In 1906, the British neurologist Sir William Gowers, in one of his clinical lectures, highlighted the resemblance between migraine and epilepsy.1 Migraine and epilepsy are considered distinct episodic disorders with some overlapping clinical and physiological features,2 and a comorbid relationship between the two conditions has been confirmed through numerous studies. 1 Several pharmacological therapies are efficacious in the prevention of attacks in both conditions, pointing to overlap in their pathophysiological process.3
The Epilepsy Family Study found that the cumulative risk of migraine was 24% among adults with epilepsy (n=1,948), 23% in relatives with epilepsy (n=88), and 12% in relatives without epilepsy (n=1,316).4 In the same study, incidence of migraine among people with epilepsy was increased vs people without epilepsy to a greater extent after onset of epilepsy than before onset.4However, the incidence was also significantly increased in people with epilepsy vs people without epilepsy more than 5 years before onset and 1–5 years before onset.4 This pattern is inconsistent with a unidirectional causation model (i.e. epileptic attacks cause migraine) and, in his presentation at EHF 2018 entitled ‘The comorbid relationship between migraine and epilepsy’, Richard Lipton suggested that common environmental and genetic risk factors predispose to hyperexcitability, which may lead to migraine and epilepsy.
Is there a genetic link between migraine and epilepsy?
In her presentation, GiselaTerwindt(Leiden, The Netherlands) covered data showing genetic links between epilepsy and familial hemiplegic migraine (FHM, migraine with aura including motor weakness and where there is ≥1 first- or second-degree relative with the same condition).5 Mutations in the ion transportation genes CACNA1A, ATP1A2, and SCN1A can all cause hemiplegic migraine, and the familial forms caused by these mutations are referred to as FHM1, FHM2, and FHM3, respectively.6 As summarised in a recent review, 33.3% of CACNA1A mutations are associated with comorbid hemiplegic migraine and epilepsy and this value is 40.9% for ATP1A2, and 44.4% for SCN1A.7 Mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins have been identified among the cases with comorbid hemiplegic migraine and epilepsy.7 Furthermore, transgenic FHM1 and FHM2 mouse models show enhanced glutamatergic transmission and susceptibility to cortical spreading depression (CSD), thought to be the cause of migraine aura.8
Despite the links suggested by the implication of the same genes in FHM and epilepsy, a large scale genome-wide association (GWA) study failed to find significant associations between migraine more generally and epilepsy.9 The Brainstorm Consortium used GWA data from 265,218 patients and 784,643 control participants, in addition to 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. Although psychiatric disorders (e.g. attention-deficit hyperactivity disorder [ADHD], bipolar disorder, major depressive disorder [MDD] and schizophrenia) shared a considerable portion of their common variant genetic risk, the neurological disorders were more distinct from each other.9 There was no significant genetic correlation between migraine and epilepsy after multiple testing correction.9 Perhaps surprisingly, migraine appeared to share some of its genetic architecture with psychiatric conditions, particularly ADHD, MDD and Tourette syndrome.9
Is post-ictal headache in epilepsy similar to migraine?
Agustin Melo Carrillo (Harvard University, USA) presented data at EHF 2018 pointing to some fundamental differences between post-ictal headache in epilepsy and migraine.10,11 In mice, seizure induced the activation of C- and Aδ meningeal nociceptors as well as central trigeminovascular neurones, but not spinal trigeminal nucleus neurones that are not dura-sensitive.11 This activation was inhibited by lignocaine application to the dura. These results suggest that post-ictal headache is caused by the seizure activating trigeminovascular neurones, and the controversial phenomenon of CSD is not necessary to explain post-ictal headache in epilepsy.10
Impact of comorbidity on cognitive performance
A study conducted by Olivia Begasse de Dhaem (Columbia University, USA) and colleagues shed some light on the putative impact of the co-existence of migraine and epilepsy on cognition.12 Patients with newly diagnosed focal epilepsy enrolled in the Human Epilepsy Project will be tested using Wide Range Achievement Test 4 (WRAT4) and elements of the Cogstate test battery.12 Patients with comorbid epilepsy and migraine reported greater memory and language impairment than those with epilepsy only, but this was not observed on the cognitive tests. Depression was more common among the patients with migraine compared with those without migraine and may have been a confounder in this study.12 In patients with epilepsy who complain of memory or language problems, it is important to adequately address the comorbidities of migraine and/or depression.
Migraine and epilepsy frequently overlap, and there may be commonalities in the pathophysiological processes at the heart of both conditions. The risk of migraine is more than twice as high in people with epilepsy than in people without epilepsy.4 As more becomes uncovered about their similarities and differences, the more we learn about the pathophysiological mechanisms driving both conditions.