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Keywords:

  • triptans;
  • migraine epidemiology;
  • pathophysiology

Abstract

  1. Top of page
  2. Abstract
  3. LESSONS FROM CLINICAL SCIENCE
  4. LESSONS FROM EPIDEMIOLOGY
  5. LESSONS FROM PATHOPHYSIOLOGY
  6. CONCLUSIONS
  7. REFERENCES

The triptan era has been a time of remarkable progress for migraine diagnosis and treatment. In this paper, we review some of the advances achieved in migraine science during this era focusing on 3 themes: lessons from clinical practice, lessons from epidemiology and lessons from pathophysiology. Science has shown that migraine is a disorder of the brain, and that the key events happen in the the trigeminal neuronal pathways, not on blood vessels. Clinical science has led to the observation that migraine sometimes progresses or remits. This in turn led to longitudinal epidemiologic studies focusing on factors that determine migraine prognosis. In addition, these studies raised questions about the mechanisms of migraine progression, including the role of allodynia, obesity, inflammation, and medications as determinants of progression. This in turn opens a new set of scientific questions about the neurobiologic determinants of migraine, as well as of its clinical course, and exciting opportunities to develop new therapies for this highly disabling brain disorder.

Attempts to alleviate the suffering caused by migraine span millennia and encompass treatments as primitive as trepanation of the skull, to increasingly specific medications that act on receptor subtypes implicated in the pathophysiology of migraine.1 Ergots, introduced in the 1860s,2 were the first class of migraine-specific medications targeting the then presumed mechanism of migraine pain – vasodilation of the cerebral and extracranial vasculature.3 Triptans, serotonin 5-HT1B/1D receptor agonists introduced in the early 1990s, were also developed as cranial vasoconstrictors to mimic the desirable effects of ergotamine and serotonin while avoiding its unfavorable adverse effects.4 Triptans resulted in groundbreaking insights into the anatomy, physiology, and molecular pharmacology of migraine5 and from the outset their mechanism of action was debated.6

The triptan era has been a time of remarkable progress for migraine diagnosis and treatment. In this paper, we review some of the advances achieved in migraine science during the triptan era focusing on 3 themes: lessons from clinical practice, lessons from epidemiology, and lessons from pathophysiology. This list of lessons is far from a comprehensive list and is intended to summarize some of the more important observations. Lessons from treatment strategies and specific issues on recognition and adherence to treatment are discussed in a separate manuscript from this issue (Hu et al).

LESSONS FROM CLINICAL SCIENCE

  1. Top of page
  2. Abstract
  3. LESSONS FROM CLINICAL SCIENCE
  4. LESSONS FROM EPIDEMIOLOGY
  5. LESSONS FROM PATHOPHYSIOLOGY
  6. CONCLUSIONS
  7. REFERENCES

Clinical Lesson 1: Premonitory Symptoms Are Frequent and May Increase the Awareness of Migraine.— Despite 2 decades of clinician and patient education, migraine remains underdiagnosed and undertreated.7,8 Although 4 phases of the migraine attack have long been recognized (premonitory phase, aura, headache phase, resolution phase), recent interest has focused on headache predictors. If the onset of migraine can be predicted by the patients, awareness of the disorder would increase and create opportunities for pre-emptive or for very early treatment. Candidate headache predictors emerge from 3 domains: external events, internal events and premonitory symptoms. External events are often conceptualized as headache triggers, such as exposure to certain foods, and or alcohol, weather changes, and changes in sleep patterns, among other factors. Internal events are based on endogenous biological changes which increase the probability of headache; menstruation is the best example. Finally, premonitory features encompass changes in mood or behavior, as well as potentially predictable symptoms (eg, pain in the neck, pain in the back, flu-like symptoms, premonitory photophobia) that often represent the beginning of the migraine attack and precede the onset of headache.

Premonitory symptoms may occur hours before a migraine attack. The proportion of migraine sufferers with premonitory features ranges from 12% to 79%. In the Dutch population, a prospective study found that at least one premonitory symptom was reported by 86.9%, and 71.1% reported 2 or more. The most frequently reported premonitory symptoms were fatigue (46.5%), phonophobia (36.4%), and yawning (35.8%).9 In a multinational diary study, about 70% of the migraineurs had premonitory symptoms, the most common being feeling tired and weary (72% of attacks with warning features), having difficulty concentrating (51%), and a stiff neck (50%).

An electronic diary study demonstrated that a substantial proportion of the migraineurs could accurately predict their migraine attack based on the premonitory symptoms.10 Accordingly, strategies of making individuals aware of their premonitory symptoms in order to facilitate migraine recognition and treatment with specific medications have been recently proposed. Initial studies suggested such an approach was possible,11,12 although properly designed, randomized controlled trials are needed to fully explore this issue. The identification of premonitory symptoms and contributions to understanding their biology add to an understanding that migraine is much more than simply a pain problem.

Clinical Lesson 2: Migraine As a Masquerader.— Population studies show that many migraineurs (as much as 50%) believe that they have tension-type headache, sinus headache, or stress-related headaches. This is due to misinterpretation of symptoms associated with migraine attacks.

For example, neck pain is a common symptom occurring during a migraine attacks. Furthermore, due to the overlap in cervicotrigeminal pain processing,13 neck pain and tenderness may trigger, or worsen, migraine pain and migraine may be accompanied by neck pain,10 which may lead to a diagnosis of cervicogenic headache.13 If a migraine sufferer experiences headaches triggered by stress and with prominent neck pain, he/she may be diagnosed as suffering from “tension headaches.” The convergence of the occipital and trigeminal sensory systems in the trigeminocervical complex explains these symptoms.

Similarly, referred facial pain with cranial autonomic symptoms, frequently experienced by migraineurs,14 can explain the “sinus headache” diagnosis. It is well established that trigeminal stimulation leads to cranial autonomic activation with symptoms such as tearing, conjunctival injection, and nasal congestion.15 This may be seen in healthy volunteers with capsaicin injection into the forehead,16 and has a highly functionotopic expression.17 It is clear that activation of trigeminal afferents through a reflex that traverses the superior salivatory nucleus in the pons18 and thence is distributed through the facial/greater superficial petrosal nerve pathway is the likely basis for these symptoms.15 Awareness that between one-quarter and one-third of migraineurs have some level of cranial autonomic symptoms that can lead to a misdiagnosis of “sinus” headache would reduce this misdiagnosis.

Other symptoms that are common in migraine include dizziness or vertigo and these can also contribute to an erroneous diagnosis. Vertigo or dizziness are occasionally experienced by up to 51.7% of migraine patients vs 31.5% in those without migraine.19,20

LESSONS FROM EPIDEMIOLOGY

  1. Top of page
  2. Abstract
  3. LESSONS FROM CLINICAL SCIENCE
  4. LESSONS FROM EPIDEMIOLOGY
  5. LESSONS FROM PATHOPHYSIOLOGY
  6. CONCLUSIONS
  7. REFERENCES

Epidemiologic Lesson 1: Despite Significant Efforts, Migraine Remains Underdiagnosed and Undertreated.— In the past 15 years, the prevalence of migraine has been stable while the proportion of patients who have been diagnosed with migraine has only slightly increased;8,21,22 this suggests that there is still considerable need for improvement in diagnosis. In 2004, only half of the migraineurs from the US population had ever received a migraine diagnosis,8 while the others were wrongly considered as suffering from tension-type headaches, sinus headaches, or other headache disorders.

Both episodic migraine and chronic migraine remain undertreated. According to the American Migraine Prevalence and Prevention study, in the year 2006, triptans were used by only 23.8% of individuals with episodic migraine, while 21.1% used opioids or compounds containing barbiturates. For chronic migraine, 31.6% used migraine-specific treatment while 43.3% used opioids and barbiturates. According to expert recommendations, 25.7% of those with migraine in the population met criteria for “offer prevention” and an additional 13.1% should be considered for prevention. However, just 13.0% were using medications specifically to prevent migraine.8

Epidemiologic Lesson 2: Comorbidities Complicate Diagnosis and Influence Treatment.— For comorbid conditions, the principle of parsimony does not apply. Diagnosing one increases the suspicion for the others. Migraine is comorbid to many disorders (Table 1).

Table 1.—. Migraine Comorbidities (from Reference90)
Conditions reported comorbid with migraine
  • Data from clinical samples only.

 Psychiatric
  Depression
  Anxiety
  Panic disorder
  Bipolar
 Neurological
  Epilepsy
  Tourette's
 Vascular
  Raynaud's phenomenon
  Blood pressure (inconsistent)
  Ischemic stroke, subclinical stroke, white matter abnormalities
 Heart
  Patent foramen ovale
  Mitral valve prolapse
  Atrial septal aneurysm
 Other
  Snoring/sleep apnea
  Asthma/allergy
  Systemic lupus erythematosus
  Non-headache pain

In addition to the “traditional” comorbidities of migraine, interest has recently been paid to several conditions that seem to be more common in migraine and predispose to cardiovascular events. For example, recent evidence suggests that obesity, although not comorbid to migraine, increases migraine attack frequency and the rate of transformation from episodic to chronic migraine.23 Additionally, individuals with migraine with aura (MWA) are more likely to have insulin resistance, high levels of cholesterol and lower levels of high-density lipoprotein cholesterol, as well as high levels of homocysteine and hypertension. Thus, migraineurs, especially those with aura, are more likely to have a “poor” cholesterol profile, lower Framingham scores, and family history of cardiovascular disease (CVD) (see below). Clinic-based evidence also suggests that those with MWA are more likely to have patent foramen ovale,24 although the closure of the defect does not seem to alter the disorder at all.25

Given the data, we have expanded our view on the importance of assessing migraine's comorbidities. Furthermore, migraine may be, per se, a modifiable risk factor for cardiovascular events, an issue that we discuss in detail in the next topic.

Epidemiologic Lesson 3: Migraine Is Like a Chronic Disorder With Episodic Attacks.— Migraine, like asthma or epilepsy, is a chronic disorder with episodic attacks. Between headaches, migraine sufferers have an enduring predisposition to attacks including abnormalities in brain excitability26 and impaired health related quality of life.27,28 For example, between attacks, individuals exhibit alterations of event-related potentials that indicate an inter-ictal state of altered brain activation.29,30

Epidemiologic Lesson 4: Episodic Migraine Sometimes Progresses to Chronic Migraine.— The natural history and the prognosis of migraine have not been fully characterized, but 4 nonexclusive patterns are suggested. Some migraine sufferers clinically remit, becoming symptom-free for prolonged periods of time (Clinical Remission). Others continue to have headaches with fewer or less typical migraine features; in these patients, attacks come to resemble probable migraine or even tension-type headache, rather than full-blown migraine. Migraine attacks may continue over many years without major changes in frequency, severity, or symptom profile (Persistence). Finally, in some, migraine attack frequency and disability may increase over time (Progression).

Typically, progression refers to increases in attack frequency over time leading to chronic migraine; we term this clinical progression. Clinical progression is often associated with emergence of cutaneous allodynia due to central sensitization at some level within the trigeminal nociceptive pathway from the trigeminocervical complex through the thalamus perhaps even to the cortex; we term this physiological progression. In addition, there may be anatomic correlates of attack frequency including stroke and deep white matter lesions,31 which we term anatomical progression (Fig. 1). We emphasize that these anatomic findings have not been demonstrated to be a consequence of migraine in longitudinal studies. Furthermore, limited data suggest that sometimes these lesions vanish over time.32

image

Figure 1.—. Pathway in the natural history of migraine. PAG = periaqueductal gray. From reference 92.

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Many risk factors for headache progression have been identified, at different levels of evidence, including high baseline headache frequency, overuse of opioids and barbiturates, obesity, snoring, excessive use of caffeine, and stressful life events (Table 2).33 Migraine may worsen over time, and addressing modifiable risk factors for migraine progression may be associated with improved outcomes.

Table 2.—. Modifiable Risk Factors for Headache Progression and Candidate Interventions
 InterventionComments
Attack frequency• Effective preventive treatment 
Obesity• Weight loss• Most migraine-preventive medications are not weight neutral.
Medication overuse• Detoxification• Evidence suggests that detoxification only is associated with chronic daily headache remission over a 1-year period.
Stressful life events• Stress management 
Caffeine overuse• Reduction in caffeine consumption 
Snoring (sleep apnea)• Weight loss 
• Continuous positive airway pressure 
Allodynia• Effective early acute treatment 
• Preventive treatment 
Other pain syndromes• Treatment of chronic pain 

Epidemiologic Lesson 5: Opioids and Barbiturates Increase the Risk of Migraine Progression.— Clinic-based and limited population suggest that symptomatic acute medication overuse is associated with migraine progression.34 In patients with coexistent migraine, daily use of opioids to control bowel movements,35 as well as analgesics for arthritis36 and triptans for cluster headache,37 are associated with the development of chronic migraine, suggesting that both biological predispositon (migraine status) and exposure (medication overuse) are necessary.38 Data from the population partially supported these clinic-based studies and suggested that headache frequency and medication consumption independently predicted the development of chronic daily headache after 1 year of follow-up. Unanswered questions regarded the causality of the relationship, and if acute medication overuse was a risk factor for chronic migraine overall, or if just specific classes of medication induced transformation.

As a part of the American Migraine Prevalence and Prevention study, probability of transition from episodic into chronic migraine over a 1-year period was assessed as a function of medication use status at baseline. The most important conclusions of the study were: (1) In individuals with migraine, both frequency of headaches and use of specific classes of acute medication are independently associated with the development of chronic migraine. (2) Use of barbiturates and opioids doubled the rate of transformation 1 year later, after adjusting for headache frequency. Overall, triptans and nonsteroidal anti-inflammatory drugs neither increased nor reduced the transformation rate; (3) Headache frequency modified the effects of medication exposure. Triptans induced transformation in men with high frequency of headaches10-14at baseline, but not in women or in lower frequencies. Nonsteroidal anti-inflammatory drugs protected against transformation, unless individuals had high frequency of headaches, suggesting that, after a certain frequency, progression is self-perpetuated and less dependent of medication overuse.

Epidemiologic Lesson 6: Migraine Is Associated With Cardiovascular Disease and With Subclinical Brain Lesions.—

Migraine and Stroke.— A meta-analysis of 11 case–control and 3 cohort studies published before 2004 showed that, relative to individuals without migraine, the risk of stroke was increased in migraineurs (relative risk [RR] = 2.16, 95% confidence interval [CI] = 1.9-2.5). This risk was higher for MWA (RR = 2.27, 95% CI = 1.61-3.19), but was also significant in migraine without aura (MWoA; RR = 1.83, 95% CI = 1.06-3.15).

More recently, the Women's Health Study assessed the relationship between migraine and a range of prospectively determined cardiovascular end points, using data gathered from nearly 28,000 presumably healthy women.39 Similar to previous findings, MWA was associated with incident ischemic stroke (hazard ratio [HR] = 1.70, 95% CI = 1.1-2.6). These associations remained significant after adjusting for cardiovascular risk factors and did not occur in MWoA. Finally, as part of the Physician's Health Study, men with migraine (with or without aura) were at increased risk for major CVD (HR = 1.24, 95% CI = 1.06-1.46). The HR for ischemic stroke was not significant (HR = 1.12, 95% CI = 0.84-1.50; P = .43).

Migraine and Coronary Heart Disease.— The data on migraine and coronary heart disease are still controversial, since some studies are negative, but 3 recent population studies supported the relationship between MWA and CVD. The Atherosclerosis Risk in Communities Study found individuals with severe headache were roughly twice as likely to have a history of angina, with the risk most elevated in the headache group with aura. In the Women's Health Study, MWA but not MWoA increased the risk of angina, nonfatal ischemic stroke, myocardial infarction, as well as death related to cardiovascular events. These associations remained significant after adjusting for many cardiovascular risk factors. Finally, in the Physicians Health Study, migraine was also a risk factor for heart disease, although the association with stroke was weak.

Subclinical Changes on Brain Magnetic Resonance Imaging.— Changes in brain imaging that would be consistent with subclinical lesions, found incidentally in neuroimaging exams, have long been reported as happening more frequently in migraineurs. However, most studies did not have a contemporaneous control group and the pathology of these changes have never been studied. In a well-designed double-blind population study, conducted in the Netherlands, individuals with MWA had significant increase of subclinical infarcts in the cerebellar region of the posterior circulation, although no increase in clinical stroke.31 The highest risk for these lesions was seen in those with MWA and more than one headache attack per month (OR = 15.8 [1.8-140]). In addition, women with migraine were roughly twice as likely to have deep white matter lesions as the nonmigraineurs (OR = 2.1 [1.0-4.1]).

LESSONS FROM PATHOPHYSIOLOGY

  1. Top of page
  2. Abstract
  3. LESSONS FROM CLINICAL SCIENCE
  4. LESSONS FROM EPIDEMIOLOGY
  5. LESSONS FROM PATHOPHYSIOLOGY
  6. CONCLUSIONS
  7. REFERENCES

Pathophysiology Lesson 1: Migraine Is a Familial Disorder Likely to Have a Genetic Basis.— There is abundant evidence that migraine is a familial disorder with a probable genetic basis.40 Migraine aggregates in the family and, among migraineurs, probands with early onset illness or severe disease are more likely to have affected first-degree relatives.41,42

For some uncommon forms of migraine, such as familial hemiplegic migraine (FHM), specific pathogenic genes have been identified. Mutations in FHM1 affect the function of Cav2.1 calcium channels, expressed presynaptically throughout the brain and in the peripheral nervous system at the neuromuscular junction.43 FHM1 mutant channels open at more negative voltages than do normal channels and have an enhanced channel open probability. This “gain-of-function” effect results in increased Ca2+ influx, which would predict increased neurotransmission.44

FHM2 mutations in the ATP1A2 gene affect the Na+,K+ pumps that are primarily expressed in neurons and glial cells.45 Astrocytic Na+,K+ pumps are essential for the clearance of neurotransmitters and potassium from the synaptic cleft. FHM2 mutations result in a “loss-of-function,” leading to a reduced uptake of ions and neurotransmitters from the synaptic cleft and to an increased susceptibility to cortical spreading depression (CSD).

FHM3 mutations in the SCN1A gene cause a more rapid recovery from fast inactivation of neuronal Nav1.1 sodium channels after depolarization.46 Because these sodium channels are crucial for the generation and propagation of action potentials, the overall effects of FHM3 mutations most likely are increased frequency of neuronal firing and enhanced neuronal excitability and neurotransmitter release.

Pathophysiology Lesson 2: Migraine Is a True Neurological Disorder.— For many years regarded as a vascular disorder, migraine is actually the prototype of a neurological condition. The fundamental problem in migraine is in the brain. Herein we discuss important neurological phenomena related to migraine.

Cortical Spreading Depression.— CSD is a slowly propagating (2-6 mm/minute) wave of sustained neuronal depolarization, which is followed by potent, relatively long-lasting neural suppression.47 CSD is considered to be the electrophysiological substrate of migraine aura47 and many consider it as being necessary for the development of headache.48 However, evidence questions this last assumption. Aura occurs in less than 30% of migraine patients; aura can be experienced without pain at all, and is seen in the other primary headaches.49 Indeed, most of the symptoms of migraine, including photophobia, phonophobia, and osmophobia, may be explained by abnormal central processing of a normal signal. Perhaps electrophysiological changes in the brain have been mislabelled as hyperexcitability whereas dyshabituation might be a simpler explanation, where symptoms may be explained by disturbance of subcortical sensory modulation system.50

Cortical spreading depression does have the property of causing inflammation at the peripheral vascular component and of activating the trigeminal nucleus caudalis.51 Although it may not be the substrate of pain, CSD may explain some of the consequences of migraine that happen in individuals with aura only (see below).

Subcortical Structures and Migraine.— Functional brain imaging with positron emission tomography has demonstrated activation of the dorsal midbrain, including the periaqueductal gray (PAG), and in the dorsal pons, near the locus coeruleus, in studies during MWoA.52 Dorsolateral pontine activation is seen with positron emission tomography in spontaneous episodic53 and chronic migraine,54 and with nitroglycerin-triggered attacks.55,56 The activation corresponds with the brain region that has been reported in the past to cause migraine-like headache when stimulated in patients with electrodes implanted for pain control.57,58 Migraine can develop with pathology in the region of the PAG,59,60 or with a lesion of the pons.61,62 Altogether, the evidence suggests that brainstem networks involving most likely aminergic neurons are a crucial part of the neuronal network dysfunction that underlies migraine.

The Trigeminal System.— Following brainstem changes, or CSD, or both, activation of the trigeminal system occurs, or is at least thought to occur. When this system is activated, neuropeptides, including calcitonin gene-related peptide (CGRP), and substance P, are released from peripheral nerve endings in the cranium.63,64 These neuropeptides act at peripheral sites and within the brain and may play an important role in the generation and maintenance headache pain and possibly other symptoms of migraine (Fig. 2).65

image

Figure 2.—. Glutamate and calcitonin gene-related peptide (CGRP) are involved in relaying peripheral pain signals centrally to the brain and in central sensitization of the trigeminovascular system (TGVS). NMDA = N-methyl-D-aspartate; TNC = trigeminal nucleus caudalis.

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Pain generation in migraine accordingly involves both central activation in pain-important pathways, as well as peripheral mechanisms. The peripheral events have been characterized as being associated with meningeal neurogenic inflammation consisting of vasodilatation, plasma protein extravasation, and the release of proinflammatory mediators by mast cells. However, treatment strategies aimed at blocking neurogenic inflammatory responses have been unsuccessful when studied in migraine for both acute and preventive treatment.66 CGRP acting on the CGRP receptors stands as the crucial link in understanding activation of the trigeminal system in migraine since CGRP receptor antagonists, such as olcegepant67 and telcagepant,68 have proved effective in the acute treatment of migraine ushering in a new era for migraine therapeutics.69

Summary—The Migraine Pain.— As outlined above, neurogenic dural inflammation is produced with nonspecific trigeminal activation,70 although this phenomenon has never been conclusively shown to occur in migraine.66,71 Migraine pain may be understood as a combination of altered perception, due to peripheral or central sensitization of stimuli that are usually not painful, as well as the activation of a feed-forward neurovascular dilator mechanism in the first (ophthalmic) division of the trigeminal nerve. CSD is the presumed substrate of migraine aura even without it needing to produce pain.

Lesson 3: Allodynia Is Common in Migraine and Arises As a Consequence of Central Sensitization. — An interesting event in the pathophysiology of migraine is the sensitization of brain synaptic connections that transmit nociceptive impulses within the brain since this may be at the basis of the very common symptom of allodynia in migraine.72 Central sensitization of synapses between the trigeminovascular neurons and second-order brainstem trigeminal neurons is thought to arise from escalating barrage of input from trigeminal neurons.73 Central sensitization of trigeminal nucleus caudalis neurons could account for allodynia and the prolongation of the migraine attack.74 Alternatively, or in addition, facilitation of trigeminovascular transmission by central neuromodulatory sites may be the crucial step in sensitization and allodynia. Descending PAG neurons that normally inhibit trigeminovascular nociceptive inputs75 can facilitate second-order neuronal transmission when the P/Q voltage-gated calcium channel blocker agatoxin is injected into the PAG.76 Indeed triptans can have antitrigeminal nociceptive effects when injected locally into the PAG77 as can orexins.78 Moreover, activation of orexin pathways from the hypothalamus can have both inhibitory and facilitatory effects on nociceptive trigeminal processing.79 Furthermore, the dopaminergic A11 nucleus in the posterior hypothalamus80 can both inhibit and facilitate trigeminal action at the level of second-order neurons through a D2-family receptor action.81 These data link dopamine modulation of trigeminocervical neurons82 to the well-described dopamine dysfunction in migraine that include yawning as a premonitory feature.10,83,84 Taken together with the functional imaging data in migraine85 dysfunction of central control mechanisms may be as important, if not more important, in the generation of allodynia in migraine. Central sensitization plays an important role in migraine pathogenesis, especially in the later stages of an acute attack, and may be important in the development of chronic forms of the disorder.

It has been demonstrated that central sensitization, as determined by cutaneous allodynia, maps onto migraine biology. Its prevalence is higher in chronic migraine than episodic migraine, and is very low in tension-type headache. Accordingly, central sensitization may be a risk factor or a marker of migraine progression. It may be hypothesized that repetitive activation of trigeminovascular neurons and consequently repetitive activation of modulatory pain pathways involving the PAG or hypothalamic regulatory sites may lead to impairment of function or partial neuronal cell damage, through the liberation of free radicals, in the PAG or eventually in areas involved with migraine generation. Iron deposits in the PAG demonstrated using magnetic resonance imaging methods is consistent with this concept.86

Pathophysiology Lesson 4: Cortical Spreading Depression Is the Substrate of Migraine Aura and Has Specific Consequences.— As previously mentioned, CSD may not be a necessary event needed to initiate migraine pain. However, it may explain the relationship between aura and some of the migraine consequences, such as stroke and deep brain lesions.

Cortical spreading depression is a self-propagating wave of neuronal and glial depolarization. Cascading depolarization marching across the cortical mantle initiates a series of cellular and molecular events, resulting in transient loss of membrane ionic gradients, as well as massive surges of extracellular potassium, neurotransmitters, and intracellular calcium.47 In animal models, CSD rapidly activated and upregulated matrix metalloproteinases (MMPs), via constitutive expression of MMPs in the blood vessels.87 MMP-9 activation occurs within 15-30 minutes of CSD propagation. MMP-9 has been shown to be elevated in plasma of migraineurs, especially those with aura, with further increase during attacks. During CSD, oxygen-free radicals, nitric oxide, and proteases – factors that have been implicated in MMP activation – are dramatically increased. The CSD-related MMP activation may underlie changes in vascular permeability in the central nervous system. The disruption in the steady state of the brain, leading to perfusion changes, may also explain why MWA is consistently found as a risk factor for stroke and deep brain lesions. Recent human studies using neuroimaging have demonstrated thickness abnormalities in area V3A, previously described as a source in spreading changes involved in visual aura, as well as differences between the white matter immediately below the V3A.88 One plausible explanation for the anatomical finding is that this is an inherited structural change as opposed to a functional consequence of CSD. As a clinical corollary, effective migraine prophylactics seem to share the ability to block CSD in rats despite being from different pharmacological classes.89

Pathophysiology Lesson 5: Glial Waves May Maintain and Support the Migraine Attack.— Glial cells have long been assigned a supporting role in the nervous system, whereby they help maintain and modulate neuronal metabolism. However, recent attention has focused on the ability of astrocytes to propagate long-range calcium signals and actively communicate with each other, as well as with neurons and vascular cells. Synaptic activity in neurons triggers an increase in the intracellular calcium concentration ([Ca2+]i) of neighboring astrocytes, stimulating the release of ATP and glutamate. The released ATP stimulates an increase in [Ca2+]i in neighboring astrocytes so that a “calcium wave” is propagated from cell to cell. Released glutamate is cotransported with Na+ into neighboring cells; thus, glutamate uptake leads to an increase in astrocyte intracellular sodium concentration ([Na+]i) that is also propagated from cell to cell. This increase in [Na+]i stimulates an increase in glucose uptake and metabolism that leads to the formation of lactate, which is delivered to nearby – and perhaps distant – neurons as an energy substrate. The clinical relevance of astrocyte waves is that, being longer, they maintain the neuronal excitability, therefore predisposing to future migraine attacks and recurrence of migraine pain.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. LESSONS FROM CLINICAL SCIENCE
  4. LESSONS FROM EPIDEMIOLOGY
  5. LESSONS FROM PATHOPHYSIOLOGY
  6. CONCLUSIONS
  7. REFERENCES

In the past little was known about the mechanism leading to migraine, and this disease was treated empirically. The vascular theory led to the use of potent vasoconstrictors (ergots). The search for medicines with less adverse events led to the development of the triptans. Science has shown that their important mechanism of action in migraine is on the trigeminal neuronal pathways, not on blood vessels. The triptan era has led to remarkable progress in the diagnosis and treatment of migraine and in our understanding of migraine mechanisms. Many lessons have emerged from clinical science, epidemiology and from pathophysiologic studies. Clinical science has led to the observation that migraine progresses and often remits. This in turn led to longitudinal epidemiologic studies focused on both prognosis and factors that determine migraine prognosis. In addition, the epidemiologic studies raised questions about the mechanisms of migraine and of migraine progression, including the role of allodynia, obesity, inflammation, and medications as determinants of progression.91 This in turn opens a new set of scientific questions about the neurobiologic determinants of clinical course and exciting opportunities to develop new therapies for this highly disabling brain disorder.

REFERENCES

  1. Top of page
  2. Abstract
  3. LESSONS FROM CLINICAL SCIENCE
  4. LESSONS FROM EPIDEMIOLOGY
  5. LESSONS FROM PATHOPHYSIOLOGY
  6. CONCLUSIONS
  7. REFERENCES