAS of these lesions are located in the anterior mucoid
positive, but the adenomas derived from these wedge, where the thyrotroph cells are usually con-
cells are chromophobic and only faintly PAS posi- centrated. Electron microscopy shows peripherally
tive, with positive granules located at the periphery placed sparse secretory granules.
of their cytoplasm. There is marked variability of
immunoexpression in these tumors. Some tumors
4.1. 7 . PITUITARY ADENOMA WITH
demonstrate diffuse positive immunoreactivity for
NEURONAL METAPL ASIA
the beta subunits of the gonadochorionic hormone
(HCG), FSH and LH, with or without immunore- Rare GH-producing pituitary adenomas and even
activity for the alpha subunit, and some tumors fail more rarely other types of pituitary adenomas may
A B
FIGURE 14.5 ACTH-producing adenoma seen on the left, with well-defined borders from the normal pitu-
itary (A). (B) Higher-power view (Immunohistochemistry for ACTH).
A B
C D
E F
FIGURE 14.6 Gonadotrophic adenoma. Note that the tumor cells are arranged in a papillary fashion around
fine capillaries (A). A variable number of tumor cells stain the beta subunits of the human chorionic gonadotro-
phin (B), LH (C), FSH (D), and TSH (E), and the alpha subunit (F).
contain ganglion cells. The neurons react with to represent neuronal metaplasia of adenoma
neuronal markers such as neurofilament protein as cells; this is supported by immunocytochemical
well as epithelial markers and hormonal immuno- and ultrastructural demonstration of cells with
profile of the adenoma cells. These ganglion cells transitional features between neurons and pitui-
may be scant or may represent the great majority cytes. Alternatively, the presence of neurons in
of tumor cells and may or may not be accompa- an adenoma might represent a developmental
nied by neuropil. The ganglion cells are thought malformation.

Table 14.11. Clinical Presentations of sphenoid sinus, mouth, or nasal cavity or in the supra-
Gonadotroph Adenomas sellar region. These ectopic adenomas can be hormon-
ally producing tumors or null cell adenomas.
Neurological symptoms/mass effect
Visual impairment, headache, diplopia, and 4.4. Invasive pituitary adenomas
seizures
Pituitary adenomas are classified as invasive, if
Cerebrospinal fluid rhinorrhea
invasion of the dura, adjacent bone, cavernous
Other sinus, or sinus mucosa can be demonstrated on the
Incidental finding basis of imaging or operative findings. There are
Hormonal symptoms no light or ultrastructural features distinguishing
Oligomenorrhea or amenorrhea, premenopausal noninvasive adenomas from invasive and aggres-
woman sive adenomas. Mitoses are more often present in
Ovarian hyperstimulation (FSH increased), invasive tumors than in noninvasive lesions. p53
premenopausal woman immunohistochemical expression is higher in
invasive adenomas
Precocious puberty (intact LH secreted),
prepubertal boy
Symptoms of hormonal deficiencies
4.5. Atypical adenoma
An adenoma with clinicopathological character-
istics intermediate between a typical adenoma
and pituitary carcinoma is defined as “an adenoma
4.2. Adenomas not associated
with atypical morphological features suggestive of
with hormone production (null cell
aggressive behavior.” These are macroadenomas,
adenomas)
with invasive behavior and frequent recurrences,
These adenomas account for approximately one demonstrating their potential for aggressive behav-
third of all pituitary adenomas. They have no clini- ior. Atypical pituitary adenomas have increased
cal evidence of hormonal production and are char- mitotic activity, possibly including occasional atypi-
acterized by no or scant hormone immunoreactivity cal mitosis, with a proliferative MIB-1 index greater
and ultrastructural features of cells without specific than 3% (Fig.14.7) and, often, p53 over-expression
differentiation. These lesions include a heteroge- with or without p53 gene mutation (Table 14.12).
neous group of adenomas, despite the similar clini-
copathological features. Due to the lack of hormonal 4.6. Pituitary carcinoma
overproduction, they tend to present with symptoms
and signs associated with compression and, if there is Adenohypophyseal neoplasms with craniospinal
extensive normal pituitary tissue destruction, hypo- spread and brain invasion and metastases to extra-
pituitarism. Some of these patients may have mild cranial sites are designated pituitary or adenohy-
hyperprolactinemia if there is pituitary stalk com- pophyseal carcinomas. They are extremely rare.
pression by the adenoma. The pathological diagnosis Metastatic potential distinguishes pituitary carci-
of null cell adenoma is based on the morphological noma from the other adenohypophyseal tumors.
features, hormonal immunoprofile, and electron The metastases are usually to lymph nodes, bone,
microscopy. Most null cell adenomas are silent liver, or skull (Fig.14.8A). Pituitary carcinomas are
gonadotrophic adenomas with minimal glycoprotein more frequently hormonally inactive tumors; how-
expression, such as beta-FSH, LH, or alpha-subunit ever, prolactin-producing and ACTH-producing
immunoreactions. Some of the null cell adenomas carcinomas have been described.
have oncocytic changes (oncocytomas), indicating a It is not possible to make a diagnosis of pitu-
large concentration of mitochondria. itary carcinoma based on histological criteria alone.
Most carcinomas do not show much cellular pleo-
morphism or nuclear atypia. However, they have
increased mitotic activity, high MIB-1 labeling
4.3. Ectopic adenoma index (Figure 14.8B) and p53 immunoreactivity
Ectopic adenomas are extremely rare. They are derived (Table 14.12) when compared with typical, and
from pituitary cells in the pharynx and can occur in the atypical adenomas.
A B
FIGURE 14.7 Atypical pituitary adenoma with recurrence. Histological appearance (A), high MIB-1 index
(B), and adenoma cell nuclei with positivity for p53 (C).
4.7. Pituitary hyperplasia pituitary cell types; it is distinct from neoplasia.

Anterior pituitary hyperplasia can be classified as
A rare cause of pituitary hyperfunction is pituitary primary hyperplasia (idiopathic); secondary hyper-
hyperplasia. It may cause a clinical syndrome such plasia due to lack of negative feedback stimulation
as acromegaly, Cushing syndrome, and hypothy- and end-organ failure; or tertiary hyperplasia due to
roidism. By definition, pituitary hyperplasia is an hypothalamic hormone stimulation. Idiopathic pitu-
increase in number of one or more specific anterior itary hyperplasia is probably due to hypothalamic
Table 14.12 . Differences Between Pituitary Adenomas, Atypical Adenomas, and

Pituitary Carcinomas
TUMOR CHAR AC TERISTICS ADENOMA AT Y P I C A L A D E N O M A CA RCINOMA
Mitosis rare few present

MIB-1 0–3% >3% high
P53 negative 0–15% 100%
Tumor size micro/macro macro macro
Gross invasion possible probable required
Metastases no no required

A B
FIGURE 14.8 Metastases of pituitary carcinoma. Gross appearance (A) and histological appearance similar to
pituitary adenomas with high proliferative activity, as seen by MIB-1 and presence of mitosis (B).
dysfunction with excess of hypothalamic hormone or the postpartum period; it is a cause of pituitary
production (Table 14.13). insufficiency of pregnancy. The clinical presentation
Hyperplastic cells are usually found in foci, but is that of pan-hypopituitarism and often headache.
the process can be nodular or diffuse. The diagno-
sis is based on histological findings of expansion of
the acinar architecture, seen with a reticulin stain. Table 14.13 . Pituitary Hyperplasia
Immunohistochemistry can help in identifying the
Prolactin cell (Lactotroph cell)
hyperplastic cell type. The differential diagnosis
from adenoma can be difficult (Table 14.14). Physiological: Pregnancy and estrogen therapy
Secondary to decreased dopamine release to
anterior pituitary from hypothalamus, secondary
5. HYPOPITUITARISM to suprasellar space-occupying lesions
AND INFLAMMATORY AND Hypothyroidism (TRH effect)
VASCULAR LESIONS GH cell (Somatotroph cell)
Hypopituitarism is caused by deficiency of the pitu- Primary hyperplasia: Hypothalamic hamartoma
itary trophic hormones due to a variety of causes. or ectopic sources of GHRH
With the loss of 50% of the pituitary cells, the patient Primary hyperplasia: Neuroendocrine neoplasia
may be asymptomatic. When more than 80% of the by GnRH excess
anterior pituitary cells are destroyed, hypopituita- Mammosomatotroph cell hyperplasia in
rism becomes evident. McCune-Albright syndrome
Adrenocorticotrophin (Corticotrophin cell)
5.1. Inflammatory lesions Secondary hyperplasia: Glucocorticoid
Inflammatory lesions of the pituitary can cause insufficiency in untreated Addison disease
hypopituitarism, mass effect, and/or diabetes insipi- Primary hyperplasia: Excessive secretion of
dus. Inflammatory disorders of the pituitary can be corticotrophin-releasing hormone by ectopic
divided into those that are primary (or idiopathic) or neuroendocrine neoplasms or gangliocytic
and those that are secondary to lesions elsewhere in hamartoma
the body (Table 14.15).
Idiopathic
LH/FSH (Gonadotroph cell)
5.1.1. PRIMARY OR IDIOPATHIC
Secondary hyperplasia: Hypogonadism,
I NFLAMMATORY LE SIONS
Klinefelter and Turner syndrome
5.1.1.1. Lymphocytic hypophysitis Lympho- TSH (Thyrotroph cell)
cytic hypophysitis is a chronic autoimmune pro- Secondary hyperplasia: Primary hypothyroidism
cess that is particularly associated with pregnancy
Table 14.14 . Pituitary Adenoma and Hyperplasia
ADENOMA HYPERPL ASIA
Pattern of growth Diffuse Nodular and diffuse

Normal pituitary Compressed No distinction
HE stain Loss of acinar pattern, one cell Acinar pattern maintained and
population distinct cells
Reticulin stain Disruption of the acinar pattern, Preserved pattern, with expanded
pseudo-capsule acini
Immunohistochemistry Specific hormone strong reactivity Specific hormone weak reactivity
Decompressive biopsy is part of the treatment. Microscopically, granulomatous hypophysi-

The adenohypophyseal interstitium and the acini tis is characterized by large collections of histio-
are infiltrated by lymphocytes and plasma cells cytes, occasional multinucleated giant cells, and a
with occasional histiocytes. Lymphoid follicles lymphoplasmacytic infiltrate (Fig.14.10). It must
with well-developed germinal centers can occur be differentiated from other causes of granuloma-
(Fig.14.9). Fibrosis may be found in chronic phases. tous inflammation such as tuberculosis, fungi, and
Both humoral and cell-mediated immunity is sarcoidosis.
apparently involved, with the development of anti-
pituitary antibodies. 5.1.1.3. Xanthomatous hypophysitis Xant-
homatous hypophysitis is a rare idiopathic entity
5.1.1.2. Granulomatous hypophysitis Granu- that may represent a reactive process. It occurs in
lomatous hypophysitis is a rare chronic inflam- young women who present with a combination
matory disease of unknown pathogenesis. Unlike of menstrual irregularities, diabetes insipidus,
lymphocytic hypophysitis, granulomatous hypoph- headache, and nausea with a localized lesion in
ysitis occurs equally in both sexes. The usual clinical the pituitary. Histologically the adenohypophysis
presentation is a variable degree of adenohypophy- is infiltrated by foamy histiocytes, immunoreac-
seal failure, hyperprolactinemia, headache with tive for CD68 and immunonegative for CD1a and
nausea and vomiting, and diabetes insipidus. S-100 protein.
Table 14.15. Inflammatory Lesions of the

Pituitary Gland
1. Primary or idiopathic
• Lymphocytic hypophysitis
• Granulomatous hypophysitis
• Xanthomatous hypophysitis
• Giant cell granuloma
2. Secondary
• Infections: Pneumocystis, Toxoplasma,
cytomegalovirus, meningitis, syphilis,
brucellosis, fungi, mycobacteria
• Systemic diseases: sarcoidosis, Wegener
granulomatosis, Takayasu disease, Crohn disease
• Adenoma undergoing necrosis FIGURE 14.9 Lymphocytic hypophysitis. The
• Ruptured Rathke’s cleft cyst anterior pituitary tissue is almost replaced by a lym-
phocytic infiltrate.

5.2. 3 . SHEEHAN SYNDROME
Sheehan syndrome is hypopituitarism in women
following delivery of a baby and is due to ischemic
necrosis of the pituitary gland secondary to hypoten-
sion from postpartum hemorrhage. The posterior
pituitary is spared due to its independent blood sup-
ply. There is a rim of normal viable adenohypophyseal
cells at the periphery of the gland, with almost total
necrosis of the gland. Fibrosis follows the necrosis.
6. HEREDITARY AND
FIGURE 14.10 Granulomatous hypophysitis. There DEVELOPMENTAL DISORDERS
is a well-formed granuloma in the anterior pituitary
with epithelioid cells and some scattered multinucle- 6.1. Persistence of Rathke’s
ated giant cells at the periphery. pouch remnants
These are small nests of squamous cells in the poste-
5.1.1.4. Giant cell granuloma of the pituitary rior lobe adjacent to the cleft. They can be found in
Giant cell granuloma of the pituitary is another rare 30% of normal human pituitaries at autopsy. The nests
cause of hypophysitis. It occurs in both sexes and is have no hormonal function and are an unlikely origin
not associated with pregnancy. Histologically, the of a neoplasm, although it has been postulated that
pituitary is infiltrated by non-caseating granulo- craniopharyngiomas may arise from these remnants.
mas with occasional Schaumann bodies. Systemic
evidence of sarcoidosis or other diseases has to be
6.2. Persistence of cleft
excluded.
of Rathke’s pouch
This developmental abnormality is frequent, with-
5.1.2. SECONDARY HYPOPHYSITIS out significant functional and clinical problem. It is a
A variety of systemic diseases and infections can also colloid-filled space between the anterior and poste-
cause hypophysitis (Table 14.15). rior pituitary that can give rise to Rathke’s cleft cysts.
These cysts are usually small, but when large, they
can be symptomatic either from pressure or hypopi-
5.2. Vascular lesions of the pituitary tuitarism, including diabetes insipidus. When supra-
sellar extension is present, headaches and visual
5.2.1. PITUITARY INFARCTION
fields defects can occur.
Diverse diseases can cause ischemic necrosis of The cyst contains watery to mucinous fluid and
the pituitary gland, such as hemorrhagic shock, is lined by columnar epithelium or ciliated cuboidal
thrombocytopenia and other coagulopathies, epithelium with occasional goblet cells. Squamous
head injury, massive cerebrovascular accidents, metaplasia, xanthomatous inflammation, and amy-
and heparin therapy. This condition is followed by loid deposition can be seen (Fig.14.11).
hypopituitarism.
6.3. Cysts
5.2.2. PITUITARY APOPLEXY
Arachnoid cysts, congenital or acquired, and dermoid
This is a medical emergency presenting with or, more commonly, epidermoid cysts originating
acute headache and sometimes visual loss, sec- from ectopic or implanted epithelial cells can be
ondary to hemorrhage or infarction, usually of a found in the sella or parasellar regions. The clinical
pituitary macroadenoma. It can be seen also in presentation of patients with these cysts is that due
the setting of an enlarged pituitary gland during to mass effect from suprasellar extension or hypopi-
pregnancy. tuitarism due to pituitary compression.
Table 14.16. Classification of MEN and
Pituitary Involvement in These Diseases
Type 1
Primary hyperparathyroidism (>90%)
Pituitary tumors (10–20%)
Prolactinoma
GH secreting
Corticotrophin secreting
Non-hormone secreting
Enteropancreatic tumors (60–70%)
Gastrinoma (Zollinger-Ellison syndrome)
FIGURE 14.11 Rathke’s pouch cyst. Note the
multilayered cuboidal epithelium lying on a connec- Insulinoma
tive tissue base. Vasoactive intestinal polypeptide secreting
Glucagonoma
Pancreatic polypeptide secreting
6.4. Pituitary aplasia and hypoplasia Non-hormone secreting
Congenital absence of the pituitary is rare and is Other
usually associated with hypoplasia of the adrenals,
thyroid, and gonads. Even if the anterior pituitary
Type 2A
is not formed, the posterior pituitary may be pres-
ent. Pituitary hypoplasia is an incomplete develop- Medullary thyroid cancer (>90%)
ment of the pituitary gland, as a result of atrophy or Pheochromocytoma (40–50%)
because of a developmental defect. It may be asso- Parathyroid hyperplasia (10–20%)
ciated with anencephaly, where the number of cells Cutaneous lichen amyloidosis
may be normal but the ACTH-producing cells are
decreased and have poorly developed organelles.
Type 2B
Medullary thyroid cancer
6.5. Empty sella syndrome Pheochromocytoma
Empty sella syndrome is an anatomical description Other
of the appearance of the sella turcica. Empty sella Mucosal neuromas
syndrome can be primary or secondary. The primary Intestinal ganglioneuromas
empty sella syndrome is a developmental disorder due Marfanoid habitus
to incomplete development of the diaphragma sellae.
The arachnoid membrane invaginates and compresses
the pituitary. This condition is usually asymptomatic; Familial medullary thyroid cancer (variant of 2A)
however, imaging studies may reveal an enlarged sella, Medullary thyroid cancer
mimicking a pituitary adenoma. The secondary empty
sella syndrome occurs after resection, irradiation,
necrosis, or infarction of a pituitary adenoma. (MEN1). MEN1 is inherited as an autosomal domi-
nant disorder. The gene responsible is located on
7. OTHER LESIONS chromosome 11q13; it is a suppressor gene and
produces a protein called menin. An abnormality
of this gene is related to pituitary gland, pancreas,
7.1. Pituitary diseases in familial and parathyroid gland hyperplasia and neoplasia
syndromes (Table 14.16). The pathophysiological findings in
Pituitary adenomas are integral components of MEN1-associated pituitary adenomas are related to
the type 1 multiple endocrine neoplasia syndrome genetic events involving the MEN1 gene. Both genes

have to be mutated for the development of pituitary 7.3. Tumors of the hypothalamus,
neoplasia: one copy has inherited a mutation, and neurohypophysis, and sellar region
the other copy acquires a mutation. Other genes
may be mutated and some hormonal factors may The region of the sella has a variety of tissues
be involved both in the formation of adenomas and and cell types, including central and peripheral
in the hormone production of pituitary adenomas nervous system, endocrine, germinal, epithe-
associated with MEN1. The pituitary adenomas in lial, meningeal, mesenchymal, and hematopoi-
the MEN1 syndrome are usually hormonally active, etic cells. Besides the great variety of neoplasms
with a preponderance of PRL and/or GH produc- that can occur in this region, the neoplasms can
tion. Other syndromes associated with pituitary mimic each other, clinically and morphologically.
adenomas are MEN4, Carney complex, and familial Immunohistochemistry is, most of the time, nec-
isolated pituitary adenoma (FIPA). essary for the differential diagnosis of the lesions
in this region (Table 14.17).
7.2. Metastatic neoplasms to the

7.3. 1 . CRANIOPHARYNGIOMA
pituitary gland
Metastatic neoplasms to the pituitary gland are Craniopharyngiomas are an uncommon neoplasm
rare (Fig.14.12). The metastases are usually from but are the second most common neoplasm of the
carcinomas in patients with widespread systemic sellar region, following pituitary adenomas and the
metastases. Metastatic sarcomas are extremely rare. most common suprasellar neoplasm in children.
Metastases occur more often to the posterior lobe The vast majority of craniopharyngiomas are in the
because of the systemic arterial blood supply and suprasellar region. The usual symptoms are head-
present with diabetes insipidus. The most com- ache and visual changes.
mon primary sites of origin in women are breast, Adamantinomatous craniopharyngiomas are
lung, and stomach, and in men, lung and prostate. usually cystic, irregular nodular masses of firm
Occasional metastases of melanoma and germ tissue with yellow-brown viscid contents, often
cell tumors to the pituitary are seen. The anterior described as “crank case oil”(Fig.14.13A). The
lobe can be the only region involved by metastatic fluid contains large numbers of cholesterol crystals.
tumor; in such cases the differential diagnosis Pseudostratified columnar cells palisade around stel-
from a pituitary adenoma has to be considered, late cells, forming the adamantinomatous pattern.
and this often requires immunohistochemistry The basaloid epithelium keratinizes without matur-
(Table 14.17). ing, giving rise to nests of keratin in the tumor (wet
keratin). A squamous cell pattern can be intermixed
with the adamantinomatous, forming a mixed pat-
tern (Fig.14.13B, C). The tumors frequently contain
calcified debris, cholesterol clefts, and foreign body
giant cells.
Papillary craniopharyngioma is more often a
tumor of adults. Histologically, it differs from the
adamantinomatous form by the formation of squa-
mous papillomatous growth without the basal epi-
thelium or calcification. Radical excision is rarely
curative and may lead to hypothalamic dysfunction
and psychological abnormalities as well as hypopi-
tuitarism; recurrence is common.
7.3. 2 . GRANUL AR CEL L TUMORS

FIGURE 14.12 Metastatic carcinoma to the
pituitary gland. The atypical glandular cells are sur- Granular cell tumors are benign tumors of the neu-
rounded by pituicytes, seen in the upper portion of rohypophysis or distal pituitary stalk with uncer-
the figure. The patient had widely metastatic breast tain histogenesis. Most are slow-growing tumors,
cancer. and affected patients are asymptomatic. They may
Table 14.17. Immunoreactivity of Tumors of the Pituitary and Sellar Region
TUMOR PITUITARY EMA CK S100 SYN CHROMO- CEA PLAP LCA VIMENTIN
HORMONES PROTEIN GRANIN
Pituitary + ACTH ACTH – + Null cell > – – – –

adenoma (Null cell –) + + LH/FSH,
GH ± TSH
Metastatic – + + ± ± ± ± – ±
carcinoma
Myeloma – ± – – – – – – ± –
Germinoma – – 10% + – – – – + – 15% +
Granular – – – + – – ± – – +
cell tumor
Chordoma – + + + – – + – – +
10%
EMA, epithelial membrane antigen; CK, cytokeratin; SYN, synaptophysin; CEA, carcinoembryonic antigen; PLAP, placental alkaline
phosphatase; LCA, leukocyte common antigen.
A B
FIGURE 14.13 Craniopharyngioma. (A) Gross appearance. The coronal section of the brain at the level of
the hypothalamus shows a craniopharyngioma occupying the region of the hypothalamus. Microscopy showing
the adamantinomatous pattern with the basaloid epithelium (B) and the lacy type of epithelial maturation with
keratin nests (C).

be found incidentally in 1% to 17% of autopsies if
careful sectioning of the pituitary is performed.
Macroscopically they are firm, well-demarcated,
non-encapsulated lesions. The characteristic histo-
logical findings are similar to granular cell tumors of
other locations.
7.3.3. CHORDOMA
Chordomas of the sellar region, clivus, and sphe-
noid bone account for about half of all chordo-
mas, corresponding to the most cranial portion of
the notochord. Visual field changes are the most
FIGURE 14.15 Germinoma. The picture shows a
common presentation, and bony destruction of
densely cellular tumor composed mostly of lympho-
the sella and clivus is frequent. The myxoid mul-
cytes interspersed with some much larger cells with
tilobular neoplasm has characteristic histological
clear cytoplasm and prominent nucleoli.
features. It is composed of cords of physalifer-
ous cells (Fig.14.14), with vacuoles that contain
mucin. The extracellular matrix is Alcian Blue 7.3. 5 . PL ASMACYTOMA
positive.
A difficult histological differential diagnosis from
pituitary adenoma is a plasmacytoma of the sel-
7.3.4. GERM CELL TUMORS lar region (Fig.14.16). The majority of the sellar
plasmacytomas will evolve into systemic multiple
Germ cell tumors are usually located in the mid- myeloma. Immunohistochemistry is usually helpful
line and are derived from residual germ cells. The in distinguishing these entities.
germ cell tumors of the pituitary are rare and
include germinomas (Fig.14.15), embryonal car-
7.3. 6 . HAMARTOMA OR CHORISTOMA
cinomas, endodermal sinus tumors, teratomas,
and choriocarcinomas. The histological findings Hamartomas or choristomas are rare and located
are similar to the corresponding tumor found usually in the hypothalamus. Hamartomas are
elsewhere. lesions attached to the tuber cinereum or the
FIGURE 14.16 Plasmacytoma. This is a rare

FIGURE 14.14 Chordoma. The neoplasm is neoplasm of the pituitary usually in association with
derived from notochord and has a similar histological systemic multiple myeloma. The picture shows pleo-
appearance. morphic atypical plasma cells.
mammillary bodies, located usually behind the 7.3.7 . OTHER TUMORS
pituitary stalk. The patient may present with visual
Other primary neoplasms in the region of the sella
field defects or endocrinological disturbances, such
turcica are rare and include meningioma, paragan-
as precocious puberty. The association of neuronal
glioma, oligodendroglioma, ependymoma, glioma,
hamartomas and GH-producing pituitary adeno-
esthesioneuroblastoma, histiocytosis X, fibromas,
mas has suggested that the GH-releasing factor has
sarcomas, giant cell tumor of bone, osteosarcoma,
a paracrine effect. Hamartomas and choristomas are
melanomas, vascular tumors, and lymphomas,
firm, round masses formed by mature neurons in
among others (Table 14.3).
clusters separated by unmyelinated axons.

Appendix
Brief Survey of Neuropathological Techniques

H O M A ADLE -BI AS S ETTE A N D JA C Q U EL I N E MI K O L
THE PRACTICE of neuropathology depends on the entire length of the spinal cord and dorsal root
a number of specialized techniques, most of which ganglia need to be examined or can occur after evis-
are derived from those used in general pathology. ceration (anterior approach). The procedure includes
the following steps:
1. METHODS OF REMOVAL
A. Posterior approach
• The body is turned face down.
1.1. Autopsy • The skin and underlying soft tissues are incised
Autopsy of the nervous system cannot be regarded along the spinous processes from the exter-
as an isolated procedure; the findings should be cor- nal occipital protuberance to the base of the
related with those of the general autopsy. The pro- sacrum.
cedure must be performed without delay, since the • The soft tissues are freed, first with the knife
central nervous system (CNS) is very rapidly altered and then with a scraper, to expose the vertebral
by postmortem autolysis. CNS tissue is delicate and, lamina on either side of the spinous processes.
being enclosed within bony structures (skull and The prosector should angle the blade of the saw
spine), dissection is complex and requires special so as to cut as far laterally as possible from the
training. posterior spinous processes.
• The vertebral laminae are then sectioned along
the entire spine.
1.1.1. REMOVAL OF THE SPINAL CORD
• The spinous processes down the length of the
Removal of the spinal cord may proceed at the begin- dissection, together with their connecting tendi-
ning of the autopsy via the posterior approach, when nous aponeuroses, are lifted and pulled off.
• 365
• The rostral end of the cervical cord, as high up as (optic nerves, internal carotid arteries, pituitary
possible, is severed with a scalpel. stalk).
• The spinal cord is then carefully removed by • The tentorium cerebelli is incised along at the
lifting the dura with a pair of forceps at each outer edge of its attachment to the upper border
segmental level, working carefully from the of the petrous bone.
top, down to the cauda equina, cutting with a • The posterior connecting structures (cranial
scalpel or scissors each of the spinal nerve roots nerves, vertebral arteries) are sectioned while,
and sequentially dissecting out the dorsal root with one hand, the prosector supports the brain,
ganglia. which will otherwise tend to topple backward.
B. Anterior approach • The brain is then delivered; with one hand the
• The bodies of the vertebrae are peeled off and prosector continues to support the brain while
the peduncles of the vertebrae are cut along the placing the palm of the other hand on the ventral
length of the cord. The anterior vertebral arch is surface of the pons, inserting the index finger to
then lifted and then the spinal cord is removed the left and the middle finger to the right of the
following the procedure described above. medulla. If the spinal cord has not been removed
beforehand, it will be necessary to section the
Once the cord is removed, the dural sheath is upper cervical cord with a long, thin scalpel. The
opened longitudinally with scissors along the mid- cut end of the medulla is then delivered, follow-
line, on both the dorsal and ventral surface, to iden- ing which the prosector inserts two fingers under
tify any lesions and also to permit better penetration each cerebellar hemisphere. With the left hand the
by the fixative and thus avoid possible shrinkage and prosector is then able to lift the entire brain, and it
distortion of the underlying cord. only remains for the dura of the posterior fossa to
The spinal cord is then stretched out flat, secured be incised for the brain to be completely freed.
on a cardboard or other suitable surface, and fixed by • The brain is weighed.
immersion in 10% formalin. • A string is tied around the basilar artery (or other
method of suspending the brain) and the brain is
immediately immersed in 10% formalin, base fac-
1.1.2. REMOVAL OF THE BRAIN
ing up, within a receptacle large enough to allow it
Removal of the brain entails the following steps: to float and thus avoid future distortion resulting
• The body is turned face up. from potential postmortem compression.
• The scalp is incised along a coronal plane from
one pinna to the other. In cases of suspected infection, meningeal swabs or
• The scalp is freed and reflected forward up to the portions of the brain itself are sent to the microbiol-
supraorbital ridges and backward to the external ogy laboratory for culture. These specimens must be
occipital protuberance. secured before immersion of the brain in formalin.
• The cranial cavity is opened with an electric saw. Similarly, if the case is part of a research protocol, or if
• The skull cap thus obtained is lifted by exerting tissue is needed for biochemical analysis, selected sam-
firm traction from front to back, using the wedge ples are taken and, if necessary, frozen before fixation.
of the autopsy hammer inserted in the center
of the cut frontal bone. The dura should remain
1.1. 3 . REMOVAL OF PORTIONS OF
intact up to this point.
THE PERIPHERAL NERVOUS SYSTEM
• The dura is then incised first longitudinally,
AND SAMPL ES OF THE SKEL ETAL
approximately 2 cm on either side of the midline
MU SCUL ATURE
from front to back, and then in a semicircular
fashion, along the edge of the cut bone. The removal of samples of skeletal muscle and
• The anterior attachment of the falx cerebri is peripheral nerves is both easy and essential,
incised down to the crista galli. although it is well known that, because of various
• The olfactory bulbs are lifted off and gently dis- artifacts, histopathological examination of autopsy
sected off the base of the skull. material gives less valuable information than exami-
• The frontal lobes are very gradually raised and nation of biopsies. In obtaining these samples it is,
freed from front to back, sequentially sectioning of course, important to avoid multiple skin incisions
with scissors the anterior connecting structures and disfigurement of the body.
366 • APPENDIX
1.1.4. SPECIAL PROCEDURES neurosurgeon. Ideally, separate portions of the spec-
imen should also be snap frozen for molecular stud-
Removal of the spinal cord, brain, samples of the
ies in most brain tumor biopsy specimens, in muscle
peripheral nervous system, and the skeletal mus-
and nerve biopsy specimens, and in cases where
culature is part of a complete routine autopsy. In
there is a strong clinical suspicion of prion disease or
some cases this must be supplemented by dissection
in certain infectious diseases.
of certain areas of the body that are not ordinarily
For purposes of intraoperative consultation with
examined as part of a routine autopsy procedure.
the neurosurgeon, frozen sections and smear and
This includes, for example, removal of the eyes and
touch preparations are prepared; these permit a gen-
the petrous portion of the temporal bone and inner
eral diagnostic assessment to be rendered within a
ear, examination and sampling of the base and the
few minutes. This information can be very useful, so
vault of the skull, and removal en bloc of the cervi-
long as the interpretative shortcomings of the proce-
cal spine to include the vasculature of the neck.
dure are recognized by all involved.
Removal of the pituitary gland is part of any routine
autopsy.
Special consent must be obtained if necropsy 1.3. Biopsy procedures
study of these areas is to be performed. Indeed, the
legal consent requirements for the autopsy have 1.3.1 . MUSCL E BIOPSY
greatly changed in many parts of the world, and the This is a minor surgical procedure, but it is impor-
prosector must strictly adhere to the authorization tant to stress the strict and meticulous technical
as stipulated in the autopsy form when determining care with which it must be performed. Muscle tis-
if retention of organs is permitted or if all these must sue is very delicate, and if it is not removed with
be returned to the body, except those portions of all necessary precautions, the microscopic evalu-
tissue strictly necessary for diagnosis. The physician ation of lesions may be hampered by the presence
requesting the autopsy must inform the family of the of artifacts (see Chapter 12). The operation is per-
implications of a restricted autopsy as regards the formed under local anesthesia, care being taken not
limited extent of information that can be expected to inject the local anesthetic beneath the level of the
from a postmortem examination under such cir- investing aponeurotic fascia. The incision must be
cumstances, particularly in a nonhomogeneous generous enough to permit easy dissection of the
organ such as the brain. Tissue retained for research muscle. After the deep fascia and the perimysium
purposes ordinarily requires family consent in many have been incised, the muscle is dissected by follow-
countries. ing the plane of cleavage of the muscle bundles in
a direction parallel to that of the fibers. A segment
of muscle measuring about 2 cm in length by 1 cm
1.2. Surgical specimens in thickness (smaller in young children) is then iso-
Neurosurgical specimens must be immedi- lated, care being taken to avoid traction, and, finally,
ately placed in fixative after their removal by the sectioned at either end (Fig. A-1).
A B
FIGURE A-1. Muscle biopsy. (A) Dissection and isolation. (B) Removal of muscle fragment.
Appendix • 367
1.3.2. PERIPHERAL NERVE BIOPSY 1.3. 4 . STEREOTACTIC BIOPSY
Biopsy of a sensory peripheral nerve is most com- Stereotactic biopsy samplings are obtained with
monly performed on the sural nerve at its ret- a trocar guided by CT/MRI. The indications for
romalleolar portion. It may also be done on the stereotactic biopsy most often involve expanding
musculocutaneous (superficial peroneal) nerve, space-occupying lesions, especially tumors.
at the junction of the middle and inferior thirds of
the lateral surface of the lower leg. This permits con-
comitant sampling of the peroneus brevis muscle 1.3. 5 . OTHER BIOPSY PROCEDURES
(see Chapter 13). A skin incision is made 1 cm ante- In some neurological disorders, particularly lipido-
rior to the line that joins the head of the fibula to the ses, rectal biopsy is sometimes performed to exam-
external malleolus (Fig. A-2A, B). A 2-cm-long seg- ine the ganglion cells of Meissner’s plexus. It is also
ment of the entire nerve (Fig. A-2A), or a selected possible to examine these structures in the intesti-
number of fascicles within the nerve (Fig. A-2B), nal appendix. Skin and conjunctival biopsies may
may be sampled, first by sectioning the proximal end provide additional information in some cases (e.g.
of the nerve. Peripheral nerve biopsy results in per- capillary blood vessel walls, terminal nerve end-
manent hypesthesia of the dorsum of the foot and ings, cellular inflammatory infiltrates). Skin biopsy
sometimes paresthesias. can be used to obtain fibroblast cultures allowing
for genetic analysis in hereditary diseases, although
with the advent of more sophisticated methods for
1.3.3. BRAIN BIOPSY
molecular diagnosis, this procedure is now less com-
Diagnostic biopsy of the cerebral cortex or subcorti- monly performed.
cal lesions is performed only in highly selected cases.
After administration of the local anesthetic and inci-
sion of the scalp, a small disc of bone is drilled with 1.4. CEREBROSPINAL F L UID
CYT OL OGICAL EXAMINATION
the lobotomy trephine, the dura is incised, and a
small fragment of cortex and underlying white mat- Cytological study of the lumbar puncture cerebro-
ter is removed with the scalpel or a cutting curette. spinal fluid (CSF) is a simple and rapid method of
Following this procedure the bone disc is placed back diagnosis. It allows for the study of neoplastic and
in position and the scalp is closed. The biopsy is most inflammatory processes spreading through the CSF
often taken from the right frontal or occipital lobe. pathways. Samples of CSF for cytological analysis
The risk of hemorrhage, infection, reactive edema, or can also be obtained by the neurosurgeon during
posttraumatic epilepsy is minimal, ordinarily. operative procedures.
A B
FIGURE A-2. Peripheral nerve biopsy. (A) Dissection of a fragment of the superficial branch of the musculo-
cutaneous nerve of the leg. (B) Removal of nerve segment.
368 • APPENDIX
2. FIXATION OF TISSUES 3.2. Brain dissection and slices
Formalin is almost always the fixative of choice used 3.2.1 . USUAL PROTOCOL
in neuropathology. The most frequently employed
This includes the following steps:
formalin concentration is 10%. Ten percent forma-
lin represents a solution prepared by mixing 10 mL • Severing the cerebral hemispheres from the brainstem.
of commercial formalin with 90 mL of water. Neutral The arachnoid membranes, which usually obscure
formalin (calcium formalin) is recommended and is the structures of the interpeduncular fossa and
obtained by pouring powdered calcium carbonate into the floor of the third ventricle, are first delicately
the fixative container. An alternative method consists removed with forceps or fine scissors. The blood
of the use of marble chips in the formalin solution. In vessels of the circle of Willis are then inspected
some laboratories, buffered formalin-zinc is used for and the cranial nerves are identified in sequence.
fixation of tumor tissue, and alcohol-formalin-acetic The posterior fossa structures are then separated
acid (AFA) may be used for muscle tissue. from the supratentorial portion of the brain by
The amount of fixative to be used depends on the cutting through the rostral part of the cerebral
amount of tissue to be fixed and should be approxi- peduncles with a scalpel, along a plane parallel to
mately 15 to 20 times the volume of tissue. Thus, for the base of the brain.
the brain as a whole, 5 to 6 liters of a 10% formalin • Coronal hemispheric slices. The brain resting on the
solution is required for optimal results; the fixative convexity is placed sideways on a suitable cutting
may be renewed at regular intervals. board. The first section is through the mammil-
Good fixation requires a minimum amount of lary bodies, and all subsequent sections are cut
time, depending on the size of the tissue (2 to 3 from the base by placing the cut surface flat on the
weeks for a whole brain). The preservation of tissues board and cutting slices parallel to the ground at
in formalin is almost indefinite, provided the fluid, approximately 1 cm thick from the frontal to the
which turns yellow with age, is changed from time occipital poles (Figs. A-3, A-4). The slices are then
to time, and provided the container is well sealed placed on an examining board in sequence from
to avoid evaporation. Long-term fixation will jeop- front to back.
ardize some staining procedures and immunohisto- • Horizontal sections through the brainstem and cer-
chemical techniques. ebellum. Without separating the cerebellum from
the brainstem, horizontal sections approximately
3. MACROSCOPIC 1 cm thick are cut from the cerebral peduncles to
EXAMINATION OF THE CNS the medulla (Fig. A-5). An alternative method is
to separate the brainstem from the cerebellum by
Gross dissection of the CNS (brain and spinal cord) cutting through the peduncles. In such a case, the
is performed traditionally after 2 to 3 weeks of for- cerebellar hemispheres are hemisected in the sag-
malin fixation. Increasingly, laboratories prefer to fix ittal plane at the vermis and subsequently cut in
the brain for shorter periods of time to accelerate the the same plane from medial to lateral. The brain-
workup and reporting of the findings. When organs stem is then cut in serial horizontal sections. For
must be returned to the body, the brain is cut fresh purposes of orientation at the time of microscopic
and photographed. Selected blocks are then fixed in examination, either the right or the left side of the
formalin for shorter periods. brainstem (depending on convention) is nicked
Fresh tissue for microbiological, toxicological, superficially.
or molecular studies or for brain banking must be • Transverse sections through the spinal cord. The
obtained fresh at the time of autopsy. spinal cord is placed flat on the cutting board,
and transverse sections, approximately 1 cm
thick, are made using a fresh razor blade held
3.1. Inspection of the brain by forceps (Fig. A-6). For precise macroscopic
and spinal cord localization of the segmental level of the cord
The brain and spinal cord are carefully exam- lesion, careful counting of dorsal roots is
ined, and any abnormal or interesting features are required, usually by identifying the T1 level,
recorded on schematic diagrams and photographed just below the cervical enlargement, as a starting
before and after fixation. point.
Appendix • 369
A1 A2
B1 B2
C1 C2
FIGURE A-3. Coronal sections through the cerebral hemispheres. Gross appearance after fixation (left);
myelin stain of corresponding slices after celloidin embedding (right). (A) Frontal poles. (B) Section through
the rostral portion of the basal ganglia. (C) Section through the mammillary bodies.
-Documentation. After the hemispheric, brainstem, 3.2. 2 . SECTIONING IN THE AXIAL PL ANE
and spinal cord slices have been examined with OF CT OR MRI
the naked eye and a magnifying glass, the lesions
In some cases, it may be preferable to compare
are recorded on standard stenciled diagrams that
axial CT scan or MRI images to neuropathological
depict the main neuroanatomical structures, and
data; the brain is then sectioned in the appropriate
photographs are taken.
plane.
370 • APPENDIX
A1 A2
B1 B2
C1 C2
FIGURE A-4. Coronal sections through the cerebral hemispheres. Gross appearance after fixation (left);
myelin stain of corresponding slices after celloidin embedding (right). (A) Section through the thalami and
lateral geniculate bodies. (B) Section through the splenium of corpus callosum. (C) Posterior section through
the occipital horns.
3.3. Histological sampling for the systematic analysis of certain diseases (e.g.
Alzheimer disease and other dementias).
After the slices have been examined grossly, the tis-
sue is sampled for histological study. In this selec-
tion, the neuropathologist is guided by the clinical 4. EMBEDDING,
data, the general autopsy findings, the gross study of SECTIONING, AND
the slices, and the type of histological technique to
be applied to the tissues. The samples are then care-
STAINING METHODS
fully identified and labeled. Many laboratories have The indications for, advantages of, and disadvan-
a standardized series of blocks required, particularly tages of the various techniques are reviewed here
Appendix • 371
solely in the context of neuropathological practice. 4.1. Paraffin embedding
For details on embedding and sectioning tech-
niques, the reader is referred to general reference • Advantages. In most neuropathology labora-
works on histological methods. tories, this is the embedding method of choice
for autopsy and biopsy samples. It is rapid
A1 A2
B1
B2
C1 C2
FIGURE A-5. Horizontal sections through the brainstem and cerebellum. Gross appearance after fixa-
tion (left); myelin stain of corresponding slices after celloidin embedding (right). (A) Rostral portion of the
midbrain (cerebral peduncles, red nuclei, superior corpora quadrigemina). (B) Caudal portion of the midbrain
(dentatorubral decussation, inferior corpora quadrigemina). (C) Upper pons and superior cerebellar vermis.
(D) Midpons and cerebellar hemispheres with dentate nuclei. (E) Upper medulla and cerebellar hemispheres
with dentate nuclei and inferior vermis. (F) Lower medulla and inferior portion of cerebellar hemispheres.
372 • APPENDIX
D1 D2
E1 E2
F1 F2
FIG. A-5 (Continued)
and allows for relatively thin sections (5 to temperature relatively poorly, and this may result
7 μm) as well as serial or step sections. Many in some artifacts.
stains and immunostains can be performed • Stains. See Table A-1.
on paraffin sections. With the use of special
microtomes, it is now also possible to cut large
paraffin-embedded blocks of brain, and even an 4.2. Celloidin embedding
entire slab of brain cut in the coronal or hori-
zontal plane. Celloidin embedding is no longer the method of
• Disadvantages. Paraffin embedding requires choice in neuropathology, and very few laboratories
preliminary treatment with alcohol and toluene, around the world still use it. It is mentioned here for
which are lipid solvents. The tissues must be completeness and in historical context.
heated during part of the procedure in an oven
at a temperature of 56°C (for the paraffin to be -Advantages. The technique permitted embed-
melted). Nervous tissue tolerates this level of ding and sectioning of very large sections, such
Appendix • 373
A B as a cerebral hemisphere, or even an uncut whole
brain. Such preparations are still available in archi-
val material in specialized laboratories around the
world.
• Disadvantages. The procedure has largely been
abandoned because it is lengthy, time-consuming,
and very expensive. At present, celloidin is not
available in many countries, and its use has been
prohibited for safety reasons (mixture with explo-
sive ether-alcohol).
• Stains. See Table A-1.
4.3. Frozen sections

• Advantages. The tissues are not processed
through lipid solvents, thus permitting preserva-
C
tion of a number of cell constituents (which dis-
C2 appear after paraffin or celloidin embedding) and
the application of special techniques (histochem-
istry, enzyme analysis, immunocytochemistry)
that are not always possible otherwise. Frozen
sections can be examined under the microscope
soon after removal (after a few minutes); this is of
C6
practical importance when rapid histological diag-
nosis is important (e.g. in intraoperative consulta-
tions of brain biopsies).
• Disadvantages. These sections are usually not as
thin as those obtained after paraffin embedding.
T6 The technique also carries distinctive artifactual
problems. The preparations are less permanent
than embedded specimens.
• Stains. See Table A-1.
L2
4.4. Special techniques
4.4. 1 . EL ECTRON MICROSCOPY
For electron microscopy, immediate fixation is nec-
L5 essary. This is done with a buffered glutaraldehyde in
solution at 0°C, followed by postfixation in osmic acid.
4.4. 2 . IMMUNOHISTOCHEMISTRY
S2 All immunohistochemical methods have as a com-
mon aim the visualization on histological sections
FIGURE A-6. Gross appearances of the spinal cord. of antigenic sites that have become immunoreac-
(A) Cervicothoracic cord. Note the thin thoracic roots tive with antibodies with which the sections have
(except T1, arrow) compared to the cervical roots. been incubated. These techniques may also be
(B) Lower part of spinal cord. Note exits of L1 roots applied to dissociated cells, as in the CSF. There
from the dura at the level of conus medullaris (arrow). are numerous technical variants that are based on
(C) Diagrammatic depiction of the gray and white the demonstration of different antigens. These
matter of the spinal cord sectioned at various levels. can be demonstrated by immunofluorescence or
374 • APPENDIX
Table A-1. Traditional Staining Methods
PA R A F F I N C E L L O I D I N FROZEN
SEC TION
General histological stains Hematoxylin-eosin ++ ++ ++

Masson trichrome + - -
Van Gieson + + +
Nerve cell stains Nissl bodies Thionin (Nissl variant) ± ++ -
Cresyl violet ++ + ++
Neurofibrils Bielschowsky ± ± ++
Gallyas ++ ND +
Axons Bodian ++
Gros - - ++
Myelin stains Loyez ± ++ +
Heidenhain-Woelcke + ++ ++
Luxol fast blue ++ + +
Glial cell stains Astrocytes Hortega lithium - - ++
carbonate
Holzer + - ++
Mallory P.T.A.H. + + +
Microglia Silver carbonate - - +
Connective and Collagen fibers Masson trichrome + -
vascular tissue Van Gieson + + +
stains Reticulin fibers Perdrau; Wilder; ++ ±
Gordon-Sweets;
Gomori; Laidlaw; Foot
Elastic fibers Orcein; Weigert-Hart; ++ + +
Verhoeff;
resorcin-fuchsin
ND, not done.
immunoperoxidase techniques. Various procedures 4.4.3 . IN SITU HYBRIDIZATION

may be used to retrieve the antigens. The specificity
In situ hybridization refers to the use of nucleic acid
of monoclonal antibodies may sometimes be supe-
probes (DNA or RNA) to demonstrate and localize,
rior to that of polyclonal antisera, but their sensitiv-
within cells or tissues, nucleic acid sequences that
ity may be inferior.
show base pairing with the probe. The probes used
Positive and negative controls are mandatory.
are most often double-stranded DNA, less often
Immunohistochemical methods have replaced
single-stranded DNA or messenger RNA. The probes
many of staining techniques used in the past
may be tagged with radioactive isotopes, such as 3H,
(Table A-1). 32
P, or 35S, or with nonradioactive compounds, such
However, in some circumstances the highly spe-
as biotin (so-called cold probes). With the former,
cific detection of a single target molecule may give
demonstration is made by autoradiography and with
a restricted view of a disease and may need to be
the latter, by different means (e.g. by the avidin-biotin
combined with classical stains. Commonly used
complex technique). Counting the silver grains in
antibodies in general neuropathology are listed in
autoradiographs allows for semiquantitative analysis.
Table A-2.
Appendix • 375
Table A-2. Antibodies Widely Used in General Neuropathology
CELL T YPES AN TIBODY CHAR AC TERISTICS
Neuronal NF Family of neuronal intermediate filaments: the three subunits

compartment are expressed separately or together (NFL, NFM, NFH)
NeuN “Neuron-specific nuclear protein” expressed in several
postmitotic neuronal celltypes in the central and peripheral
nervous system, not expressed in Purkinje, mitral, and
photoreceptor cells
MAP2 Belongs to the microtubule-associated protein family
Calbindin Calcium-binding protein labeling interneurons. 29 kDa
calbindin is also known as Calretinin.
Synaptophysin Integral membrane protein of small synaptic vesicles
Chromogranin Secretory protein, found in secretory vesicles of neurons and
endocrine cells
APP Amyloid beta (A4) precursor protein is a cell surface
receptor and transmembrane precursor protein accumulated
early in axonal lesions.
Astrocytes GFAP Glial fibrillary acidic protein: filament of mature astrocytes
Oligodendrocytes Olig2 Oligodendrocyte lineage transcription factor 2
Microglia Iba-1 Calcium binding protein, specifically expressed in

macrophages/microglia
CD68 110-kD transmembrane glycoprotein highly expressed by
human monocytes and tissue macrophages
Stem cells Nestin Intermediate filament protein that is expressed

predominantly in stem cells of the CNS in the neural tube
Myelin MBP Myelin basic antibody

PLP Myelin proteolipid protein
4.4.4. HISTOBLOT AND PET BLOT enhancing the immunoreactivity. Histoblot was
at first described using cryostat sections, but
These techniques are mainly used in prion pro-
paraffin-embedded tissue sections can also be pro-
tein research. Based on a combination of immu-
cessed. Both are more sensitive than immunohis-
nohistochemistry and Western blot, they allow
tochemistry, which in turn has a better cellular and
sensitive detection of the scrapie prion protein
subcellular resolution.
isoforms (PrPSc) and the analysis of their general
distribution in different areas of the CNS. A nitro-
cellulose membrane is used instead of a glass slide
4.4. 5 . OTHER TECHNIQUES
as a mount for tissue sections. This porous mem-
brane allows optimal proteolysis of the cellular Neurochemical studies must be performed on
isoform of the prion protein (proteinase K) and freshly unfixed material (e.g., biopsy samples or nec-
protein denaturation (guanidine thiocyanate), ropsy tissues that are promptly frozen).
376 • APPENDIX
For virological studies, particularly in tissue cul- setting of overgrowth of gas-forming organisms con-
ture, sampling is performed in a sterile fashion on sequent to inadequate or late fixation.
the brain in situ, after aseptic removal of the skullcap Inadequate fixation is likewise responsible for
and dura. the pinkish appearance (pink spots) and soft con-
sistency of the white matter (formalin solution of
insufficient concentration). Conversely, fixation that
5. BRAIN BANK is either excessive (because of a formalin solution
Tissue samples from biopsies and autopsies are col- of excessive concentration) or unduly prolonged
lected in tissue banks for research purposes. Some may be responsible for a yellowish, parchment-like
samples (e.g. from tumors) are also kept for diagnos- appearance of the cortex. Under these circum-
tic purposes since new molecular tools are develop- stances, the application of most histological tech-
ing at an accelerating pace. niques is difficult or impossible.
The samples have to be neuropathologically Congestion with vascular dilatation is most
documented, and clinically and, as far as possible, frequently the result of terminal asphyxial distur-
genetically annotated. Neuroimaging and biomark- bances. The so-called “respiratory brain” is a swollen
ers (blood and CSF) data must be integrated. To and soft organ that cannot be fixed properly or stud-
allow the collection of a large number of samples ied histologically in a meaningful manner.
necessary for scientific investigation, collaboration
with multiple centers is required. The diagnostic
criteria must therefore be reliable, with high inter- 6.2. Microscopic artifacts
rater agreement. The quality control of the samples, Many of the artifacts encountered in histological
biopsies, and postmortem tissues must be ensured. preparation of any organ may also be seen in micro-
The collection of control cases appears often diffi- scopic neuropathology. Some, however, are specific
cult, and the definition of normal and pathological to brain tissue.
material may raise problems. Multiple microscopic elongated cavities, often
Legal and ethical rules vary from country to predominating in the cortex, are sometimes seen as
country, but it is generally agreed that informed the result of improper freezing of tissue.
consent from the patient or next of kin is required Nerve cell retraction, with clear pericellular
before any investigational use of the samples begins. spaces, is very frequently seen in paraffin-embedded
The ideal use of large collections of neuropatho- tissues and is related to the temperature to which
logical data and of clinical and molecular records the paraffin has been heated. The same applies
requires powerful computer databases. Most tissue to the apparent dilatation of the perivascular
banks have adopted a thematic approach, bringing spaces, which needs to be differentiated from
together experts in a specific field of research, some- possible edema.
times with the help of patient advocacy associations. Dark neurons result from neuronal retrac-
tion with nuclear shrinkage and basophilia. These
abnormal neurons are frequently found in material
6. ARTIFACTS removed by cerebral biopsy and are related to pok-
Neural tissue is subject to a wide range of artifacts. ing at the tissue at the time of removal or to immer-
These may be the result of agonal changes (i.e. termi- sion fixation.
nal circulatory and hypoxic disturbances), the con- Pale ballooned neurons may be caused by exces-
ditions of removal and fixation, or problems related sive washing of the nervous tissue fragments with
to embedding, sectioning, and staining procedures. water before fixation. An artifact consisting of cellu-
lar pallor with blurring of the nuclear outlines of the
neurons in the cerebellar granular layer (état glacé or
6.1. Macroscopic artefacts
conglutination artifact) is the result of a postmor-
Large bullous cavities with sharp edges tem autolytic change, particularly when the body
(“Swiss-cheese artifact”), visible to the naked eye, has not been refrigerated properly. It is seen more
are the result of postmortem putrefaction in the often in lateral lobes.
Appendix • 377
Index
AA type amyloid, 341 systemic disease, CNS changes, 221–226

abetalipoproteinemia, 238 hepatic encephalopathy, 221
abnormal prion protein, 150–151 multifocal necrotizing leukoencephalopathy, 221
abusive head trauma (AHT), 75 paraneoplastic encephalomyelopathies, 221–226
acceleration and deceleration brain injury, 60 respiratory encephalopathies, 221
acid maltase deficiency, 303 toxic encephalopathies, 215–221
acidophil stem cell adenoma, 350 aluminum, 219
acquired amyloid neuropathies, 341 arsenic, 219–220
acquired metabolic disorders, 205–226 ethanol, 215–217
cerebral hypoxia, 205–210 ethylene glycol, 217–218
carbon monoxide poisoning, 208–209 heavy metals, 219–221
cardiovascular arrest, 208 lead, 220
cellular reactions, 206 manganese, 220
cerebral infarcts, 208 mercury, 220
cyanides, 209 metalloids, 219–221
hyperthermia, 210 methanol, 217
hypoglycemia, 209–210 phenytoin, 218–219
electrolytic disturbances, 210–211 thallium, 220
calcium metabolism, 211 tin, 220–221
central pontine myelinolysis, 210–211 vitamin deficiency, 211–215
iron metabolism, 211 pellagra, 212–214
ethanol thiamine deficiency, 211–212
acute alcohol intoxication, 215 vitamin B12 deficiency, 214–215
chronic alcoholism, 215–217 acquired prion diseases, 156–158
paraneoplastic encephalomyelopathies iatrogenic Creutzfeldt-Jakob disease, 157–158
paraneoplastic cerebellar degeneration, 224 kuru, 156–157
paraneoplastic encephalomyelitis, 224–226 actinomycosis, 120
paraneoplastic opsoclonus-myoclonus syndrome, acute bacterial meningitis, 115–116
226 acute disseminated encephalomyelitis, 132, 170–171
• 379
acute disseminated leukoencephalitis, 132 Alzheimer neurofibrillary degeneration, 5
acute hemorrhagic leukoencephalopathy of Hurst, 132–133, 170 Alzheimer type II glia, 11, 221
acute multiple sclerosis, 169 amebiasis, 125
acute neuronal necrosis, 2–3 amino acid metabolism disorders, 250–253
acute postinfectious/postvaccinial perivenous encephalitis, 132, Canavan disease, 251
170 Hartnup disease, 252
acute viral lymphocytic meningitis, 132 homocystinuria, 252
Adamantinomatous craniopharyngiomas, 360 hyperglycinemia, 252–253
ADEM. See Acute disseminated encephalomyelitits maple syrup urine disease, 252
adenomas, pituitary, 347–356 phenylketonuria, 251–252
adipose tissue lipoma tumors, 52 urea-cycle disorders, 253
adrenoleukodystrophy, 242–243, 342 amplification of EGFR, 26
adrenomyeloneuropathy, 242–243 amputation neuroma, 336
adult polyglucosan body disease, 246–247 amyloid angiopathy
agenesis of septum pellucidum, 264 Alzheimer disease, 178
agyria, 268 cerebral amyloid angiopathy, 86–88
AIDS, 146–148, 327–329 complications, 88
akinetic rigid syndromes, 186–193 etiology, 86–87
corticobasal degeneration, 189–191 pathology, 87–88
gross appearance, 190 amyloid neuropathies, 341
microscopic lesions, 190–191 acquired amyloid neuropathies, 341
multiple system atrophy, 191–192 familial amyloid polyneuropathies, 341
gross appearance, 191 amylopectinosis, 246
microscopic lesions, 192 amyotrophic lateral sclerosis, 201–202
Parkinson disease, 186–188 gross appearance, 201
gross appearance, 187 microscopic lesions, 201–202
microscopic lesions, 187–188 anaplastic astrocytoma, 22–23
molecular biology, 188 anaplastic ependymoma, 34
progressive supranuclear palsy, 188–189 anaplastic medulloblastoma, 42
genetics, 189 anaplastic meningioma, 50–51
gross appearance, 188–189 anaplastic oligoastrocytoma, 32
microscopic lesions, 189 anaplastic oligodendroglioma, 31
secondary parkinsonian syndromes, 192–193 Andersen disease, 246
carbon monoxide poisoning, 192 anemic hypoxia, 206
pharmacologic/toxic, 192 anemic infarction, 91–92
postencephalitic parkinsonism, 192 anencephaly, 258
trauma, 193 angiocentric glioma, 35–36
vascular disease, 192 angiokeratoma corporis diffusum, 233
AKT, 25 angiomatous meningioma, 49–50
AL type amyloid, 341 angiosarcoma, 53
alcohol intoxication, 215 Angiostrongylus cantonensis, 130
alcoholic cerebellar degeneration, 216 anoctamin 5, 294
alcoholism, 215–217 anoctaminpathies (LGMD2L), 293
chronic, 215–217 anti-MAG (myelin associated glycoprotein), 331
Alexander disease, 253 ApoE g4 genotype, 178
alobar holoprosencephaly, 262 apolipoprotein A1, 341
Alpers syndrome, 246 apoptotic processes, 173
alpha 5-integrin, 290 aprosencephaly, 262
alpha 7-integrin, 290 aquaporin 4, 171
alpha B-crystallin, 6, 253 aqueduct of Sylvius, 274
alpha-dystroglycan, 294 aqueduct of sylvius abnormalities, 274
alpha-galactosidase A deficiency, 233 arachnoid cysts, 358
alpha-sarcoglycan, 294 arbovirus encephalitides, 134–135
alpha-synucleinopahty, 174 argyrophilic brain disease, 185
aluminum, 219 Arnold-Chiari malformation, 260–261
toxic encephalopathy, 219 arrhinencephaly, 262
Alzheimer disease, 175–179 arsenic, 219–220
amyloid angiopathy, 178 toxic encephalopathy, 219–220
Aβ peptide deposits, 176 arterial dissections, 81–82
diagnostic criteria, 178 arteriopathic leukoencephalopathies, 112
gross appearance, 175 arteriovenous malformations, 88–89
microscopic lesions, 175–178 arthropod-borne virus, 134–135
molecular pathology, 178–179 artifacts, 377
neurofibrillary tangles, 176–178 macroscopic artifacts, 377
neuronal loss, 176–178 microscopic artifacts, 377
plaques, 176 arylsulfatase A deficiency, 235–236
staging, 178 aseptic meningitis, 132
synaptic loss, 176–178 aspartoacylase deficiency, 251
380 • INDEX
aspergillosis, 126 Babès nodules, 135
astroblastoma, 36 bacterial infections, 114–124
astrocytic lesions, 11–13 actinomycosis, 120
Alzheimer type II glia, 11 atypical mycobacteriosis, 119
inclusions, 12–13 Borreliosis, 122
Rosenthal fibers, 12 Brucellosis, 122–123
storage material, 12–13 chronic pachymeningitis, 123
astrocytic tumors, 21–29 neurosyphilis, 120–122
circumscribed astrocytomas, 26–28 meningovascular neurosyphilis, 121
pilocytic astrocytoma, 26–28 neurosyphilis and HIV infection, 122
pilomyxoid astrocytoma, 28 parenchymatous neurosyphilis, 122
pleomorphic xanthoastrocytoma, 28 nocardiosis, 120
subependymal giant cell astrocytoma, 28–29 pyogenic infections, 114–117
diffusely infiltrating astrocytomas, 21–26 acute bacterial meningitis, 115–116
anaplastic astrocytoma, 22–23 brain abscesses, 116–117
diffuse astrocytoma, 21–22 empyema, 115
giant cell glioblastoma, 25–26 epidural abscesses, 115
glioblastoma, 23–25 septic embolism, 117
gliomatosis cerebri, 26 subdural abscesses, 115
astrocytoma, 21 suppurative intracranial phlebitis, 117
ataxia-telangiectasia, 198–199, 249–250 sarcoidosis, 123
ataxic disorders, 195–201 toxin-induced neurological disease, 123–124
atelencephaly, 262 tuberculosis, 117–119
atherosclerosis, 94–96 brain tuberculomas, 118
atherosclerotic thrombosis, 95–96 spinal cord tuberculomas, 118
atlanto-axial subluxation, 74 tuberculous abscess, 118–119
atresia, 274 tuberculous epidural abscess, 117–119
atrophic fibers, 282 tuberculous meningitis, 117–118
atrophy tuberculous subdural abscesses, 117–119
cerebral atrophy, 14 Whipple disease, 119–120
nerve cell atrophy, 2 bacterial meningitis, 115–116
ATRX, 25 bacterial myositis, 306
atypical choroid plexus papilloma, 35 balloon cells, 270
atypical meningioma, 50 ballooned neurons, 180
atypical mycobacteriosis, 119 Baló concentric sclerosis, 169–170
atypical pituitary adenoma, 346 basket brain, 275
atypical teratoid/rhabdoid tumor, 44 basophilic fibers, 283
autophagic vacuoles, 284 Bassen-Kornzweig disease, 238
autopsy, 365–367 Bassen-Kornzweig syndrome, 342
brain, 366 Batten disease, 238–240
peripheral nervous system, 366 Becker disease, 298
skeletal musculature, 366 berry aneurysm, 77–81
spinal cord, 365–366 beta-galactosidase-1 deficiency, 235
autosomal dominant cerebellar ataxias, 199–200 beta-sarcoglycan, 294
autosomal dystrophies, 293–296 Binswanger arteriopathic subcortical encephalopathy, 112
autosomal recessive cerebellar ataxias, 198–199 binucleated neurons, 4
ataxia-telangiectasia, 198–199 biochemical abnormalities, 228–229
cerebellar ataxia with isolated vitamin E deficiency, energy metabolism disorders, 228
199 intoxication syndromes, 228
Friedreich ataxia, 198 lipid metabolism disorders, 228
gross appearance, 198 metal metabolism disorders, 228–229
microscopic findings, 198 neurotransmitter metabolism disorders, 228
axonal alterations, 8–10 biopsy procedures, 367–369
axonal atrophy, 320 brain biopsy, 368
axonal degeneration, 318–321 muscle biopsy, 367
axonal injury, 166 peripheral nerve biopsy, 368
axonal injury in mild head injury, 71 stereotactic biopsy, 368
axonal pathology n MS lesions, 165 Birbeck granules, 57
axonal regeneration, 321 blast injuries, 60, 73
axonal sprouting, 321 blastomycosis, 126
axonal swelling, 320, 335 blood transfusion, 160
axonal swellings or spheroids, 9 blood vessel tumors hemangiomas, 53
axons, 317–318 Bornholm disease, 305
myelin sheaths, 317–318 borreliosis, 122, 329
myelinated axons, 318 BRA FV600E point mutations, 28
Schwann cells, 318 Braak & Braak staging, 177
unmyelinated fibers, 318 Braak staging scheme for AD, 178
AZT myopathy, 306 brain abscesses, 116–117
Index • 381
brain autopsy, 366 cellular Schwannomas, 46
brain bank, 377 central autonomic system involvement, 203–204
brain biopsy, 368 central chromatolysis, 3–4
brain herniation, 16–18 central neurocytoma, 38
infratentorial lesions, 17–18 central pontine myelinolysis, 210–211, 216
supratentorial lesions, 17 CERAD system, 178
brain iron accumulation, neurodegeneration with, 194–195 ceramidase deficiency, 233
brain size disorders, 265 cerebellar ataxia with isolated vitamin E deficiency, 199
brain swelling, 72 cerebellar atrophy types, 195–198
brain tuberculomas, 118 cerebellar cortical atrophies, 195–196
brainstem lesions, 68 cerebellofugal atrophies, 197–198
branched-chain ketoaciduria, 252 olivopontocerebellar atrophies, 197
Brownell-Oppenheimer variant, 152 secondary cerebellar atrophies, 198
Brucellosis, 122–123 crossed cerebellar atrophy, 198
bubble brain, 275 pseudohypertrophy of inferior olive, 198
bulbar muscular atrophy, 203 cerebellar cortical atrophies, 195–196
Bunina bodies, 7 cerebellar degeneration, paraneoplastic, 224
burnt-out forms of treatable infections, 147 cerebellar degenerations, 195–201
autosomal dominant cerebellar ataxias, 199–200
CADASIL, 107–109 autosomal recessive cerebellar ataxias, 198–199
calcium metabolism, 211 ataxia-telangiectasia, 198–199
calcium oxalate, 218 cerebellar ataxia with isolated vitamin E deficiency,
calcium oxalate crystals, 219 199
calpain-3, 290, 294 Friedreich ataxia, 198
calpainopathies (LGMD2A), 293 fragile X tremor/ataxia syndrome, 200
Canavan disease, 251 Friedreich ataxia
candidiasis, 126 gross appearance, 198
capillary telangiectases, 90 microscopic findings, 198
carbohydrate metabolic disorders, 246–247 secondary cerebellar atrophies
carbon monoxide poisoning, 208–209 crossed cerebellar atrophy, 198
cardiac emboli, 97 pseudohypertrophy of inferior olive, 198
cardiovascular arrest, 208 sporadic degenerative ataxia, 200–201
Carney complex, 360 types of cerebellar atrophy, 195–198
carnitine deficiency, 301–302 cerebellar cortical atrophies, 195–196
carnitine palmityl transferase deficiency, 302 cerebellofugal atrophies, 197–198
carotid territory infarcts, 97–100 olivopontocerebellar atrophies, 197
carpal tunnel syndrome, 336 secondary cerebellar atrophies, 198
caveolin-3, 290, 294 cerebellar liponeurocytoma, 38
caveolinopathy, 293 cerebellar tonsillar herniation, 18
cavernomas, 90 cerebellofugal atrophies, 197–198
cavernous hemangiomas, 90 cerebral amyloid angiopathy, 86–88, 155
cavitary orthochromatic leukoencephalopathy, 254 complications, 88
cavitating MS, 170 etiology, 86–87
Cavum septi pellucid, 264 pathology, 87–88
cavum septi vergae, 264 cerebral atrophy, 14
CDKN2A, 25 cerebral cortex, lesions sufficient in MS, 166–167
CDKN2A /p16/ARF deletions, 31 cerebral edema, 14–15
CDKN2A/p16/ARF, 23 cerebral hypoxia, 205–210
celloidin embedding, 373–374 carbon monoxide poisoning, 208–209
cellular ependymomas, 32 cardiovascular arrest, 208
cellular reactions cellular reactions, 206
astrocytic lesions cerebral infarcts, 208
Alzheimer type II glia, 11 cyanides, 209
inclusions, 12–13 hyperthermia, 210
Rosenthal fibers, 12 hypoglycemia, 209–210
storage material, 12–13 tissue lesions, 206–207
neuronal lesions cerebral infarcts, 97–104, 208
acute neuronal necrosis, 2–3 complications of therapy, 102–104
Alzheimer neurofibrillary degeneration, 5 infarcts of carotid territory, 97–100
axonal alterations, 8–10 infarcts of vertebrobasilar territory, 100–102
binucleated neurons, 4 cerebral malaria, 125
central chromatolysis, 3–4 cerebral microbleeds, 110–111
granulovacuolar degeneration, 5 cerebrohepatorenal syndrome, 242
intraneuronal inclusion bodies, 5–8 cerebrospinal fluid cytological examination, 368
nerve cell atrophy, 2 cerebrotendinous xanthomatosis, 238, 342
neuronal storage, 4–5 ceroid lipofuscinosis, neuronal, 238–240
neuropil, 4 chaperone protein 14–3-3, 152
vacuolated neurons, 4 Charcot-Bouchard (C-B) microaneurysms, 84
382 • INDEX
Charcot-Marie-Tooth (CMT) disease microglial lesions, 13–14
axonal form, 337–338 neuronal lesions, 2–10
hypertrophic form, 336–337 oligodendrocyte lesions, 13
cherry red spot, 230 neuronal lesions
Chiari I malformation, 273 acute neuronal necrosis, 2–3
Chiari II malformation, 260 Alzheimer neurofibrillary degeneration, 5
Chiari III malformation, 273 axonal alterations, 8–10
Chiari malformations, 273 binucleated neurons, 4
Chloroquine neuromyopathy, 305 central chromatolysis, 3–4
cholesterol emboli, 312 granulovacuolar degeneration, 5
cholesterol metabolism, disorders of, 237–240 intraneuronal inclusion bodies, 5–8
abetalipoproteinemia, 238 nerve cell atrophy, 2
cerebrotendinous xanthomatosis, 238 neuronal storage, 4–5
ceroid lipofuscinosis, neuronal, 238–240 neuropil, 4
Tangier disease, 237–238 vacuolated neurons, 4
Wolman disease, 237 CNS primitive neuroectodermal tumors, 43–44
chondroma, 53 CNS/supratentorial PNET, 43
chordoid glioma, third ventricle, 36 ependymoblastoma, 44
chordoid meningioma, 50 medulloepithelioma, 43–44
chordoma, pituitary gland, 362 CNS/supratentorial PNET, 43
choreoacanthocytosis, 195 CNS trauma, 59–75
choristoma, pituitary gland, 362–363 blast injuries, 73
choroid plexus carcinoma, 35 chronic traumatic encephalopathy, 73–74
choroid plexus papilloma, 35 classification, 59–60
choroid plexus tumors, 34–35 diffuse brain injury, 68–72
atypical choroid plexus papilloma, 35 brain swelling, 72
carcinoma, 35 diffuse traumatic axonal injury, 69–72
papilloma, 35 diffuse vascular injury, 72
chromatolysis, central, 3–4 ischemia, 68–69
chromomycosis, 126 diffuse traumatic axonal injury
chronic alcoholism, 215–217 axonal injury in mild head injury, 71
chronic neurogenic processes, 288 focal axonal injury, 71–72
chronic pachymeningitis, 123 focal injury, 60–68
chronic traumatic encephalopathy (CTE), 73–74 contusions, 61–62
Churg-Strauss syndrome, 329 intracranial hemorrhage, 62–68
CIDP, 333 lacerations, 61–62
circumscribed astrocytomas, 26–28 scalp lesions, 60
pilocytic astrocytoma, 26–28 skull lesions, 61
pilomyxoid astrocytoma, 28 intracranial hemorrhage
pleomorphic xanthoastrocytoma, 28 brainstem lesions, 68
subependymal giant cell astrocytoma, 28–29 extradural hemorrhage, 63–64
CJD. See Creutzfeldt-Jakob disease intracerebral hemorrhage, 67
cladosporiosis, 126 intraventricular hemorrhage, 67
clear cell ependymomas, 32–33 subarachnoid hemorrhage, 67
clear cell meningioma, 50 subdural hemorrhage, 64–66
CLN Santavuori-Haltia, 239 subdural hygroma, 66–67
CMT1, 336 vascular, 67–68
CMT2, 337 pediatric head injury, 75
CMV (cytomegalovirus) infection, 142 penetrating injuries, 72–73
encephalitides, 142 spinal cord injuries, 74–75
CNS lesions, 1–19 cobblestone lissencephaly, 268
astrocytic lesions coccidioidomycosis, 127
Alzheimer type II glia, 11 Cockayne syndrome, 249
inclusions, 12–13 coenuriasis, 130
Rosenthal fibers, 12 coiled body, 189
storage material, 12–13 collagen VI, 289
brain herniation collagenopathies (Ullrich/Bethlem myopathies), 296
infratentorial lesions, 17–18 congenital fiber type disproportion, 300
supratentorial lesions, 17 congenital form of Seitelberger, 253–254
brain tissue reactions, 14–18 congenital hypomyelinating neuropathy, 338
brain herniation, 16–18 congenital malformations, 258–274
cerebral atrophy, 14 cortical plate malformations, 264–272
cerebral edema, 14–15 brain size disorders, 265
hydrocephalus, 15–16 focal malformations, 270–272
intracranial pressure, 16–18 lissencephaly, 268–270
cellular reactions, 2–14 localized malformations, 270–272
astrocytic lesions, 11–13 neuronal heterotopia, 265–266
ependymal cells, 14 polymicrogyria, 266–268
Index • 383
congenital malformations (Cont.) cryoglobulinemias, 332–333
disorders of hindbrain development, 272–274 cryptococcosis, 127
abnormalities of aqueduct of sylvius, 274 cyanides, 209
malformations of cerebellum, 272–274 cystatin-C, 7
lissencephaly cysticercosis, 129–130
type I, 268 cysts, pituitary gland, 358
type II, 268–270 cytoplasmic body myopathy, 300
localized malformations cytoskeletal proteins, 290
cortical development, 272
focal cortical dysplasia, 270–272 Dandy-Walker malformation, 273
malformations of cerebellum Danon disease, 303
Chiari malformations, 273 dark neurons, 2
Dandy-Walker malformation, 273 debranching enzyme amylo-1,6 glucosidase, 303
Joubert syndrome, 273 deficit of, 303
posterior fossa arachnoid cyst, 274 defective DNA repair, 248–249
rhombencephalosynapsis, 273–274 ataxia-telangiectasia, 249–250
midline structures, septum pellucidum anomalies, 264 Cockayne syndrome, 249
neuronal heterotopia xeroderma pigmentosum, 248–249
laminar heterotopia, 265 deficiency of ornithine carbamoyltransferase, 253
periventricular nodular heterotopia, 265–266 deficiency of vitamins, 211–215
subcortical band heterotopia, 265 pellagra, 212–214
neurulation failure, 258–261 thiamine deficiency, 211–212
cranial NTDs, 258–259 vitamin B12 deficiency, 214–215
spinal NTDs, 259–261 degenerating neuritis, 176
prosencephalon development, 261–264 degenerative disease, 173–204
holoprosencephalies, 262–263 akinetic rigid syndromes
midline structures, 263–264 corticobasal degeneration, 189–191
conjunctival biopsy, 368 multiple system atrophy, 191–192
consensus classifi cation system of FCD, 272 Parkinson disease, 186–188
contrecoup lesions, 62 progressive supranuclear palsy, 188–189
contusions, 61–62 secondary parkinsonian syndromes, 192–193
copper metabolism, 250 Alzheimer disease, 175–179
Menkes disease, 250 amyloid angiopathy, 178
Wilson disease, 250 Aβ peptide deposits, 176
core myopathies, 300 diagnostic criteria, 178
C9orf72, 181 gross appearance, 175
corneal graft, 158 microscopic lesions, 175–178
corpora amylacea, 12 molecular pathology, 178–179
cortical demyelnation, 167 neurofibrillary tangles, 176–178
cortical development malformations, 272 neuronal loss, 176–178
cortical dysplasia, 270–272 plaques, 176
cortical plate malformations, 264–272 staging, 178
disorders of brain size, 265 synaptic loss, 176–178
focal cortical dysplasia, 270–272 amyotrophic lateral sclerosis
lissencephaly, 268–270 gross appearance, 201
type I lissencephaly, 268 microscopic lesions, 201–202
type II lissencephaly, 268–270 argyrophilic grain disease, 185
mild malformations of cortical development, 272 autosomal recessive cerebellar ataxias
neuronal heterotopia, 265–266 ataxia-telangiectasia, 198–199
laminar heterotopia, 265 cerebellar ataxia with isolated vitamin E deficiency,
periventricular nodular heterotopia, 265–266 199
subcortical band heterotopia, 265 Friedreich ataxia, 198
polymicrogyria, 266–268 central autonomic system involvement, 203–204
corticobasal degeneration, 189–191 cerebellar degenerations, 195–201
gross appearance, 190 autosomal dominant cerebellar ataxias, 199–200
microscopic lesions, 190–191 autosomal recessive cerebellar ataxias, 198–199
corticotroph cell adenomas, 351 fragile X tremor/ataxia syndrome, 200
coup lesions, 62 sporadic degenerative ataxia, 200–201
COX-negative fiber, 301 types of cerebellar atrophy, 195–198
Coxsackie B, 305 corticobasal degeneration
cramps syndromes, 304 gross appearance, 190
craniopharyngioma, 360 microscopic lesions, 190–191
Creutzfeldt-Jakob disease dementia with Lewy bodies, 184–185
familial, 154–155 gross appearance, 184
iatrogenic, 157–158 microscopic findings, 184–185
sporadic, 151–153 Friedreich ataxia
variant, 158–160 gross appearance, 198
Crow-Fukase syndrome, 331 microscopic findings, 198
384 • INDEX
frontotemporal lobar degenerations, 179–184 dense fibrillary (Antoni A) tissue, 46
FTD lacking inclusions, 183 dentato-rubral atrophy, 197
FTLD associated with TDP-43-positive lesions, 181–182 dermatomyositis, 306–307
FTLD-FUS, 182–183 dermoid cysts, 358
FTLD-TAU, 179–181 desmin, 294
FTLD-UPS, 183 desmin myopathy, 300
FTLD associated with TDP-43-positive lesions desmoplastic infantile ganglioglioma/astrocytoma, 38
gross appearance, 181 desmoplastic/nodular medulloblastoma, 42
microscopic findings, 181–182 developing brain, 274–277
FTLD-TAU gray matter lesions, 274–277
FTLD-tau without tau mutations, 181 basal ganglia, encephaloclastic lesions, 276
FTLD with MAPT mutations, 180–181 ganglionic eminence, 276–277
gross appearance, 179–180 neocortex, encephaloclastic lesions, 274–278
microscopic lesions, 179–181 thalamus, encephaloclastic lesions, 276
Pick disease, 179–180 neocortex, encephaloclastic lesions
hippocampal sclerosis, 185 basket brain, 275
Huntington disease hydranencephaly, 275
gross appearance, 193–194 ischemic strokes, 276
microscopic lesions, 194 multicystic encephalomalacia, 275–276
hyperkinetic movement disorders porencephaly, 274–275
choreoacanthocytosis, 195 selective neuronal necrosis, 276
HD-like disease, 194 white matter, lesions of, 277
Huntington disease, 193–194 diabetes, 333
neurodegeneration with brain iron accumulation, diastematomyelia, 260
194–195 diffuse astrocytoma, 21–22
motor neuron diseases, 201–203 diffuse axonal injury (DAI), 69
amyotrophic lateral sclerosis, 201–202 diffuse brain injury, 68–72
bulbar muscular atrophy, 203 brain swelling, 72
hereditary spastic paraparesis, 203 diffuse traumatic axonal injury, 69–72
spinal muscular atrophy, 202–203 axonal injury in mild head injury, 71
X-linked spinal and bulbar muscular atrophy, 203 focal axonal injury, 71–72
X-linked spinal atrophy, 203 diffuse vascular injury, 72
movement disorders, 186–195 ischemia, 68–69
akinetic rigid syndromes, 186–193 diffuse infiltrative lymphocytosis syndrome, 329
hyperkinetic movement disorders, 193–195 diffuse traumatic axonal injury, 69–72
multiple system atrophy axonal injury in mild head injury, 71
gross appearance, 191 focal axonal injury, 71–72
microscopic lesions, 192 diffuse vascular injury, 72
Parkinson disease diffusely infiltrating astrocytomas, 21–26
gross appearance, 187 anaplastic astrocytoma, 22–23
microscopic lesions, 187–188 diffuse astrocytoma, 21–22
molecular biology, 188 giant cell glioblastoma, 25–26
progressive supranuclear palsy glioblastoma, 23–25
genetics, 189 gliomatosis cerebri, 26
gross appearance, 188–189 diphtheria, tetanus, botulism, 123
microscopic lesions, 189 diseases with accumulation of TAR DNA-binding protein
secondary cerebellar atrophies 43, 174
crossed cerebellar atrophy, 198 disorders of lipid metabolism, 342
pseudohypertrophy of inferior olive, 198 dissecting aneurysms, 81–82
secondary parkinsonian syndromes disseminated encephalomyelitis, 132, 170–171
carbon monoxide poisoning, 192 disseminated leukoencephalitis, 132
pharmacologic/toxic, 192 distal symmetrical sensorimotor neuropathy, 333
postencephalitic parkinsonism, 192 DNA-binding protein 43, 174
trauma, 193 DNA repair, disorders of, 248–249
vascular disease, 192 ataxia-telangiectasia, 249–250
vascular cognitive impairment, 185 Cockayne syndrome, 249
vascular dementia, 185 xeroderma pigmentosum, 248–249
Déjerine-Sottas disease, 338 Down syndrome, 178
delta-sarcoglycan, 294 Dracunculus medinensis, 130
dementia, vascular, 185 drug-induced neuropathies, 335
dementia with Lewy bodies, 184–185 dura mater graft, 158
diagnostic classification, 185 Duret hemorrhages, 17
gross appearance, 184 dying-back neuropathy, 318
microscopic findings, 184–185 dysembryoplastic neuroepithelial tumor, 38
demyelinated lesions, white matter, 162–166 dysferlin, 290, 294
demyelinating disease diagnosis, 172 dysferlinopathies, 293
denervation atrophy, 286 dysplastic gangliocytoma of cerebellum, 37–38
Denny-Brown neuropathy, 330 dystroglycans, 290
Index • 385
dystrophic neurite, 10 encephalopathies, toxic, 215–221
dystrophic neuritis, 176 aluminum, 219
dystrophin, 290–291 arsenic, 219–220
ethanol, 215–217
ectopic adenoma, pituitary gland, 354 acute alcohol intoxication, 215
edema, cerebral, 14–15 chronic alcoholism, 215–217
EGFR, 25 ethylene glycol, 217–218
electrolytic disturbances, 210–211 heavy metals, 219–221
calcium metabolism, 211 lead, 220
central pontine myelinolysis, 210–211 manganese, 220
iron metabolism, 211 mercury, 220
electron microscopy, 374 metalloids, 219–221
embedding, 371–377 methanol, 217
celloidin embedding, 373–374 phenytoin, 218–219
frozen sections, 374 thallium, 220
paraffin embedding, 372–373 tin, 220–221
embryonal tumors, 42–44 encephalopathy, chronic traumatic, 73–74
atypical teratoid/rhabdoid tumor, 44 enclosed fibers, 286
CNS primitive neuroectodermal tumors, 43–44 endocrine myopathies, 304
CNS/supratentorial PNET, 43 steroid myopathy, 304
ependymoblastoma, 44 thyroid myopathy, 304
medulloepithelioma, 43–44 energy metabolism disorders, 228
medulloblastoma, 42–43 enterovirus, 305
anaplastic medulloblastoma, 42 entrapment neuropathy, 336
desmoplastic/nodular medulloblastoma, 42 enzyme deficiencies, 248–250
with extensive nodularity, 42 defective DNA repair, 248–249
large cell medulloblastoma, 42 ataxia-telangiectasia, 249–250
with melanotic differentiation, 42–43 Cockayne syndrome, 249
with myogenic differentiation, 42 xeroderma pigmentosum, 248–249
emerin, 290 neuroaxonal dystrophies, 248
empty sella syndrome, 359 infantile neuroaxonal dystrophy, 248
empyema, 115 neuroaxonal dystrophy, 248
encephalitides, 140–143 porphyrias, 250
DNA viruses, 140–143 eosinophilic meningitis, 130
CMV infection, 142 eosinophilic myositis, 310
HSV encephalitis, 140–142 ependymal cells, 14
progressive multifocal leukoencephalitis, 142–143 ependymal granulations, 16
VZV infection, 142 ependymal tumors, 32–34
RNA viruses, 133–140 anaplastic ependymoma, 34
arbovirus encephalitides, 134–135 ependymoma, 32–34
henipaviruses, 137–139 myxopapillary ependymoma, 34
human T-cell leukemia-associated myelopathy, 140 subependymoma, 34
infection by human immunodeficiency virus, 139–140 ependymoblastoma, 44
lymphotrophic virus-1-associated myelopathy, 140 ependymoma, 32–34, 363
measles encephalitides, 135–137 epidemic encephalitis of von Economo, 143
poliomyelitis, 133–134 epidermoid cysts, 358
progressive rubella panencephalitis, 139 epidural abscesses, 115
rabies, 135 epidural hemorrhage, 63–64
encephalitis, 143–144 epithelial membrane antigen (EMA), 32
encephalitis lethargica (von Economo disease), 143, 192 epithelioid hemangioendothelioma, 53
encephalitis of von Economo, 143 Epstein-Barr virus (EBV), 52
encephalocele, 259 esthesioneuroblastoma, 363
encephaloclastic lesions ethanol, 215–217
basket brain, 275 acute alcohol intoxication, 215
hydranencephaly, 275 chronic alcoholism, 215–217
ischemic strokes, 276 toxic encephalopathy, 215–217
multicystic encephalomalacia, 275–276 ethylene glycol, 217–218
porencephaly, 274–275 toxic encephalopathy, 217–218
selective neuronal necrosis, 276 etiology, 92–97
encephalomalacia, multicystic, 275–276 excessive variation in fiber size, 281
encephalomyelitis, 132 exencephaly, 259
acute disseminated, 170–171 experimental autoimmune encephalomyelitis, 168
paraneoplastic, 224–226 extradural hemorrhage, 63–64
encephalomyelopathies, paraneoplastic, 221–226
paraneoplastic cerebellar degeneration, 224 Fabry disease, 233, 342
paraneoplastic encephalomyelitis, 224–226 factor VIII or CD31, 53
paraneoplastic opsoclonus-myoclonus syndrome, 226 Fahr syndrome, 211
386 • INDEX
familial amyloid polyneuropathies, 341 microscopic findings, 181–182
familial amyloid polyneuropathy, type III, 341 frozen sections, 367, 374
familial Creutzfeldt-Jakob disease, 150, 154–155 fukutin, 290, 294
familial dysautonomia, 340–341 fukutin-related protein (FKRP), 293–294
familial isolated pituitary adenoma (FIPA), 360 fungal myositis, 306
familial prion diseases, 153–156 fusiform aneurysms, 82–83
with cerebral amyloid angiopathy, 155
familial Creutzfeldt-Jakob disease, 154–155 galactocerebrosidase deficiency, 231
fatal familial insomnia, 156 gamma-sarcoglycan, 294
with octapeptide repeat region insertional mutations, 155–158 gangliocytoma, 36
Farber lipogranulomatosis, 233 ganglioglioma, 36–38
fasciitis, 310 desmoplastic infantile ganglioglioma/astrocytoma, 38
fatal familial insomnia, 156 dysplastic gangliocytoma of cerebellum, 37–38
fatal sporadic insomnia, 152 gangliocytoma, 36
fenestrated neurons, 4 ganglioglioma, 36–37
fiber groupings, 286–288 gangliosidoses, 233–235
fibrillary astrocytoma, 22 GM1 gangliosidosis type I, 235
fibroblastic meningioma, 49 GM2 gangliosidosis type II, 234–235
fibrohistiocytic tumors, 53 Tay-Sachs disease, 234
fibromas, 363 Gaucher cells, 230
fibrous meningioma, 49 Gaucher disease, 230–231
fibrous tumors solitary fibrous tumor, 52–53 GBM (glioblastoma) with PNET-like foci, 26
Finnish form of familial amyloid polyneuropathy, type IV, 341 GC. See Gliomatosis cerebri
Finnish variant CLN, 239 gelsolin, 341
FISH, 38 gemistocytic astrocytes, 11
fixation of tissues, 369 germ cell tumors, pituitary gland, 362
florid plaques, 159 GFAP, 22–23
fluorescence in situ hybridization [FISH], 30 giant axonal neuropathy, 339
foam cells, 232–233 giant cell granuloma, 358
focal axonal injury, 71–72 giant cell tumor of bone, 363
focal cortical dysplasia, 270–272 Glasgow Coma Scale (GCS), 59
focal injury, 60–68 glial lipid storage, 12
brainstem lesions, 68 glial tumors, 35–36
contusions, 61–62 angiocentric glioma, 35–36
intracranial hemorrhage, 62–68 astroblastoma, 36
brainstem lesions, 68 chordoid glioma, third ventricle, 36
extradural hemorrhage, 63–64 glioblastoma, 21, 23–25
intracerebral hemorrhage, 67 glioblastoma variants giant cell glioblastoma, 25–26
intraventricular hemorrhage, 67 glioma, 26, 35–36, 363
subarachnoid hemorrhage, 67 gliomatosis cerebri, 26
subdural hemorrhage, 64–66 glioneuronal tumors, 38–40
subdural hygroma, 66–67 dysembryoplastic neuroepithelial tumor, 38
vascular, 67–68 olfactory neuroblastoma, 40
lacerations, 61–62 papillary glioneuronal tumor, 38–39
scalp lesions, 60 paraganglioma, 39–40
skull lesions, 61 Rosette-forming glioneuronal tumor of fourth ventricle, 39
focal pontine leukoencephalopathy, 221 gliosarcoma, 25–26
Forbes disease, 246, 303 globoid-cell leukodystrophy, 231
formalin, 369 globoid cells, 231
Fowler’s hydrancephaly, 275 glucocerebrosidase deficiency, 230–231
fragile X tremor/ataxia syndrome, 200 glycogen metabolic disorders, 246–247
frequent amplification of MYC/NMYC, 42 glycogenoses, 246, 302–304
Friedreich ataxia, 198, 339 Forbes disease, 303
gross appearance, 198 McArdle disease, 303–304
microscopic findings, 198 Pompe disease, 303
frontotemporal lobar degenerations, 179–184 Tarui disease, 304
FTD lacking inclusions, 183 glycogenosis disorders, 304
FTLD-FUS, 182–183 GM2 gangliosidosis AB variant, 234–235
FTLD-TAU, 179–181 GM2-gangliosidosis B variant, 234
FTLD-tau without tau mutations, 181 GM1 gangliosidosis type I, 235
FTLD with MAPT mutations, 180–181 GM2 gangliosidosis type II, 234–235
gross appearance, 179–180 Gnathostoma spinigerum, 130
microscopic lesions, 179–181 gonadotroph cell adenoma, 352
Pick disease, 179–180 granular atrophy of cerebral cortex, 99–100
FTLD-UPS, 183 granular cell tumors, pituitary gland, 360–362
FTLD with TDP-43-positive lesions, 181–182 granulocytic disorders, 146
gross appearance, 181 granulomatous hypophysitis, 357
Index • 387
granulomatous polymyositis, 310 hereditary metabolic diseases, 227–256
granulovacuolar degeneration, 5 adult polyglucosan body disease, 246–247
gray matter, developing brain, 274–277 amino acid metabolism, 250–253
basal ganglia, encephaloclastic lesions, 276 Canavan disease, 251
developing neocortex, encephaloclastic lesions, Hartnup disease, 252
274–278 homocystinuria, 252
basket brain, 275 hyperglycinemia, 252–253
hydranencephaly, 275 maple syrup urine disease, 252
ischemic strokes, 276 phenylketonuria, 251–252
multicystic encephalomalacia, 275–276 urea-cycle disorders, 253
porencephaly, 274–275 biochemical abnormalities, 228–229
selective neuronal necrosis, 276 energy metabolism disorders, 228
ganglionic eminence, 276–277 intoxication syndromes, 228
thalamus, encephaloclastic lesions, 276 lipid metabolism disorders, 228
Grinker’s myelinopathy, 209 metal metabolism disorders, 228–229
group atrophy, 286 neurotransmitter metabolism disorders, 228
growing fracture, 61 carbohydrate metabolic disorders, 246–247
cholesterol metabolism disorders
HAART. See Highly active antiretroviral therapy abetalipoproteinemia, 238
Hallervorden-Spatz disease, 248 cerebrotendinous xanthomatosis, 238
hamartoma, pituitary gland, 362–363 ceroid lipofuscinosis, neuronal, 238–240
Hansen bacilli Tangier disease, 237–238
Hartnup disease, 252 Wolman disease, 237
HD-like disease, 194 copper metabolism, 250
HD-like diseases, 194 Menkes disease, 250
heat stroke, 210 Wilson disease, 250
heavy metals, 219–221 defective DNA repair
toxic encephalopathy, 219–221 ataxia-telangiectasia, 249–250
Heidenhain variant, 152 Cockayne syndrome, 249
hemangioblastoma, 53–54 xeroderma pigmentosum, 248–249
hemangiomas enzyme deficiencies, 248–250
blood vessel tumors, 53 defective DNA repair, 248–249
cavernous, 90 neuroaxonal dystrophies, 248
hemangiopericytoma, meningeal, 51–52 porphyrias, 250
hematological diseases, 330–333 gangliosidoses
hemimeganencephaly (HME), 270 GM1 gangliosidosis type I, 235
hemochromatosis, 211 GM2 gangliosidosis type II, 234–235
hemodynamic factors, 93–94 Tay-Sachs disease, 234
anastomotic pathways of vascular supply, 93 glycogen metabolic disorders, 246–247
occlusion site, 93–94 Lafora disease, 246–247
occlusion type, 94 lysosomal disorders, 230–240
hemorrhage cholesterol metabolism, 237–240
intracerebral, 76–90 lipid metabolism, 237–240
intracranial, 62–68 lipoprotein metabolism, 237–240
brainstem lesions, 68 mucopolysaccharidoses, 236–237
extradural hemorrhage, 63–64 sphingolipidoses, 230–238
intracerebral hemorrhage, 67 metabolic disorders, 246–247
intraventricular hemorrhage, 67 adult polyglucosan body disease, 246–247
subarachnoid hemorrhage, 67 glycogenoses, 246
subdural hemorrhage, 64–66 Lafora disease, 246–247
subdural hygroma, 66–67 polyglucosan body disease, 246–247
vascular, 67–68 mitochondrial diseases, 244–246
subarachnoid, 67, 76–83 Alpers syndrome, 246
berry aneurysm, 77–81 Kearns-Sayre syndrome, 245–246
dissecting aneurysms, 81–82 Leigh disease, 244
fusiform aneurysms, 82–83 mitochondrial encephalopathy, 244–245
inflammatory aneurysm, 81 myoclonic epilepsy, 245
saccular aneurysm, 77–81 neuroaxonal dystrophies
hemorrhagic infarction, 92 infantile neuroaxonal dystrophy, 248
hemorrhagic leukoencephalopathy of Hurst, 132–133, neuroaxonal dystrophy, 248
170 orthochromatic leukodystrophies, 254–256
henipaviruses, 137–139 peroxisomal disorders, 240–244
hepatic encephalopathy, 216, 221 adrenoleukodystrophy, 242–243
HER2/neu, 58 Refsum disease, 243–244
hereditary ataxia, 339 Zellweger syndrome, 242
hereditary ceruloplasmin deficiency, 250 polyglucosan body disease, 246–247
hereditary giant axonal neuropathy, 320 sphingolipidoses
hereditary inclusion body myopathy, 310 Fabry disease, 233
388 • INDEX
Farber lipogranulomatosis, 233 human T-cell leukemia, 140
gangliosidoses, 233–235 lymphotrophic virus-1-associated myelopathy, 140
Gaucher disease, 230–231 Hunter syndrome, 237
Krabbe disease, 231 Huntington disease, 193–194
metachromatic leukodystrophy, 235–236 gross appearance, 193–194
Niemann-Pick disease, 231–233 microscopic lesions, 194
structural protein disorders, 253–254 Huntington disease-like disease, 194
Alexander disease, 253 Hurler syndrome, 237
Pelizaeus-Merzbacher disease, 253–254 Hyams grade I and II or high-grade (Hyams grade III and IV), 40
hereditary motor and sensory neuropathy, 336–338 hydatidosis, 130
hereditary neuropathies, 336–342 hydranencephaly, 275
amyloid neuropathies, 341 hydrocephalus, 15–16
acquired amyloid neuropathies, 341 hydromyelia, diplomyelia, 260
familial amyloid polyneuropathies, 341 hypercontracted fibers, 281
disorders of lipid metabolism, 342 hyperflexion and hyperextension injuries, 75
giant axonal neuropathy, 339 hyperglycinemia, 252–253
hereditary ataxia, 339 hyperkalemic periodicparalysis, 297
hereditary motor, sensory neuropathy, 336–338 hyperkinetic movement disorders, 193–195
infantile neuroaxonal dystrophy, 339–340 brain iron accumulation, 194–195
porphyria, 341–342 choreoacanthocytosis, 195
tomaculous neuropathy, 338–339 HD-like disease, 194
hereditary sensory and autonomic neuropathy, Huntington disease, 193–194
340–341 gross appearance, 193–194
HSAN type II, 340 microscopic lesions, 194
HSAN type III, 340–341 hypermyelination, 324
hereditary spastic paraparesis, 203 hyperpituitarism, 347–356
heterotopia hyperplasia, 347–356
laminar, 265 hypertensive cerebrovascular disease, 83–86
neuronal, 265–266 hyperthermia, 210
periventricular nodular, 265–266 hypertrophied fibers, 282
subcortical band, 265 hypoglycemia, 209–210
hexane neuropathy, 320 hypokalemic myopathy, 305
hexosaminidase A deficiency, 234 hypokalemic periodic paralysis type 1, 297
H3F3A, 25 hypokalemic periodic paralysis type 2, 297
highly active anti-retroviral therapy (HAART), 146 hypomyelinated fibers, 323
hindbrain development disorders, 272–274 hypophysitis, 358
aqueduct of sylvius abnormalities, 274 hypopituitarism, 356–358
cerebellum malformations, 272–274 hypothalamus tumors, 360–363
Chiari malformations, 273 hypoxia, 205–210
Dandy-Walker malformation, 273 carbon monoxide poisoning, 208–209
Joubert syndrome, 273 cardiovascular arrest, 208
posterior fossa arachnoid cyst, 274 cellular reactions, 206
rhombencephalosynapsis, 273–274 cerebral infarcts, 208
hippocampal sclerosis, 185, 271 cyanides, 209
Hirano bodies, 7 hyperthermia, 210
histiocytic tumors, 56–58 hypoglycemia, 209–210
Langerhans cell histiocytosis, 56–57 tissue lesions, 206–207
non-Langerhans cell histiocytoses, 57–58
histiocytosis X, 363 iatrogenic Creutzfeldt-Jakob disease, 157–158
histoblot, 376 IDH-1, 38
histochemistry, muscle enzyme, 279–280 IDH1/2, 25
histological sampling, 371 IDH1(R132H) mutant protein, 29
histoplasmosis, 127 IgG4-related disease, 123
HIV-1. See Human immunodeficiency virus immune-mediated necrotizing myopathy, 307–308
HIV-associated myopathy, 305 immune reconstitution inflamatory syndrome (IRIS), 147
HIV infection, 122 Immunoglobulin G4 syndrome , IgG4 syndrome, 123
HMSN I, 336 immunohistochemistry, 374–375
holoprosencephalies, 262–263 muscle biopsy, 280
homocystinuria, 252 immunopathological disorders, 325–327
HSAN. See Hereditary sensory and autonomic inflammatory demyelinating polyradiculoneuropathy, 326–327
neuropathy sarcoidosis, 327
HSAN type II, 340 impact injuries, 60
HSAN type III, 340–341 in situ hybridization, 375
HSV encephalitis, 140–142 inclusion bodies, intraneuronal, 5–8
human gonadotrophin, 158 inclusion body myositis, 309–310
human growth hormone, 158 hereditary inclusion body myopathy, 310
human immunodeficiency virus, 139–140 inclusions, 12–13
human pituitary hormone recipients, 158 infantile neuroaxonal dystrophy, 248, 339–340
Index • 389
infantile spinomuscular atrophy, 288 pseudiallescheriosis, 127
infarction, 90–107 zygomycosis, 127
anemic infarction, 91–92 neurosyphilis
anterior choroidal artery territory, 98 and HIV infection, 122
atherosclerosis, 94–96 meningovascular neurosyphilis, 121
cardiac emboli, 97 parenchymatous neurosyphilis, 122
carotid territory, 97–100 syphilis, 122
cerebral artery territory, 97–98 nonspecific CNS involvement in viral infections
complications of therapy, 102–104 acute disseminated encephalomyelitis, 132
hemodynamic factors, 93–94 acute hemorrhagic leukoencephalopathy of Hurst, 132–133,
anastomotic pathways, vascular supply, 93 170
occlusion site, 93–94 acute viral lymphocytic meningitis, 132
occlusion type, 94 aseptic meningitis, 132
hemorrhagic infarction, 92 opportunistic infections, 144–148
middle cerebral artery territory, 98 AIDS, 146–148
pale infarction, 91–92 in combined granulocytic, lymphocytic disorders, 146
spinal intramedullary infarcts, 104–107 granulocytic disorders, 146
arterial organization, spinal cord, 104–105 lymphocytic disorders, 146–148
etiology, 107 protozoal infections, 125–128
microscopic features, 105 amebiasis, 125
topographical features, 105 cerebral malaria, 125
vertebrobasilar territory, 100–102 toxoplasmosis, 125–128
infection by human immunodeficiency virus, 139–140 trypanosomiasis, 128–129
infections of CNS, 114–148 pyogenic infections
bacterial infections, 114–124 acute bacterial meningitis, 115–116
actinomycosis, 120 brain abscesses, 116–117
atypical mycobacteriosis, 119 empyema, 115
Borreliosis, 122 epidural abscesses, 115
Brucellosis, 122–123 septic embolism, 117
chronic pachymeningitis, 123 subdural abscesses, 115
neurosyphilis, 120–122 suppurative intracranial phlebitis, 117
nocardiosis, 120 rickettsiosis, 144
pyogenic infections, 114–117 RNA viruses
sarcoidosis, 123 arbovirus encephalitides, 134–135
toxin-induced neurological disease, 123–124 henipaviruses, 137–139
tuberculosis, 117–119 human T-cell leukemia/lymphotrophic virus-1-associated
Whipple disease, 119–120 myelopathy, 140
DNA viruses infection by human immunodeficiency virus, 139–140
CMV infection, 142 lymphotrophic virus-1-associated myelopathy, 140
HSV encephalitis, 140–142 measles encephalitides, 135–137
progressive multifocal leukoencephalitis, 142–143 poliomyelitis, 133–134
VZV infection, 142 progressive rubella panencephalitis, 139
encephalitides rabies, 135
DNA viruses, 140–143 tuberculosis
RNA viruses, 133–140 brain tuberculomas, 118
infective viral encephalitis spinal cord tuberculomas, 118
encephalitis, 143–144 tuberculous abscess, 118–119
encephalitis lethargica, 143 tuberculous epidural abscess, 117–119
Rasmussen encephalitis, 144 tuberculous meningitis, 117–118
metazoal infections, 128–131 tuberculous subdural abscesses, 117–119
cysticercosis, 129–130 viral infections, 131–144
eosinophilic meningitis, 130 infective viral encephalitis, 133–144
hydatidosis, 130 nonspecific CNS involvement, 132
schistosomiasis, 130 infectious vasculitides, 109
Strongyloides stercoralis infection, 131 infective viral encephalitis, 133–144
toxocariasis, 130 DNA viruses
trichinosis, 130–131 CMV infection, 142
mycotic infections, 125–127 HSV encephalitis, 140–142
aspergillosis, 126 progressive multifocal leukoencephalitis,
blastomycosis, 126 142–143
candidiasis, 126 VZV infection, 142
chromomycosis, 126 encephalitides
cladosporiosis, 126 DNA viruses, 140–143
coccidioidomycosis, 127 RNA viruses, 133–140
cryptococcosis, 127 encephalitis, 143–144
histoplasmosis, 127 encephalitis lethargica, 143
paracoccidioiodomycosis, 127 Rasmussen encephalitis, 144
390 • INDEX
RNA viruses systemic disease, 90
arbovirus encephalitides, 134–135 vascular malformations, 88–90
henipaviruses, 137–139 arteriovenous malformations, 88–89
human T-cell leukemia-associated myelopathy, 140 capillary telangiectases, 90
infection by human immunodeficiency virus, 139–140 cavernous hemangiomas, 90
measles encephalitides, 135–137 venous angiomas, 89–90
poliomyelitis, 133–134 intraventricular hemorrhage, 67
progressive rubella panencephalitis, 139 invasive pituitary adenomas, 354
rabies, 135 IRIS. See Immune reconstitution inflammatory syndrome
inflammatory aneurysm, 81 iron accumulation, neurodegeneration with, 194–195
inflammatory demyelinating disease, 161–172 iron accumulation type I, neuroaxonal dystrophy,
inflammatory demyelinating polyradiculoneuropathy, 326–327 248
inflammatory/infective aneurysms, 81 iron metabolism, 211
inflammatory myopathy, 305 ischemia, 68–69
inflammatory neuropathy, 325–330 ischemic strokes, 276
inflammatory polyneuropathies, 325–330 isocitrate dehydrogenase genes 1 or 2 (IDH1/2), 22
infection, neuropathies due to, 327–329
AIDS, 327–329 Jansky- Bielschowsky, 239
borreliosis, 329 Joubert syndrome, 273
leprosy, 327
inflammatory demyelinating polyradiculoneuropathy, 326–327 Kaposi sarcoma, 53
leprosy Kearns-Sayre syndrome, 245–246, 301–302
intermediate forms of leprosy, 327 Kennedy disease, 203
multibacillary leprosy, 327 Ki-67/MIB-1 labeling, 23–24
paucibacillary leprosy, 327 Ki-67/MIB-1 labeling index, 21
sarcoidosis, 327 KIAA 1549, 27
vasculitic neuropathies, 329–330 KIAA1549-BRA F aberrations, 28
microvasculitis, 330 kinky hair disease, 250
polyarteritis nodosa, 329–330 Korsakoff psychosis, 212
inflammatory polyradiculoneuropathies, 327 Krabbe disease, 231, 342
influenza virus, 305 Kufs disease, 238–240
infratentorial lesions, 17–18 Kugelberg-Welander disease, 288
INIBD (intranuclear inclusion body disease), 7 kuru, 156–157
iniencephaly, 259
INI1protein, 44 lacerations, 61–62
insertional mutations, octapeptide repeat region, 155–158 lactic acidosis, mitochondrial encephalopathy, 244–245
insomnia, fatal familial, 156 lacunar infarcts, 111–112
intermediate forms of leprosy, 327 Lafora bodies, 7
interstitial changes, 285 Lafora disease, 246–247, 304
intoxication syndromes, 228 Laing distal myopathy, 295
intracerebral hemorrhage, 67, 76–90 Lambert-Eaton syndrome, 289
intracranial fibrosarcomas, 52 lamin A/C, 290, 293–294
intracranial hemorrhage, 62–68 laminar heterotopia, 265
brainstem lesions, 68 LAMP-2, 303
extradural hemorrhage, 63–64 Langerhans cell histiocytosis, 56–57
intracerebral hemorrhage, 67 large cell medulloblastoma, 42
intraventricular hemorrhage, 67 lead, 220
subarachnoid hemorrhage, 67 toxic encephalopathy, 220
subdural hemorrhage, 64–66 Leber’s hereditary optic neuropathy, 301
subdural hygroma, 66–67 legionellosis, 123
vascular, 67–68 Leigh’s disease, 244, 301
intracranial pressure, raised, 16–18 lepromatous leprosy, 327
infratentorial lesions, 17–18 leprosy, 327
supratentorial lesions, 17 intermediate forms of leprosy, 327
intraneural perineurioma, 47 multibacillary leprosy, 327
intraneuronal inclusion bodies, 5–8 paucibacillary leprosy, 327
intranuclear inclusion body disease, 7 leukocytoclastic vasculitis, 330
intraparenchymal hemorrhage, 83–90 leukodystrophies, orthochromatic, 254–256
cerebral amyloid angiopathy, 86–88 leukoencephalopathy, 132, 206–207, 221
complications, 88 leukoencephalopathy with vanishing white matter, 254
etiology, 86–87 Lewy bodies, 6, 184
pathology, 87–88 Lewy body diseases, 185
hypertension, 83–86 Lhermitte-Duclos disease, 37–38. See also Dysplastic gangliocytoma
evolution, 84–85 of cerebellum
mechanisms, 83–84 lilac brain, 221
topography, 85–86 limbic encephalitis, 224–225
hypertensive cerebrovascular disease, 83–86 lipid metabolism disorders, 228
Index • 391
lipid myopathies, 301–302 massive hemispheric infarct, 98
carnitine deficiency, 301–302 McArdle disease, 246, 303–304
carnitine palmityl transferase deficiency, 302 measles encephalitides, 135–137
lipofuscin accumulation, 5 measles inclusion body encephalitis, 136
lipoprotein metabolism, 237–240 Meckel-Gruber syndrome, 258
lissencephaly, 268–270 medulloblastoma, 42–43
type I lissencephaly, 268 anaplastic medulloblastoma, 42
type II lissencephaly, 268–270 desmoplastic/nodular medulloblastoma, 42
lobar holoprosencephaly, 262 with extensive nodularity, 42
localized myositis, 311 large cell medulloblastoma, 42
loose reticulated (Antoni B) tissue, 46 with melanotic differentiation, 42–43
Louis-Bar disease, 249–250 with myogenic differentiation, 42
Lyme disease, 329 medulloblastoma with extensive nodularity, 42
lymphocytic disorders, 146–148 medulloepithelioma, 43–44
lymphocytic hypophysitis, 356–357 melanomas, 363
lymphocytic microvasculitis, 330 melanotic Schwannomas, 46
lymphomas, 54–58, 363 MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis
primary CNS lymphomas, 54–55 and stroke-like episodes), 301
secondary CNS involvement, 55–56 MEN4, 359–360
lymphoplasmacyte-rich meningioma, 50 meningeal hemangiopericytoma, 51–52
lymphorrhages, 289 meninges tumors, 48–54
lymphotrophic virus-1-associated myelopathy, 140 meningiomas, 48–51
lysosomal acid lipase deficiency, 237 WHO grade I meningiomas, 48–50
lysosomal disorders, 230–240 WHO grade II meningiomas, 50
disorders of cholesterol metabolism, 237–240 WHO grade III meningiomas, 50–51
abetalipoproteinemia, 238 mesencyhmal non-meningothelial tumors
cerebrotendinous xanthomatosis, 238 adipose tissue lipomas, 52
ceroid lipofuscinosis, neuronal, 238–240 blood vessel tumors hemangiomas, 53
Tangier disease, 237–238 chondroma, 53
Wolman disease, 237 fibrous tumors solitary fibrous tumor, 52–53
gangliosidoses muscle tumors Leiomyosarcoma, 53
GM1 gangliosidosis type I, 235 osteocartilaginous tumors, 53
GM2 gangliosidosis type II, 234–235 osteochondroma, 53
Tay-Sachs disease, 234 osteoma, 53
lipid metabolism, disorders of, 237–240 nonmeningothelial tumors, 51–54
lipoprotein metabolism, 237–240 hemangioblastoma, 53–54
mucopolysaccharidoses, 236–237 meningeal hemangiopericytoma, 51–52
sphingolipidoses, 230–238 mesencyhmal non-meningothelial tumors, 52–53
Fabry disease, 233 primary melanocytic lesions, 53
Farber lipogranulomatosis, 233 WHO grade I meningiomas
gangliosidoses, 233–235 angiomatous meningioma, 49–50
Gaucher disease, 230–231 fibrous meningioma, 49
Krabbe disease, 231 lymphoplasmacyte-rich meningioma, 50
metachromatic leukodystrophy, 235–236 meningothelial meningioma, 49
Niemann-Pick disease, 231–233 metaplastic meningiomas, 50
lysosomal storage diseases, 230–240 microcystic meningioma, 50
psammomatous meningioma, 49
macrophage proliferation and phagocytosis, 13 secretory meningioma, 50
macrophagic myofasciitis, 310–311 transitional meningioma, 49
macroscopic examination, CNS, 369–371 WHO grade II meningiomas
histological sampling, 371 atypical meningioma, 50
inspection, 369 chordoid meningioma, 50
slicing, 369–371 clear cell meningioma, 50
malformations, vascular, 88–90 WHO grade III meningiomas
malignant glioma with PNET-like foci, 26 anaplastic meningioma, 50–51
malignant hyperpyrexia syndrome, 304 papillary meningioma, 51
malignant lymphomas, neuropathies associated with, 330–331 rhabdoid meningioma, 51
malignant peripheral nerve sheath tumor, 47–48 meningioma, 363
mammosomatotrophic cell adenoma, 350 meningitis, aseptic, 132
manganese, 220 meningocele, 259
toxic encephalopathy, 220 meningoencephalocele, 259
MAPK/ERK signaling pathway, 27 meningothelial meningioma, 49
maple syrup urine disease, 252 meningovascular neurosyphilis, 121
Marburg type MS, 169 Menkes disease, 250
Marchiafava-Bignami disease, 217 mercury, 220
Marinesco bodies, 7 toxic encephalopathy, 220
Markesbery-Griggs distal myopathy, 295 merosin, 290
392 • INDEX
merosin-negative congenital muscular dystrophy, 295 Leigh disease, 244
merosin-positive congenital muscular dystrophy, 295 mitochondrial encephalopathy, 244–245
MERRF (myoclonus epilepsy with ragged red fibers), 301 myoclonic epilepsy, 245
mesencyhmal non-meningothelial tumors, 52–53 neuroaxonal dystrophies
adipose tissue lipomas, 52 infantile neuroaxonal dystrophy, 248
blood vessel tumors hemangiomas, 53 neuroaxonal dystrophy, 248
chondroma, 53 orthochromatic leukodystrophies, 254–256
fibrous tumors solitary fibrous tumor, 52–53 peroxisomal disorders, 240–244
muscle tumors Leiomyosarcoma, 53 adrenoleukodystrophy, 242–243
osteocartilaginous tumors, 53 Refsum disease, 243–244
osteochondroma, 53 Zellweger syndrome, 242
osteoma, 53 polyglucosan body disease, 246–247
MET, 25 sphingolipidoses
metabolic diseases, hereditary, 227–256 Fabry disease, 233
adult polyglucosan body disease, 246–247 Farber lipogranulomatosis, 233
amino acid metabolism, 250–253 gangliosidoses, 233–235
Canavan disease, 251 Gaucher disease, 230–231
Hartnup disease, 252 Krabbe disease, 231
homocystinuria, 252 metachromatic leukodystrophy, 235–236
hyperglycinemia, 252–253 Niemann-Pick disease, 231–233
maple syrup urine disease, 252 structural protein disorders, 253–254
phenylketonuria, 251–252 Alexander disease, 253
urea-cycle disorders, 253 Pelizaeus-Merzbacher disease, 253–254
biochemical abnormalities, 228–229 metabolic disorders, 205–226, 246–247
energy metabolism disorders, 228 adult polyglucosan body disease, 246–247
intoxication syndromes, 228 cerebral hypoxia, 205–210
lipid metabolism disorders, 228 carbon monoxide poisoning, 208–209
metal metabolism disorders, 228–229 cardiovascular arrest, 208
neurotransmitter metabolism disorders, 228 cellular reactions, 206
carbohydrate metabolic disorders, 246–247 cerebral infarcts, 208
cholesterol metabolism cyanides, 209
abetalipoproteinemia, 238 hyperthermia, 210
cerebrotendinous xanthomatosis, 238 hypoglycemia, 209–210
ceroid lipofuscinosis, neuronal, 238–240 tissue lesions, 206–207
Tangier disease, 237–238 electrolytic disturbances, 210–211
Wolman disease, 237 calcium metabolism, 211
copper metabolism, 250 central pontine myelinolysis, 210–211
Menkes disease, 250 iron metabolism, 211
Wilson disease, 250 ethanol
defective DNA repair acute alcohol intoxication, 215
ataxia-telangiectasia, 249–250 chronic alcoholism, 215–217
Cockayne syndrome, 249 glycogenoses, 246
xeroderma pigmentosum, 248–249 Lafora disease, 246–247
enzyme deficiencies, 248–250 paraneoplastic encephalomyelopathies
defective DNA repair, 248–249 paraneoplastic cerebellar degeneration, 224
neuroaxonal dystrophies, 248 paraneoplastic encephalomyelitis, 224–226
porphyrias, 250 paraneoplastic opsoclonus-myoclonus syndrome, 226
gangliosidoses polyglucosan body disease, 246–247
GM1 gangliosidosis type I, 235 systemic disease, CNS changes, 221–226
GM2 gangliosidosis type II, 234–235 hepatic encephalopathy, 221
Tay-Sachs disease, 234 multifocal necrotizing leukoencephalopathy, 221
glycogen metabolic disorders, 246–247 paraneoplastic encephalomyelopathies, 221–226
Lafora disease, 246–247 respiratory encephalopathies, 221
lysosomal disorders, 230–240 toxic encephalopathies, 215–221
cholesterol metabolism, 237–240 aluminum, 219
lipid metabolism, 237–240 arsenic, 219–220
lipoprotein metabolism, 237–240 ethanol, 215–217
mucopolysaccharidoses, 236–237 ethylene glycol, 217–218
sphingolipidoses, 230–238 heavy metals, 219–221
metabolic disorders, 246–247 lead, 220
adult polyglucosan body disease, 246–247 manganese, 220
glycogenoses, 246 mercury, 220
Lafora disease, 246–247 metalloids, 219–221
polyglucosan body disease, 246–247 methanol, 217
mitochondrial diseases, 244–246 phenytoin, 218–219
Alpers syndrome, 246 thallium, 220
Kearns-Sayre syndrome, 245–246 tin, 220–221
Index • 393
metabolic disorders (Cont.) amyotrophic lateral sclerosis, 201–202
vitamin deficiency, 211–215 gross appearance, 201
pellagra, 212–214 microscopic lesions, 201–202
thiamine deficiency, 211–212 bulbar muscular atrophy, 203
vitamin B12 deficiency, 214–215 hereditary spastic paraparesis, 203
metabolic neuropathy, 333–334 spinal muscular atrophy, 202–203
diabetes, 333 X-linked bulbar muscular atrophy, 203
metachromasia, 235 X-linked spinal atrophy, 203
metachromatic leukodystrophy, 235–236, 342 movement disorders, 186–195
metal metabolism disorders, 228–229 akinetic rigid syndromes, 186–193
metalloids, 219–221 corticobasal degeneration, 189–191
toxic encephalopathy, 219–221 multiple system atrophy, 191–192
metaplastic meningiomas, 50 Parkinson disease, 186–188
metastatic neoplasms, pituitary gland, 360 progressive supranuclear palsy, 188–189
metazoal infections, 128–131 secondary parkinsonian syndromes, 192–193
cysticercosis, 129–130 corticobasal degeneration
eosinophilic meningitis, 130 gross appearance, 190
hydatidosis, 130 microscopic lesions, 190–191
schistosomiasis, 130 Huntington disease
Strongyloides stercoralis infection, 131 gross appearance, 193–194
toxocariasis, 130 microscopic lesions, 194
trichinosis, 130–131 hyperkinetic movement disorders, 193–195
methanol, 217 choreoacanthocytosis, 195
toxic encephalopathy, 217 HD-like disease, 194
methylator phenotype (G-CIMP), 25 Huntington disease, 193–194
MGMT locus, 25 neurodegeneration with brain iron accumulation, 194–195
microcystic meningioma, 50 multiple system atrophy
microglial lesions, 13–14 gross appearance, 191
microglial nodules, 14 microscopic lesions, 192
microscopic artifacts, 377 Parkinson disease
microvasculitis, 330 gross appearance, 187
middle-caliber arterioles, 329 microscopic lesions, 187–188
systemic vasculitis, 329–330 molecular biology, 188
midline structures, 263–264 progressive supranuclear palsy
anomalies of septum pellucidum, 264 genetics, 189
Minamata disease, 220 gross appearance, 188–189
minicore myopathy, 300 microscopic lesions, 189
mitochondrial diseases, 244–246 secondary parkinsonian syndromes
Alpers syndrome, 246 carbon monoxide poisoning, 192
Kearns-Sayre syndrome, 245–246 pharmacologic/toxic, 192
Leigh disease, 244 postencephalitic parkinsonism, 192
mitochondrial encephalopathy, 244–245 trauma, 193
myoclonic epilepsy, 245 vascular disease, 192
mitochondrial DNA depletion syndrome 4A, 246 MPNST. See Malignant peripheral nerve sheath tumor
mitochondrial encephalomyelomyopathies, 244–246 MSA. See Multiple system atrophy
mitochondrial encephalomyopathy lactic acidosis stroke (MELAS), mucopolysaccharidoses, 236–237
302 multibacillary leprosy, 327
mitochondrial encephalopathy, 244–245 multicore myopathy, 300
mitochondrial myopathies, 300–301 multicystic encephalomalacia, 275–276
mixed gliomas, 31–32 multifocal necrotizing leukoencephalopathy, 221
anaplastic oligoastrocytoma, 32 multiminicore myopathy, 300
oligoastrocytoma, 31 multiple sclerosis, 161–169
mixed meningioma, 49 acute, 169
Miyoshi myopathy, 295 cerebral cortex, MS lesions in, 166–167
MNGIE syndrome (mitochondrial myopathy, neurogastrointestinal deep gray matter, MS lesions in, 166–167
encephalomyopathy), 301 etiology, 168–169
molecular alterations of EGFR amplifi cation and EGFRvIII, 23 inflammation, 162
monoclonal gammopathies, 331–332 normal-appearing white, gray matter, 167–168
monoclonal gammopathy-associated peripheral neuropathy, pathogenesis, 168–169
331–332 pathology, 162–168
monoclonal IgM, 331 white matter, demyelinated lesions in, 162–166
mononeuropathies, 333 multiple system atrophy, 191–192
Morel’s laminar sclerosis, 217 gross appearance, 191
morphologic analysis, CNS lesions, 1–18 microscopic lesions, 192
Morton neuroma, 336 muscle biopsy, 367
moth-eaten fibers, 283–284 muscle tumors Leiomyosarcoma, 53
motor neuron diseases, 201–203 muscular dystrophies, 280, 289, 293, 295
394 • INDEX
musculocutaneous (superficial peroneal) nerve, 368 neuroepithelial tissue tumors, 21–44
mutation in INI1/SNF5, 44 astrocytic tumors, 21–29
mutation in serine/threonine kinase, BRA F (V600E), 57 circumscribed astrocytomas, 26–28
mutation of APC gene, 42 diffusely infiltrating astrocytomas, 21–26
mutations in IDH1/2, 25 choroid plexus tumors, 34–35
mutations of transthyretin ( TT R ) gene, 341 atypical choroid plexus papilloma, 35
myalgias, 304 carcinoma, 35
myasthenia gravis, 288–289 papilloma, 35
myasthenic syndromes, 289 circumscribed astrocytomas
Mycobacterium leprae pilocytic astrocytoma, 26–28
mycoses of the CNS, 125–127 pilomyxoid astrocytoma, 28
aspergillosis, 126 pleomorphic xanthoastrocytoma, 28
blastomycosis, 126 subependymal giant cell astrocytoma, 28–29
candidiasis, 126 CNS primitive neuroectodermal tumors
chromomycosis, 126 CNS/supratentorial PNET, 43
cladosporiosis, 126 ependymoblastoma, 44
coccidioidomycosis, 127 medulloepithelioma, 43–44
cryptococcosis, 127 desmoplastic infantile ganglioglioma/astrocytoma, 38
histoplasmosis, 127 diffusely infiltrating astrocytomas
paracoccidioiodomycosis, 127 anaplastic astrocytoma, 22–23
pseudiallescheriosis, 127 diffuse astrocytoma, 21–22
zygomycosis, 127 giant cell glioblastoma, 25–26
mycotic aneurysms, 81 glioblastoma, 23–25
mycotic infections, 125–127 gliomatosis cerebri, 26
aspergillosis, 126 dysplastic gangliocytoma of cerebellum, 37–38
blastomycosis, 126 embryonal tumors, 42–44
candidiasis, 126 atypical teratoid/rhabdoid tumor, 44
chromomycosis, 126 CNS primitive neuroectodermal tumors, 43–44
cladosporiosis, 126 medulloblastoma, 42–43
coccidioidomycosis, 127 ependymal tumors, 32–34
cryptococcosis, 127 anaplastic ependymoma, 34
histoplasmosis, 127 ependymoma, 32–34
paracoccidioiodomycosis, 127 myxopapillary ependymoma, 34
pseudiallescheriosis, 127 subependymoma, 34
zygomycosis, 127 gangliocytoma, 36
myelin protein zero, 337 ganglioglioma, 36–38
myeloma with monoclonal IgG, 331 astrocytoma, 38
myelomeningocele, 259 desmoplastic infantile ganglioglioma, 38
myoadenylate deaminase deficiency, 304 dysplastic gangliocytoma of cerebellum, 37–38
myoclonic epilepsy, 245 gangliocytoma, 36
myoclonic epilepsy ragged red fibers (MERRF), 302 ganglioglioma, 36–37
myofibrillar myopathies, 295 glial tumors, 35–36
myopathy with tubular aggregates, 304 angiocentric glioma, 35–36
myophosphorylase deficiency, 303–304 astroblastoma, 36
myotilin, 290, 294 chordoid glioma of third ventricle, 36
myotilinopathy, 293 glioneuronal tumors, 38–40
Myotonia congenital, 297 dysembryoplastic neuroepithelial tumor, 38
myotonic dystrophy, 296–298 olfactory neuroblastoma, 40
myxopapillary ependymoma, 34 papillary glioneuronal tumor, 38–39
paraganglioma, 39–40
NBAI. See Neurodegeneration with brain iron accumulation Rosette-forming glioneuronal tumor of fourth ventricle, 39
necrosis, acute neuronal, 2–3 medulloblastoma
necrotizing changes, 283 anaplastic medulloblastoma, 42
Negri bodies, 7, 135–136 desmoplastic/nodular medulloblastoma, 42
nerve cell atrophy, 2 with extensive nodularity, 42
nerve disease, peripheral, 313–342 large cell medulloblastoma, 42
nerve teasing, 314–316 with melanotic differentiation, 42–43
neural tube closure defects, 258 with myogenic differentiation, 42
neuroaxonal dystrophy, 248 mixed gliomas, 31–32
infantile neuroaxonal dystrophy, 248 anaplastic oligoastrocytoma, 32
neuroaxonal dystrophy, 248 oligoastrocytoma, 31
neurochemical studies, 376 neurocytic tumors, 38
neurocytic tumors, 38 central neurocytoma, 38
central neurocytoma, 38 cerebellar liponeurocytoma, 38
cerebellar liponeurocytoma, 38 oligodendroglial tumors, 29–31
neurodegeneration with brain iron accumulation (NBAI), anaplastic oligodendroglioma, 31
194–195 oligodendroglioma, 29–31
Index • 395
neuroepithelial tissue tumors (Cont.) surgical specimens, 367
pineal parenchymal tumors, 40–41 sectioning, 371–377
papillary tumor of pineal region, 41 in situ hybridization, 375
pineal parenchymal tumor of intermediate differentiation, 40 staining, 371–377
pineoblastoma, 40–41 neuropathy, 341
pineocytoma, 40 neuropil, 4
neurofibrillary degeneration, Alzheimer, 5 neurosurgical specimens, 367
neurofibrillary tangles, Alzheimer disease, 176–178 neurosyphilis, 120–122
neurofibroma, 46–47 and HIV infection, 122
neurohypophysis tumors, pituitary gland, 360–363 meningovascular neurosyphilis, 121
neuromuscular transmission defects, 288–289 parenchymatous neurosyphilis, 122
Lambert-Eaton syndrome, 289 neurotransmitter metabolism disorders, 228
myasthenia gravis, 288–289 neurulation failure, 258–261
neuromyelitis optica, 171–172 cranial NTDs, 258–259
neuronal ceroid lipofuscinosis, 342 spinal NTDs, 259–261
neuronal cytoplasmic inclusions (NCIs), 182 NF2 gene, 34, 45, 47
neuronal intranuclear inclusion disease, 7 NF2 tumor suppressor gene, 34
neuronal intranuclear inclusions, 183 Niemann-Pick disease, 231–233, 342
neuronal lesions, 2–10 NIID (neuronal intranuclear inclusion disease), 7
acute neuronal necrosis, 2–3 nocardiosis, 120
Alzheimer neurofibrillary degeneration, 5 nodular focal myositis, 310
apoptosis, 2 nodular medulloblastoma, 42
axonal alterations, 8–10 non-infectious CNS vasculitides, 109–110
binucleated neurons, 4 non-Langerhans cell histiocytoses, 57–58
central chromatolysis, 3–4 nonaccidental injury, 75
fenestrated neurons, 4 Nonaka distal myopathy, 295
granulovacuolar degeneration, 5 Nonaka myopathy, 310
intraneuronal inclusion bodies, 5–8 nondystrophic myotonias, 296–298
nerve cell atrophy, 2 nonmeningothelial tumors, 51–54
neuronal storage, 4–5 hemangioblastoma, 53–54
neuropil, 4 meningeal hemangiopericytoma, 51–52
programmed cell death, 2 mesencyhmal non-meningothelial tumors, 52–53
vacuolated neurons, 4 adipose tissue lipomas, 52
neuronal necrosis, 2–3 blood vessel tumors hemangiomas, 53
neuronal storage, 4–5 chondroma, 53
neuropathic beriberi, 334 fibrous tumors solitary fibrous tumor, 52–53
neuropathological techniques, 365–377 muscle tumors Leiomyosarcoma, 53
artifacts, 377 osteocartilaginous tumors, 53
macroscopic artifacts, 377 osteochondroma, 53
microscopic artifacts, 377 osteoma, 53
autopsy primary melanocytic lesions, 53
brain, 366 nonspecific CNS involvement in viral infections, 132
peripheral nervous system, 366 acute disseminated encephalomyelitis, 132
skeletal musculature, 366 acute hemorrhagic leukoencephalopathy of Hurst, 132–133, 170
spinal cord, 365–366 acute viral lymphocytic meningitis, 132
biopsy procedures aseptic meningitis, 132
brain biopsy, 368 normal prion protein, 150
muscle biopsy, 367 Northern epilepsy, 239
peripheral nerve biopsy, 368 NTDs. See Neural tube closure defects
stereotactic biopsy, 368 nuclear anomalies, 283
brain bank, 377 nuclear bags, 282
electron microscopy, 374 nuclear pleomorphism, 21
embedding, 371–377 null cell adenomas, 354
celloidin embedding, 373–374 nutritional neuropathy, 333–334
frozen sections, 374
paraffin embedding, 372–373 occlusion of aqueduct, 274
fixation of tissues, 369 octapeptide repeat region insertional mutations, 155–158
histoblot, 376 in prion diseases, 155–158
immunohistochemistry, 374–375 oculocraniosomatic syndrome, 301
macroscopic examination, CNS, 369–371 olfactory neuroblastoma, 40
histological sampling, 371 OLIG2, 23–24
inspection, 369 oligoastrocytoma, 31
slicing, 369–371 oligodendrocyte lesions, 13
PET blot, 376 oligodendroglial tumors, 29–31
removal methods, 365–368 anaplastic oligodendroglioma, 31
autopsy, 365–367 oligodendroglioma, 29–31
biopsy procedures, 367–369 oligodendroglioma, 29–31, 363
396 • INDEX
olivopontocerebellar atrophy [OPCA], 191, 197 perinatal telencephalic leukoencephalopathy, 277
Onchocerca vulvulus, 130 perineurial cells, 336
1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 192 peripheral nerve, 313–342
onion bulb formation, 324 amyloid neuropathies
onion bulbs, 326 acquired amyloid neuropathies, 341
ophthalmoplegia plus, 301 familial amyloid polyneuropathies, 341
opportunistic infections, 144–148 anatomy, 317–318
AIDS, 146–148 autonomic neuropathy, 340–341
with combined granulocytic, lymphocytic disorders, 146 hereditary sensory and autonomic neuropathy, 340–341
granulocytic disorders, 146 hereditary sensory neuropathy, 340–341
lymphocytic disorders, 146–148 HSAN type II, 340
opsoclonus-myoclonus syndrome, 226 HSAN type III, 340–341
orthochromatic leukodystrophies, 235, 254–256 axonal degeneration
osteocartilaginous tumors, 53 axonal caliber abnormalities, 320
osteochondroma, 53 dying-back neuropathy, 318–319
osteoma, 53 neuronopathy, 319–320
osteosarcoma, 363 Wallerian degeneration, 318
overexpression of mutant EGFRvIII, 25 cryoglobulinemias, 332–333
overlap myositis, 308–309 demyelinating, 324–325
ovoids, 320 hematological diseases, 330–333
hereditary neuropathies, 336–342
pachygyria, 268 amyloid neuropathies, 341
pachymeningitis, 123 disorders of lipid metabolism, 342
pale infarction, 91–92 giant axonal neuropathy, 339
pallidal necrosis, 208 hereditary ataxia, 339
papillary craniopharyngioma, 360 hereditary motor, sensory neuropathy, 336–338
papillary ependymomas, 32 infantile neuroaxonal dystrophy, 339–340
papillary glioneuronal tumor, 38–39 porphyria, 341–342
papillary meningioma, 51 tomaculous neuropathy, 338–339
papillary tumor of pineal region, 41 hereditary sensory neuropathy
paracoccodioidomycosis, 127 HSAN type II, 340
paraffin embedding, 372–373 HSAN type III, 340–341
paraganglioma, 39–40, 363 immunopathological disorders
paragonimiasis, 130 inflammatory demyelinating polyradiculoneuropathy, 326–327
Paramyotonia congenital, 297–298 sarcoidosis, 327
paraneoplastic cerebellar degeneration, 224–225 infection, neuropathies due to
paraneoplastic encephalomyelitis, 224–226 AIDS, 327–329
paraneoplastic encephalomyelopathies, 221–226 borreliosis, 329
paraneoplastic cerebellar degeneration, 224 leprosy, 327
paraneoplastic encephalomyelitis, 224–226 inflammatory polyneuropathies, 325–330
paraneoplastic opsoclonus-myoclonus syndrome, 226 immunopathological disorders, 325–327
paraneoplastic neuropathies, 330 infection, neuropathies due to, 327–329
paraneoplastic opsoclonus-myoclonus syndrome, 226 vasculitic neuropathies, 329–330
paraneoplastic sensory neuropathy, 226, 330 leprosy
parasitic myositis, 306 intermediate forms of leprosy, 327
parenchymatous neurosyphilis, 122 multibacillary leprosy, 327
Parkinson disease, 186–188 paucibacillary leprosy, 327
gross appearance, 187 malignant lymphomas, neuropathies associated with,
microscopic lesions, 187–188 330–331
molecular biology, 188 metabolic neuropathy, 333–334
paucibacillary leprosy, 327 diabetes, 333
PDGFRA , 25 monoclonal gammopathies, 331–332
PDGRA , 25 peripheral neuropathy, 331–332
pediatric head injury, 75 morphometric analysis methods, 316–317
Pelizaeus-Merzbacher disease, 253–254 neoplasm invasion of nerve, 333
pellagra deficiency, 212–214 neoplasms, 330–333
penetrating injuries, 60, 72–73 nutritional neuropathy, 333–334
peptide-hormone-producing adenomas, 347–354 paraneoplastic neuropathies, 330
ACTH-producing adenomas, 351–352 peripheral nerve biopsy, 313–317
corticotroph cell adenomas, 351 biopsy site, 313–314
silent corticotroph adenoma, 351–352 frozen sections, 316
GH cell adenomas, 350 indications, 313
acidophil stem cell adenoma, 350 methods, 314–317
GH-only pituitary adenomas, 350 molecular analysis, 316
mammosomatotrophic cell adenoma, 350 plastic embedding, 314
mixed GH cell/PRL cell adenoma, 350 quantitative analysis, 316–317
perinatal ischemic strokes, 276 routine histology, 314
Index • 397
peripheral nerve (Cont.) inflammatory polyneuropathies, 325–330
primary axonal degeneration, 318–321 immunopathological disorders, 325–327
axonal degeneration, 318–320 infection, neuropathies due to, 327–329
primary segmental demyelination, 321–324 vasculitic neuropathies, 329–330
acute segmental demyelination, 323 leprosy
onion bulb formation, 324 intermediate forms of leprosy, 327
remyelination, 323 multibacillary leprosy, 327
Schwann cell proliferation, 324 paucibacillary leprosy, 327
reactions to disease, 318–325 malignant lymphomas, neuropathies associated with, 330–331
toxic neuropathies, 334–335 metabolic neuropathy, 333–334
accidental exposure, 334–335 diabetes, 333
arsenic, 334 methods, morphometric analysis, 316–317
diphtheria toxin, 334 monoclonal gammopathies, 331–332
hexane, 335 monoclonal gammopathy-associated peripheral neuropathy,
hexane and related compounds, 335 331–332
industrial exposure, 334–335 neoplasm invasion of nerve, 330–333
lead, 334–335 nutritional neuropathy, 333–334
organophosphorus compounds, 335 paraneoplastic neuropathies, 330
therapeutic agent complications, 335–340 peripheral nerve biopsy, 313–317
traumatic neuropathies, 335–336 biopsy site, 313–314
vasculitic neuropathies frozen sections, 316
microvasculitis, 330 indications, 313
polyarteritis nodosa, 329–330 methods, 314–317
peripheral nerve biopsy, 313–317, 368 molecular analysis, 316
biopsy site, 313–314 plastic embedding, 314
frozen sections, 316 quantitative analysis, 316–317
indications, 313 routine histology, 314
methods, 314–317 primary axonal degeneration, 318–321
morphometric analysis, 316–317 axonal degeneration, 318–320
molecular analysis, 316 primary segmental demyelination, 321–324
plastic embedding, 314 acute segmental demyelination, 323
quantitative analysis, 316–317 Schwann cell proliferation, 324
routine histology, 314 toxic neuropathies, 334–335
peripheral nerve disease, 313–342 accidental exposure, 334–335
amyloid neuropathies arsenic, 334
acquired amyloid neuropathies, 341 diphtheria toxin, 334
familial amyloid polyneuropathies, 341 hexane, 335
axonal degeneration industrial exposure, 334–335
axonal caliber abnormalities, 320 lead, 334–335
dying-back neuropathy, 318–319 organophosphorus compounds, 335
neuronopathy, 319–320 therapeutic agent complications, 335–340
Wallerian degeneration, 318 traumatic neuropathies, 335–336
cryoglobulinemias, 332–333 vasculitic neuropathies
disease reactions, primary segmental demyelination microvasculitis, 330
onion bulb formation, 324 polyarteritis nodosa, 329–330
remyelination, 323 peripheral nerve sheath tumors, 44–48
hematological diseases, 330–333 intraneural perineurioma, 47
hereditary neuropathies, 336–342 malignant peripheral nerve sheath tumor, 47–48
amyloid neuropathies, 341 neurofibroma, 46–47
disorders of lipid metabolism, 342 Schwannoma, 44–46
giant axonal neuropathy, 339 cellular Schwannomas, 46
hereditary ataxia, 339 melanotic Schwannomas, 46
hereditary motor, sensory neuropathy, 336–338 plexiform Schwannomas, 46
infantile neuroaxonal dystrophy, 339–340 peripheral nervous system autopsy, 366
porphyria, 341–342 perivascular microglia, 13
tomaculous neuropathy, 338–339 periventricular hemorrhages, 276
hereditary sensory and autonomic neuropathy, 340–341 periventricular leukomalacia (PVL), 277
HSAN type II, 340 periventricular nodular heterotopia, 265–266
HSAN type III, 340–341 peroneus brevis muscle, 368
immunopathological disorders peroxisomal disorders, 240–244
sarcoidosis, 327 adrenoleukodystrophy, 242–243
subacute/chronic inflammatory demyelinating Refsum disease, 243–244
polyradiculoneuropathy, 326–327 Zellweger syndrome, 242
infection, neuropathies due to PET blot, 376
AIDS, 327–329 phenylketonuria, 251–252
borreliosis, 329 phenytoin, 218–219
leprosy, 327 toxic encephalopathy, 218–219
398 • INDEX
phosphofructokinase deficiency, 304 pituitary diseases in familial syndromes, 359–360
phytanic acid oxidase deficiency, 243–244 type 1 multiple endocrine neoplasia syndrome (MEN1), 359
Pick bodies, 5, 180 plasmacytoma, 362
Pick cells and FTDP-17, 180 Rathke’s pouch, cleft persistence, 358
Pick disease, 179–180 Rathke’s pouch remnants, persistence of, 358
pigmentary orthochromatic leukodystrophy of Van Bogaert and sellar region tumors, 360–363
Nyssen, 256 vascular lesions, 356–358
PIK3CA, 25 apoplexy, 358
pilocytic astrocytoma, 26–28 infarction, 358
pilomyxoid astrocytoma, 28 Sheehan syndrome, 358
pineal parenchymal tumors, 40–41 plasmacytoma, pituitary gland, 362
papillary tumor of pineal region, 41 pleomorphic xanthoastrocytoma (PXA), 28
pineal parenchymal tumor, 40 plexiform Schwannomas, 46
pineoblastoma, 40–41 plurihormonal adenoma, 350
pineocytoma, 40 PNETs. See CNS primitive neuroectodermal tumors
pineoblastoma, 40–41 POEMS syndrome, 331–332
pineocytoma, 40 poliomyelitis, 133–134
pituitary adenoma, 346 polyarteritis nodosa, 329–330
pituitary aplasia, 359 polyglucosan bodies, 304
pituitary carcinoma, 354 polyglucosan body disease, 246–247
pituitary gland, 343–363 polyglucosan myopathy, 304
ACTH-producing adenomas polyglutamine diseases, 174
corticotroph cell adenomas, 351 polymicrogyria, 266–268
silent corticotroph adenoma, 351–352 polymyositis, 307
adenomas, 347–356 polyneuropathies, 325–330
aplasia, 359 immunopathological disorders, 325–327
atypical adenoma, 354 inflammatory demyelinating polyradiculoneuropathy, 326–327
carcinoma, 354 sarcoidosis, 327
chordoma, 362 infection, neuropathies due to, 327–329
craniopharyngioma, 360 AIDS, 327–329
cysts, 358 borreliosis, 329
developmental disorders, 358–359 leprosy, 327
ectopic adenoma, 354 inflammatory, 325–330
empty sella syndrome, 359 immunopathological disorders, 325–327
germ cell tumors, 362 infection, neuropathies due to, 327–329
GH cell adenomas vasculitic neuropathies, 329–330
acidophil stem cell adenoma, 350 leprosy
GH-only pituitary adenomas, 350 intermediate forms of leprosy, 327
mammosomatotrophic cell adenoma, 350 multibacillary leprosy, 327
mixed GH cell/PRL cell adenoma, 350 paucibacillary leprosy, 327
granular cell tumors, 360–362 vasculitic neuropathies, 329–330
hamartoma, 362–363 microvasculitis, 330
hyperpituitarism, 347–356 polyarteritis nodosa, 329–330
hyperplasia, 347–356 POMGnT1, 294
hypopituitarism, 356–358 Pompe disease, 246, 303
hypoplasia, 359 POMT1, 294
hypothalamus tumors, 360–363 POMT2, 294
inflammatory lesions, 356–358 porencephaly, 274–275
giant cell granuloma, 358 porphyria, 250, 341–342
granulomatous hypophysitis, 357 posterior fossa arachnoid cyst, 274
idiopathic, 356–358 postinfectious perivenous encephalitis, 132
lymphocytic hypophysitis, 356–357 postmortem autolysis, 365
primary, 356–358 postsynaptic congenital myasthenic syndromes, 289
secondary hypophysitis, 358 postvaccinial perivenous encephalitis, 132
xanthomatous hypophysitis, 357 potassium-aggravate dmyotonia, 297
invasive adenomas, 354 presynaptic congenital myasthenic syndrome, 289
lesions, 345–347 primary amyloidosis, 341
metastatic neoplasms, 360 primary axonal degeneration, 318–321
neurohypophysis tumors, 360–363 axonal caliber abnormalities, 320
peptide-hormone-producing adenomas, 347–354 dying-back neuropathy, 318–319
ACTH-producing adenomas, 351–352 neuronopathy, 319–320
GH cell adenomas, 350 Wallerian degeneration, 318
gonadotroph cell adenoma, 352 primary CNS lymphomas, 54–55
with neuronal metaplasia, 352–354 primary lateral sclerosis, 201
plurihormonal adenoma, 350 primary melanocytic lesions, 53
prolactin cell adenoma, 347–349 primary neoplasms, CNS, 21–54
thyrotroph cell adenoma, 352 primary progressive MS (PPMS), 162
Index • 399
primary segmental demyelination, 321–324 pyogenic infections, 114–117
acute segmental demyelination, 323 acute bacterial meningitis, 115–116
onion bulb formation, 324 brain abscesses, 116–117
remyelination, 323 empyema, 115
Schwann cell proliferation, 324 epidural abscesses, 115
prion diseases, 149–160 septic embolism, 117
abnormal prion protein, 150–151 subdural abscesses, 115
acquired prion diseases, 156–158 suppurative intracranial phlebitis, 117
Creutzfeldt-Jakob disease, 157–158
kuru, 156–157 quality control of samples, 377
biology, 149–151 quantitative analysis peripheral nerve biopsy, 316–317
diagnostic methods, PrPsc, 151
familial prion diseases, 153–156 rabies, 135
cerebral amyloid angiopathy, 155 ragged red fiber, 285, 301
familial Creutzfeldt-Jakob disease, 154–155 RAS/MAPK signaling pathway, 37
fatal familial insomnia, 156 Rasmussen encephalitis, 144, 271
octapeptide repeat region insertional mutations, 155–158 Rathke’s pouch
infectious agent, 149–150 cleft persistence, 358
normal prion protein, 150 remnant persistence, 358
sporadic Creutzfeldt-Jakob disease, 151–153 RB, 23
variably protease-sensitive prionopathy, 153 RB1, 25
variant Creutzfeldt-Jakob disease, 158–160 RB pathway, 25
prion protein, 149–150 rectal biopsy, 368
prion protein gene, 150 Refsum disease, 243–244, 342
prion protein gene polymorphisms, 151 regeneration fascicles, 322
prionopathy, variably protease-sensitive, 153 relapsing/remitting MS (RRMS), 161
PRL cell adenoma. See Prolactin cell adenoma removal en bloc of cervical spine, 367
PRNP mutations, 154 removal methods, 365–368
PRNP polymorphisms, 150 autopsy, 365–367
programmed cell death (apoptosis), 2 brain, 366
progranulin, 181 peripheral nervous system, 366
progressive distal axonopathy, 318–319 skeletal musculature, 366
progressive multifocal leukoencephalitis, 142–143 spinal cord, 365–366
progressive muscular atrophy, 201 biopsy procedures, 367–369
progressive rubella panencephalitis, 139 brain biopsy, 368
progressive supranuclear palsy, 188–189 muscle biopsy, 367
cell biology, 189 peripheral nerve biopsy, 368
genetics, 189 stereotactic biopsy, 368
gross appearance, 188–189 surgical specimens, 367
microscopic lesions, 189 removal of eyes, 367
prolactin cell adenoma, 347–349 remyelination, 323
prolactinoma, 347–349 remyelination in MS lesions, 166
PROMM (proximal myotonic myopathy), 297 resident microglia, 13
prosencephalon development, 261–264 respiratory encephalopathies, 221
holoprosencephalies, 262–263 retinal/pineal specific transcription factor, CRX, 40
midline structures, 263–264 rhabdoid meningioma, 51
anomalies of septum pellucidum, 264 rhabdomyolysis, 304–305
protein, prion rhabdomyosarcoma, 53
abnormal, 150–151 rheumatic fibromyalgia, 304
normal, 150 rheumatoid arthritis, 330
protein disorders, 253–254 rhombencephalosynapsis, 273–274
Alexander disease, 253 rickettsiosis, 144
Pelizaeus-Merzbacher disease, 253–254 Riley-Day syndrome, 340–341
protein misfolding cyclical amplifi cation (PMCA) reaction, 150 rimmed vacuoles, 284, 296, 310
protein storage myopathies, 300 ring fibers, 284
proteinopathies, 173 ringbinden, 284
protozoal infections, 125–128 RNA viruses, encephalitides, 133–140
amebiasis, 125 rod cell proliferation, 14
cerebral malaria, 125 Rosenthal fibers, 12, 253
toxoplasmosis, 125–128 Rosette-forming glioneuronal tumor of fourth ventricle, 39
trypanosomiasis, 128–129 RRMS, 162
PrP Sc isotypes, 151 rubella panencephalitis, 139
PrPc. See Normal prion protein ruptured intervertebral disc, 74
psammomatous meningioma, 49
pseudoallescheriosis, 127 S100 protein, 51
pseuomyopathic changes, 288 saccular aneurysm, 77–81
PTEN tumor suppressor gene, 25 Sanfilippo disease, 237
400 • INDEX
sarcoglycanopathies, 293 glycogenoses
sarcoglycans, 290 Forbes disease, 303
sarcoidosis, 123, 310, 327 McArdle disease, 303–304
sarcomas, 363 Pompe disease, 303
sarcoplasmic masses, 284 Tarui disease, 304
scalp lesions, 60 idiopathic inflammatory myopathies
Schilder type of MS, 169 dermatomyositis, 306–307
Schindler disease, 248, 339 eosinophilic myositis, 310
schistosomiasis, 130 fasciitis, 310
Schwannoma, 44–46 immune-mediated necrotizing myopathy, 307–308
cellular Schwannomas, 46 inclusion body myositis, 309–310
melanotic Schwannomas, 46 localized myositis, 311
plexiform Schwannomas, 46 macrophagic myofasciitis, 310–311
sCJD. See Sporadic Creutzfeldt-Jakob disease nodular focal myositis, 310
sclerosing panencephalitis, 135 overlap myositis, 308–309
secondary alpha-dystroglycanopathies, 295 polymyositis, 307
secondary amyloidosis, 341 sarcoidosis, 310
secondary cerebellar atrophies, 198 vasculitis involving skeletal muscle, 311–312
crossed cerebellar atrophy, 198 inclusion body myositis, 310
pseudohypertrophy of inferior olive, 198 inflammatory myopathies, 305–312
secondary neoplasms of CNS, 58 bacterial myositis, 306
secondary Parkinsonian syndromes, 192–193 fungal myositis, 306
carbon monoxide poisoning, 192 idiopathic inflammatory myopathies, 306–312
pharmacologic/toxic, 192 inflammatory myopathies caused by microorganisms, 305–306
postencephalitic parkinsonism, 192 parasitic myositis, 306
trauma, 193 viral myositis, 305–306
vascular disease, 192 interstitial changes, 285
secondary progressive MS (SPMS), 161–162 lipid myopathies
secretory meningioma, 50 carnitine deficiency, 301–302
sectioning brain, 371–377 carnitine palmityl transferase deficiency, 302
SEGA. See Subependymal giant cell astrocytoma metabolic myopathies
segmental demyelination, 323 endocrine myopathies, 304
acute segmental demyelination, 323 glycogenoses, 302–304
onion bulb formation, 324 lipid myopathies, 301–302
remyelination, 323 malignant hyperpyrexia syndrome, 304
Schwann cell proliferation, 324 mitochondrial myopathies, 300–301
Seitelberger disease, 248 myalgias/cramps syndromes, 304
selective vulnerability, 205 muscle fiber changes, 281
sellar region tumors, pituitary gland, 360–363 atrophy, 282
semilobar holoprosencephalies, 262 deficiency, 282–283
septic embolism, 117 hypertrophy, 282
septum pellucidum anomalies, 264 muscle fiber structural anomalies, 283–285
serine/threonine kinase BRA F, 27 shape variations, 281
SHH-PTCH-SMO signaling pathway, 42 size variations, 281
shigellosis, Bordetella pertussis infection, melioidosis, muscle fiber structural anomalies
123 basophilic fibers, 283
Shulman syndrome, 310 inclusions, 284
Shy-Drager syndrome, 191 moth-eaten fibers, 283–284
silent corticotroph adenoma, 351–352 necrotizing changes, 283
Sjögren syndrome, 330 nuclear anomalies, 283
Skein-like inclusions, 7 ragged red fibers, 285
skeletal muscle, 278–312 split fibers, 283
biopsy, 278–281 target fibers, 283
site of biopsy, 278 tubular aggregates, 285
techniques, 279–280 vacuoles, 284–285
biopsy techniques muscular dystrophies
immunohistochemistry, 280 autosomal dystrophies, 293–296
muscle enzyme histochemistry, 279–280 Becker muscular dystrophy, 291–293
congenital myopathies, 298–300 central core disease, 299–300
endocrine myopathies centronuclear or myotubular myopathy, 299
steroid myopathy, 304 congenital fiber type disproportion, 300
thyroid myopathy, 304 congenital muscular dystrophies, 295–296
genetically determined disease, 289–304 distal myopathies/muscular dystrophies, 295
congenital myopathies, 298–300 Duchenne muscular dystrophy, 291
metabolic myopathies, 300–304 dystrophic myotonias, 296–298
muscular dystrophies, 289–298 facio-scapulo-humeral muscular dystrophy, 296
myofibrillar myopathies, 300 limb-girdle muscular dystrophies, 293–294
Index • 401
skeletal muscle (Cont.) spinal dysraphism, 259
myotonic dystrophy, 296–298 spinal intramedullary infarcts, 104–107
nemaline myopathy, 298–299 arterial organization of spinal cord, 104–105
nondystrophic myotonias, 296–298 etiology, 107
oculopharyngeal dystrophy, 296 microscopic features, 105
related disorders, 298 topographical features, 105
x-linked Emery-Dreifuss muscular dystrophy, 293 spinal muscular atrophy, 202–203
x-linked muscular dystrophies, 291–293 spinocerebellar ataxias (SCA), 199
neurogenic atrophy, 285–288 split fibers, 283
acute neurogenic processes, 288 spongiform change, 149–150
chronic neurogenic processes, 288 spongiform encephalopathies, 149–150
denervation atrophy, 286 spongy degeneration of CNS, 251
grouping of fibers of same histochemical type, 286–288 spongy leukodystrophy, 251
infants, 288 sporadic Creutzfeldt-Jakob disease, 151–153
target fibers, 288 sporadic degenerative ataxia, 200–201
neuromuscular transmission defects, 288–289 sporadic fatal insomnia, 150
Lambert-Eaton syndrome, 289 stagnant hypoxia, 206
myasthenia gravis, 288–289 staining of tissue, 371–377
rhabdomyolysis, 305 Steele-Richardson-Olszewski syndrome, 188
structural anomalies stereotactic biopsy, 368
inclusions, 284 steroid myopathy, 304
lateral sarcoplasmic masses, 284 storage material, 12–13
toxic myopathies, 304–305 striatonigral degeneration, 191
skeletal musculature autopsy, 366 stroke, mitochondrial encephalopathy, 244–245
skin biopsy, 368 Strongyloides stercoralis, 130–131
skull lesions, 61 structural protein disorders, 253–254
SMA 3 (Kugelberg-Welander disease), 202, 288 Alexander disease, 253
SMA 1 (Werdnig-Hoffmann disease), 202, 288 Pelizaeus-Merzbacher disease, 253–254
small angulated fibers, 281, 286 subacute/chronic inflammatory demyelinating
small cell GBM, 26 polyradiculoneuropathy, 326–327
small intraparenchymal hemorrhages, 110 subacute combined degeneration of spinal cord, 214
small vessel disease, 107–112 subacute necrotizing encephalomyelopathy, 301
parenchymal changes, 110–112 subacute necrotizing encephalopathy, 244
arteriopathic leukoencephalopathies, 112 subacute necrotizing encephalopathy infantile, 244
cerebral microbleeds, 110–111 subacute necrotizing myopathy, 305
lacunar infarcts, 111–112 subarachnoid hemorrhage, 67, 76–90
small intraparenchymal hemorrhages, 110 berry aneurysm, 77–81
vascular diseases, 107–110 dissecting aneurysms, 81–82
CADASIL, 107–109 fusiform aneurysms, 82–83
systemic disorders, 109 infective aneurysm, 81
vasculitis, 109–110 inflammatory aneurysm, 81
vasculitis saccular aneurysm, 77–81
infectious vasculitides, 109 subcortical band heterotopia, 265
non-infectious CNS vasculitides, 109–110 subdural abscesses, 115
smear preparations, 367 subdural hemorrhage, 64–66
sparganosis, 130 subdural hygroma, 66–67
spheroid body myopathy, 300 subependymal giant cell astrocytoma, 28–29
sphingolipidoses, 230–238 subependymoma, 34
Fabry disease, 233 sudanophilic leukodystrophy, 235
Farber lipogranulomatosis, 233 sulfatides, 235
gangliosidoses, 233–235 suppurative intracranial phlebitis, 117
GM1 gangliosidosis type I, 235 supratentorial lesions, 17
GM2 gangliosidosis type II, 234–235 sural nerve, 368
Tay-Sachs disease, 234 surgical specimens, 367
Gaucher disease, 230–231 Swiss-cheese artifact, 377
Krabbe disease, 231 synuclein, 6
metachromatic leukodystrophy, 235–236 syringomyelia, 260–261
Niemann-Pick disease, 231–233 systemic disease, CNS changes, 221–226
sphingomyelin lipidosis, 231–233 hepatic encephalopathy, 221
Spielmeyer-Sjögren-Vogt disease, 239 multifocal necrotizing leukoencephalopathy, 221
spina bifida, 259 paraneoplastic encephalomyelopathies, 221–226
spinal cord, arterial organization, 104–105 paraneoplastic cerebellar degeneration, 224
spinal cord autopsy, 365–366 paraneoplastic encephalomyelitis, 224–226
spinal cord injuries, 74–75 paraneoplastic opsoclonus-myoclonus syndrome, 226
spinal cord injury without radiographic abnormality (SCIWORA), respiratory encephalopathies, 221
75 systemic lupus erythematosus, 330
spinal cord tuberculomas, 118 systemic vasculitis, 329–330
402 • INDEX
T-cell leukemia, 140 transitional schlerosis, 169
T8 encephalitis, 148 transmissible spongiform encephalopathies, 149–150
Tangier disease, 237–238, 342 transthyretin, 341
tanycytic ependymomas, 33 traumatic axonal injury (TAI), 69
targetoid fiber, 283 traumatic brain injury, 59–75
Tarui disease, 304 blast injuries, 73
tau protein, 12 chronic traumatic encephalopathy, 73–74
tauopathy, 174 classification, 59–60
Tay-Sachs disease, 234 diffuse brain injury, 68–72
TDP43, 181 brain swelling, 72
telethonin, 290, 294 diffuse traumatic axonal injury, 69–72
temozolomide, 31 diffuse vascular injury, 72
Thai stages, 178 ischemia, 68–69
thalamic variant of sCJD, 152 diffuse traumatic axonal injury
thallium, 220 axonal injury in mild head injury, 71
toxic encephalopathy, 220 focal axonal injury, 71–72
thiamine deficiency, 211–212 focal injury, 60–68
third ventricle, chordoid glioma, 36 contusions, 61–62
Thomsen disease, 298 intracranial hemorrhage, 62–68
thorn-shaped astrocytes, 190 lacerations, 61–62
thyroid myopathy, 304 scalp lesions, 60
thyrotroph cell adenoma, 352 skull lesions, 61
tick-bite meningoradiculoneuritis, 329 intracranial hemorrhage
tigroid demyelination, 249 brainstem lesions, 68
tigroid leukodystrophy, 253 extradural hemorrhage, 63–64
tin, 220–221 intracerebral hemorrhage, 67
toxic encephalopathy, 220–221 intraventricular hemorrhage, 67
tissue fixation, 369 subarachnoid hemorrhage, 67
titin, 290, 294 subdural hemorrhage, 64–66
tomacula, 324 subdural hygroma, 66–67
tomaculous neuropathy, 338–339 vascular, 67–68
tonsil biopsy, 159 pediatric head injury, 75
touch preparations, 367 penetrating injuries, 72–73
toxic encephalopathies, 215–221 spinal cord injuries, 74–75
aluminum, 219 traumatic encephalopathy, 73–74
arsenic, 219–220 traumatic neuropathies, 335–336
ethanol, 215–217 Trichinella spiralis, 306
acute alcohol intoxication, 215 trichinosis, 130–131
chronic alcoholism, 215–217 Triethyl-tin, 220
ethylene glycol, 217–218 TRIM32, 294
heavy metals, 219–221 trypanosomiasis, 128–129
lead, 220 TSC1 gene, 28
manganese, 220 TSC2 gene, 28
mercury, 220 tuberculoid leprosy, 327
metalloids, 219–221 tuberculosis, 117–119
methanol, 217 brain tuberculomas, 118
phenytoin, 218–219 spinal cord tuberculomas, 118
thallium, 220 tuberculous abscess, 118–119
tin, 220–221 tuberculous epidural abscess, 117–119
toxic myopathies, 304–305 tuberculous meningitis, 117–118
toxic neuropathies, 334–335 tuberculous subdural abscesses, 117–119
accidental exposure, 334–335 tuberculous abscess, 118–119
arsenic, 334 tuberculous epidural abscess, 117–119
diphtheria toxin, 334 tuberculous meningitis, 117–118
hexane, 335 tuberculous subdural abscesses, 117–119
industrial exposure, 334–335 tuberous sclerosis, 271
lead, 334–335 tubular aggregates, 285
organophosphorus compounds, 335 tufted astrocytes, 12, 190
therapeutic agent complications, 335–340 tumor suppressor gene, 22
toxin-induced neurological disease, 123–124 tumors of CNS, 20–58
toxocariasis, 130 astrocytic tumors
toxoplasma, 306 circumscribed astrocytomas, 26–28
toxoplasmosis, 125–128 diffusely infiltrating astrocytomas, 21–26
TP53, 22, 25, 31 choroid plexus tumors
TP53 gene, 25 atypical papilloma, 35
TP53 signaling, and reduced signaling of RB pathway, 25 carcinoma, 35
transitional meningioma, 49 papilloma, 35
Index • 403
tumors of CNS (Cont.) osteochondroma, 53
circumscribed astrocytomas osteoma, 53
pilocytic astrocytoma, 26–28 mixed gliomas
pilomyxoid astrocytoma, 28 anaplastic oligoastrocytoma, 32
pleomorphic xanthoastrocytoma, 28 oligoastrocytoma, 31
subependymal giant cell astrocytoma, 28–29 neurocytic tumors
classification, 20–21 central neurocytoma, 38
CNS primitive neuroectodermal tumors cerebellar liponeurocytoma, 38
CNS/supratentorial PNET, 43 neuroepithelial tissue tumors, 21–44
ependymoblastoma, 44 astrocytic tumors, 21–29
medulloepithelioma, 43–44 choroid plexus tumors, 34–35
diffusely infiltrating astrocytomas desmoplastic infantile ganglioglioma/astrocytoma, 38
anaplastic astrocytoma, 22–23 dysplastic gangliocytoma of cerebellum, 37–38
diffuse astrocytoma, 21–22 embryonal tumors, 42–44
giant cell glioblastoma, 25–26 ependymal tumors, 32–34
glioblastoma, 23–25 gangliocytoma, 36
gliomatosis cerebri, 26 ganglioglioma, 36–38
embryonal tumors glial tumors, 35–36
atypical teratoid/rhabdoid tumor, 44 glioneuronal tumors, 38–40
CNS primitive neuroectodermal tumors, 43–44 mixed gliomas, 31–32
medulloblastoma, 42–43 neurocytic tumors, 38
ependymal tumors oligodendroglial tumors, 29–31
anaplastic ependymoma, 34 pineal parenchymal tumors, 40–41
ependymoma, 32–34 nonmeningothelial tumors
myxopapillary ependymoma, 34 hemangioblastoma, 53–54
subependymoma, 34 meningeal hemangiopericytoma, 51–52
ganglioglioma, 36–37 mesencyhmal non-meningothelial tumors, 52–53
desmoplastic infantile ganglioglioma/astrocytoma, 38 primary melanocytic lesions, 53
dysplastic gangliocytoma of cerebellum, 37–38 oligodendroglial tumors
gangliocytoma, 36 anaplastic oligodendroglioma, 31
glial tumors oligodendroglioma, 29–31
angiocentric glioma, 35–36 peripheral nerve sheath tumors, 44–48
astroblastoma, 36 intraneural perineurioma, 47
chordoid glioma, third ventricle, 36 malignant peripheral nerve sheath tumor, 47–48
glioneuronal tumors neurofibroma, 46–47
dysembryoplastic neuroepithelial tumor, 38 Schwannoma, 44–46
olfactory neuroblastoma, 40 pineal parenchymal tumors
papillary glioneuronal tumor, 38–39 papillary tumor of pineal region, 41
paraganglioma, 39–40 pineal parenchymal tumor of intermediate differentiation, 40
Rosette-forming glioneuronal tumor of fourth ventricle, 39 pineoblastoma, 40–41
histiocytic tumors, 56–58 pineocytoma, 40
Langerhans cell histiocytosis, 56–57 primary neoplasms, 21–54
non-Langerhans cell histiocytoses, 57–58 Schwannoma
lymphomas, 54–58 cellular Schwannomas, 46
primary CNS lymphomas, 54–55 melanotic Schwannomas, 46
secondary CNS involvement, 55–56 plexiform Schwannomas, 46
medulloblastoma secondary neoplasms, 58
anaplastic medulloblastoma, 42 WHO grade I meningiomas
desmoplastic/nodular medulloblastoma, 42 angiomatous meningioma, 49–50
with extensive nodularity, 42 fibrous meningioma, 49
large cell medulloblastoma, 42 lymphoplasmacyte-rich meningioma, 50
with melanotic differentiation, 42–43 meningothelial meningioma, 49
with myogenic differentiation, 42 metaplastic meningiomas, 50
meninges tumors, 48–54 psammomatous meningioma, 49
meningiomas, 48–51 secretory meningioma, 50
nonmeningothelial tumors, 51–54 transitional meningioma, 49
meningiomas WHO grade II meningiomas
WHO grade I meningiomas, 48–50 atypical meningioma, 50
WHO grade II meningiomas, 50 chordoid meningioma, 50
WHO grade III meningiomas, 50–51 clear cell meningioma, 50
mesencyhmal non-meningothelial tumors WHO grade III meningiomas
adipose tissue lipomas, 52 anaplastic meningioma, 50–51
blood vessel tumors hemangiomas, 53 papillary meningioma, 51
chondroma, 53 rhabdoid meningioma, 51
fibrous tumors solitary fibrous tumor, 52–53 Type 1 atrophy, 282
muscle tumors Leiomyosarcoma, 53 Type 2 atrophy, 282
osteocartilaginous tumors, 53 Type 2 fiber atrophy, 305
404 • INDEX
Type 1 multiple endocrine neoplasia syndrome (MEN1), 359 spinal intramedullary infarcts
Type 2B deficiency, 283 arterial organization of spinal cord, 104–105
type grouping, 286–288 etiology, 107
Type I fiber predominance, 283 microscopic features, 105
Type IV glycogenosis, 304 topographical features, 105
subarachnoid hemorrhage, 67, 76–90
ubiquitin, 6 berry aneurysm, 77–81
Udd myopathy, 295 dissecting aneurysms, 81–82
ulegyria, 276 fusiform aneurysms, 82–83
Ullrich/Bethlem myopathies, 296 inflammatory/infective aneurysms, 81
uncommitted/undiff erentiated cells, 270 saccular aneurysm, 77–81
urea-cycle disorders, 253 systemic disorders, 109
uremic neuropathy, 334 vascular malformations
arteriovenous malformations, 88–89
vacuolar myopathy with lysosomal hyperactivity, capillary telangiectases, 90
305 cavernous hemangiomas, 90
vacuolated neurons, 4 venous angiomas, 89–90
vacuoles, 284–285 vasculitis, 109–110
valosin-containing protein (VCP), 181 infectious vasculitides, 109
variably protease-sensitive prionopathy, 153 non-infectious CNS vasculitides, 109–110
variant Creutzfeldt-Jakob disease, 158–160 vascular lesions, pituitary gland, 358
vascular cognitive impairment, 185 apoplexy, 358
vascular dementia, 185 infarction, 358
vascular disease, 76–113 Sheehan syndrome, 358
CADASIL, 107–109 vascular malformations, 88–90
cerebral amyloid angiopathy arteriovenous malformations, 88–89
complications, 88 capillary telangiectases, 90
etiology, 86–87 cavernous hemangiomas, 90
pathology, 87–88 venous angiomas, 89–90
cerebral infarcts vascular supply, anastomotic pathways, 93
carotid territory, 97–100 vascular tumors, 363
complications of therapy, 102–104 vasculitic neuropathies, 329–330
vertebrobasilar territory, 100–102 microvasculitis, 330
hemodynamic factors polyarteritis nodosa, 329–330
anastomotic pathways of vascular supply, 93 vasculitis involving skeletal muscle, 311–312
occlusion site, 93–94 vasogenic edema, 14
occlusion type, 94 venous angiomas, 89–90
hypertension ventricle, chordoid glioma, 36
evolution, 84–85 vertebral dysraphism, 259
mechanisms, 83–84 vertebral fracture, 74
topography, 85–86 vertebrobasilar territory infarcts, 100–102
infarction, 90–107 VHL tumor suppressor, 54
anemic infarction, 91–92 viral inclusions, 7
atherosclerosis, 94–96 viral infections, 131–144
cardiac emboli, 97 DNA viruses
cerebral infarcts, 97–104 CMV infection, 142
etiology, 92–97 HSV encephalitis, 140–142
hemodynamic factors, 93–94 progressive multifocal leukoencephalitis, 142–143
hemorrhagic infarction, 92 VZV infection, 142
pale infarction, 91–92 encephalitides
spinal intramedullary infarcts, 104–107 DNA viruses, 140–143
intracerebral hemorrhage, 76–90 RNA viruses, 133–140
intraparenchymal hemorrhage, 83–90 infective viral encephalitis, 133–144
cerebral amyloid angiopathy, 86–88 encephalitis, 143–144
hypertension, 83–86 encephalitis lethargica, 143
hypertensive cerebrovascular disease, 83–86 Rasmussen encephalitis, 144
systemic disease, 90 nonspecific CNS involvement, 132
vascular malformations, 88–90 acute disseminated encephalomyelitis, 132
parenchymal changes acute hemorrhagic leukoencephalopathy of Hurst, 132–133,
arteriopathic leukoencephalopathies, 112 170
cerebral microbleeds, 110–111 acute viral lymphocytic meningitis, 132
lacunar infarcts, 111–112 aseptic meningitis, 132
small intraparenchymal hemorrhages, 110 RNA viruses
pathology, 112–113 arbovirus encephalitides, 134–135
small vessel disease, 107–112 henipaviruses, 137–139
parenchymal changes, 110–112 human T-cell leukemia/lymphotrophic virus-1-associated
vascular diseases, 107–110 myelopathy, 140
Index • 405
viral infections (Cont.) Wilson disease, 250
infection by human immunodeficiency virus, 139–140 Wilson hepatolenticular degeneration, 221
measles encephalitides, 135–137 WNT-β-catenin pathway, 42
poliomyelitis, 133–134 Wolman disease, 237
progressive rubella panencephalitis, 139
rabies, 135 X-linked bulbar muscular atrophy, 203
viral lymphocytic meningitis, 132 X-linked muscular dystrophies, 291–293
viral myositis, 305–306 Becker muscular dystrophy, 291–293
virological studies, 377 central core disease, 299–300
vitamin B12 deficiency, 214–215 centronuclear or myotubular myopathy, 299
vitamin deficiencies, 211–215 congenital muscular dystrophies, 295–296
pellagra, 212–214 distal myopathies/muscular dystrophies, 295
thiamine deficiency, 211–212 Duchenne muscular dystrophy, 291
vitamin B12 deficiency, 214–215 dystrophic myotonias, 296–298
von Economo encephalitis, 143 Emery-Dreifuss muscular dystrophy, 293
VZV infection, 142 facio-scapulo-humeral muscular dystrophy, 296
encephalitides, 142 limb-girdle muscular dystrophies, 293–294
nemaline myopathy, 298–299
Waldenström macroglobulinemia, 332 nondystrophic hereditary myotonias, 298
Walker-Warburg syndrome, 258, 270, 295 oculopharyngeal dystrophy, 296
watershed infarct or boundary-zone infarct, 98–99 related disorders, 298
Wegener granulomatosis, 330 X-linked spinal atrophy, 203
Welander, Udd, and Markesbery-Griggs distal myopathies, xanthomatosis, cerebrotendinous, 238
295 xanthomatous hypophysitis, 357
Welander myopathy, 295 xeroderma pigmentosum, 248–249
Werdnig-Hoffmann disease, 288
Wernicke-Korsakoff encephalopathy, 216 YWHAE, 268
Wernicke-Korsakoff syndrome, 211
Whipple disease, 119–120 Zellweger syndrome, 242, 266
white matter, developing brain, lesions of, 277 zygomycosis, 127
406 • INDEX

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V R

FRANÇ O IS E G RAY, MD, PHD

© Françoise Gray, Charles Duyckaerts, Umberto De Girolami 2014

You must not circulate this work in any other form

- 5. Infections of the Central Nervous

14. Diseases of the Pituitary Gland 343

- This fifth edition of the Manual attempts to delib-

AUTOPSY DIAGNOSIS in neuropathology is characterized morphologically by the co-expression of

1.1.1.1. Nerve cell “atrophy” Neuronal “atro-

1.1.1.3. Central chromatolysis Central chroma-

Chapter 1 Basic Pathology of the Central Nervous System • 3

FIGURE 1.8 Distended nerve cell bodies in a case

Chapter 1 Basic Pathology of the Central Nervous System • 5

Chapter 1 Basic Pathology of the Central Nervous System • 7

In conditions associated with nerve cell “atro-

FIGURE 1.16 Intranuclear inclusions. (A) Marinesco bodies: small intranuclear inclusion in a pigmented

Chapter 1 Basic Pathology of the Central Nervous System • 9

Chapter 1 Basic Pathology of the Central Nervous System • 11

1.1.2.4. Inclusions and storage material

Chapter 1 Basic Pathology of the Central Nervous System • 13

Chapter 1 Basic Pathology of the Central Nervous System • 15

FIGURE 1.24 Cerebral edema: principal ultrastructural forms.

FIGURE 1.25 Principal types of cerebral herniation.

Chapter 1 Basic Pathology of the Central Nervous System • 17

as well as secondary lesions due to vascular 2. TOPOGRAPHIC ANALYSIS

FIGURE 1.27 Cerebellar tonsillar herniation. (A) Posterior view. (B) Anterior view.

2.1. Diffuse Distribution systems—for example, involvement of upper and

Chapter 1 Basic Pathology of the Central Nervous System • 19

1. CLASSIFICATION when alterations occur in growth regulatory genes,

Table 2.1. Grading of Diffuse Astrocytoma

Chapter 2 Tumors of the Central Nervous System • 21

Chapter 2 Tumors of the Central Nervous System • 23

Chapter 2 Tumors of the Central Nervous System • 25

on tumor location, with an evolution in keeping of pilocytic astrocytoma. Pilocytic astrocytomas

Chapter 2 Tumors of the Central Nervous System • 27

Chapter 2 Tumors of the Central Nervous System • 29

FIGURE 2.5 Microscopic appearance of oligodendroglioma. (A) Oligodendroglioma with microcalcifica-

Chapter 2 Tumors of the Central Nervous System • 31

Chapter 2 Tumors of the Central Nervous System • 33

Chapter 2 Tumors of the Central Nervous System • 35

FIGURE 2.8 Neuronal-glial tumors (microscopic appearance). (A) Gangliocytoma (H&E). (B) Ganglioglioma

Chapter 2 Tumors of the Central Nervous System • 37

2.1.7.1.4. Desmoplastic infantile ganglioglioma/ 2.1.7.2.2. Cerebellar liponeurocytoma (WHO grade

FIGURE 2.9 Neuronal-glial tumors (microscopic appearance). (A)Central neurocytoma (H&E).

structures consisting of a central hyalinized blood 2.1.7.3.4. Paraganglioma Tumors of extra-

Chapter 2 Tumors of the Central Nervous System • 39

2.1.8.2 Pineal parenchymal tumor of inter-

Chapter 2 Tumors of the Central Nervous System • 41

2.1.9.2. CNS primitive neuroectodermal glial, neuronal, sometimes mesenchymal) by ultra-

Chapter 2 Tumors of the Central Nervous System • 43

Chapter 2 Tumors of the Central Nervous System • 45

FIGURE 2.13 Microscopic appearance of neurofi- 2.2.4 . MAL IGNANT PERIPHERAL NERVE

Chapter 2 Tumors of the Central Nervous System • 47

2.3.1.1.1. Meningothelial meningioma This is 2.3.1.1.2. Fibrous (fibroblastic) meningioma This

Chapter 2 Tumors of the Central Nervous System • 49

Chapter 2 Tumors of the Central Nervous System • 51

Chapter 2 Tumors of the Central Nervous System • 53

Chapter 2 Tumors of the Central Nervous System • 55

3.2. Histiocytic Tumors 3 .2 . 1. LAN GERHAN S CELL

Chapter 2 Tumors of the Central Nervous System • 57

FOCAL DIF F USE

T YPE DESCRIP TION

Chapter 3 Central Nervous System Trauma • 61