Clinical manifestations

Presentation and course

A migraine attack and an epilepsy attack are typically similar in that they both encompass all or part of four phases.

Premonitory phase. A premonitory phase occurs hours or days before headache onset in as many as 60% of migraineurs (01). It occurs with equal frequency in migraines with and without auras. It may consist of an alteration in mental state (eg, depression, hyperactivity, euphoria, irritability, or restlessness), an alteration in neurologic state (eg, photophobia, phonophobia, yawning, or hyperosmia), or an alteration in general (eg, food cravings, anorexia, diarrhea, constipation, or stiff neck).

Premonitory symptoms have also been reported by patients with epilepsy prior to seizure onset (21).

Aura phase. The migraine aura is a collection of focal neurologic symptoms that occur up to 60 minutes before the onset of a headache. It develops over five to 20 minutes and usually lasts no more than 60 minutes. This is unlike the aura of epilepsy, which is usually brief, lasts seconds, develops rapidly, and can be associated with unusual symptoms, such as feelings of fear, déjà vu, or jamais vu. Visual illusions or hallucinations can occur in both. Migraine auras may be visual, sensory, or motor, and they can occur in progression. They frequently occur before a headache; however, they may occur with a headache, or a headache may not follow.

The visual symptoms of migraine range from minor visual disturbances, such as phosphenes and scotomas, to complex auras, such as teichopsia, micropsia, macropsia, and palinopsia (75). In contrast, the visual auras experienced by patients with seizure normally consist of multiple brightly colored, small, circular spots, circles, or balls (56). Long duration (five minutes or greater) of visual aura suggests migraine rather than epilepsy (30). Automatisms are frequent in complex-partial seizures but unusual in migraine, as are olfactory symptoms. However, it is not always easy to separate these two conditions based on the above criteria alone. The “Alice-in-Wonderland syndrome,” where alteration of shape (metamorphopsia) with micropsia, macropsia, impaired sense of passage of time, and zooming of the environment occurs, has been described in temporo-occipital epilepsy, parietal-occipital-temporal epilepsy, and migraine (11).

Migraine sensory auras usually consist of cheiro-aural paresthesias with numbness migrating from the hand up the arm to the face; this normally occurs together with a visual aura. This progression of symptoms occurs from five to 60 minutes as opposed to the paresthesia of epilepsy, which occurs over seconds to minutes (64).

Motor auras normally consist of unilateral weakness and occur together with sensory auras.

Headache and seizure phase. The features of migraine without aura are outlined in Table 1. Not all the features are required, and the headache may be bilateral, occur more frequently on arising in the morning, and last between four and 72 hours. Associated with the pain may be a host of symptoms, including concentration and memory problems, stiff neck, irritability, anorexia, dizziness, diarrhea, and polyuria, among others.

Resolution phase. In this phase, the pain is terminating in migraine, and the patient may suffer from scalp tenderness, mood changes, or loss of energy. Euphoria or depression can accompany this phase.

Clinical interrelationships between migraine and epilepsy exist. The new headache classification criteria, ICHD-III, recognizes three seizure-related headaches (Headache Classification Committee of the International Headache Society (IHS) 2018). Migraine aura-triggered seizure (code 1.4.4) refers to a seizure occurring during or within one hour after an attack of migraine with aura. Hemicrania epileptic (code 7.6.1) refers to headaches occurring during a partial epileptic seizure, ipsilateral to the epileptic discharge, and remitting soon after the seizure has terminated. Postictal headache (code 7.6.2) indicates any headache caused by and occurring within 3 hours after an epileptic seizure and remitting spontaneously within 72 hours after seizure termination. Accordingly, headaches may be a preictal, ictal, or postictal seizure phenomenon.

Regarding the postictal headache, a longitudinal study conducted in a tertiary center in Brazil recruited 302 patients with adult-onset epilepsy and reported that 46.3% of patients had postictal headache. Tension-type postictal headache was present in 55% of the subjects, and migrainous headache in 32.1%. In this study, family history of migraine, diagnosis of drug-resistant epilepsy, months since last visit, and generalized seizure onset type of epilepsy were significant determinants of postictal headache on multilevel linear modeling (08).

There was no relationship between the localization of the epileptogenic focus, localization of the headache, or the headache classification in a clinic-based study enrolling 110 patients with epilepsy (23). In a study of 100 consecutive patients with mesial temporal lobe epilepsy and hippocampal sclerosis, those patients who had unilateral hippocampal sclerosis and predominantly unilateral headache (irrespective of the type) tended to present pain ipsilateral to the hippocampal sclerosis (51). However, another study enrolled 56 consecutive patients with mesial temporal lobe epilepsy and hippocampal sclerosis, and no relationship was found between the lateralization of the headache and the side of hippocampal sclerosis in patients with migraine (27).

Table 1. Diagnostic Criteria of Migraine Without Aura

Prognosis and complications

Velioglu and colleagues looked at the effect of migraine on the prognosis of epilepsy. The aim of this prospective 5- to 10-year follow-up study was to examine some outcome measures and the cumulative probability of being seizure-free in epilepsy patients with migraine and to compare their results with those of epilepsy patients without migraine. Fifty-nine patients (40 women; mean age 25 years) were diagnosed with both epilepsy and migraine. The control group consisted of 56 patients with epilepsy but without migraine. The study group had a significantly lower cumulative probability of being seizure-free over 10 years compared with the control group. The other epilepsy outcome measures at follow-up differed significantly between the groups, with the study group having a longer duration of epilepsy, a lower early treatment response, and a higher incidence of intractable epilepsy and achieving remission with polytherapy, and more seizure control and medication problems for at least the last two years of follow-up. They concluded then that comorbid migraine had a negative effect on the prognosis of epilepsy (74).

For the patients with familial hemiplegic migraine developing epilepsy, a systematic review searched for four mutations of familial hemiplegic migraine (CACNA1A, ATP1A2, SCN1A, PRRT2), and drug resistant forms of epilepsy are rare in all familial hemiplegic migraine mutations, accounting for only 3.5% (31).

In children and adolescents, some chronic neurologic conditions in childhood, such as migraine and epilepsy, may be associated with difficulties in social cognition skills (54). These difficulties may be related to a deficit in executive functions.

Clinical vignette

A 35-year-old woman presented with a history of migraine with aura since the age of 12 years. Her aura consisted of visual symptoms of phosphenes followed by palinopsia. It occurred one hour before headache onset and lasted for 20 to 25 minutes. Her migraines occurred five to six times a month. She was treated with propranolol, with a reduction of migraine frequency. She had her first seizure episode at the age of 23 years. The seizure occurred just as the aura phase ended. The seizures were generalized tonic-clonic in nature and lasted up to five minutes. In the postictal period, she would get migraine attacks. She continued to get seizures with her migraine attacks 25% of the time. Interictal EEG was normal and MR imaging of her head was unremarkable. She was switched from propranolol to valproic acid. This prevented any further seizure attacks, although she would still get an occasional migraine with aura.

Biological basis

Etiology and pathogenesis

The relationship between migraine and epilepsy is incompletely understood. The unidirectional causal explanation has been put forward, ie, migraine causes epilepsy by way of causing cerebral ischemia and brain injury. It has also been postulated that epilepsy may trigger migraines by activating the trigeminovascular system. This second hypothesis appears to have been disproved by Marks and Ehrenberg, who collected 79 patients with both migraine and epilepsy and found that 66 (84%) of them had attacks that were completely independent. In the remaining patients, a seizure followed the migraine aura (migralepsy) (47).

Another hypothesis is that of shared environmental risk factors, eg, head injury as a risk factor for both epilepsy and migraine. However, this does not explain the fact that the risk of migraine is also increased in patients with idiopathic epilepsy.

A shared genetic link is another possibility and there is new evidence suggesting a genetic link between epilepsy and migraine. A linkage analysis in a large Belgian family with occipitotemporal lobe epilepsy associated with migraine with visual aura provided evidence for a novel epilepsy and migraine susceptibility locus on chromosome 9q21-q22 (17). A genome-wide linkage study in 36 Finnish families with at least two family members having scintillating scotoma revealed the same locus for visual aura (71). Intriguingly, one of the genes in this region, SCH3, is highly expressed in occipital and temporal lobes, and regulates the neuronal adaptation against environmental stress (72). Another genome-wide linkage analysis in a large Finnish family (60 family members, of whom 12 had idiopathic epileptic seizures and 33 had migraines) found chromosome 14q12-q23 and 12q24.2-q24.3 as shared loci for migraine and epilepsy (57).

The finding of shared genetic susceptibility to migraine and epilepsy is further consolidated in a study that investigated the contribution of genetic factors (78). In a sample of 730 participants with nonacquired focal or generalized seizures from 501 families containing two or more individuals with epilepsy of unknown cause, the prevalence of migraine with aura (but not migraine without aura) was increased in those who have two or more additional affected first-degree relatives (OR=2.5, n=549), as compared to those with only one affected first-degree relative (OR=1.1, n=133), or the controls (n=549).

Epilepsy and migraine can also be secondary to a common underlying disease, eg, an arteriovenous malformation of the occipital lobe (29), Sturge-Weber syndrome (40), and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) (48).

The pathogenesis of the migraine aura is believed to be due to the cortical spreading depression where depolarization of neural structures is followed by vascular hypoperfusion (62). This results in activation of the trigeminovascular system with release of inflammatory neuropeptides, eg, substance P, calcitonin gene related peptide, and neurokinin A. These neuropeptides cause a sterile inflammatory response with sensitization of sensory nerve fibers originating from the ophthalmic division of the trigeminal nerve. These sensitized nerve fibers then respond to the previously innocuous stimuli of blood vessel pulsations and venous pressure changes and generate the pain of headache (68).

The causes of epileptic disorders are believed to be multifactorial, involving both genetic and acquired factors. Genetic factors include genetically inherited neurologic disorders, eg, phenylketonuria and tuberous sclerosis, and also genetically influenced increases in neuronal excitability. Acquired factors include developmental defects, hippocampal sclerosis, neoplasms, and cerebral insults from trauma, strokes, and infections.

The association between migraine and epilepsy is also implicated by some migraine-epilepsy syndromes. Benign epilepsy of childhood with occipital paroxysms is a rare childhood seizure disorder accounting for less than 5% of seizures in children. The seizures usually begin with visual symptoms including amaurosis, elementary visual hallucinations (phosphenes), complex visual hallucinations, and visual illusions, including micropsia, metamorphopsia, or palinopsia. The visual symptoms are often followed by hemi-clonic, complex partial, or generalized tonic-clonic seizures. Following the seizure, approximately half of the patients develop migraine-like headaches (09).

Rolandic epilepsy, a more common idiopathic partial epilepsy in childhood, also has evidence of migraine comorbidity. Clarke and colleagues used cohort and reconstructed cohort designs to respectively assess the relative risk of migraine in 72 children with rolandic epilepsy and their 88 siblings (13). Incidences were compared in 150 age- and geographically matched nonepilepsy probands and their 188 siblings. Prevalence of migraine in rolandic epilepsy probands was 15% versus 7% in non-epilepsy probands, and in siblings of rolandic epilepsy probands prevalence was 14% versus 4% in nonepilepsy siblings. The sex-adjusted hazard ratio of migraine for a rolandic epilepsy proband was 2.46, and the adjusted hazard ratio of having one or more siblings with migraine in a rolandic epilepsy family was 3.35.

On the other hand, familial hemiplegic migraine, a rare, monogenic, autosomal dominant subtype of migraine with aura with unilateral motor weakness during the aura phase, may present with epileptic seizures. All three familial hemiplegic migraine genes identified thus far encode α1 subunit of CaV2.1 calcium channels (CACNA1A: FHM type 1) (55), α2 subunit of Na-K ATPases (ATP1A2: FHM type 2) (15) and Nav1.1 sodium channels (SCN1A: FHM type 3) (18). Co-occurrence of childhood epilepsy has been reported in familial hemiplegic migraine type 1 (12; 16; 79), type 2 (42), and type 3 (10). A family with electroclinical features indicative of temporal-parietal-occipital epilepsy had common occurrence of postictal migraine, occurring in up to five out of the six (83%) epilepsy patients. A missense mutation (c.1130 G> A; p.R377Q) affecting the S5-S6 segment (pore region) of the sodium channel alpha 1 subunit was identified in all affected, and in four unaffected, subjects (61). A 2017 systemic review reported the penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA2A gene (60%) and lower in those having ATP1A2 (30.9%) and SCN1A (33.3%) mutations (58). Notably, the above three culprit genes do not account for all forms of FHM. The mutation of the PRRT2 (proline-rich-transmembrane protein) gene has been found to cause hemiplegic migraine (60), and PRRT2 was regarded as the fourth autosomal dominant gene for familial hemiplegic migraine (59). PRRT2 interacts with synaptosomal-associated protein 255 kDA (SNAP25), a protein involved in the fusion of synaptic vesicles to the plasma membrane and calcium triggered exocytosis and may link infantile convulsions and paroxysmal dyskinesia with migraine (67; 14). Among these four genetic mutations, a systematic review showed that the highest number of cases associated with epilepsy belongs to the ATP1A2 mutation (57.7%), followed by PRRT2 mutation (17.9%), and SCN1A mutation (16.7%) (31).

Recessive mutations in the SLC4A4 gene were reported to cause a coexistence of epilepsy, status epilepticus, and hemiplegic migraine in four affected members of a Spanish family (24). The novel mutation c.2562+2T>G, which affected a canonical splice site and was predicted to abolish the wild-type donor site, predicting a premature truncated NBCe1 protein with cotransport activity, was identified in the homozygous state in all diseased members of the family. All patients suffered from severe proximal renal tubular acidosis and ocular abnormalities. The adults also suffered from neurologic complications, such as hemiplegic migraine or epilepsy. Two patients developed life-threatening status epilepticus, although they fully recovered and remained free of seizures after treatment with valproate.

Taken together, the bidirectional comorbidity between migraine and epilepsy may be accounted for by a shared genetic factor that up-regulates the susceptibility to both disorders. Given the functional link of familial hemiplegic migraine-related genes to ion channels or neurotransmission, the underpinning of migraine-epilepsy comorbidity may be central to excitability changes. Note the process of kindling (repetitive seizures make the cortex more susceptible to the stimulus) shows similarities with the process of painful sensitization (increased pain after stimulus repetitions). A study using transcranial magnetic stimulation confirmed a common feature of central excitability changes in migraine and epilepsy that suggested an impaired intracortical inhibition in both disorders (04). The investigators measured motor evoked potential (MEP) to paired pulse stimulations at short (2, 5, 10, and 15 ms) and long (50-400 ms) interstimulus intervals in 26 patients with migraine (with or without aura), 50 patients with focal or idiopathic generalized epilepsy, and 19 controls. The cortical excitability was computed by the ratio of the mean MEP amplitudes when the test stimulus was given with versus without a preconditioning stimulus. Compared with controls, cortical excitability was higher in migraine only at 250 ms, whereas higher in epilepsy at 2, 5, 250 and 300 ms. The excitability measures in migraine and in epilepsy did not differ except for a lower excitability in migraine at 250 ms.

However, the exact role of genetic factors underpinning this excitability change needs further investigations. A study of 155 ion transport genes on 841 unrelated Finnish patients with migraine with aura and 884 unrelated controls unfortunately reveals that common variants in these genes do not have a major role in susceptibility of migraine with aura (53). On the other hand, a genome-wide association study identified the sequence variant rs1835740 on 8q22.1 as the first genetic risk factor for migraine (03). Note that this genetic marker may be involved in glutamate homeostasis because one of its nearby genes, MTDH/AEG-1, can downregulate EAAT2/GLT1, the major glutamate transporter in the brain (50). Mice lacking the EAAT2 gene have been shown to suffer from lethal spontaneous epileptic seizures (69). One study used single nucleotide polymorphism genotyping and next-generation sequencing technologies to perform linkage, haplotype, and variant analyses in an extended Finnish migraine-epilepsy family (n = 120) and suggested that NCOR2 may have a role in both migraine and epilepsy (52).

Epidemiology

Migraine is a common condition with a lifetime prevalence of 16%. Migraine prevalence is age- and gender-dependent. Before puberty, migraine is more common in boys, with the highest incidence occurring between six and 10 years of age. In women, the incidence is highest between 14 and 19 years of age and, in general, women are more commonly affected (lifetime prevalence 12% to 17%) than men (4% to 6%). In the American Migraine Study, the one-year prevalence of migraine increased with age among women and men, reaching the maximum at ages 35 to 45 and declining thereafter (66).

The prevalence of epilepsy in the United States is generally reported to be 0.5% when only chronic epileptic conditions are considered. The incidence rate is approximately 50 per 100,000 per year.

Andermann examined the relationship between migraine and epilepsy and found the prevalence of epilepsy in patients with migraine to range between 1% and 17% with a median of 5.9%, which is substantially higher than the epilepsy prevalence rate of 0.5% in the general population. Correspondingly, the migraine prevalence in patients with epilepsy is somewhat higher than that of the general population, ranging from 8% to 15% (02). A prospective study revealed that interictal headaches were reported in 81% patients with epilepsy, and 50% met ICHD-III criteria for migraine (77). A retrospective study from Iceland showed children aged five to 15 years with epilepsy had an almost 4-fold higher chance of also having migraine, especially migraine with aura (46). Another U.S. study in 400 children with epilepsy at a single tertiary care center found the prevalence of migraine in this pediatric epilepsy population was 25%, greater than that reported for children without epilepsy (3% to 23%) (37). Moreover, migraine was more prevalent in children at age 10 or older (p=0.0009), children with benign epilepsy with centrotemporal spikes (p=0.003), and children with juvenile myoclonic epilepsy (p=0.008). A single-center study in China investigated the characteristics and prevalence of headaches in Asian patients with epilepsy (n=1109) (76). Interictal headaches were reported by 34.62% of patients, and 12.53% of patients had interictal migraine, which was a higher percentage than reported in a large population-based study from the same area (9.3%) using the same screening question.

In patients with comorbid epilepsy and headache, headache attacks are often associated with the postictal stage. In epilepsy, a meta-analysis showed that 43.1% of patients had postictal headache, and 42.2% of patients had interictal headache. The pooled prevalence of headache among patients with epilepsy was considerably higher among females (63.0%) when compared to males (33.3%) (19).

A study by Ito and colleagues looked at the association between postictal headache and seizure type (34). Of 364 patients with partial epilepsy, 40% had postictal headache, and 26% of these patients fulfilled International Headache Society criteria for migraine headache. Migraine-like postictal headache occurred significantly more often in cases of temporal lobe epilepsy and occipital lobe epilepsy than in cases of frontal lobe epilepsy.

In another study in generalized epilepsy, 104 out of 200 consecutive adult patients reported postictal headache, with 63% having headache after every seizure (06). International Headache Society criteria classified 47% as migraine, 38% as tension-type, and 15% as unclassified.

Differential diagnosis

The differential diagnosis between migraine and epilepsy can often be made by taking a precise clinical history. Migraine onset is more gradual, and attacks last longer and may be associated with nausea and vomiting. Postictal confusion or lethargy favors the epilepsy diagnosis.

The difference in migraine and epilepsy auras is described above. A study supports this difference (49). A total of 67 self-illustrations from 54 patients were obtained: 28 with epilepsy, 23 with migraine, and three with migraine-epilepsy syndrome. Positive visual manifestations of epileptic patients were predominantly centrally localized (83%), whereas those of patients with migraine were predominantly peripherally localized (77%). Negative visual symptoms in epilepsy were commonly diffuse (71%) compared with those in migraine, which were peripheral (75%). Another comparative study between 28 patients with epilepsy and 28 age-matched patients with migraine showed that visual auras of epileptic etiology were characterized by restriction to a visual hemifield (74% vs. 30% in migraine, p = 0.002) with stereotypic affection of one hemifield (56% vs. 7%, p = 0.002) (30). Moreover, centrifugal or centripetal spread of visual phenomena only occurred in migraine (37%), but not in epilepsy (p < 0.001).

Diagnostic workup

The EEG is an important diagnostic tool for the evaluation of epilepsy and its myriad subtypes. It has been less useful in the diagnosis of migraine and its subtypes, although striking EEG patterns have been seen in basilar migraine, hemiplegic migraine, and prolonged migraine auras. These changes include slowing and paroxysmal, lateralizing, epileptiform, discharge-like activity (05).

The epilepsy monitoring unit may be a useful tool for differentiating between epilepsy and migraine as well as migralepsy (28). This has been used by Marks and Ehrenberg to show the difference between the migraine and epilepsy auras (20).

Management

When deciding on therapeutic options for the treatment of migraine and epilepsy, it is best to choose a single agent that is efficacious for both. Common migraine-preventive drugs, such as tricyclic antidepressants and neuroleptics, should be avoided as they can increase the risk for seizures. Anticonvulsants such as divalproex sodium and topiramate should be considered.

Divalproex sodium is the first FDA-approved anticonvulsant for migraine prophylaxis. The efficacy of divalproex has been supported by open and double-blind, placebo-controlled studies (36; 43). The doses that are effective in migraine are generally lower than those used for epilepsy; 500 mg a day is often sufficient. Topiramate, is also FDA-approved for migraine prophylaxis. Large double-blind, placebo-controlled trials have confirmed its efficacy, with an optimal dose of 100 mg/day (07; 63). The tolerability and effectiveness of topiramate is often favorable in comparison to divalproex, so topiramate has been adopted as first line therapy in patients with comorbid migraine and epilepsy (65). Further studies are warranted to determine if topiramate is the most effective option to treat this patient population.

An observational, multicenter study included 31 adult patients with epilepsy and comorbid migraine (22). Perampanel was found to control epileptic seizures. At the 12-month follow-up visit, 27 patients were continuing perampanel concomitantly with one (45.2%) or two antiseizure medications (54.8%). A significant reduction in epileptic seizures, migraine attacks, and the monthly use of rescue migraine medications between baseline and both 6- and 12-month follow-up visits was documented.

Ketogenic diet has also been discussed for the management of migraine and epilepsy. For epilepsy, several expert consensus guidelines on patient care have been published that attempt to define the mechanisms of action of this form of therapy (39; 41; 38; 73). For migraine, case studies reviewed by Gross and colleagues indicate that patients using ketogenic diet notice a reduction in migraine frequency and severity (26).

Vagus nerve stimulation has been shown to be effective in treating seizures. A study showed that it was also effective in controlling migraine headaches in these vagus nerve stimulator-treated epileptic patients. Of four patients in the study with both migraine and epilepsy, one reported good improvement, two reported moderate improvement, and one reported mild improvement in their migraines after implantation of their stimulators (33). In a retrospective review of 10 epileptic patients with comorbid migraine, eight (80%) had a reduced monthly frequency of migraine by 50% or more after vagus nerve stimulation (44). These observations suggest that vagus nerve stimulation may have a prophylactic effect on comorbid migraine in epileptic patients.