pathophysiology of migraine

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

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

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.


Classic Vascular Theory of MigraineClassic Vascular Theory of Migraine

CBF=cerebral blood flow.Laurizen M. Brain. 1994;118:199-210.


Blood Flow During Aura and Headache PhaseBlood Flow During Aura and Headache Phase


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

FHM=familial hemiplegic migraine.Figure courtesy of AHS Ambassadors Program. Ophoff RA et al. Cell. 1996;87:543-552.


The P/Q Gene ProductThe P/Q Gene Product

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 neurotransmissionNaNa++, Ca, Ca++++ channels, glutamate channels, glutamate

– Lower activity of inhibitory neurotransmissionLower activity of inhibitory neurotransmissionGABAGABA

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


Hyperexcitable CortexHyperexcitable Cortex

0.00.10.20.30.40.50.60.70.80.91.0

0 10 20 30 40 50 60 70 80 90 100

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.


Threshold Levels for Triggered HeadachesThreshold Levels for Triggered Headaches

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


Imaging of Cortical Spreading Depression (CSD)Imaging of Cortical Spreading Depression (CSD)

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.


Cortical Spreading DepressionCortical Spreading Depression

NeuropeptideRelease

CentralSensitization

Pain SignalTransmission

Vasodilatation

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


Trigeminovascular Migraine Pain PathwaysTrigeminovascular Migraine Pain Pathways

Preventive medication target

Acute medication target

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.


Brain Stem Involvement in Migraine Brain Stem Involvement in Migraine

Mammillary Body

Inferior Colliculus

Oblique Imaging Plane


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.


Iron HomeostasisIron Homeostasis


Red Nuclei

Substantia Nigra

Periaqueductal Grey Matter

R2* Map

0

2

4

6

8

10

12

14

16

Control Episodic migraine Chronic dailyheadache

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)


Changes in Periaqueductal GrayChanges in Periaqueductal Gray


Changes, observed over time in the PAG—center of the brain’s Changes, observed over time in the PAG—center of the brain’s powerful descending analgesic neuronal networkpowerful descending analgesic neuronal network

–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 duration of Degree of PAG structural alteration depends on duration of headache history, not the age of the patientheadache history, not the age of the patient

Repeated migraine attacks, repetitive damage, decreased Repeated migraine attacks, repetitive damage, decreased threshold for further migraine attacksthreshold for further migraine attacks


Disease Progression: Changes in PAG



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



0

1

2

3

4

5

6

Migraineurs Controls0

1

2

3

4

5

6

7

8

9

Migraine with aura Migraine withoutaura

P=.02 P=.03

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

Posterior Circulation Infarct

Prevalence (%)



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 1/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 1/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.

TGVS=trigeminal vascular sensitization.Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398.

VasodilationNeurogenic

Inflammation

HeadachePain

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


Proposed Mechanisms of Migraine HeadacheProposed Mechanisms of Migraine Headache


Migraine MechanismsMigraine Mechanisms

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

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


Central SensitizationCentral Sensitization

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/kainatereceptorreceptor

GABAGABAAA

receptorreceptor

NaNa++ channel channel

ClCl--

CaCa2+2+ channel channel

Ligand-Gated Ion ChannelsLigand-Gated Ion Channels

= = TopiramateTopiramate

ClCl--ClCl--

KK++ channel channel

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.

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

SSS stimulatedSSS stimulated– Record from TNCRecord from TNC

Topiramate reduced SSS-Topiramate reduced SSS-evoked TNC firing withinevoked TNC firing within30 minutes30 minutes

Mechanism of action in Mechanism of action in migraine migraine

% Inhibition

35

4853

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.

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


Summary

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


Summary

pathophysiology of migraine

Health & Medicine

patients migraine

hyperexcitable brains

familial hemiplegic

headache phasecbf

headache cbf changes

brain stemactivation

cerebral blood flow

cerebral artery consistent