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

Figure 56-2 Cortical spreading depression (CSD). The relationship between CSD and headache in migraine with aura. CSD releases H⁺, K⁺, and other agents, including arachidonic acid (AA) and nitric oxide (NO), in the extracellular space of the neocortex. These agents diffuse toward local blood vessels and depolarize perivascular trigeminal terminals, which, in turn, causes activation of the caudal portion of the trigeminal nucleus (TGN) in the brainstem. At the same time, collateral axons of activated neurons in the trigeminal ganglion (TGG) release proinflammatory peptides in the meninges and their vessels, which leads to a local inflammatory reaction. The activation from the superior salivatory nucleus (SSN) and reaching meningeal blood vessels via the sphenopalatine ganglion (SPG). The perception of pain is mediated by higher order projections from the TGN. The dashed lines between TGN, SSN, and regions generating the pain indicate that these connections either are unknown or have not been depicted.

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 reduced^27–29; 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 colleagues^34,35 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 studies^{28,29,37–40} 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-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E, and 5-HT_1F.⁷² The 5-HT_1B receptor is located on intracranial blood vessels and CNS neurons. The 5-HT_1D receptor is located on CNS neurons and trigeminal nerve endings. The 5-HT_1F receptors are located on trigeminal nerve endings.⁷³ Ergots and triptans act at the 5-HT_1B, 5-HT_1D, and, in part, 5-HT_1F 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-HT_1D and 5-HT_1F 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.

Aura

The migraine aura consists of focal neurological symptoms that precede, accompany, or (rarely) follow an attack. Aura usually develops over 5 to 20 minutes; lasts less than 60 minutes; can be visual, sensory, or motor; and may involve language or brainstem disturbances.³ Headache usually follows within 60 minutes of the end of the aura. Patients can have multiple aura types; most patients with a sensory aura also have a visual aura.⁸⁴

Auras vary in complexity. Simple auras include scotomata, simple flashes (phosphenes), specks, geometrical forms, and shimmering in the visual field. More complicated visual auras include teichopsia or fortification spectra (the characteristic aura of migraine), metamorphopsia, micropsia, macropsia, zoom vision, and mosaic vision. Paresthesias are often cheiro-aural: Numbness starts in the hand, migrates up the arm, and jumps to involve the face, lips, and tongue.^2,85 Weakness is rare, occurs in association with sensory symptoms, and is unilateral.⁸⁶ Apraxia, aphasia, agnosia, states of altered consciousness associated with déjà vu or jamais vu, and elaborate dreamy, nightmarish, trancelike, or delirious states can occur.⁸²

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

Resolution Phase

After the headache, many patients feel tired, “washed out,” irritable, and listless and may have impaired concentration, scalp tenderness, or mood changes. Some patients feel unusually refreshed or euphoric after an attack; others experience depression and malaise.

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

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.

Nonspecific Medication