Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 274
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
1. Migraine
   1.1 Migraine without aura
   1.2 Migraine with aura
      1.2.1 Typical aura with migraine headache
      1.2.2 Typical aura with nonmigraine headache
      1.2.3 Typical aura without headache
      1.2.4 Familial hemiplegic migraine
      1.2.5 Sporadic hemiplegic migraine
      1.2.6 Basilar-type migraine
   1.3 Childhood periodic syndromes that are commonly precursors of migraine
      1.3.1 Cyclical vomiting
      1.3.2 Abdominal migraine
      1.3.3 Benign paroxysmal vertigo of childhood
   1.4 Retinal migraine
   1.5 Complications of migraine
      1.5.1 Chronic migraine
      1.5.2 Status migrainosus
      1.5.3 Persistent aura without infarction
      1.5.4 Migrainous infarction
      1.5.5 Migraine-triggered seizures
   1.6 Probable migraine
      1.6.1 Probable migraine without aura
      1.6.2 Probable migraine with aura
      1.6.3 Probable chronic migraine
From Headache Classification Committee. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24:1–160.
Table 2 Migraine without Aura
Diagnostic Criteria
  1. At least five attacks87 fulfilling criteria B–D
  2. Headache attacks lasting 4–72 hours (untreated or unsuccessfully treated)
  3. Headache has at least two of the following characteristics:
    1. Unilateral location
    2. Pulsating quality
    3. Moderate or severe pain intensity
    4. Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs)
  4. During headache at least one of the following:
    1. Nausea and/or vomiting
    2. Photophobia and phonophobia
  5. Not attributed to another disorder
From Headache Classification Committee. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24:1–160.
Table 3 Migraine with Aura (41)
Diagnostic Criteria
  1. At least two attacks fulfilling criterion B
  2. Migraine aura fulfilling criteria B and C for one of the subforms 1.2.1–1.2.6
  3. Not attributed to another disorder
Typical aura with migraine headache
Diagnostic Criteria
  1. At least two attacks fulfilling criteria B–D
  2. Aura consisting of at least one of the following, but no motor weakness:
    1. Fully reversible visual symptoms including positive features (e.g., flickering lights, spots, or lines) and/or negative features (i.e., loss of vision)
    2. Fully reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness)
    3. Fully reversible dysphasic speech disturbance
  3. At least two of the following:
    1. Homonymous visual symptoms and/or unilateral sensory symptoms
    2. At least one aura symptom develops gradually over ≥5 minutes and/or different aura symptoms occur in succession over ≥5 minutes
    3. Each symptom lasts ≥5 and ≤60 minutes
  4. Headache fulfilling criteria B–D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes
  5. Not attributed to another disorder
From Headache Classification Committee. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24:1–160.
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.
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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
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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
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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
Confusional Migraine40,43
No longer part of the ICHD-2 classification, confusional migraine is probably a form of basilar-type migraine or hemiplegic migraine. It is characterized by a typical migraine aura, a headache (which may be insignificant), and confusion, which may precede or follow the headache. During the confused period the patient is inattentive, is distracted, and has difficulty maintaining speech and other motor activities. The electroencephalogram (EEG) may be abnormal during the attack. Agitation, memory disturbances, obscene utterances, and violent behavior have been reported. Single attacks are most common; multiple attacks rare. Attacks may be triggered by mild head trauma. A more profoundly disturbed level of consciousness may lead to migraine stupor, which can last from hours up to 5 days. The confusional state is usually followed by sleep, resembling postictal depression of mental status. Confusional migraine may be difficult to diagnose. The differential diagnosis includes drug ingestion, metabolic encephalopathies (Reye syndrome, hypoglycemia), viral encephalitis, and acute psychosis. Acute confusional states also occur during complex partial seizures and in the postictal state. The patient may be delirious, hyperactive, restless, and, on occasion, combative. Acute migraine confusional states may recur over a period of days or months and then evolve into typical migraine episodes. A history of typical migraine aura supports a diagnosis of migraine.52
Benign Paroxysmal Vertigo of Childhood
Now classified as one of the “childhood periodic syndromes,” this condition is a precursor of migraine (1.3.3). This disorder is characterized by recurrent, brief episodic attacks of vertigo. Attacks occur without warning and resolve spontaneously in otherwise healthy children. Children with this disorder cannot stand, and lie silently on the floor or wish to be held during attacks. Attacks last a few minutes and tend to recur at irregular intervals over a period of 6 to 12 months. While headache may not be present at the onset, as the disorder evolves the vertigo may be replaced by attacks of headache and vomiting,
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facilitating diagnosis. When simple partial seizures give rise to vertigo, the vertigo is usually less prominent than it is in migraine.
Aura without Headache
Migraine aura can occur without headache,112 although diagnosis is more difficult in this setting. These periodic neurologic phenomena (scintillating scotomata or recurrent sensory, motor, or mental phenomena) should be accepted as migraine only after a full investigation. Headache occurring in association with some attacks will help confirm the diagnosis.88 Ziegler and Hassanein116 reported that 44% of their patients who had headache with aura had aura without headache at some time.
Late-life migrainous accompaniments are characterized by attacks of aura without headache beginning in late life.31,32 Many patients have a history of migraine in early or midlife, often with an attack-free hiatus. Because focal neurologic defects occur without headache, they can be confused with transient ischemic attacks (TIAs) or seizures. Late-life migrainous accompaniment remains a diagnosis of exclusion.
Migraine-triggered Seizure
New to the ICHD-2 is a seizure triggered by a migraine aura (1.5.5). This diagnosis requires migraine that fulfills the criteria for 1.2 Migraine with aura and a seizure fulfilling diagnostic criteria for one type of epileptic attack that occurs during or within 1 hour after a migraine aura. This phenomenon is sometimes referred to as migralepsy.
Epidemiologic Connections between Migraine and Epilepsy
Andermann and Andermann5 summarized a number of studies that examined the association between migraine and epilepsy. The prevalence of epilepsy in persons with migraine ranged from 1% to 17% with a median of 5.9%, substantially higher than epilepsy’s population prevalence of 0.5%. Migraine prevalence in patients with epilepsy ranged from 8% to 15%. Many of these studies were limited by the method of patient identification, the lack of appropriate control groups, and poorly specified definitions of migraine and epilepsy. Nonetheless, these studies powerfully argue that migraine and epilepsy are associated.
Ottman and Lipton79 examined the association between migraine and epilepsy using data from Columbia University’s Epilepsy Family Study. Subjects with epilepsy (probands) who were over 18 years of age were identified and recruited from voluntary organizations for persons with epilepsy. Among the probands with epilepsy, migraine prevalence was 24%. Migraine prevalence was 26% in the relatives with epilepsy. In the control group of relatives without epilepsy, only 15% had migraine. The gender-adjusted rate ratio for migraine in probands with epilepsy compared with relatives without epilepsy was 2.4 (95% confidence interval [CI]: 2.0 to 2.9). For relatives with epilepsy compared with relatives without epilepsy the rate ratio was also 2.4 (95% CI: 1.6 to 3.8). These statistics indicate that the incidence of migraine is 2.4 times higher in persons with epilepsy than in persons without epilepsy.
Risk of migraine was not associated with the age of onset of epilepsy. The risk of migraine was elevated in both partial and generalized seizures, although the risk was higher for probands with partial-onset versus those with generalized-onset seizures (relative risk [RR] = 1.3; 95% CI: 1.00 to 1.86). The risk of migraine was elevated in both idiopathic and symptomatic epilepsy. Probands with epilepsy caused by head trauma had a higher risk of migraine than probands with idiopathic/cryptogenic epilepsy (RR = 1.8, 95% CI: 1.32 to 2.43). Nonetheless, migraine risk was elevated in every subgroup of epilepsy defined by seizure type, age of onset, and etiology of epilepsy.70
Although migraine and epilepsy are associated, the mechanisms of the association are complex and may be multifactorial. One possibility is a simple unidirectional causal explanation. For example, migraine may cause epilepsy by inducing brain ischemia and injury. Under this hypothesis, we would expect the incidence of migraine to be elevated before, but not after, the onset of epilepsy. Alternatively, epilepsy may cause migraine by activating the trigeminovascular system. This hypothesis leads us to expect an excess risk of migraine after, but not before, the onset of epilepsy. The data show that there is an excess risk of migraine both before and after seizure onset, leading to the rejection of both unidirectional causal models.
Marks and Ehrenberg67 explored the timing and features of headache in patients with epilepsy. They found that of 79 of 395 patients with epilepsy, 20% also had IHS migraine. In 84% of patients with both migraine and epilepsy (66 of 79), the attacks were completely independent. In 16% of patients (13 of 79), a seizure immediately followed the migraine aura (migralepsy); 11 of 13 were women, seven of whom had a catamenial pattern. Migralepsy was also seen in refractory patients with both migraine and epilepsy in Andermann’s series,6 although this phenomenon does not account for the majority of the comorbidity.
Velioglu and Ozmenoglu109 studied the relationship between migraine and epilepsy in 412 adults with epilepsy. Fourteen percent of adults with seizures had IHS migraine. Migraine-induced epilepsy (migralepsy) was found in seven patients (1.7%); all had migraine with aura. The authors at times found it difficult clinically to distinguish the aura of migraine from the aura of epilepsy. Patients were at increased risk for both conditions if they had migraine with aura and catamenial epilepsy. Three of the patients with refractory seizures had improved control with the combination of antimigraine and antiepilepsy drugs.
Lenaerts57 evaluated the degree of comorbidity and tried to establish the pattern of temporal relationship between migraine and epilepsy in 201 patients from tertiary care clinics. He systematically reviewed charts, obtained additional information by telephone interviews where necessary, and applied IHS and ILAE diagnostic criteria. Two-tier grouping according to reason for referral (migraine or epilepsy) was done. Adequate information was obtained from 185 patients (113 females, 72 males). In the epilepsy-referred patient group (n = 103), 23% had migraine, a risk ratio of 1.9 (p = 0.01). In the migraine-referred group (n = 82), 11% had epilepsy, a risk ratio of 21 (p = 0.05). Of the 33 comorbid cases, 21 had their attacks in close temporal relation. The migraine attack preceded the seizure in 12 patients (nine migraine with aura) (57%) and followed it in nine (six migraine with aura) (43%). Migraine attacks equally precede or follow seizures, but migraine aura more often precedes the seizure (migralepsy).
Shared environmental risk factors may contribute to comorbidity. The risk of migraine is higher in subjects with epilepsy caused by head injury. Since head injury is also a risk factor for migraine,8 comorbidity may result, in part, from an effect of head injury on the risk of both disorders. Because risk is also significantly increased in persons with idiopathic/cryptogenic epilepsy, known environmental risk factors cannot account for all of the comorbidity.
Table 4 Migraine and Epilepsy Relationships
  1. Coexisting epilepsy and migraine Both disorders occur together at an increased prevalence, but attacks occur independently
  2. Migraine-induced epilepsy (migralepsy) Seizures are triggered by migraine aura
  3. Epilepsy-induced headache (ictal or postictal) Headache occurs as part of seizure or postictal state
  4. Primary epilepsy–migraine syndromes Syndromes with features of both migraine and epilepsy without a specific underlying cause
       –Occipital epilepsies (e.g., benign occipital epilepsy)
       –Benign rolandic epilepsy
  5. Secondary epilepsy–migraine syndromes Both migraine and epilepsy occur in the same individual with a common underlying cause
       –Mitochondrial disorders (MELAS)
       –Symptomatic (e.g., arteriovenous malformation of occipital lobe)
    • Neurofibromatosis
    • stürge-Weber
Modified from Andermann F. Migraine and epilepsy: an overview. In: Andermann F, Lugaresi E, eds. Migraine and Epilepsy. Boston: Butterworths, 1987:405–421; and Welch KM, Lewis D. Migraine and epilepsy. Neurol Clin. 1997;15:107–114.
Ottman and Lipton79 tested the alternative hypothesis, that shared genetic risk factors might account for comorbidity. They
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argued that the risk of migraine should be higher in families with genetic versus nongenetic forms of epilepsy if genetic factors account for comorbidity. They further argued that the risk of epilepsy should be greater in the relatives of probands with migraine and epilepsy versus the relatives of probands with epilepsy alone. In a series of analyses, they adjusted for a number of potentially confounding factors including age, gender, the familial aggregation of migraine, and the comorbidity of migraine and epilepsy. The analyses failed to confirm either of the authors’ hypotheses, leading them to reject the idea that genetic susceptibility accounts for comorbidity.79
Having rejected the unidirectional model, the environmental model, and the genetic hypothesis, they proposed that an altered brain state (increased excitability) might increase the risk of both migraine and epilepsy and account for comorbidity. Enhanced neuronal hyperexcitability and a reduced threshold to attacks figure prominently in the pathophysiologic models of migraine and epilepsy. Reduction in brain magnesium or perturbations in neurotransmitter systems may provide a basis for these alterations in brain excitability. In theory, genetic or environmental factors could produce these alterations. Regardless of mechanisms, these findings are important for clinical practice.
Interrelationships between Headache and Epilepsy
Apart from the causal epidemiologic issues discussed above, there are many possible clinical interrelationships between headache and epilepsy (Table 4). The disorders may exist independently. Migraine may trigger epilepsy (migralepsy) or epilepsy may initiate headache. Seizure and headache seem to be associated in certain syndromes, such as benign occipital epilepsy of childhood with occipital paroxysms (BOEP). In addition, both disorders may have a common underlying cause such as head trauma, an arteriovenous malformation,66 or neurofibromatosis.21,85 Finally, migraine may be a predictor of poor outcome in persons with epilepsy. We will now consider some of these interrelationships.
Headache as a Consequence of Seizures
Although headache is commonly associated with seizures as a preictal, ictal, or postictal phenomenon, it is often neglected because of the dramatic neurologic manifestations of the seizure. Patients with migraine-triggered epilepsy seek medical attention because of seizures, which may overshadow the migraine and be overlooked by the patient and physician.
Preictal and Ictal Headache
Palmini and Gloor80 presented a descriptive study of auras in partial seizures. Cephalic auras, defined by the symptoms of nonvertiginous dizziness, lightheadedness, or head pressure, occurred in 22 of 196 patients. In Blume and Young’s epilepsy unit, 2.8% of 858 patients had brief ictal pain and 1.3% (11 patients) had headache. Only two patients described the pain as throbbing; the others described it as sharp or steady. Headache preceded the seizure in eight patients and accompanied the other ictal symptoms in three; all three of these patients had partial seizures, although the nature and location of EEG abnormalities varied considerably from patient to patient.
Isler et al.47 found that hemicranial attacks of pain coincided with seizure activity and lasted for seconds to minutes (hemicrania epileptica). Two exceptions were noted: One a case of complex partial status in which the headache lasted for hours and another in which the headache lasted most of the 20 minutes of a recorded seizure. Overall, 20% of this group of drug-resistant epileptics had cephalic symptoms.
In a more recent study,114 nearly half of patients undergoing continuous EEG monitoring for intractable epilepsy experienced peri-ictal headache, the majority being postictal. Interestingly, preictal headache lateralized to the side of seizure focus in 9 of 10 patients.
Headache can also be the sole or most predominant clinical manifestation of epileptic seizures, although this is a relatively rare situation.54 Headache was noted to be a true ictal manifestation during intracranial monitoring, in two cases relieved by resective epilepsy surgery.54
Postictal Headache
In a telephone interview of 372 patients attending an epilepsy clinic, 45% had experienced postictal headache (PIH) and 21% always had PIH. Of those who always had PIH, headache was severe 39% of the time; in contrast, it was severe in only 10% of patients with occasional PIH. Twenty-seven percent of patients had independent headaches that were usually similar to their seizure-related headache. Headaches lasted <6 hours in 81% of patients, 12 to 24 hours in 11%, and >24 hours in 8%.92 The headache was throbbing in over two thirds.
Schön and Blau94 reported on 100 epileptic patients, 51 of whom had PIH either always (n = 35), usually (n = 5), or 25% to 50% of the time (n = 11). PIH was more commonly associated with generalized tonic–clonic seizures than with focal seizures; 9% of the patients with PIH also had independent migraine attacks. The headaches were either bilateral or unilateral. They were associated with photophobia and phonophobia, throbbing pain, vomiting, nausea, and visual aura, and lasted 6 to 72 hours. Epileptic migraineurs recognized these headaches as being similar to their migraine. Postictal headaches with migraine features respond to triptans.49
Ito et al. reported that 40% of 364 patients with partial epilepsies had PIH and that 26% had postictal migraine.
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Migraine-like PIH was more likely in temporal and occipital lobe epilepsy and less likely in frontal lobe epilepsy.48
The mechanism of ictal and postictal headaches is uncertain. In recent years, the theory of migraine pathogenesis has focused on the trigeminovascular system; activation of this system gives rise to neurogenic inflammation of cranial blood vessels and pain.70 In animal models, Moskowitz et al. have shown that seizures activate the trigeminovascular system, providing a potential mechanism for the associated headaches. This mechanism would account for the triptan response in postictal headache.46 Velioglu et al. examined the effect of migraine on the prognosis of epilepsy in a prospective study of 59 patients with both disorders and a control group of 56 patients with epilepsy but not migraine. The group with migraine and epilepsy was less likely to become seizure free and more likely to have intractable seizures and medication problems than patients with epilepsy alone. Thus, comorbid migraine may be a predictor of poor outcome in epilepsy.108
In summary, preictal and ictal headaches are relatively rare and short lived. The seizure itself may limit the patient’s ability to observe or recall the manifestations of these headaches. In contrast, PIH is common and can impact the quality of life of the person with epilepsy. It is most common with generalized tonic–clonic seizures, but is also common in complex partial seizures; it is less common with simple partial seizures.92
Migraine–epilepsy Syndromes
Benign Epilepsy of Childhood with Occipital Paroxysms
BEOP is a clinical syndrome characterized by a partial seizure with visual symptoms, followed by postictal migraine and occipital spikes on EEG. A rare disorder, it accounts for <5% of epilepsy in children (mean age of onset 7.5 years).24,33,82 BEOP has features of both epilepsy and migraine.33,35,105 The visual symptoms may include amaurosis, elementary visual hallucinations (phosphenes), complex visual hallucinations, or visual illusions, including micropsia, metamorphopsia, or palinopsia.11,33,73 The visual symptoms are often followed by hemiclonic, complex partial, or secondarily generalized tonic–clonic seizures. Following the seizure, approximately 25% to 40% of the patients develop migraine-like headaches.105
The interictal EEG is characterized by normal background activity and distinct occipital discharges. The occipital spikes typically have a high voltage (200 to 300 μV), diphasic morphology, and a unilateral or bilateral occipital and posterior temporal distribution. The spikes disappear with eye opening and reappear 1 to 20 seconds after eye closure.
Gastaut reviewed the clinical and EEG features of 53 patients with BOEP. Only 55% had the “complete” syndrome of occipital spikes, ictal visual symptoms followed by a partial seizure, and postictal migraine. In patients with nocturnal seizures, motor symptoms predominated; in those with daytime seizures, visual symptoms were more common. Nocturnal seizures are more common in younger children and bear a good prognosis.33,82 Seizures starting after 8 years of age are more likely to be frequent, diurnal, and persistent,33,82 although overall, complete seizure control is achievable in about 60% of patients.
Occipital spikes are not specific for BOEP. They have been reported in people with migraine, and in children under 4 they may not be associated with epilepsy or any other defined disorders.41,58,102 Occipital spikes can also be seen in other disorders, including myoclonic, absence, and photosensitive epilepsies, as well as celiac disease.19,33
Benign Rolandic Epilepsy
Benign rolandic epilepsy is characterized by unilateral somatosensory or motor seizures and centrotemporal spikes; both clinical and electrographic features can shift from side to side. Speech arrest, pooling of saliva, and (usually) preservation of consciousness are also typical, although secondary generalization may occur. Most patients respond well to anticonvulsant medication. In one series, 75% of patients were seizure free after 5 years.10 The seizures almost invariably disappear by age 15. An association with migraine has been reported in some, but not all, studies.15,16 Rossi et al.89 found that migraine prevalence in male controls (11.1%) was much higher than one would expect in boys between the age of 6 and 15 years. Giroud et al.,36 in a control study, found that epilepsy with rolandic paroxysms and migraine were associated. Migraine incidence was studied in four groups of patients: Patients with centrotemporal epilepsy, patients with absence epilepsy, patients with partial epilepsy, and nonepileptic patients with a history of cranial trauma. Migraine was present in 62% of the patients with centrotemporal epilepsy, 34% of the patients with absence epilepsy, 8% of the patients with partial epilepsy, and 6% of the patients with cranial trauma. These results suggest that centrotemporal epilepsy and, to a lesser degree, absence epilepsy are associated with migraine.36 The association between benign rolandic epilepsy and migraine may be part of the comorbidity of migraine with all forms of epilepsy.85
Differential Diagnosis and Concomitant Diagnosis of Migraine and Epilepsy: Clinical and Electroencephalographic Features
The most important tool in differentiating between migraine without aura and epilepsy is the history.82 Table 5 illustrates high levels of symptomatic overlap between migraine and epilepsy. Tables 6 and 7 present the features most useful in distinguishing them. In general, in comparison with epilepsy, attacks of migraine are more gradual in onset and of longer duration. Nausea and vomiting are more commonly associated with migraine, while prolonged confusion or lethargy after the attack favors epilepsy.
Table 5 Symptoms Common to Both Migraine and Epilepsy
Symptom Migraine Epilepsy
Systemic
Vomiting + +/-
Nausea + +/-
Diarrhea +/- -
Headache + +/-
Visual disturbances
Colored circles - +
Black and white lines + -
Blindness +/- +/-
Blurred vision + +
Visual triggering factors + +
Other neurologic
Olfactory +/- +
Vertigo + +/-
Confusion +/- +
Loss of consciousness +/-* +
Impaired consciousness +/- +
Loss of memory +/- +
Postevent lethargy + +
Depersonalization +/- +
Paresthesias + +
Hemiparesis +/-** +
Hemisensory loss +/-** +
Aphasia +/-** +
*More complex.
**Hemiplegic migraine.
At times, differentiating migraine with aura from epilepsy can be difficult, particularly when motor manifestations such as tonic or clonic movements are absent. The characteristics of the aura may help29: The migraine aura is longer (5+ minutes) and the aura of epilepsy is brief (usually <1 minute).5 In addition, the aura symptom profiles differ. Autonomic, psychic, or somatosensory features favor epileptic auras, while a mix of positive and negative visual features, such as a scintillating scotoma, favors migraine.81
Table 6 Prodrome and Aura in Migraine and Epilepsy
Symptom Migraine Epilepsy
Premonitory Common Often
Duration of aura 15–60 min Brief, often <1 min
Automatisms Unusual Absent in aura, present in complex partial seizures
Gastrointestinal aura Abdominal pain (rare); nausea (common) “Butterflies”—rising epigastric sensation
Visual disturbances Positive/negative Complicated visual phenomenon
Paresthesias Common (5–60 min) Common (seconds to minutes)
Altered consciousness Usually responsive Responsive during aura, altered responsiveness during complex partial seizure
Olfactory Very uncommon More common
Aphasia Common Common
Déjàvu Rare Common
The characteristics of the visual features present in migraine and epilepsy bear further discussion. Colorless glittering scotomata are typical of migraine, as are black-and-white zigzag patterns that appear concentrically around the point of fixation, usually unilaterally. (These are also termed fortification spectra.) The phenomenon of a geometric pattern with expansion from the center to the periphery of the visual field (rarely in the reverse direction) and a simultaneous increase in size over a period of several minutes suggests CSD and migraine. The regular angular patterns in the photopsias that accompany migraine correspond to the cortical structures that generate them.44,45,46 Photopsias in migraine may evolve into a scotoma or a temporary homonymous hemianopia. Resolution of the visual field
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defect typically occurs without any positive visual phenomena. Colors may be seen as well, or spots, circles, and beads with or without colors. When these occur, they are usually part of the scintillating scotoma or teichopsia and not a predominant independent feature of the migrainous visual hallucination.
In contrast, visual epileptic auras are predominantly multicolored, with a circular or spherical pattern, as opposed to the predominantly black-and-white zigzag pattern of migraine.83 During a seizure, hallucinations that begin unilaterally may later encompass the whole visual field, and simple hallucinations may develop into complex forms. In contrast to migraine, epileptic visual auras last for only seconds (with the rare exception of persistent visual auras),113 thus limiting the patient’s opportunity to observe and describe the hallucinations. The auras are often associated with head or eye movement and alteration of consciousness. Formed visual hallucinations are rare in migraine; when present in epilepsy, this manifestation may localize the seizure onset to the temporal or temporo-occipital region.14
The sensory auras of migraine and epilepsy also differ. In migraine, the auras are paresthesias (pins and needles) that typically begin in the hand, move up the arm, skip the shoulder, and move into the face and tongue over a period of 10 to 15 minutes. They are often associated with a visual aura.92 The sensory aura of epilepsy is typically briefer and is often described as burning, cramping, stinging, aching, electric, or throbbing.
Correctly diagnosing and separating epilepsy and migraine can be more difficult in children than in adults. Young children may give incomplete descriptions of their symptoms; features useful in diagnosing epilepsy or migraine in adults may be absent or difficult to elicit in children. Hemicranial pain and visual auras occur less often in children with migraine than in adults. In children, the first symptoms of migraine may not even be associated with headaches.42 Children are also less likely to experience feelings of déjà vu or to have olfactory hallucinations as part of a simple partial seizure or temporal lobe epilepsy. Furthermore, the epilepsies most commonly mistaken for migraine are childhood syndromes, as discussed above.
While the EEG is extraordinarily useful in diagnosing epilepsy and differentiating subtypes, it is less valuable in diagnosing migraine. EEGs recorded during an attack of migraine with aura, unlike those recorded during a clinical seizure, are usually normal. Focal slowing sometimes occurs during migraine auras, although this is not a consistent finding. Previously recommended EEG markers of migraine, such as robust photic driving at high flash frequencies and slowing with hyperventilation, can be seen in children without a history of migraine and are not very specific.37
Table 7 Features of Epilepsy and Migraine
Clinical features Migraine Epilepsy
Consciousness Usually clear Usually clouded
Duration Hours Minutes
Family history Often positive for migraine Sometimes positive for epilepsy
Onset Gradual Sudden
Electroencephalogram Nonspecific abnormalities Spikes and sharp waves, ictal patterns
The incidence of epileptiform activity in patients with migraine appears to be higher than that of the general population. In a large multicenter study, the incidences of spikes and paroxysmal rhythmic events in 10-hour overnight EEGs of normal adult volunteers (n = 135) was 0.7%, as compared to 12.5% for subjects with a history of migraine and 13.3% for subjects with a family history of epilepsy.86 However, this finding does
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not contribute to the diagnosis of patients with migraine, and may in fact confuse the issue. Currently, the Quality Standards Subcommittee of the American Academy of Neurology has concluded that the EEG is not useful in the routine assessment of headache patients.2 It does not identify headache subtypes or effectively screen for structural causes of headache. The EEG is useful if headache patients have symptoms that suggest a seizure disorder, such as atypical migrainous aura or episodic loss of consciousness. Assuming head-imaging capabilities are readily available, EEG is not recommended to exclude a structural cause for headache.2,91
There is, however, clearly a role for 24-hour closed-circuit television EEG recording; when differentiating migraine aura from epileptic aura is difficult on clinical grounds, these procedures can also facilitate the diagnosis of comorbid epilepsy and migraine as well as the migralepsy syndrome. Marks and Ehrenberg29 studied patients with migralepsy using multiple 24-hour video EEG telemetry recordings. The entire migraine–epilepsy sequence of two patients was captured, showing changes during the clinical migraine aura that were atypical for electrographic epilepsy. During migraine aura, bursts of spike activity may resemble the ictal EEG during an epileptic seizure. In most reported cases, however, the EEG does not show the usual temporal evolution with progressive increases and declines in the frequency and amplitude of rhythmic, repetitive epileptiform activity typical of ictal EEGs in epilepsy. In addition, the EEG during migraine aura may show “waxing and waning” patterns, separated by completely normal EEG activity despite the persistence of clinical symptoms.
Manzoni et al.65 and Terzano et al.106,107 coined the term intercalated seizures to denote epileptic seizures occurring between the migrainous aura and the headache phase of migraine. They found that 16 of 450 patients with migraine (3.6%) also had seizures. The two conditions appeared to be coincidental in 4 of the 16 patients. In another five patients, the two types of attacks were quite distinct, but often an epileptic seizure was followed by a migraine attack and vice versa. The remaining seven patients had intercalated seizures. All had a family history of migraine and two also had relatives with epilepsy. All had visual seizures consisting of highly stylized contours of plain figures, or single or multicolored spots that often rotated. The seizures lasted for 1 to 2 minutes and came out of a scintillating scotoma, slowly developing in the visual field and evolving into unilateral or bilateral hemianopia. DeRomanis et al.25,26 studied patients who had brief ictal visual hallucinations of “colored dots or discs” and interictal occipital paroxysms on EEG. EEG during a seizure showed that they had occipital epilepsy and not migraine with aura.85
Striking EEG patterns have been described in specific subtypes of migraine.12 The brain regions most often involved in the published EEG samples in basilar-type migraine include the posterior temporal, parietal, and occipital regions. The posterior electrographic localization may not pertain to other forms of migraine.71 Paroxysmal lateralized epileptiform discharges (PLEDs) or PLED-like activity has been associated with hemiplegic migraine, prolonged migraine aura, or incipient migrainous infarction. Those patients with PLED-like activity did not have any of the usual entities associated with PLEDs, such as stroke, brain abscess, glioblastoma, or viral encephalitis; their PLEDs usually resolved within 24 hours. Certain migralepsy patients had clinical seizures when PLEDs were present on their EEGs.67
Treatment Considerations
Because migraine and epilepsy are associated, clinicians should be sensitive to the issue of concomitant diagnoses. When diseases are comorbid, the principle of diagnostic parsimony does not apply. Individuals with one disorder are more likely, not less likely, to have the other. In the Epilepsy Family Study, only 44% of probands with epilepsy who were classified as having migraine on the basis of their self-reported symptoms reported physician-diagnosed migraine.78 In the general population, 29% of men and 40% of women with migraine reported a medical diagnosis.63 The proportion of probands reporting a physician’s diagnosis of migraine was surprisingly low, given that all were already being treated for epilepsy.
Why is the comorbidity of migraine and epilepsy not recognized? Epilepsy may be viewed as a more serious disorder than migraine. As a result, the migrainous symptoms of patients with a diagnosis of epilepsy may have been overlooked or attributed to the seizure disorder. In addition, the diagnosis of atypical migraine symptoms can be quite difficult, and a number of epileptic and nonepileptic syndromes may mimic migraine. Some patients with epilepsy and migraine may not report their headaches because the headaches are being effectively treated with an antiepileptic drug without a diagnosis of migraine. Finally, the interview used in the Epilepsy Family Study may lead to overdiagnosing migraine in some patients.
When planning treatment strategies for epilepsy and migraine, the possibility of comorbid disease should be considered. Although tricyclic antidepressants and neuroleptic drugs are often used to treat migraine in patients with comorbid epilepsy, caution is advisable, as these medications may lower seizure thresholds. When selecting drugs for migraine prophylaxis, it is sometimes advantageous to treat comorbid conditions with a single agent; for example, when migraine and hypertension occur concomitantly, a beta-blocker or calcium channel blocker is commonly used.97 In the same way, anticonvulsants with efficacy for both migraine and epilepsy (divalproex sodium and topiramate) should be considered in patients with both disorders.
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Divalproex sodium is a Food and Drug Administration (FDA)-approved anticonvulsant for migraine prophylaxis. The efficacy of divalproex has been supported by recent open and double-blind, placebo-controlled studies.50,68,96,104 The doses that are effective in migraine are generally lower than those used for epilepsy; 500 mg/day is often sufficient. Topiramate is a second FDA-approved anticonvulsant for migraine prophylaxis. In both open and small, placebo-controlled, double-blind trials, doses of 50 to 100 mg/day have been shown to be effective for migraine.99 Other antiepileptic drugs that have been shown to be superior to placebo for migraine include gabapentin, levetiracetam, tiagabine, and zonisamide, but large-scale studies are needed. Lamotrigine may be effective for migraine aura, but not headache.
An advantage to the use of anticonvulsants as migraine prophylactic agents is that they can be administered to patients with depression, Raynaud disease, asthma, and diabetes, circumventing the contraindications to beta-blockers.98
In addition, the recognition of potentially similar mechanisms and response to therapy between the disorders has led to crossover of other treatment modalities. For example, the vagal nerve stimulator, an FDA-approved device for the add-on treatment of intractable partial epilepsy, is under investigation for migraine.72 Similar efforts are likely to continue.
Summary and Conclusions
In summary, migraine and epilepsy are comorbid conditions, and the presence of one disorder increases the likelihood of the other. Because of its greater prevalence, migraine is very common in persons with epilepsy, while epilepsy is rare in migraineurs. The comorbidity of migraine and epilepsy presents both pitfalls and opportunities, and the diagnosis and treatment of each disorder must take into account the potential presence of the other.
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