Pathophysiology of Migraine

By Tariq Faridi

Pathophysiology of Migraine Blood Flow During Aura and Headache Phase

CBF=cerebral blood flow.

Laurizen M. Brain. 1994;118:199-210.

Pathophysiology of Migraine

Outline

Migraine is an inherited central nervous system (CNS) disorder

Migraineurs have hyperexcitable brains Migraine can be progressive in some patients Migraine is progressive during an attack

Central sensitization Multiple mechanisms Reduced CNS excitation in animal model

Topiramate mechanism of action in migraine prevention

Pathophysiology of Migraine Chiropractic Management of VSC (Not Imitrex)

Focus had been on acute therapy to manage individual migraine episodes

New advances in pathophysiology have transformed the concept of what migraine is

Migraine is a CNS disorder

Genetic predisposition (SIDS RA Also) C1-C3 Convergence Trigeminocervical Nucleus Treatment of migraine as a disorder Emphasis on preventive + acute

This has paved the way for improved treatment

C1 C2 NikolaI Boduk Letter to MDs (for all 26)

Pathophysiology of Migraine

Classic Vascular Theory of Migraine

Aura Phase Spasm of Cerebral Arteries
Headache Phase Vasodilation of Cerebral Arteries

Wolf HG. Headache and Other Head Pain. 1963.

Pathophysiology of Migraine

The Genetic Basis

P/Q type Ca++ channel

Presynaptic Voltage gated Occipital cortex Trigeminal nucleus caudalis Linkage to chromosome 19 Linkage to Chromosome 1

Na-K ATP Pump

Figure courtesy of AHS Ambassadors Program. Ophoff RA et al. Cell. 1996;87:543-552. De Fusco M et al. Nat Genet. 2003;33:192-196.

Pathophysiology of Migraine

The P/Q Gene Product

FHM=familial hemiplegic migraine.

Figure courtesy of AHS Ambassadors Program. Ophoff RA et al. Cell. 1996;87:543-552.

Pathophysiology of Migraine

Hyperexcitable Cortex

Migraineurs have a lower threshold for occipital cortex excitation than controls
Genetic component:

P/Q calcium channel, Na+/K+ ATPase Mitochondrial defects Hyperactivity of excitatory neurotransmission
Na+,

Probably due to:

Ca++ channels, glutamate

Lower activity of inhibitory neurotransmission

GABA
GABA=gamma aminobutyric acid.
Aurora SK et al. Neurology. 1998;50:1111-1114.

Pathophysiology of Migraine

Threshold Levels for Triggered Headaches

1.0 0.9 0.8 Probability 0.7 0.6 of Phosphene 0.5 0.4 0.3 0.2 0.1 0.0
0 10 20 30 40 50 60

P=.053, Cox Regression

70

80

90

100

Stimulus Intensity No Triggered HA Triggered HA

HA=headache.
Aurora SK et al. Headache. 1999;39:469-476.

Pathophysiology of Migraine

Imaging of Cortical Spreading Depression (CSD)

Hadjikhani N et al. Proc Natl Acad Sci USA. 2001;98:4687-4692.

Pathophysiology of Migraine

Cortical Spreading Depression

Wave of oligemia begins in occipital cortex and spreads forward at rate of 2-3 mm/min

Begins with aura and persists for hours after headache CBF changes not in distribution of any cerebral artery Consistent with primary neuronal event producing secondary vascular changes

James MF et al. J Physiol. 1999;519:415-425.

Pathophysiology of Migraine

Trigeminovascular Migraine Pain Pathways

Preventive medication target

Neuropeptide Release

Vasodilatation
Central Sensitization Pain Signal Transmission

Acute medication target

Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl 3):S12-S19.

Pathophysiology of Migraine

Brain Stem Involvement in Migraine

Brain stem aminergic nuclei can modify trigeminal pain processing PET demonstrates brain stem activation in spontaneous migraine attacks Brain stem activation persists after successful headache treatment

Brain stem: generator or modulator?

PET=positron emission tomography.

Weiller C et al. Nat Med. 1995;1:658-660.

Pathophysiology of Migraine

Red Nucleus and Substantia Nigra

Sagittal View of Imaging Plane

Inferior Colliculus Mammillary Body

Oblique Imaging Plane

Welch KMA et al. Headache. 2001;41:629-637.

Pathophysiology of Migraine

Iron Homeostasis
R2* Map Substantia Nigra Red Nuclei

Periaqueductal Grey Matter

Welch KMA et al. Headache. 2001;41:629-637.

Pathophysiology of Migraine

Changes in Periaqueductal Gray

16 14 12 10

PAG
*

Red nucleus

R2 (1/ms)

8 6 4 2 0 Control Episodic migraine Chronic daily headache

*

Group-wise Comparison: ANOVA (One-way Analysis of Variance). *Significant difference, P<.05. PAG=periaqueductal gray.
Welch KMA et al. Headache. 2001;41:629-637.

Pathophysiology of Migraine

Disease Progression: Changes in PAG

Changes, observed over time in the PAGcenter of the brains powerful descending analgesic neuronal network
Iron

deposition

Secondary

to free-radical cell damage during migraine attacks

Degree of PAG structural alteration depends on duration of headache history, not the age of the patient
Repeated migraine attacks, repetitive damage, decreased threshold for further migraine attacks
Welch KMA et al. Headache. 2001;41:629-637.

Pathophysiology of Migraine

Disease Progression: White Matter Lesions

Study setting: Holland

Population:

Migraineurs with or without aura

Group-matched controls
3-mm magnetic resonance imaging sections

Methods:

One neuroradiologist, blinded to the migraine diagnosis and clinical data, rated infarcts and white matter lesions

Kruit et al. JAMA. 2004; 291:427-434

Pathophysiology of Migraine

Disease Progression: White Matter Lesions

Posterior Circulation Infarct
6 5 4

9 8 7 6
P=.02 P=.03

Prevalence 3 (%)
2 1 0
Migraineurs

5 4 3 2 1 0

Controls

Migraine with aura

Migraine without aura

Kruit et al. JAMA. 2004; 291:427-434.

Pathophysiology of Migraine

Disease Progression: White Matter Lesions

Migraineurs have more MRI-detectable white matter lesions than controls

Lesions increase with attack frequency, possibly indicating progression

Increased risk of posterior circulation infarcts highest in migraineurs with aura with an attack frequency 1/month

Increased risk of deep white mater lesions highest in female migraineurs (with or without aura) with an attack frequency 1/month

Even one headache per month could predispose migraineurs to subclinical brain lesions
Kruit et al. JAMA. 2004;291:427-434.

Pathophysiology of Migraine

Proposed Mechanisms of Migraine Headache

Abnormal cortical activity Hyperexcitable brain (Ca++, Glu, Mg++) Cortical Spreading Depression Abnormal brain stem function Excitation of brain stem, PAG, etc.

Activation/Sensitization of TGVS
Vasodilation Neurogenic Inflammation Central Sensitization

Headache Pain

TGVS=trigeminal vascular sensitization.

Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398.

Pathophysiology of Migraine

Migraine Mechanisms

Iadecola C. Nature Medicine. 2002;8:111-112.

Pathophysiology of Migraine

Central Sensitization

Migraineurs develop increased sensitivity to stimuli due to increased nerve excitability

79% of migraine patients suffered from cutaneous allodynia during attacks due to central sensitization

Burstein R et al. Ann Neurol. 2000;47:614-624; Burstein R et al. Headache. 2002;42:390-391.

Topiramate: A Neuromodulator With Stabilizing Properties

Mechanisms of Action
Voltage-Gated Ion Channels = Topiramate Ca2+ channel Na+ channel

K+ channel Ligand-Gated Ion Channels

AMPA/kainate receptor ClClCl-

GABAA receptor

Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-9.

Topiramate

Neuroprotective Potential

Attenuates glutamate-, NMDA-, AMPA-, and Kainateinduced neurotoxicity in vitro

Promotes neurite outgrowth in neuronal cells in culture

Enhances nerve regeneration and recovery of function after injury in vivo (facial nerve compression model)
Demonstrated Disease Modification In Models of: Focal and global hypoxia Periventricular leukomalacia Traumatic brain injury Status epilepticus Peripheral nerve regeneration
Smith-Swintosky VL et al. Neuroreport. 2001;12:1031-034.

Topiramate

Inhibition of Neuronal Activation

Mechanism of topiramate action in migraine investigated using anesthetized cat model

Superior sagittal sinus (SSS) electrically stimulated to mimic nociceptive activation

Recordings taken in the Trigeminal Nucleus Caudalis (TNC)

Topiramate reduced SSS-evoked firing of neurons in the TNC in a dose-dependent fashion (IC50 5 mg/kg)

Storer RJ, Goadsby PJ. Poster presented at: American Academy of Neurology 2003; June 5-8, 2003; Honolulu, Hawaii.

Topiramate

Inhibition of Trigeminovascular Traffic

SSS stimulated

% Inhibition
60
50 48 35 53

Record from TNC

Topiramate reduced SSSevoked TNC firing within 30 minutes Mechanism of action in migraine

40

30 20

10 0 3 mg/kg 5 mg/kg 50 mg/kg

Storer RJ, Goadsby PJ. Poster presented at: American Academy of Neurology 2003; June 5-8, 2003; Honolulu, Hawaii.

Pathophysiology of Migraine

Summary

Understanding pathophysiologic events may help physicians to manage migraine better

Current research indicates that migraine is a familial disorder of the brain characterized by neuronal hyperexcitability and often central sensitization Migraine may be due to an imbalance in excitatory and inhibitory neurotransmission and ion channel abnormalities

Pathophysiology of Migraine

Summary

Imaging data suggest anatomic changes occur in chronic migraineurs Central sensitization may result in cutaneous allodynia, a marker for severe headache Modern acute and preventive migraine treatments, such as triptans and neuromodulators, interact with pre- and postjunctional targets; their mechanism of action may help explain pathophysiologic pathways

Topiramate reduces neuronal activation in trigeminal nucleus caudalis