MIGRAINE

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CHAPTER 56 MIGRAINE

Migraine is a primary episodic headache disorder characterized by various combinations of neurological, gastrointestinal, and autonomic changes. The word migraine is derived from the Greek word “hemicrania” (Galen, circa 200 AD).1 Diagnosis is based on the headache’s characteristics and associated symptoms.2 The International Headache Society diagnostic criteria for headache disorders (1988)3 have been revised (2004) and describe a total of seven subtypes of migraine.4 Data in this chapter5 are from the Technical Reports of the Agency for Healthcare Policy and Research,69 the U.S. Headache Consortium Guidelines,10,11 and the triptan metaanalysis.12

EPIDEMIOLOGY

Migraine prevalence rates are similar and stable in European countries and in the United States.13 In the United States, according to one study, 17.6% of women and 6% of men had had one migraine attack in the previous year.14 A second study 10 years later had similar prevalence estimates (Fig. 56-1).15 Migraine prevalence varies by age, gender, race, and income. Before puberty, migraine prevalence is approximately 4%.16 After puberty, the prevalence increases more rapidly in girls than in boys. It increases until approximately age 40, then declines. The prevalence is lowest among Asian-Americans, intermediate among African-Americans, and highest among white persons.16 In the United States, migraine prevalence decreases as household income increases.14,16,17

image

Figure 56-1 Adjusted age-specific prevalence of migraine by sex.

(From Lipton RB, Stewart WF, Diamond S, et al: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41:646-657.)

Migraine substantially affects quality of life. The World Health Organization ranks migraine among the world’s most disabling medical illnesses.18 Approximately 28 million Americans have severe, disabling migraine headaches.15 Migraine’s annual cost to employers is approximately $13 billion, and related annual medical costs exceed $1 billion.16 Instruments to quantify migraine disability include the Migraine Disability Assessment Scale19 and the Headache Impact Test.20

PATHOPHYSIOLOGY

Genetics

Migraine is a group of familial disorders with a genetic component. Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by attacks of migraine, with and without aura, and hemiparesis. The gene has been mapped to chromosome 19p13 in approximately two thirds of cases.21,22 The defect arises from at least 10 different missense mutations in the CACNA1A gene, which codes for the α1 subunit of a voltage-dependent P/Q Ca2+ channel.23 The same gene is associated with episodic ataxia with cerebellar vermix atrophy.21 P-type neuronal Ca2+ channels mediate 5-hydroxytriptamine (5-HT) and excitatory neurotransmitter release. Dysfunction may impair 5-HT release and predispose patients to migraine attacks or impair their self-aborting mechanism. Voltage-gated P/Q-type calcium channels mediate glutamate release, are involved in cortical spreading depression (CSD), and may be integral in initiating the migraine aura (Fig. 56-2).24 A second gene has been mapped to chromosome 1q21-23. The defect is due to a mutation in the α2 subunit of the Na/K pump.25

Aura

The migraine aura was believed to be caused by cerebral vasoconstriction and the headache by reactive vasodilation.26 This explained the headache’s throbbing quality and its relief by ergots. It is now believed that the migraine aura is caused by neuronal dysfunction, not ischemia; ischemia rarely, if ever, occurs. Headache often begins while cortical blood flow (CBF) is reduced2729; thus, headache is not caused by simple reflex vasodilation.30,31

The migrainous fortification spectrum corresponds to an event moving across the cortex at 2 to 3 mm/minute.32 Noxious stimulation of the rodent cerebral cortex produced a spreading decrease in electrical activity that moved at 2 to 3 mm/minute (CSD).33 CSD is characterized by shifts in cortical steady-state potential; transient increases in potassium, nitric oxide, and glutamate levels; and transient increases in CBF, followed by sustained decreases.27

The aura is associated with an initial hyperemic phase followed by reduced CBF, which moves across the cortex (spreading oligemia).34 Olesen and colleagues34,35 found 17% to 35% reductions in posterior CBF, which spread anteriorly at 2 to 3 mm/minute. It crossed brain areas supplied by separate vessels and is thus not caused by segmental vasoconstriction.35 Reduced CBF persisted from 30 minutes to 6 hours, and then CBF slowly returned to baseline or even increased. The rates of progression of spreading oligemia are similar to those of migrainous scotoma and CSD, which suggests that they are related.31,33,36

Additional studies28,29,3740 support the hypothesis that CSD produces the aura.27 During visual auras, CBF decreased 15% to 53%, cerebral blood volume decreased 6% to 33%, and mean transit time increased 10% to 54% in the occipital cortex contralateral to where the aura was experienced. The perfusion defect moved anteriorly.29 The absence of diffusion abnormalities suggests that ischemia does not occur during the aura.41

Blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging (MRI) reflects the relative concentration of deoxyhemoglobin in venous blood. Visual stimulation was used to trigger headache in migraineurs.37 A wave of increased BOLD signal (reflecting hyperoxygenated blood) and then decreased BOLD signal (possibly reflecting neuronal metabolic flow coupling) propagated into the contiguous occipital cortex at 3 to 6 mm/minute. When visual stimulation was used to test the visual cortex response, the BOLD signal and the BOLD response to visual activation diminished after progression of the visual aura.30

Magnetoencephalography demonstrates changes that are consistent with CSD in migraineurs but not in controls.42,43 Using transcranial magnetic stimulation (which applies magnetic fields of increasing intensity) to evaluate occipital cortex excitability, Aurora and associates44 and Young and coworkers,45 but not Afra and colleagues,46 found that phosphenes were generated in migraineurs at lower thresholds than in controls and that it was easier to visually trigger headaches in subjects with lower thresholds. Other evidence of increased central nervous system (CNS) excitability comes from studies of visual and brainstem auditory evoked potentials.47 Migraine with aura may be caused by neuronal hyperexcitability, which perhaps arises from cortical disinhibition.

Headache

Headache probably results from the activation of meningeal and blood vessel nociceptors in combination with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Reflex connections to the cranial parasympathetic nerves form the trigeminoautonomic reflex. Activation results in vasoactive intestinal polypeptide release and vasodilation.31

Trigeminal sensory neurons contain substance P, calcitonin gene–related peptide (CGRP), and neurokinin A.48 Stimulation results in release of substance P and CGRP from sensory C-fiber terminals49 and neurogenic inflammation.50 The neuropeptides interact with the blood vessel wall, producing dilation, plasma protein extravasation, and platelet activation.51 One study suggests that neurogenic inflammation occurs in humans.52 Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization) that then respond to previously innocuous stimuli, such as blood vessel pulsations,53 causing, in part, the pain of migraine.54 Central sensitization can also occur. After meningeal irritation, expression of c-fos (a marker for neuronal activation) occurs in the trigeminal nucleus caudalis55 and in the dorsal horn at the C1 and C2 levels.56,57

Superior sagittal sinus stimulation results in release of CGRP but not substance P.58 This is important: Levels of CGRP, not substance P, is elevated in external jugular venous blood during migraine.59 Sumatriptan reduced elevated CGRP levels in a migraine attack and in experimental animals during trigeminal ganglion stimulation.60,61 CGRP may play a role in migraine headache.62,63 A potent specific CGRP antagonist64 has been reported to be effective in acute migraine treatment.65

Applying an “inflammatory soup” to the dura sensitizes second-order trigeminovascular neurons (increased spontaneous activity and response to mechanical and thermal skin stimulation).53 Triptans administered early prevented central sensitization: Dural and facial receptive fields did not expand; spontaneous activity, mechanical sensitivity, and thermal sensitivity did not increase. Late triptan intervention did not reverse central sensitization but shrank the expanded dural receptive fields and normalized intracranial mechanosensitivity. Central sensitization may play a key role in maintaining the headache.66,67

Affected patients often develop cutaneous allodynia (nonpainful stimuli are experienced as painful) during migraine attacks because of trigeminal sensitization.66 Triptans can prevent but not reverse cutaneous allodynia.67 Cutaneous allodynia can be used to predict triptans’ effectiveness.66 In the absence of allodynia, triptans completely relieved the headache and blocked the development of allodynia. In 90% of attacks with established allodynia, triptans provided little or no headache relief and did not suppress allodynia. However, late triptan therapy eliminated peripheral sensitization (throbbing pain aggravated by movement), even when pain relief was incomplete and allodynia was not suppressed.66 Early intervention may work by preventing cutaneous allodynia and central sensitization.

Brainstem activation occurs in migraine without aura. On positron emission tomography, patients with right-sided migraine headache showed increased regional CBF in the left brainstem.68 Sumatriptan relieved the headache and associated symptoms but did not normalize brainstem regional CBF. This suggests that activation is caused by factors other than, or in addition to, increased activity of the endogenous antinociceptive system. A second report corroborated these findings.69

A link exists between the migraine aura and headache. CSD activates trigeminovascular afferents, causing a long-lasting increase in middle meningeal artery blood flow and plasma protein extravasation within the dura mater.70 CSD results in upregulation of inducible nitric oxide synthetase and inflammatory cytokines. This mechanism couples meningeal blood flow and neurogenic inflammation to CSD but does not explain headache ipsilateral to the aura.31,70

Serotonin (5-HT) Receptors and Migraine Treatment

There are seven classes of 5-HT receptors: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.71 In humans, there are five 5-HT1 receptor subtypes: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F.72 The 5-HT1B receptor is located on intracranial blood vessels and CNS neurons. The 5-HT1D receptor is located on CNS neurons and trigeminal nerve endings. The 5-HT1F receptors are located on trigeminal nerve endings.73 Ergots and triptans act at the 5-HT1B, 5-HT1D, and, in part, 5-HT1F receptors. They constrict extracerebral intracranial vessels, inhibit trigeminal neurons, and block transmission in the trigeminal nucleus. They minimally constrict human coronary arteries. They block plasma protein extravasation50 by activating prejunctional trigeminal 5-HT1D and 5-HT1F heteroreceptors, blocking neuropeptide release. Plasma protein extravasation can be also be blocked by nonsteroidal anti-inflammatory drugs (NSAIDs),74 γ-aminobutyric acid (GABA) agonists,75,76 neurosteroids,77 substance P antagonists,78 and the endothelin antagonist bosentan.79 Dihydroergotamine and the centrally penetrant triptans label the nuclei in the brainstem and spinal cord that are involved in pain transmission and modulation.80 The caudal trigeminal nucleus is activated by stimulation of the sagittal sinus, and this activity is transmitted to the thalamus. Ergots and triptans suppress this activation.

Conclusion

The migraine aura is probably caused by CSD. Headache probably results from activation of meningeal and blood vessel nociceptors in combination with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Stimulation results in the release of substance P and CGRP from sensory C-fiber terminals and neurogenic inflammation.51 Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization), which then respond to previously innocuous stimuli, such as blood vessel pulsations, causing, in part, the pain of migraine. Central sensitization of trigeminal nucleus caudalis neurons can also occur. Central sensitization may play a key role in maintaining the headache. Brainstem activation also occurs in migraine without aura, partly as a result of increased activity of the endogenous antinociceptive system. The migraine aura can trigger headache; CSD activates trigeminovascular afferent vessels. Stress can also activate meningeal plasma cells via a parasympathetic mechanism, leading to nociceptor activation.81

Migraine may be a result of a change in processing of pain and sensory input. The aura is triggered in the hypersensitive cortex (as a result of CSD). Headache is generated by central pain facilitation and neurogenic inflammation. Central sensitization, mediated in part by supraspinal facilitation, can occur. Decreased antinociceptive system activity and increased peripheral input may be present.

DESCRIPTION OF THE MIGRAINE ATTACK

The migraine attack can consist of premonitory, aura, headache, and resolution phases. Premonitory symptoms occur in 20% to 60% of migraineurs, hours to days before headache onset. They may include psychological, neurological, constitutional, or autonomic features, such as depression, cognitive dysfunction, and bouts of food cravings.82 Migraineurs who reported having premonitory symptoms were able to accurately predict 72% of their full-blown headaches. The most common premonitory symptoms were feeling tired/weary (72%), difficulty concentrating (51%), and stiff neck (50%). Poor functioning was commonly predictive of headache.83

Headache Phase

The median migraine attack frequency is 1.5 per month.14 The typical headache is unilateral, of gradual onset, throbbing (85%),87 moderate to marked in severity, and aggravated by movement.3 Pain may be bilateral (40%) or may start on one side and become generalized. It lasts 4 to 72 hours in adults and 2 to 48 hours in children.3

During the headache, anorexia is common. Nausea occurs in almost 90% of patients, and vomiting occurs in about one third.88 Sensory hypersensitivity results in patients’ seeking a dark, quiet room.2,88 Blurry vision, nasal stuffiness, hunger, tenesmus, diarrhea, abdominal cramps, polyuria, facial pallor, sensations of heat or cold, and sweating may occur. Depression, fatigue, anxiety, nervousness, irritability, and impairment of concentration are common. Symptom complexes may be generated by linked neuronal modules.89

FORMAL DIAGNOSTIC CRITERIA

The International Headache Society subdivides the disorder into migraine with aura and migraine without aura.4,90 To diagnose migraine without aura (Table 56-1), five attacks must have occurred. No single feature is mandatory, but recurrent episodic attacks must be documented.3 Migraine persisting for more than 3 days defines “status migrainosus.”3,4

TABLE 56-1 Migraine without Aura: Diagnostic Criteria

Migraine with aura is subdivided into migraine with typical aura, migraine with prolonged aura, hemiplegic migraine, basilar-type migraine, and migraine with acute-onset aura (Table 56-2.) The International Headache Society classification now allows the association of aura with other headache types. Prolonged aura lasts from 1 hour to 1 week; persistent aura lasts for more than 1 week (but resolves). If neuroimaging demonstrates a stroke, a migrainous infarction has occurred.

TABLE 56-2 Migraine with Aura (Classic Migraine): Diagnostic Criteria

Periodic neurological dysfunction (scintillating scotomata and recurrent sensory, motor, and mental phenomena) can occur without headache.91 Visual phenomena, which are usually benign, occurred in 1.33% of women and in 1.08% of men in a general population sample.92 Scintillating scotomata, numbness, aphasia, dysarthria, and motor weakness may occur for the first time after age 45 and be confused with transient ischemic attacks of cerebrovascular origin.93 In general, migrainous symptoms are slower to develop (>5 minutes) and consist of positive and negative phenomena.

MIGRAINE VARIANTS

Basilar-type migraine aura has brainstem symptoms: ataxia, vertigo, tinnitus, diplopia, nausea and vomiting, nystagmus, dysarthria, bilateral paresthesia, and a change in the level of consciousness and cognition.3 The diagnosis should be considered when patients have paroxysmal brainstem disturbances. Some authorities have suggested that hemiplegic migraine should be diagnosed if weakness is present.86

Ophthalmoplegic migraine results from an idiopathic inflammatory neuritis.94 There is enhancement of the cisternal segment of the oculomotor nerve, followed by resolution over several weeks as symptoms resolve.

Hemiplegic migraine can be sporadic or familial.2 Attacks are frequently precipitated by minor head injury.86 FHM is an autosomal dominant, genetically heterogeneous disorder with variable penetration. FHM includes attacks of migraine without aura, migraine with typical aura, and episodes of prolonged aura, fever, meningismus, and impaired consciousness.23 Headache may precede the hemiparesis or be absent. Hemiparesis onset may be abrupt and simulate the effects of a stroke. In 20% of unselected families whose members have FHM, patients have cerebellar symptoms and signs (nystagmus, progressive ataxia). All have mutations within CACNA1A.22

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain caused by a Notch3 gene mutation on chromosome 19.95,96 CADASIL mutations are highly stereotyped missense mutations within epidermal growth factor–like repeats in the extracellular domain of Notch3. Mutations lead to loss or gain of a cysteine, thereby creating an odd number of cysteines within a given epidermal growth factor domain.97 Notch3 expression is restricted to smooth muscle cells, and normal proteolysis of the Notch3 receptor generates a 210-kD extracellular fragment and a 97-kD intracellular fragment. Patients with CADASIL accumulate excess Notch3 ectodomain (i.e., the 210-kD fragment) within the cerebral vasculature, apparently because of impaired clearance of the receptor from the surface of vascular smooth muscle cells and pericytes. Most cases are inherited in an autosomal dominant manner, but a de novo symptomatic mutation, Arg182Cys, has been reported.98 Symptoms include recurrent subcortical lacunar infarctions (84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (31%), migraine with aura (22%), and mood disorders with severe depressive episodes (20%).99 MRI scans of at-risk individuals are often abnormal, with extensive areas of increased white matter T2 signals. The arteriopathy involves the media of small cerebral arteries and, to a lesser extent, extracerebral arteries, including skin arterioles. In skin biopsy, abnormal patches of agranular osmiophilic material within the basal membranes of vascular smooth muscle cells are diagnostic.97 A commercial genetic test is available for the most common CADASIL mutations. It currently has a false-negative rate of at least 20% because it screens only mutational hot spots located in exons 3, 4, 11, and 18. Scanning all 23 exons that encode all 34 epidermal growth factor–like repeat sequences is considered the most accurate test for CADASIL, but it is time-consuming and costly.

TREATMENT

Migraine varies widely in its frequency, severity, and impact on the patient’s quality of life. A treatment plan should account not only for the patient’s diagnosis, symptoms, and any coexistent or comorbid conditions but also for the patient’s expectations, needs, and goals.100,101 Migraine treatment begins with making a diagnosis,2 explaining it to the patient, and developing a treatment plan that considers coincidental or comorbid conditions.101 Headache calendars record headache duration, severity, and treatment response. Comorbidity indicates an association between two disorders that is more than coincidental.

Conditions that occur in migraineurs with a higher prevalence than would be expected include stroke, epilepsy, Raynaud’s disease, and affective disorders, which include depression, mania, anxiety, and panic disorder. Possibly associated disorders include essential tremor, mitral valve prolapse, and irritable bowel syndrome.

The pharmacological treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Acute treatment is an attempt to relieve or stop the progression of an attack or the pain and impairment once an attack has begun. It is appropriate for most attacks and should be used a maximum of 2 to 3 days a week. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability.

Pharmacotherapy for the Acute Migraine Headache

Acute treatment can be specific (ergots and triptans), or nonspecific (analgesics and opioids) (Table 56-3). Nonspecific medications control the pain of migraine or other pain disorders, whereas specific medications are effective in migraine (and certain other) headache attacks but are not useful for nonheadache pain disorders. Triptans are effective in the range of mild, moderate, and severe migraine attacks.102

TABLE 56-3 Acute Medications: Efficacy, Adverse Events, Relative Contraindications, and Indications

  Comorbid Condition
Drug Relative Contraindication Relative Indication
Acetaminophen (Paracetamol) Liver disease Pregnancy
Aspirin Kidney disease CAD
Ulcer disease Transient ischemic attack
PUD
Gastritis (age <15)
NSAIDs Kidney disease Arthritis
PUD
Gastritis
Butalbital, caffeine, and analgesics Use of other sedative
History of medication overuse
Caffeine adjuvant Sensitivity to caffeine
Isometheptene Uncontrolled HTN, CAD, PVD
Opioids Drug or substance abuse Pregnancy
Rescue medication
Neuroleptics Parkinson’s disease Nausea
Prolonged QTc Vomiting
Pregnancy
Rescue medication
Dihydroergotamine
Injections CAD Orthostatic hypotension
Intranasal instillation PVD  
Uncontrolled HTN Prominent nausea or vomiting
Ergotamine
Tablets Prominent nausea or vomiting
Suppositories CAD  
PVD
Uncontrolled HTN
Triptans
Almotriptan (tablets) CAD
PVD
Uncontrolled HTN
Eletriptan (tablets) CAD
PVD
Uncontrolled HTN
Frovatriptan (tablets) CAD
PVD
Uncontrolled HTN
Naratriptan (tablets) CAD
PVD
Uncontrolled HTN
Rizatriptan (tablets) CAD
PVD
Uncontrolled HTN
Zolmitriptan (tablets, intranasal) CAD Prominent nausea or vomiting
PVD
Uncontrolled HTN
Sumatriptan (subcutaneous injection, intranasal instillation, tablets) CAD
PVD
Uncontrolled HTN

CAD, coronary artery disease; HTN, hypertension; NSAID, nonsteroidal anti-inflammatory drug; PUD, peptic ulcer disease; PVD, peripheral vascular disease; QTc, corrected QT interval.

Treatment choice depends on attack severity, frequency, associated symptoms, coexistent disorders, prior treatment response, and the medication’s efficacy, its potential for overuse, and adverse events. A nonoral route of administration and an antiemetic should be considered for severe nausea or vomiting.11 Injections provide rapid relief. Headaches can be stratified by severity and disability (on the Migraine Disability Assessment Scale or Headache Impact Test). Analgesics are used for mild to moderate headaches.11 Triptans and dihydroergotamine are first-line drugs for severe attacks and for less severe attacks that do not adequately respond to analgesics.11 Patients with moderate or severe headaches with moderate or severe disability (according to the Migraine Disability Assessment Scale score) who were given a triptan did better than patients given aspirin and metoclopramide.103

Early intervention prevents escalation and may increase efficacy.104 Triptans can prevent the development of cutaneous allodynia, and cutaneous allodynia is predictive of triptans’ effectiveness.66 Before the clinician decides that a drug is ineffective, at least two attacks should be treated. It may be necessary to change the dose, formulation, or route of administration or add an adjuvant. When the response is inadequate, the headache recurs, or adverse events are bothersome, a medication change may be needed. Limiting acute treatment to 2 to 3 days a week can prevent medication-overuse headache. When headaches are very frequent, early intervention may not be appropriate.

All treatment occasionally fails; therefore, rescue medications (opioids, neuroleptics, and corticosteroids) are needed. They provide relief but often limit function by causing sedation or other adverse events.