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Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
Pathophysiology of migraine
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Pathophysiology of migraine

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  • Migraine is a complex neurobiological disorder that has been recognized since antiquity. Many current books cover the subject in great detail The core features of migraine are headache, which is usually throbbing and often unilateral, and associated features of nausea, sensitivity to light, sound, and exacerbation with head movement Migraine has long been regarded as a vascular disorder because of the throbbing nature of the pain. However, as we shall explore here, vascular changes do not provide sufficient explanation of the pathophysiology of migraine. Up to one-third of patients do not have throbbing pain Modern imaging has demonstrated that vascular changes are not linked to pain and diameter changes are not linked with treatment This presentation aims to demonstrate that: Migraine should be regarded as neurovascular headache The cortex is hyperexcitable in migraine and is genetically determined Understanding the anatomy and physiology of migraine can enrich clinical practice Explanation of how therapies may work in migraine
  • Key Point: Historical view of the vascular theory is in question. Historically, migraine was believed to be the result of primary vascular events The aura of migraine was attributed to intracerebral vasoconstriction, and the headache was understood to result from the reactive vasodilation of the carotid artery The theory explains some of the characteristics associated with migraine, but recent advances in technology and research have led many to question the validity of the vascular theory Silberstein SD et al. The pathophysiology of primary headache. In: Silberstein SD, Goadsby PJ, eds. Headache in Clinical Practice . Oxford, UK: Isis Medical Media, Ltd; 1998:41-58.
  • Key Point: Aura occurs before vasodilation, suggesting that vasodilation is not the sole cause of migraine. One of the most powerful arguments against the vascular theory is that it is in absolute conflict with the blood flow data that should be its greatest support It is clear from Olesen’s studies 1 , and reinforced by the more recent studies of Cutrer and colleagues 2 , that the headache phase of migraine with aura starts while blood flow is still reduced. Thus, the headache pain cannot be due simply to vasodilatation Illustration adapted from Olesen et al 1 1. Olesen J et al. Timing and topography of cerebral blood flow, aura and headache during migraine attacks. Ann Neurol . 1990;28:791-798. 2. Cutrer FM et al. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann Neurol . 1998;43:25-31.
  • Key Point: Migraine is linked to mutations in calcuim channels and sodium potassium pump. There seems to be an increasing body of evidence for the concept of central neuronal hyperexcitability as a pivotal physiological disturbance predisposing to migraine. 1 The reasons for increased neuronal excitability may be multifactorial. Most recently, abnormality of calcium channels has been introduced as a potential mechanism of interictal neuronal excitability. 2 Mutant voltage-gated P/Q type calcium channel genes likely influence presynaptic neurotransmitter release, possibly of excitatory amino-acid systems or inhibitory. It could therefore be hypothesized that genetic abnormalities result in a lowered threshold of response to trigger factors. Knight performed physiological studies on the trigeminal nucleus caudalis using  agaratoxin and found that P/Q channel shows specificity on the nucleus Recently migraine has been linked to Chromosome 1 the gene mutation is linked to Na/K Atpase. De Fusco and colleagues 3 show that the gene ATP1A2 , which encodes the alpha2 subunit of the Na+/K+ pump, is associated with familial hemiplegic migraine type 2 (FHM2) and is linked to chromosome 1q23. This mutation results in a loss of function of a single allele of ATP1A2 . This is the first report that associates a mutation in the Na+/K+ pump to the genetics involved in migraine This may lend support to the prediliction to SCD (Spreading cortical depression) which is the putative mechanism of migraine with aura 1. Welch KMA et al. The concept of migraine as a state of central neuronal hyperexcitabiliy. Neurol Clinics. 1990;8:817-828. 2. Ophoff RA et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca+2 channel gene CACNL1A4. Cell. 1996;87:543-552. 3. De Fusco M et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet . 2003;33(2):192-196.
  • Key Point: This slide shows details of mutation in calcium channel, discussed on previous slide. This diagram illustrates the four missense mutations in the  1 -subunit of the P/Q-type, voltage-gated calcium channel on chromosome 19 causing FHM 1 in some families, as well as mutations responsible for episodic ataxia type 2. This discovery has important implications for the pathophysiology of migraine. Neuronal calcium channels mediate serotonin (5HT) release within the midbrain. 2 Therefore, dysfunction of these channels might impair serotonin release and predispose patients to migraine or impair their self-aborting mechanism. Also of interest are the interactions of magnesium with calcium channels, in the light of magnesium deficiency in the cortex of migraineurs 3 , and the role of calcium channels in spreading depression, which may initiate migraine aura 1. Ophoff et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNLA4. Cell. 1996;87:543-552. 2. Yakhnista VA, et al. Modulation of the activity of midbrain central gray susbstance neurons by calcium channel antagonists in vitro. Neuroscience. 1996;70(1):159-167. 3. Ramadan NM et al.
  • Key Point: Na + channels, Ca ++ channels; glutamate, GABA, and other neurotransmitter systems may be involved in the hyperexcitability of CNS in migraineurs. Occipital cortex excitability in migraine has been evaluated by the generation of phosphenes by TMS of occipital cortex. The first study reported a low threshold for generation of phosphenes in subjects with MwA, inferring hyperexcitability of the occipital cortex 1 1. Aurora SK et al. The threshold for magnetophoshenes is lower in migraine. Neurology 52:(6) A472, 1999.
  • Key Point: Migraineurs have a lower threshold for occupied cortex excitation. Since the early reports of cortical hyperexcitability, there have been two more studies performed on the occipital cortex using TMS, both confirming the initial reports of hyperexcitability. 1,2 In one of these hyperexcitability of the occipital cortex was associated with a propensity to visually triggered headache in the same patients. 2 Recently Battelli and colleagues investigated the extrastriate visual area V5, which is important for the perception of motion. 3 Both migraine with and without aura groups required significantly lower magnetic field strength for the induction of moving phosphenes, as compared to the control group; this difference was significant for V5 in both left and right hemispheres. In addition the phosphenes were better defined and had clearer presentation in migraine groups, whereas in controls they tended to be more transient and ill-defined 1. Aggugia M et al. Transcranial magnetic stimulation in migraine with aura: further evidence of occipital cortex hyperexcitability. Cephalalgia . 1999;19:465. 2. Aurora SK et al. The occipital cortex is hyperexcitable in migraine; evidence from TMS, fMRI and MEG studies (Wolff Award 1999) Headache 1999;39:469-476. 3. Battelli L et al. Transcranial magnetic stimulation of visual area V5 in migraine. Neurology 2002;58:1066-1069.
  • Key Point: Neuronal activity precedes vascular changes during aura. Hadjikhani and colleagues 1 were able to record induced and spontaneous migraine aura. They conclude that migraine aura is not evoked by ischemia. More likely, it is evoked by aberrant firing of neurons and related cellular elements characteristic of cortical spreading depression. Vascular changes follow changes in neuronal activity during the visual aura. Future studies using similar techniques should clarify the correlation of the onset of the headache pain to better understand the relationship between cortical spreading depression and pain Shown is the entire hemisphere, from a posterior-medial view. The aura-related changes appeared first in extrastriate cortex. The spread of the aura began and was most systematic in the representation of the lower visual field, becoming less regular as it progressed into the representation of the upper visual field 1. Hadjikhani N et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA . 2001;98(8):4687-4692.
  • Bold effect fMRI performed in the cat model after application of KCl demonstrates blood flow changes similar to those found in migraine with aura (previous slide). Experimental spreading cortical depression (SCD) thus has similar characteristics to migraine with aura. This adds further evidence that SCD is the putative mechanism of migraine aura James MF et al. Cortical spreading depression in the gyrencephalic feline brain studied by magnetic resonance. J Physiol. 1991;519:415-425.
  • Key Point : The primary target of migraine preventative agents is the CNS (upstream), where as the target for acute medications is the vascular system (downstream). The trigeminovascular hypothesis states that migraine pain is caused by inflammation and dilation of the meningeal arteries, particularly those located within the dura mater. The inflammation results from the actions of neuropeptides, which are released from primary sensory nerve terminals innervating the dural vessels Anatomic and physiologic research looking into the pain of migraine provides evidence implicating trigeminal innervation of cranial vessels as a key factor in migraine pathophysiology. The unmyelinated nerve fibers of the trigeminovascular system arise from the ophthalmic division of the trigeminal nerve and upper cervical dorsal roots. 1 Localized within the nerves of the trigeminal system are the neuropeptides, including calcitonin gene-related peptide (CGRP), 2 as well as neurokinin A and substance P. CGRP is a potent neurovascular peptide and levels are elevated in migraine. Its release may be responsible for vasodilation and the increased extracerebral blood flow observed in migraine 2 The trigeminovascular pain pathway begins with transmission in the caudal brain stem and high cervical spinal cord. Impulses are relayed via the quintothalamic tract to the thalamus, which processes vascular pain. The final step in the process is the cortical connection, which continues to be investigated 1 1. Silberstein SD et al. The pathophysiology of primary headache. In: Silberstein SD, Goadsby PJ, eds. Headache in Clinical Practice . Oxford, UK: Isis Medical Media, Ltd; 1998:41-58. 2. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol . 1990;28:183-187.
  • Key Point: Brain stem is activated in migraine. The first human study to show activation in the brainstem used positron emission tomography (PET) performed in subjects during spontaneous migraine. Because PET lacks sufficient resolution for exact anatomical localization, the activation was hypothesized to be in the regions of dorsal raphe nuclei (DRN), peiaqueductal gray (PAG) and locus ceruleus (LC) 1 1. Weiller C et al. Brainstem activation in spontaneous human migraine attacks. Nature Medicine . 1995;1:658-660.
  • Key Point: Red nucleus and substantia nigra are activated in migraine. An isolated case report found red nucleus (RN) and substantia nigra (SN) to be activated in a spontaneous migraine attack. 1 The same authors also now report the RN and SN to be activated in the subjects with visually triggered migraine. 2 The RN and SN are best known for their functional roles in motor control. The RN however has also been associated with pain and or nociception. 3 Numerous animal studies have documented a response of RN neurons to a variety of sensory and noxious stimuli. In a PET study performed on normal volunteers during capsaicin induced pain ipsilateral activation of RN was documented. It remains to be clarified whether or not the RN is involved in the pain pathways or in the motor response to pain. Further studies were done in the interictal period to identify activation in these structures. The plane of imaging was through the inferior colliculus and mamillary body 1. Welch KMA et al. MRI of the occipital cortex, red nucleus, and substantia nigra during visual aura of migraine. Neurology. 1998;51:1465-1469. 2. Cao Y et al. Functional MRI of the red nucleus and occipital cortex during visual stimulation of subjects with migraine. Neurology . 2002;59:72-78. 3. Iadarola MJ et al. Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain . 1998;121:931-47.
  • Key Point: Iron homeostasis is different in migraineurs’ brains. These observations prompted study of iron homeostasis in the RN, SN and PAG of episodic and chronic migraine patients; elevation or decline in tissue iron is associated with altered cellular function. High-resolution MR techniques were used to map the transverse relaxation rates R2 (1/T2), R2* (1/T2*) and R2' (R2* - R2) in brain, and in particular the PAG, RN and SN. These measures are sensitive to shifts in the paramagnetic properties of free iron in brain tissue and blood. Representative images containing the PAG, RN or SN of a subject are shown RN=red nucleus SN=substantia nigra PAG=periaqueductal grey MR=magnetic resonance
  • Key Point: Iron deposition in periaqueductal grey in migraineurs; further increased in chronic daily headache. A positive correlation was noted between the duration of illness and the increase in R2' for the EM and CDH groups (see figure 3). The R2’ are reflective of increased tissue iron levels in the PAG of episodic migraine with and without aura and chronic daily headache sufferers that further increase with duration of the disorder. These findings may suggest a mechanism of migraine and the burden of illness EM=Episodic migraine CDH=chronic daily headache
  • Key Point: Over time, migraine attack frequency permanently changes the PAG; thus pain perception is altered. The periaqueductal gray (PAG) is the center of the brain’s powerful descending analgesic network MRI imaging has determined that iron homeostasis is selectively and progressively impaired over time. This finding may be directly attributable to iron-catalyzed, free-radical cell damage These changes correlate with duration of migraine frequency, are independent of the presence of aura, and do not correlate with patient age 1. Welch KMA et al. Periaqueductal gray matter dysfunction in Migraine: cause or burden of illness. Headache . 2001;41:629-637.
  • Key Point: This is a population based imaging study exploring the relationship between migraine and brain lesions Adult migraineurs with aura (n=161), without aura (n=134), and matched controls (n=140) were randomly selected from 2 representative Dutch municipalities. Cases and controls were matched for age, sex, and place of residence. Whole brain magnetic resonance images were acquired with 48 contiguous, 3-mm axial slices. One neuroradiologist, who was blinded to the diagnosis of migraine and clinical data, rated infarcts and white matter lesions on hard copies. Kruit MC et al. Migriane as a risk factor for subclinical brain lesions. JAMA . 2004;291:427-434.
  • Key Point: Migraineurs, especially those with aura, had a higher prevalence of infarcts in the posterior circulation territory A total of 61 infarcts, ranging in size from 2 to 21 mm, were detected in 31 individuals. Thirty four (57%) of these infarcts were located in the posterior circulation terrritory of 17 cases. Of these, 16 (5.4% of total) were cases, 1 (0.7%) was control ( P =.02) Prevalence of infarcts differed significantly between migraineurs with aura and those without aura (8.1% vs. 2.2%, respectivley; P =.03) Kruit MC et al. Migriane as a risk factor for subclinical brain lesions. JAMA . 2004;291:427-434.
  • Key Point: Subclinical, MRI-detectable brain lesions are detected in more migraineurs than controls. Lesion occurrence increases with maigraine frequency, suggesting disease progression. The risk of brain infarcts increased with migraine attack frequency ( P <.005 for trend). In patients with  1 attack per month, the risk was 9.3 times higher, compared to controls. Overall, significant differences in the prevalence of deep white matter lesions were not detected between migraineurs and controls. However, increased risk for these lesions was observed among women. The risk increased with migraine attack frequency ( P =.008 for trend). The risk was similar for patients with migraine with aura and those with migraine without aura. Due to the higher risk of brain lesions associated with increased migraine attack frequency, future studies are recommended to assess whether prevention or early abortion of migraine attacks will diminish the risk of brain lesions, and to identify any subgroups that are likely to benefit. Kruit MC et al. Migriane as a risk factor for subclinical brain lesions. JAMA . 2004;291:427-434
  • Key Point: Central neuronal hyperexcitability predisposes individuals to migraine. The exact pathogenesis of migraine remains to be determined. There is increasing evidence for the neural basis of migraine. There is now an increasing body of evidence for the concept of central neuronal hyperexcitability as a pivotal physiological disturbance predisposing to migraine. The reasons for increased neuronal excitability may be multifactorial. Most recently, abnormality of calcium channels has been introduced as a potential mechanism of interictal neuronal excitability . Mutant voltage-gated P/Q type calcium channel genes likely influence presynaptic neurotransmitter release, possibly of excitatory amino-acid systems or inhibitory. It could therefore be hypothesized that genetic abnormalities result in a lowered threshold of response to trigger factors. There is also evidence from spectroscopic studies that magnesium is low in migraine We currently conceive of a migraine attack as originating in brain. Triggers of an attack initiate a depolarizing neuroelectric and metabolic event likened to the spreading depression of Leao. This event activates the headache and associated features of the attack by mechanisms that remain to be determined, but appear to involve either peripheral trigeminovascular or brainstem pathways, or both. Excitability of cell membranes, perhaps in part genetically determined, is the brain’s susceptibility to attacks. Factors that increase or decrease neuronal excitability constitute the threshold for triggering attacks
  • Key Point: Central neuronal hyperexcitability predisposes individuals to migraine. The exact pathogenesis of migraine remains to be determined. There is increasing evidence for the neural basis of migraine. There is now an increasing body of evidence for the concept of central neuronal hyperexcitability as a pivotal physiological disturbance predisposing to migraine. The reasons for increased neuronal excitability may be multifactorial. Most recently, abnormality of calcium channels has been introduced as a potential mechanism of interictal neuronal excitability . Mutant voltage-gated P/Q type calcium channel genes likely influence presynaptic neurotransmitter release, possibly of excitatory amino-acid systems or inhibitory. It could therefore be hypothesized that genetic abnormalities result in a lowered threshold of response to trigger factors. There is also evidence from spectroscopic studies that magnesium is low in migraine We currently conceive of a migraine attack as originating in brain. Triggers of an attack initiate a depolarizing neuroelectric and metabolic event likened to the spreading depression of Leao. This event activates the headache and associated features of the attack by mechanisms that remain to be determined, but appear to involve either peripheral trigeminovascular or brainstem pathways, or both. Excitability of cell membranes, perhaps in part genetically determined, is the brain’s susceptibility to attacks. Factors that increase or decrease neuronal excitability constitute the threshold for triggering attacks
  • Key Point: Migraine is progressive during attack. Most migraine patients exhibit cutaneous allodynia inside and outside their pain-referred areas during migraine attacks. Burstein and colleagues studied the development of cutaneous allodynia in migraine by measuring the pain thresholds in the head and forearms of a patient at several points during the migraine attack (1, 2, and 4 hours after onset) and compared the pain thresholds in the absence of an attack. This study demonstrated that a few minutes after the initial activation of the patient’s peripheral nociceptors, these became sensitized and mediated the symptoms of cranial hypersensitivity. The barrage of impulses then activated second-order neurons and initiated their sensitization, mediating the development of cutaneous allodynia on the ipsilateral head. The sensitized second-order neurons activated and eventually sensitized third-order neurons leading to allodynia on the patients contralateral head and forearms by the two-hour point, a full hour after the initial allodynia on the ipsilateral head The authors concluded that this progression of symptoms calls for the early use of antimigraine drugs that target peripheral nociceptors before central sensitization occurs This diagram from Burstein and colleagues illustrates the neurally-induced plasma protein extravasation model system for migraine 1 1. Burstein R et al. The development of cutaneous allodynia during a migraine attack: clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain . 2000;123 (Pt 8):1703-1709.
  • Key Point: Topiramate has multiple mechanisms of action. These include inhibition of Na + channels, Ca ++ channels, ad glutamate receptor function Mechanisms of action of topiramate in migraine prevention has not been established
  • Key Point: Topiramate has multiple mechanisms of action and potential for neuroprotection. In laboratory studies, topiramate attenuated neurotoxic effects induced by excitatory neurotransmitters. Neurite outgrowth in tissue culture and nerve regenerations in animal models have been observed following topiramate adminitration Neuroprotective effects of topriamte have been reported in multiple modes Smith-Swintosky VL, Zhao B, Shank RP, Plata-Salaman CRl. Topiramate promotes neurite outgrowth and recovery function after nerve injury. Neuroreport . 2001;12:1031-034.
  • Key Point: Topiramate reduced CNS activation. Using a cat model Storer et al demonstrated the effect of topiramate on the trigeminocervical activation. Previous experiments have demonstrated that these neurons are targets for both triptans and ergots. Topirmate inhibited the activation of trigeminocervical neurons in response to stimulation of the superior sagittal sinus. This study demonstrates the plausible mechanism of action of preventive medicines in migraine
  • Key Point: Topiramate-induced SSS-evoked firing of neurons is dose- dependent
  • Transcript

    • 1. Pathophysiology of Migraine
    • 2. 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  Topiramate mechanism of action in migraine prevention – Multiple mechanisms – Reduced CNS excitation in animal model
    • 3. Pathophysiology of Migraine Implementing Pathophysiology Into Treatment  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  This has paved the way for improved treatment – Treatment of migraine as a disorder – Emphasis on preventive + acute
    • 4. Pathophysiology of Migraine Classic Vascular Theory of Migraine Aura Phase Headache Phase Spasm of Cerebral Arteries Vasodilation of Cerebral Arteries Wolf HG. Headache and Other Head Pain. 1963.
    • 5. Pathophysiology of Migraine Blood Flow During Aura and Headache Phase CBF=cerebral blood flow. Laurizen M. Brain. 1994;118:199-210.
    • 6. Pathophysiology of Migraine The Genetic Basis  P/Q type Ca++ channel – Presynaptic – Voltage gated – Occipital cortex – Trigeminal nucleus caudalis – Linkage to chromosome 19  Na-K ATP Pump – Linkage to Chromosome 1 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.
    • 7. 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.
    • 8. 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  Probably due to: – Hyperactivity of excitatory neurotransmission Na+, Ca++ channels, glutamate – Lower activity of inhibitory neurotransmission GABA GABA=gamma aminobutyric acid. Aurora SK et al. Neurology. 1998;50:1111-1114.
    • 9. Pathophysiology of Migraine Threshold Levels for Triggered Headaches 1.0 0.9 0.8Probability 0.7 P=.053, Cox Regression of 0.6Phosphene 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 70 80 90 100 Stimulus Intensity No Triggered HA Triggered HA HA=headache. Aurora SK et al. Headache. 1999;39:469-476.
    • 10. Pathophysiology of Migraine Imaging of Cortical Spreading Depression (CSD) Hadjikhani N et al. Proc Natl Acad Sci USA. 2001;98:4687-4692.
    • 11. 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.
    • 12. 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.
    • 13. 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.
    • 14. 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.
    • 15. Pathophysiology of Migraine Iron Homeostasis R2* Map Substantia Nigra Red Nuclei Periaqueductal Grey Matter Welch KMA et al. Headache. 2001;41:629-637.
    • 16. Pathophysiology of Migraine Changes in Periaqueductal Gray 16 PAG Red nucleus 14 * 12 * 10 R2’ 8 (1/ms) * * 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.
    • 17. Pathophysiology of Migraine Disease Progression: Changes in PAG  Changes, observed over time in the PAG—center of the brain’s 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.
    • 18. Pathophysiology of Migraine Disease Progression: White Matter Lesions  Study setting: Holland  Population: – Migraineurs with or without aura – Group-matched controls  Methods: – 3-mm magnetic resonance imaging sections – One neuroradiologist, blinded to the migraine diagnosis and clinical data, rated infarcts and white matter lesions Kruit et al. JAMA. 2004; 291:427-434
    • 19. Pathophysiology of Migraine Disease Progression: White Matter Lesions Posterior Circulation Infarct 6 9 8 5 7 4 6 Prevalence P=.02 P=.03 5 (%) 3 4 2 3 2 1 1 0 0 Migraineurs Controls Migraine with aura Migraine without aura Kruit et al. JAMA. 2004; 291:427-434.
    • 20. 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.
    • 21. Pathophysiology of Migraine Proposed Mechanisms of Migraine Headache Abnormal cortical Abnormal brain activity stem function Hyperexcitable brain Excitation of brain (↑Ca++, ↑Glu, ↓Mg++) stem, PAG, etc. Cortical Spreading Depression Activation/Sensitization of TGVS Headache Pain Vasodilation Central Sensitization Neurogenic Inflammation TGVS=trigeminal vascular sensitization. Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398.
    • 22. Pathophysiology of Migraine Migraine Mechanisms Iadecola C. Nature Medicine. 2002;8:111-112.
    • 23. 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.
    • 24. Topiramate: A Neuromodulator With Stabilizing Properties Mechanisms of Action Voltage-Gated Ion Channels = Topiramate Ca2+ channel Na+ channel K+ channel Ligand-Gated Ion Channels GABAA AMPA/kainate receptor receptor Cl- Cl- Cl- Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-9.
    • 25. Topiramate Neuroprotective Potential  Attenuates glutamate-, NMDA-, AMPA-, and Kainate- induced 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.
    • 26. 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.
    • 27. Topiramate Inhibition of Trigeminovascular Traffic % Inhibition  SSS stimulated 60 – Record from TNC 53 50 48 40 35  Topiramate reduced SSS- evoked TNC firing within 30 30 minutes % 20 10  Mechanism of action in migraine 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.
    • 28. 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
    • 29. 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

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