Migraine
Stephen D. Silberstein
Richard B. Lipton
Sheryl Haut
Introduction
Migraine and epilepsy are the most common of the chronic neurologic disorders with episodic manifestations. Each group includes a highly variable family of clinical features, natural histories, and patterns of treatment response.6,99 Therefore, there are many types of migraine, as there are many types of epilepsy. Both disorders are characterized by episodes of neurologic dysfunction that are sometimes accompanied by headache, as well as gastrointestinal, autonomic, and psychologic features.
This chapter focuses on the relationship between migraine and epilepsy for several reasons. First, abundant clinical and epidemiologic data demonstrate that migraine and epilepsy are highly comorbid, in that individuals with one disorder are at least twice as likely to have the other.5,6,7,60,61,67 Secondly, the clinical presentation of migraine and epilepsy may overlap, creating a challenge in differential diagnosis. Finally, the disorders share overlapping risk factors, brain mechanisms, and treatments.61 We will begin by describing the migraine attack, dividing it into four traditional stages—the premonitory phase, the aura, the headache phase, and the resolution phase31—and contrast the seizure using this framework. We will then review the diagnosis of migraine using the International Classification of Headache Disorders (ICHD)-2 criteria, emphasizing the variants of migraine most frequently mistaken for epilepsy. Finally, we will summarize the epidemiologic evidence that migraine and epilepsy are associated, and provide treatment considerations.
Classification
Each family of disorders has an internationally recognized classification system. The classification system for headache, developed by international consensus, was updated in 2004, and will be referred to herein as the ICHD-2.40 The classification system utilized in epilepsy was developed by the International League Against Epilepsy (ILAE).
The ICHD-2 criteria divide headache disorders into two broad groups: Primary headache disorders and secondary headache disorders.40 In a somewhat similar manner, epilepsies are regarded as idiopathic, symptomatic, or cryptogenic by ILAE criteria. In the secondary headache disorders, the headache is symptomatic of an underlying condition, such as a stroke or a mass lesion. This group is analogous to the symptomatic epilepsies in that an underlying cause has been identified. In the primary headache disorders, the headache does not have an identifiable underlying cause. Primary headaches are divided into four major categories: Migraine; tension-type headache; the trigeminal autonomic cephalgias, including cluster headache; and a group of headache disorders analogous to the idiopathic epilepsies. There is no group of headache disorders akin to cryptogenic epilepsies. Furthermore, there is no classification of headache types analogous to the classification of seizure types.
Migraine
Migraine is an extremely common disorder. Recent population-based studies have yielded remarkably consistent 1-year period prevalence estimates of about 6% in men and 15% to 18% in women.87,62,97 Most studies find that migraine is about three times more common in women than in men.62,64,97
Headache diagnosis is usually based on the retrospective reporting of attack characteristics. The results of general medical and neurologic examinations, as well as laboratory studies, are usually normal and serve to exclude other, more ominous, causes of headache. The ICHD-2 classification of migraine subtypes is presented in Table 1. The most important International Headache Society (IHS) subtypes of migraine are “migraine without aura” (formerly common migraine) (Table 2) and “migraine with aura” (formerly classic migraine) (Table 3). In migraine, the aura is a complex of focal neurologic symptoms that precedes or accompanies an attack.116 About 20% to 30% of migraineurs have migraine with aura.63 The same patient may have headache without aura, headache with aura, and aura without headache.
The migraine attack can be divided into four phases: The premonitory phase, which occurs hours or days before the headache; the aura, which comes immediately before the headache; the headache itself; and the postdrome. Although most people experience more than one phase, no one phase is absolutely required for a diagnosis of migraine, and most people do not experience all four phases.17 The epilepsy attack may also have a premonitory, aura, attack, and postictal phase. The similarity in terminology does not imply similarity in mechanisms.
Premonitory, or prodromal, phenomena occur in approximately 60% of migraineurs, often hours to days before the onset of headache.3,4,17 The phenomena of the premonitory phase has been elucidated using an electronic diary.33 Features include constitutional, autonomic, psychological (depression, euphoria, irritability, restlessness, mental slowness, hyperactivity, fatigue, and drowsiness), and neurologic (photophobia, phonophobia, and hyperosmia) features. Some patients report a poorly characterized feeling that a migraine attack is coming. Although features vary widely among individuals, they are often consistent within an individual. The most common premonitory symptoms were feeling tired/weary (72%), difficulty concentrating (51%), and stiff neck (50%). Poor functioning commonly predicted headache.35 Migraineurs who reported premonitory symptoms accurately predicted their full-blown headaches 72% of the time. Among patients who were almost certain that attacks would occur, 93% had attacks.
Table 1 International Classification of Headache Disorders (ICHD)-2 Migraine Classification | ||
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Table 2 Migraine without Aura | ||
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Table 3 Migraine with Aura (41) | ||||
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Premonitory symptoms have also been reported prior to seizure onset.30 Although less commonly present than in migraine, patients with epilepsy often report a constellation of symptoms prior to a seizure, including irritability, gastrointestinal upset, heaviness, or depression.
Aura
The migraine aura consists of focal neurologic symptoms that precede or accompany an attack. Approximately 20% to 30% of migraineurs experience auras. Most aura symptoms develop slowly over 5 to 20 minutes and usually last for <60 minutes. The aura almost always includes visual features but somatosensory, motor, language, and brainstem disturbances are not rare.
The visual aura often has a hemianoptic distribution and includes both positive (scintillations, fortification spectra, photopsia) and negative (scotoma) features. Elementary visual disturbances include colorless scotoma, photopsia, or phosphenes. Simple flashes, specks, or hallucinations of geometric forms (points, stars, lines, curves, circles, sparks, flashes, or flames) occur and may be single or number in the hundreds. More complicated hallucinations include teichopsia, or fortification spectrum, which is the most characteristic visual aura and is almost diagnostic of migraine. An arc of scintillating lights classically begins near the point of fixation and may form a herringbone-like pattern that expands to encompass an increasing portion of a visual hemifield. It migrates across the visual field with a scintillating edge of zigzag or flashing lights that are often black and white; on occasion colored dots appear at the end of the white stripe. A scotoma is a negative phenomenon consisting of a blanking or graying out of vision. Scotomas are usually accompanied by a positive visual display, but may occur independently. Complex disorders of visual perception include metamorphopsia, micropsia, macropsia, zoom vision, and mosaic vision.99,100
Numbness or tingling (paresthesia) over one side of the face and in the ipsilateral hand or arm is the most common somatosensory phenomena. Hemiparesis and dysphasia or aphasia may develop. Olfactory hallucinations are rare, unpleasant, and short lived (5 minutes to 24 hours). Anxiety, déjà vu, and jamais vu have been reported as migraine auras and are presumably of temporal lobe origin.90 One type of aura may follow
another: Sensory phenomena may occur as visual phenomena fade, or motor phenomena may develop as sensory phenomena dissipate. Although visual auras are relatively specific for migraine, related phenomena may occur in cerebrovascular disease, including carotid dissection, and in epilepsy, especially of the occipital lobes.
another: Sensory phenomena may occur as visual phenomena fade, or motor phenomena may develop as sensory phenomena dissipate. Although visual auras are relatively specific for migraine, related phenomena may occur in cerebrovascular disease, including carotid dissection, and in epilepsy, especially of the occipital lobes.
Nonvisual association cortex symptoms also occur; these include complex difficulties in the perception and use of the body (apraxia and agnosia), speech and language disturbances, states of double or multiple consciousness associated with déjà vu or jamais vu, and elaborate, dreamy, nightmarish, trance-like or delirious states.38,51,59,90,95
In epilepsy, the aura, representing an actual seizure discharge, is typically rapid in development and brief. In contrast to the common visual auras of migraine, epileptic auras are often associated with more unusual symptoms. Auras are estimated to precede up to 80% of temporal lobe seizures; in this setting, autonomic and psychic phenomena, such as a rising abdominal sensation, nausea, fear, or déjà vu, are common.103
Mechanisms of Aura
Cortical spreading depression (CSD) is believed to underlie the migraine aura. CSD consists of a wave of excitation followed by a wave of inhibition that moves across the cortical mantle at a rate of 3 mm/min. Best studied as an animal phenomenon, it can be induced by pricking the cerebral cortex with a pin, by applying potassium chloride, and in other ways.56 CSD is characterized by transient increases in metabolic and electrical activity and transient increases in cerebral blood flow (CBF), followed by sustained decreases.75 The aura is associated with an initial hyperemic phase followed by reduced CBF, which moves across the cortex (spreading oligemia).76
Several lines of evidence in humans suggest that CSD is a mechanistic substrate of migraine aura. Olesen and Lauritzen74,76 found 17% to 35% reductions in posterior CBF, which spread anteriorly at 2 to 3 mm/min. It crossed brain areas supplied by separate vessels and is, thus, not due to segmental vasoconstriction.74 Reduced CBF persisted from 30 minutes to 6 hours, then slowly returned to baseline or even increased. The rates of progression of spreading oligemia could account for the rate of expansion of the scotoma in migraine, suggesting that they are related.55,56,69,77
Magnetoencephalographic studies show similar profiles in humans during migraine aura and in experimental animals during CSD,101 implying that spreading depression may be the mechanism that produces the aura.18,53,86,87,111 Subjects with spontaneous migraine visual auras have also been studied with functional magnetic resonance imaging (fMRI).23 Interictally, using perfusion-weighted imaging, CBF, cerebral blood volume, and mean transit time were normal and symmetric. 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 gray matter contralateral to the affected visual hemifield. When multiple perfusion images were obtained during the same aura, the margin of the perfusion defect moved anteriorly. The absence of diffusion abnormalities in these patients suggests that ischemia does not occur during the migraine aura.22
Blood oxygenation level–dependent (BOLD) fMRI reflects the relative concentration of deoxyhemoglobin in venous blood. Visual stimulation was used to trigger headache in migraineurs.20 A wave of increased (hyperoxygenated blood) and then decreased (possibly reflecting neuronal metabolic-flow coupling) BOLD signals propagated into the contiguous occipital cortex at 3 to 6 mm/min. When visual stimulation was used to test the visual cortex response, the BOLD signal and the BOLD response to visual activation diminished following progression of the visual aura.39
Using transcranial magnetic stimulation–applied magnetic fields of increasing intensity to evaluate occipital cortex excitability, Aurora et al.9 and Young et al.,115 but not Afra et al.,1 found that phosphenes were generated in migraineurs at lower thresholds than controls, and that it was easier to visually trigger headaches in those with lower thresholds. Other evidence of increased central nervous system (CNS) excitability comes from studies of visual and brainstem auditory-evoked potentials.93 Migraine with aura may be due to neuronal hyperexcitability, perhaps due to cortical disinhibition.
The aura of epilepsy is a simple partial nonmotor seizure that typically precedes an observable seizure, but may occur alone. The patient experiences the aura prior to loss of consciousness, and memory of it may be retained. The aura is associated with the electroencephalographic correlate of the seizure type in which it occurs27; however, the EEG pattern is often not evident on surface recording until the seizure has progressed to involve a larger area of cortex.
Headache Phase
The typical migraine headache is unilateral and described as throbbing by 85% of patients. Headache severity ranges from moderate to marked and is aggravated by head movement or physical activity. The onset is usually gradual and the attack usually lasts 4 to 72 hours in adults and 2 to 48 hours in children.99 Anorexia is common, although food cravings can occur. Nausea occurs in up to 90% of patients, and vomiting occurs in about one third of migraineurs.63 Many patients experience sensory hyperexcitability manifested by photophobia, phonophobia, and osmophobia, and seek a dark, quiet room.28,95 To make a diagnosis of migraine, the pain must be accompanied by other features. The ICHD-2 selects particular associated features as cardinal manifestations for diagnosis (Table 2).98
Postdrome or Postictal Phase
With migraine, the patient may feel tired, washed out, irritable, and listless and may have impaired concentration. Many patients report scalp tenderness. Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise. In epilepsy, during the postictal phase, there may be a depressed level of awareness or focal neurologic deficits that sometimes provide clues to the site of seizure onset.
Formal International Classification of Headache Disorders-2 Classification
Migraine without Aura (Common Migraine) (Table 2)
To establish a diagnosis of ICHD-2 migraine without aura (1.1), five attacks lasting from 4 to 72 hours are required. The attacks must have two of the following four pain characteristics: Unilateral location, pulsating quality, moderate to
severe intensity, and aggravation by or causing avoidance of routine physical activity. In addition, the attacks must be associated with at least one of the following: Nausea or vomiting or photophobia and phonophobia. No single characteristic is mandatory for a diagnosis of migraine. A patient who has photophobia, phonophobia, and severe pain aggravated by routine activity meets these criteria, as does the more typical patient with unilateral throbbing pain and nausea.98 Attacks that persist for more than 3 days define status migrainosus. Although the frequency of attacks varies widely, the average migraineur experiences one to three headaches a month. Like epilepsy, migraine is, by definition, a recurrent phenomenon. The requirement for at least five attacks is imposed because headaches simulating migraine may be caused by such organic diseases as brain tumors, sinusitis, or glaucoma.98
severe intensity, and aggravation by or causing avoidance of routine physical activity. In addition, the attacks must be associated with at least one of the following: Nausea or vomiting or photophobia and phonophobia. No single characteristic is mandatory for a diagnosis of migraine. A patient who has photophobia, phonophobia, and severe pain aggravated by routine activity meets these criteria, as does the more typical patient with unilateral throbbing pain and nausea.98 Attacks that persist for more than 3 days define status migrainosus. Although the frequency of attacks varies widely, the average migraineur experiences one to three headaches a month. Like epilepsy, migraine is, by definition, a recurrent phenomenon. The requirement for at least five attacks is imposed because headaches simulating migraine may be caused by such organic diseases as brain tumors, sinusitis, or glaucoma.98
Migraine with Aura (Classic Migraine) (Table 3)
Descriptively, auras are focal neurologic symptoms that usually develop gradually over 5 to 20 minutes and last for <60 minutes. The diagnosis of migraine with aura (1.2) requires at least two attacks meeting the criteria of one of the subforms. In addition, it cannot be attributed to another disorder. Migraine with aura is subclassified into typical aura with migraine headache (1.2.1) (homonymous visual disturbance, unilateral numbness or aphasia); typical aura with nonmigraine headache (1.2.2); typical aura without headache (1.2.3); familial hemiplegic migraine (FHM) (1.2.4); sporadic hemiplegic migraine (1.2.5) (see Table 6); and basilar-type migraine (1.2.5). Some of these variants will be discussed in detail since they may be confused with epilepsy.
Typical aura with migraine headache (1.2.1) requires at least two attacks with the aura consisting of at least one of the following (but no motor weakness): Fully reversible visual symptoms including positive; fully reversible sensory symptoms including positive; and fully reversible dysphasic speech disturbance. Additionally, it requires at least two of the following: Homonymous visual symptoms and/or unilateral sensory symptoms; at least one aura symptom developing gradually over ≥5 minutes and/or different aura symptoms occurring in succession over ≥5 minutes; and each symptom lasting ≥5 and ≤60 minutes. Fewer attacks are required to make a diagnosis of migraine with aura because a typical aura is highly specific for migraine. Headache with the features of migraine without aura usually follows the aura symptoms. Less commonly, headache lacks migrainous features or is completely absent.40,98
If the aura includes motor weakness, it is coded as 1.2.4 Familial hemiplegic migraine or 1.2.5 Sporadic hemiplegic migraine.
The headache and associated symptoms of migraine with aura are similar to those of migraine without aura but may be less severe and/or of shorter duration. Most people who have migraine with aura also have migraine without aura. The aura usually lasts 20 to 30 minutes and typically precedes the headache, but occasionally it occurs only during the headache.
Migraine Variants
The variants of migraine as classified by the ICHD-2 have been discussed in detail elsewhere.40 In this section we will describe the migraine variants that are most commonly confused with epilepsy, using ICHD-2 terminology when possible.
Basilar-type Migraine
Originally called basilar or basilar artery migraine,40 the term Bickerstaff syndrome has also been applied to this disorder.13 It affects all age groups and both sexes, with the usual female predominance. The aura often lasts <1 hour and is usually followed by a headache. In basilar-type migraine, the visual aura is usually followed by at least one of the following: Ataxia, vertigo, tinnitus, diplopia, nystagmus, dysarthria, bilateral paresthesia, or a change in the levels of consciousness and cognition. If marked, these alterations in consciousness define confusional migraine.
The aura symptoms described above are often, but not always, followed by a severe, throbbing occipital headache and vomiting. Although attacks are usually infrequent, they can last for 1 to 3 days. These headaches can be very frightening and difficult to diagnose. On occasion, the attacks can lead to cardiac arrhythmias and brainstem stroke. A diagnosis of basilar migraine should be considered in patients with paroxysmal brainstem disturbances. Basilar migraine may be difficult to differentiate from simple or complex partial seizures and the postictal state following a primary or secondary generalized seizure. The differential diagnosis, besides occipital lobe epilepsy, includes posterior fossa tumor or malformation, urea cycle defects, and mitochondrial disorders.84
