Pathophysiology of migraine

1. Pathophysiology of MigrainePathophysiology of Migraine

2. Pathophysiology of MigrainePathophysiology of Migraine

OutlineOutline
Migraine is an inherited central nervous system (CNS) Migraine is an inherited central nervous system (CNS)
disorder disorder
Migraineurs have hyperexcitable brainsMigraineurs have hyperexcitable brains
Migraine can be progressive in some patientsMigraine can be progressive in some patients
Migraine is progressive during an attackMigraine is progressive during an attack
–Central sensitizationCentral sensitization
Topiramate mechanism of action in migraine preventionTopiramate mechanism of action in migraine prevention
–Multiple mechanismsMultiple mechanisms
–Reduced CNS excitation in animal modelReduced CNS excitation in animal model

3. Focus had been on acute therapy to manage individual Focus had been on acute therapy to manage individual
migraine episodesmigraine episodes
New advances in pathophysiology have transformed the New advances in pathophysiology have transformed the
concept of what migraine isconcept of what migraine is
–Migraine is Migraine is a CNS disordera CNS disorder
–Genetic predispositionGenetic predisposition
This has paved the way for improved treatment This has paved the way for improved treatment
–Treatment of migraine as a disorderTreatment of migraine as a disorder
–Emphasis on preventive + acuteEmphasis on preventive + acute
Pathophysiology of Migraine Pathophysiology of Migraine
Implementing Pathophysiology Into TreatmentImplementing Pathophysiology Into Treatment

4. Aura PhaseAura Phase
Spasm of Cerebral ArteriesSpasm of Cerebral Arteries
Headache PhaseHeadache Phase
Vasodilation of Cerebral ArteriesVasodilation of Cerebral Arteries
Wolf HG. Headache and Other Head Pain. 1963.
Pathophysiology of Migraine Pathophysiology of Migraine
Classic Vascular Theory of MigraineClassic Vascular Theory of Migraine

5. CBF=cerebral blood flow.
Laurizen M. Brain. 1994;118:199-210.
Pathophysiology of Migraine Pathophysiology of Migraine
Blood Flow During Aura and Headache PhaseBlood Flow During Aura and Headache Phase

6. Pathophysiology of Migraine Pathophysiology of Migraine
The Genetic BasisThe Genetic Basis
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.
P/Q type CaP/Q type Ca
++++
channel channel
–PresynapticPresynaptic
–Voltage gatedVoltage gated
–Occipital cortexOccipital cortex
–Trigeminal nucleus Trigeminal nucleus
caudaliscaudalis
–Linkage to Linkage to
chromosome 19 chromosome 19
Na-K ATP PumpNa-K ATP Pump
–Linkage to Linkage to
Chromosome 1Chromosome 1

7. FHM=familial hemiplegic migraine.
Figure courtesy of AHS Ambassadors Program. Ophoff RA et al. Cell. 1996;87:543-552.
Pathophysiology of Migraine Pathophysiology of Migraine
The P/Q Gene ProductThe P/Q Gene Product

8. Migraineurs have a lower threshold for occipital cortex Migraineurs have a lower threshold for occipital cortex
excitation than controlsexcitation than controls
Genetic component:Genetic component:
–P/Q calcium channel, NaP/Q calcium channel, Na
++
/K/K
++
ATPase ATPase
–Mitochondrial defectsMitochondrial defects
Probably due to:Probably due to:
–Hyperactivity of excitatory neurotransmissionHyperactivity of excitatory neurotransmission
NaNa
++
, Ca, Ca
++++
channels, glutamate channels, glutamate
–Lower activity of inhibitory neurotransmissionLower activity of inhibitory neurotransmission
GABAGABA
GABA=gamma aminobutyric acid.
Aurora SK et al. Neurology. 1998;50:1111-1114.
Pathophysiology of Migraine Pathophysiology of Migraine
Hyperexcitable CortexHyperexcitable Cortex

9. 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 102030405060708090100
P=.053, Cox Regression
Stimulus IntensityStimulus Intensity
No Triggered HA Triggered HA
Probability Probability
of of
PhosphenePhosphene
HA=headache.
Aurora SK et al. Headache. 1999;39:469-476.
Pathophysiology of Migraine Pathophysiology of Migraine
Threshold Levels for Triggered HeadachesThreshold Levels for Triggered Headaches

10. Hadjikhani N et al. Proc Natl Acad Sci USA. 2001;98:4687-4692.
Pathophysiology of Migraine Pathophysiology of Migraine
Imaging of Cortical Spreading Depression (CSD)Imaging of Cortical Spreading Depression (CSD)

11. Wave of oligemia begins in Wave of oligemia begins in
occipital cortex and spreads occipital cortex and spreads
forward at rate of 2-3 mm/minforward at rate of 2-3 mm/min
–Begins with aura and persists Begins with aura and persists
for hours after headachefor hours after headache
–CBF changes not in distribution CBF changes not in distribution
of any cerebral arteryof any cerebral artery
–Consistent with primary Consistent with primary
neuronal event producing neuronal event producing
secondary vascular changessecondary vascular changes
James MF et al. J Physiol. 1999;519:415-425.
Pathophysiology of Migraine Pathophysiology of Migraine
Cortical Spreading DepressionCortical Spreading Depression

12. Neuropeptide
Release
Central
Sensitization
Pain Signal
Transmission
Vasodilatation
Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl 3):S12-S19.
Pathophysiology of Migraine Pathophysiology of Migraine
Trigeminovascular Migraine Pain PathwaysTrigeminovascular Migraine Pain Pathways
Preventive medication target
Acute medication target

13. Brain stem aminergic nuclei can modify trigeminal pain Brain stem aminergic nuclei can modify trigeminal pain
processing processing
PET demonstrates brain stem activation in spontaneous PET demonstrates brain stem activation in spontaneous
migraine attacks migraine attacks
Brain stem activation persists Brain stem activation persists
after successful headache after successful headache
treatmenttreatment
Brain stem: generator or Brain stem: generator or
modulator?modulator?
PET=positron emission tomography.
Weiller C et al. Nat Med. 1995;1:658-660.
Pathophysiology of Migraine Pathophysiology of Migraine
Brain Stem Involvement in Migraine Brain Stem Involvement in Migraine

14. Mammillary
Body
Inferior
Colliculus
Oblique
Imaging
Plane
Pathophysiology of MigrainePathophysiology of Migraine

Red Nucleus and Substantia Nigra Red Nucleus and Substantia Nigra
Sagittal View of Imaging PlaneSagittal View of Imaging Plane
Welch KMA et al. Headache. 2001;41:629-637.

15. Pathophysiology of Migraine Pathophysiology of Migraine
Iron HomeostasisIron Homeostasis
Welch KMA et al. Headache. 2001;41:629-637.
Red Nuclei
Substantia Nigra
Periaqueductal Grey Matter
R2* Map

16. 0
2
4
6
8
10
12
14
16
Control Episodic migraine Chronic daily
headache
PAG Red nucleus
Group-wise Comparison: ANOVA (One-way Analysis of Variance).
*Significant difference, P<.05.
PAG=periaqueductal gray.
* *
*
*
R2’ R2’
(1/ms)(1/ms)
Pathophysiology of MigrainePathophysiology of Migraine

Changes in Periaqueductal GrayChanges in Periaqueductal Gray
Welch KMA et al. Headache. 2001;41:629-637.

17. Changes, observed over time in the PAG—center of Changes, observed over time in the PAG—center of
the brain’s powerful descending analgesic neuronal the brain’s powerful descending analgesic neuronal
networknetwork
–Iron depositionIron deposition
–Secondary to free-radical cell damage during Secondary to free-radical cell damage during
migraine attacksmigraine attacks
Degree of PAG structural alteration depends on Degree of PAG structural alteration depends on
duration of headache history, not the age of the patientduration of headache history, not the age of the patient
Repeated migraine attacks, repetitive damage, Repeated migraine attacks, repetitive damage,
decreased threshold for further migraine attacksdecreased threshold for further migraine attacks
Pathophysiology of Migraine Pathophysiology of Migraine
Disease Progression: Changes in PAG
Welch KMA et al. Headache. 2001;41:629-637.

18. Pathophysiology of MigrainePathophysiology of Migraine
Disease Progression: White Matter LesionsDisease Progression: White Matter Lesions
Study setting: HollandStudy setting: Holland
Population: Population:
–Migraineurs with or without auraMigraineurs with or without aura
–Group-matched controlsGroup-matched controls
Methods:Methods:
–3-mm magnetic resonance imaging sections3-mm magnetic resonance imaging sections
–One neuroradiologist, blinded to the migraine One neuroradiologist, blinded to the migraine
diagnosis and clinical data, rated infarcts and white diagnosis and clinical data, rated infarcts and white
matter lesionsmatter lesions
Kruit et al. JAMA. 2004; 291:427-434

19. Pathophysiology of MigrainePathophysiology of Migraine
Disease Progression: White Matter LesionsDisease Progression: White Matter Lesions
0
1
2
3
4
5
6
Migraineurs Controls
0
1
2
3
4
5
6
7
8
9
Migraine with auraMigraine without
aura
P=.02 P=.03
Kruit et al. JAMA. 2004; 291:427-434.
Posterior Circulation Infarct
Prevalence
(%)

20. Pathophysiology of MigrainePathophysiology of Migraine
Disease Progression: White Matter LesionsDisease Progression: White Matter Lesions
Migraineurs have more MRI-detectable white matter Migraineurs have more MRI-detectable white matter
lesions than controlslesions than controls
Lesions increase with attack frequency, possibly Lesions increase with attack frequency, possibly
indicating progressionindicating progression
–Increased risk of posterior circulation infarcts highest Increased risk of posterior circulation infarcts highest
in migraineurs with aura with an attack frequency in migraineurs with aura with an attack frequency
³³1/month1/month
–Increased risk of deep white mater lesions highest in Increased risk of deep white mater lesions highest in
female migraineurs (with or without aura) with an female migraineurs (with or without aura) with an
attack frequency attack frequency ³³1/month 1/month
Even one headache per month could predispose Even one headache per month could predispose
migraineurs to subclinical brain lesionsmigraineurs to subclinical brain lesions
Kruit et al. JAMA. 2004;291:427-434.

21. TGVS=trigeminal vascular sensitization.
Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398.
Vasodilation
Neurogenic
Inflammation
Headache
Pain
Abnormal cortical
activity
Hyperexcitable brain
(­Ca++, ­Glu, ¯Mg
++
)
Cortical Spreading Depression
Activation/Sensitization of TGVS
Abnormal brain
stem function
Excitation of brain
stem, PAG, etc.
Central Sensitization
Pathophysiology of Migraine Pathophysiology of Migraine
Proposed Mechanisms of Migraine HeadacheProposed Mechanisms of Migraine Headache

22. Pathophysiology of Migraine Pathophysiology of Migraine
Migraine MechanismsMigraine Mechanisms
Iadecola C. Nature Medicine. 2002;8:111-112.

23. Burstein R et al. Ann Neurol. 2000;47:614-624; Burstein R et al. Headache. 2002;42:390-391.
Migraineurs develop increased Migraineurs develop increased
sensitivity to stimuli due to increased sensitivity to stimuli due to increased
nerve excitabilitynerve excitability
79% of migraine patients suffered 79% of migraine patients suffered
from from cutaneous allodyniacutaneous allodynia during during
attacks due to central sensitizationattacks due to central sensitization
Pathophysiology of Migraine Pathophysiology of Migraine
Central SensitizationCentral Sensitization

24. Topiramate: A Neuromodulator With Stabilizing PropertiesTopiramate: A Neuromodulator With Stabilizing Properties
Mechanisms of ActionMechanisms of Action
Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-9.
Voltage-Gated Ion ChannelsVoltage-Gated Ion Channels
AMPA/kainateAMPA/kainate
receptorreceptor
GABAGABA
AA
receptorreceptor
NaNa
++
channel channel
ClCl
--
CaCa
2+2+
channel channel
Ligand-Gated Ion ChannelsLigand-Gated Ion Channels
= Topiramate= Topiramate
ClCl
--
ClCl
--
KK
++
channel channel

25. TopiramateTopiramate
Neuroprotective PotentialNeuroprotective Potential
Attenuates glutamate-, NMDA-, AMPA-, and Kainate-Attenuates glutamate-, NMDA-, AMPA-, and Kainate-
induced neurotoxicity in vitroinduced neurotoxicity in vitro
Promotes neurite outgrowth in neuronal cells in culturePromotes neurite outgrowth in neuronal cells in culture
Enhances nerve regeneration and recovery of function Enhances nerve regeneration and recovery of function
after injury in vivo (facial nerve compression model)after injury in vivo (facial nerve compression model)
Demonstrated Disease Modification In Models of:Demonstrated Disease Modification In Models of:
–Focal and global hypoxiaFocal and global hypoxia
–Periventricular leukomalaciaPeriventricular leukomalacia
–Traumatic brain injuryTraumatic brain injury
–Status epilepticusStatus epilepticus
–Peripheral nerve regenerationPeripheral nerve regeneration
Smith-Swintosky VL et al. Neuroreport. 2001;12:1031-034.

26. Mechanism of topiramate action in migraine investigated Mechanism of topiramate action in migraine investigated
using anesthetized cat modelusing anesthetized cat model
–Superior sagittal sinus (SSS) electrically stimulated to Superior sagittal sinus (SSS) electrically stimulated to
mimic nociceptive activationmimic nociceptive activation
–Recordings taken in the Trigeminal Nucleus Caudalis Recordings taken in the Trigeminal Nucleus Caudalis
(TNC)(TNC)
Topiramate reduced SSS-evoked firing of neurons in the Topiramate reduced SSS-evoked firing of neurons in the
TNC in a dose-dependent fashion (IC50 TNC in a dose-dependent fashion (IC50 »» 5 mg/kg) 5 mg/kg)
Storer RJ, Goadsby PJ. Poster presented at: American Academy of Neurology 2003;
June 5-8, 2003; Honolulu, Hawaii.
Topiramate Topiramate
Inhibition of Neuronal ActivationInhibition of Neuronal Activation

27. SSS stimulatedSSS stimulated
–Record from TNCRecord from TNC
Topiramate reduced SSS-Topiramate reduced SSS-
evoked TNC firing withinevoked TNC firing within
30 minutes30 minutes
Mechanism of action in Mechanism of action in
migraine migraine
% Inhibition
35
48
53
0
10
20
30
40
50
60
3 mg/kg 5 mg/kg 50 mg/kg
%
Topiramate Topiramate
Inhibition of Trigeminovascular TrafficInhibition of Trigeminovascular Traffic
Storer RJ, Goadsby PJ. Poster presented at: American Academy of Neurology 2003;
June 5-8, 2003; Honolulu, Hawaii.

28. Understanding pathophysiologic events may help Understanding pathophysiologic events may help
physicians to manage migraine better physicians to manage migraine better
Current research indicates that migraine is a familial Current research indicates that migraine is a familial
disorder of the brain characterized by neuronal disorder of the brain characterized by neuronal
hyperexcitability and often central sensitization hyperexcitability and often central sensitization
Migraine may be due to an imbalance in excitatory and Migraine may be due to an imbalance in excitatory and
inhibitory neurotransmission and ion channel inhibitory neurotransmission and ion channel
abnormalitiesabnormalities
Pathophysiology of Migraine Pathophysiology of Migraine
Summary

29. Imaging data suggest anatomic changes occur in Imaging data suggest anatomic changes occur in
chronic migraineurs chronic migraineurs
Central sensitization may result in cutaneous Central sensitization may result in cutaneous
allodynia, a marker for severe headacheallodynia, a marker for severe headache
Modern acute and preventive migraine treatments, Modern acute and preventive migraine treatments,
such as triptans and neuromodulators, interact with such as triptans and neuromodulators, interact with
pre- and postjunctional targets; their mechanism of pre- and postjunctional targets; their mechanism of
action may help explain pathophysiologic pathwaysaction may help explain pathophysiologic pathways
–Topiramate reduces neuronal activation in Topiramate reduces neuronal activation in
trigeminal nucleus caudalistrigeminal nucleus caudalis
Pathophysiology of Migraine Pathophysiology of Migraine
Summary