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Borderlands of Migraine and Epilepsy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315994
Keywords: Epilepsy, headache, ictal epileptic headache, migraine, migralepsy, seizure
Migraine and epilepsy share a complex relationship that has been acknowledged for several centuries. In 1906, Sir William Gowers first described this “borderland” of migraine and epilepsy, reporting that there may be “an actual blending” and that one may lead to the other.[1] Subsequently, in 1960, Lennox and Lennox-Buchthal coined the term “migralepsy” in their textbook, Epilepsy and Related Disorders.[2] In this, they reported a case of “ophthalmic migraine” where the typical symptoms of headache accompanied by nausea and vomiting were succeeded by a seizure. It follows that the term “migralepsy” refers to seizures following typical migraine although the indistinct nature of this term has been challenged because it does not define clearly the exact interrelationship between these two conditions.[3],[4],[5] Certainly, migraine and epilepsy share some similarities – both are paroxysmal neurological disorders that can be distinctly disabling and may, not uncommonly, occur in the same patient, thereby producing a “borderland.”[6] The International Classification of Headache Disorders, 3rd edition (ICHD-3), highlights the relationship between migraine and epilepsy in two subchapters: 1.4.4 Migraine aura–triggered seizures and 7.6 Headache attributed to epileptic seizure.[7] The latter is further categorized into 7.6.1 Ictal epileptic headache and 7.6.2 post-ictal headache. Subchapter 1.4.4 describes the occurrence of seizures in association with or succeeding an episode of migraine with aura. Subchapter 7.6 is followed by a brief comment on “preictal headache.” In this review, we examine the special interaction between these two neurological disorders and the implications of the same.
Assessment of the coprevalent association between migraine and epilepsy is pivotal to an understanding of their relationship. Contradictory reports have emerged from various studies. Whereas some studies have observed an increased prevalence of migraine among persons with epilepsy up to 160%,[8],[9],[10],[11],[12],[13] others have not observed this association.[14],[15],[16] According to the Centers for Disease Control and Prevention (CDC), the presence of active epilepsy increases the prevalence of migraine or severe headache from 16.2% (among patients without epilepsy) to 35.5%.[17] A systematic review and meta-analysis of population-based studies examined the lifetime relative prevalence of migraine among persons with epilepsy and vice versa.[18] The meta-analysis included 10 studies. It was observed that in comparison with people without epilepsy, patients with epilepsy harbored 52% increased migraine prevalence, with a prevalence ratio of 1.52 (95% confidence interval [CI, 1.29, 1.79]). Among persons with migraine, compared with nonmigraineurs, the prevalence of epilepsy was noted to be increased by 79% with the prevalence ratio being 1.79 (95% CI [1.43, 2.25]). Most of the heterogeneity between studies was attributable to the methodology used to ascertain the presence of migraine and epilepsy among the studies included. For the diagnosis of migraine, the tools used included unvalidated questionnaires (administered by parents to a child migraineur in some studies), semistructured interviews, structured interviews, validated questionnaires, telephone-based questionnaires, as well as International Classification of Diseases (ICD) and the International Classification of Primary Care (ICPC) codes. Similarly, for epilepsy, the tools used for epilepsy diagnosis included unvalidated and validated single-item questionnaires, telephonic single-item questionnaires, and ICD and ICPC codes. Studies that used ICD/ICPC codes and administrative information demonstrated lower prevalence estimates. The lifetime prevalence of migraine among epilepsy patients varied from 1.7% to 33.6% and among migraine patients, the lifetime prevalence of epilepsy was 0.7% to 2.3%. Several studies lacked clear definitions of epilepsy and migraine in this meta-analysis. From India, a study from Kolkata reported the occurrence of seizures among 1,000 migraineurs (800 adults and 200 children) and their first-degree relatives.[19] One or more seizures were reported to occur in only nine of these patients. However, this was a single-center clinic-based study. Further population-based studies are required to assess the incidence and coprevalence of epilepsy and migraine among Indian patients.
A few studies have assessed the risk factors for coprevalence among different patient cohorts. In a telephonic interview–based study among patients with epilepsy, their parents, and their siblings, the rate ratio for migraine was increased in both epilepsy patients and their relatives.[20] The highest risk was found to occur among female patients and among patients with epilepsy due to head trauma. In a study among 50 children, most children with comorbid migraine and epilepsy were above 10 years of age and had idiopathic epilepsy.[21] Baldin et al., in a study from Iceland, found that children who had migraine with aura demonstrated 3.7 times increased risk of developing epilepsy, and this increase was across different types of seizures and across both genders.[10] However, the increased risk did not extend to children with migraine without aura. An increased prevalence of migraine has been reported among children with Rolandic epilepsy than among children with partial epilepsy or without epilepsy.[22] Migraine frequency has also been reported to be higher among patients with juvenile myoclonic epilepsy.[23],[24]
1.4.4 Migraine aura–triggered seizure This is defined as a seizure triggered by an episode of migraine with aura. As per the ICHD-3 diagnostic criteria, the patient must have a seizure that fulfills the diagnostic criteria for one type of epileptic attack and must occur during or within 1 hour after an attack of migraine with aura. The condition, additionally, should not be better accounted for by another ICHD-3 diagnosis. True migraine followed by epilepsy termed “migralepsy” is mentioned as a comment in the ICHD-3 in this subsection. True migralepsy is considerably rare.[4] Epilepsy originating from the occipital lobe may be fallaciously considered as migraine aura–triggered seizures because it may occasionally manifest with only visual events and headaches.[25] 7.6 Headache attributed to epileptic seizure In this condition, the headache is caused by a seizure, and it may occur during and/or after the seizure. The headache may remit within hours but may last up to 3 days. As per the ICHD-3 diagnostic criteria, a headache that occurs in a patient who is having or has had a seizure recently and the causation of the headache by the seizure must be demonstrated by both the following features: headache develops along with or soon after seizure onset and headache remits once the seizure ceases. The headache should not be better accounted for by another ICHD-3 condition. Based on the temporal association between the headache and the seizure, this entity is further subdivided as ictal epileptic headache and post-ictal headache. 7.6.1 Ictal epileptic headache This headache is caused by a focal seizure, occurs ipsilateral to the epileptiform discharges, begins during the seizures, and remits with seizure cessation or soon after. The term “ictal epileptic headache” has been included recently in ICHD-3. Diagnosis is based on the presence of headache in a patient with a partial seizure. The causative association needs to fulfill specific features: For example, the headache must begin concomitantly with the seizure. Additionally, at least one of the following two characteristics must be present: headache occurs on the same side as the epileptiform discharges and/or headache shows improvement or resolution with or soon after cessation of the seizure. As emphasized by Parisi et al., underrecognition of this condition may lead to errors in appropriate treatment.[26],[27],[28] Nonconvulsive status epilepticus in a patient with occipital epilepsy manifesting with migraine alone has also been reported in one patient; this was termed status epilepticus migrainosus.[29] An extremely rare variant of ictal epileptic headache is hemicrania epileptica, which requires an ipsilateral relationship between headache and the epileptogenic focus.[7] 7.6.2 post-ictal headache Post-ictal headaches occur within 3 hours of a seizure and remit within 72 hours of the seizure. The diagnosis, as per ICHD-3, requires the occurrence of a headache in a patient with recent partial or generalized epilepsy that must also satisfy two criteria for causation: The headache should develop within 3 hours of termination of the seizure, and it should resolve within 72 hours of the termination of the seizure. Post-ictal headache may manifest in the form of tension-type headache or migraine. The frequency of post-ictal headache ranges from 12% to 52%.[30] Risk factors identified for the development of post-ictal headache include young adults, long duration of epilepsy, severe epilepsy, the occurrence of generalized tonic–clonic seizures, and interictal headaches in a patient with epilepsy.[30] Other risk factors include frequency of seizures and antiseizure medication (ASM) polytherapy.[31] The diagnostic criteria of the aforementioned conditions as per ICHD-3 are summarized in [Table 1].
Preictal headache There are limited data on preictal headache, which receives a brief mention in the ICHD-3 wherein the need for more studies “to establish the existence of preictal headache” is described.[7] This describes headache that precedes a seizure. In a small study among 11 patients with refractory epilepsy, the preictal headache was established through a standardized questionnaire.[32] The headache was observed to be ipsilateral to the epileptogenic focus in nine patients with temporal lobe epilepsy, contralateral in one patient with temporal lobe epilepsy, and contralateral in one with frontal lobe epilepsy. Among these, the headache was migrainous among four patients. Following epilepsy surgery, all patients who achieved seizure freedom also experienced resolution of headache, and two patients had infrequent seizures postsurgery. The occurrence of an interval between the headache and the seizure favors true preictal headache. However, if there is no interval, Cianchetti et al. have suggested that to differentiate this from an ictal headache, epileptiform abnormalities on the electroencephalogram (EEG) should be sought.[3] The presence of EEG discharges favors ictal headache, although the absence of the same may not rule out an ictal headache. Preictal migraine with aura may precede a seizure. The differential includes occipital epilepsy in which visual symptoms may occasionally occur in concomitance with migraine. The occurrence of a time interval would aid in the differentiation between the two as mentioned above. Additionally, characteristics of the visual aura may also help discern between the two conditions.[33] In occipital epilepsy, the visual hallucinations are elementary, colored circles develop rapidly and occur over short durations of time, that is, 2 to 3 minutes, and progress in size and number, moving from the temporal visual field to the opposite side. In migraine, the visual aura is composed of flashing zigzag lines that occur in the central visual field and have a gradual onset and longer duration up to 1 hour. However, an EEG may definitively demonstrate the epileptic nature of the visual aura. Preictal migraine without aura preceding seizures has also been reported. [Table 2] summarizes some similarities, differences, and borderlands between migraine and epilepsy.
Although migraine is known to be one of the comorbidities among epilepsy patients, certain neurological conditions may demonstrate both epilepsy and migraine as prominent clinical features [Table 3].
The foremost among these are mitochondrial disorders. Among the spectrum of mitochondrial disorders, epilepsy and migraine may be prominent in mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms (MELAS), and POLG1 mutations. Both of these conditions demonstrate occipital predilection: In MELAS, strokes tend to affect the posterior circulation, and in POLG1 mutations, epilepsy emanating from the occipital lobes is frequent. This occipital preference in both these mitochondrial disorders points toward shared underlying pathogenetic mechanisms with migraine. Defective neuronal mitochondrial phosphorylation may provoke cortical spreading depression (CSD) leading to migraine.[34] Certain channelopathies may also exhibit epilepsy as well as migraine among their gamut of clinical features. Mutations in channels CACNA1A, SCN1A, and ATP1A2 that lead to familial hemiplegic migraine (FHM) are also known to be associated with epilepsy. Abnormal function in these channels may provoke neuronal hyperexcitability and CSD.[35] In CACNA1-related conditions (CACNA1 codes for a voltage-gated calcium channel subunit), absence of epilepsy may occur along with FHM type 1, apart from episodic ataxia type 2 and spinocerebellar ataxia type 6. Mutations in ATP1A2 may lead to FHM type as well as benign familial infantile convulsions. Mutations in SCN1A are associated with several epilepsy syndromes, including Dravet syndrome, generalized epilepsy with febrile seizures plus (GEFS+), and FHM type 2. In Sturge– Weber syndrome More Details (SWS), which is a rare phakomatosis, abnormal and asymmetric cerebral microvasculature development occurs, in association with port-wine stain. It is a multisystemic disorder in which up to 90% of patients may experience drug-refractory epilepsy and up to 60% may experience migrainous headaches. The association of hemiplegic migraine and SWS have also been reported.[36],[37],[38] Post-ictal headaches have also been reported, with the possible explanation being that neuronal hypersynchrony during the seizure activates CSD. Mutations in the proline-rich transmembrane protein (PRRT2) gene lead to paroxysmal kinesigenic dyskinesia (PKD), which is a paroxysmal disorder triggered predominantly by movements. It may be associated with migraine, epilepsy, hemiplegic migraine, and a range of episodic neurological conditions.[39]
Although the pathogenetic shared underpinnings of migraine and epilepsy are not entirely understood, the following potential mechanisms have been described. Neocortical hyperexcitability Neocortical hyperexcitability, in association with genetic and molecular links, is a largely accepted hypothesis underlying both conditions.[40],[41] Neocortical hyperexcitability leads to a paroxysmal depolarizing shift in epilepsy. In patients with migraine, it is believed that neocortical hyperexcitability progressed into CSD. This spreading depolarization through the cortex also provokes fluctuations in neurotransmitter and calcium levels. This is succeeded by cortical suppression. These changes induced by CSD are believed to activate the trigeminal–vascular nociceptive system triggering pain. CSD, believed to be a shared event between migraine and epilepsy, also has a particular predilection for the occipital cortex. Other features supporting the role of CSD as a shared pathogenetic pathway include observations that post-ictal headaches are more frequent in persons with occipital epilepsy and response of migraine to ASM prophylaxis. Channelopathies and shared genes As discussed above, in FHM, mutations may occur in calcium channel 1A (CACN1A), ATP1A2, and sodium channel 1A (SCN1A). These channels are also associated with certain epilepsy syndromes, such as childhood absence epilepsy, Dravet syndrome (SCN1A), and generalized epilepsy with febrile seizures plus (GEFS+) [Table 3]. Mitochondrial dysfunction Mutations in the POLG gene, which encodes for a subdomain of mitochondrial DNA polymerase, and C10orF2, which encoded for mitochondrial DNA helicase Twinkle have also been reported to play a role in the pathogenesis of both conditions. Putatively, mitochondrial phosphorylation dysfunction triggers neocortical hyperexcitability, provoking CSD.[42],[43] “Migralepsy”: To be or not to be The term “migralepsy,” coined by Douglas Davidson but mainly attributed to and as originally used by Lennox and Lennox-Buchthal, was based on the clinical sequence of migraine followed by an epileptic seizure.[2] After their description of three cases, the term was largely forgotten until it was revived in 1993 by Marks and Ehrenberg.[44] Despite the dubiousness surrounding the term, it was included in the ICHD-II. As per the diagnostic criteria stated in the 2004 ICHD-II, migralepsy could be diagnosed if the patient had migraine fulfilling the criteria for a migraine with aura and a seizure fulfilling the criteria for one type of epileptic attack that should occur during or within 1 hour after the migraine aura.[45] However, the fallacies of this description were underscored in a study by Sances et al. who found that among the 50 cases of migralepsy reported in the literature up to that point in time, only two satisfied the definition as per ICHD-II.[4] Moreover, they reported a high prevalence of solely epileptic disorders among the so-called migralepsy reports. In a multicentric retrospective study published by Verrotti et al. in 2011, all cases of migralepsy reported in the literature were revisited and 16 probable cases were identified. None of the remaining cases could satisfy the ICHD-II diagnostic criteria.[5] Many authors called for a revision of the then definition of migralepsy.[5],[46] There was wide consensus that many visual seizures and ictal headaches were mistaken for migraine and that the epilepsy–migraine sequence was more common than the migraine–epilepsy sequence (referred to as “migralepsy”). Many discouraged the use of the term “migralepsy” to describe the sequence of visual aura followed by seizure because the former may be either epileptic or migrainous in origin.[47],[48] To confound matters further, there have been reports of both epileptic and migrainous visual aura occurring in the same patient.[49] A plethora of case reports of the so-called migralepsy preceded the diagnostic criteria put forth by ICHD-II.[50] Subsequently, the term was encompassed within Subchapter 1.4.4 in ICHD-3. However, this term does not find a place in the classification of seizures put forth by the International League Against Epilepsy.[51],[52] Therapeutic implications Migraine prophylaxis armamentarium in adults includes several ASMs. Most robust evidence among adults is available for valproate and topiramate. Among patients who have epilepsy in conjunction with migraine, antiepileptic therapy would be naturally preferred for antimigraine prophylaxis as well. Topiramate may be preferred for glutamate antagonism, which may inhibit neuronal hyperexcitability responsible for both the seizure and cortical spreading depression of migraine.[6] Lamotrigine has been described to be effective in managing migraine in patients with SWS, including hemiplegic migraine. The efficacy of lamotrigine in this condition is attributed to sodium channel blockade, leading to suppression of glutamate release, thereby negating the development of CSD.[38],[53]
Migraine and epilepsy share several clinical manifestations and have linked genetic and molecular underpinnings that may contribute to common pathogenesis. Therapeutically, ASMs may be effective when both are clinically expressed in a patient. Diagnostic guidelines for some of the conditions have been provided within the ICHD-3. Diagnosis may need EEG in certain selected cases where the suspicion of epilepsy masquerading as or in combination with migraine is high. Further and extensive research is necessary on pathophysiological mechanisms as well as optimum effective therapeutic strategies among patients harboring both migraine and epilepsy. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]
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