Epilepsy and migraine: a diagnostic and therapeutic challenge

Abstract

Migraine and epilepsy are two common, chronic, disabling, paroxysmal neurological disorders. A growing body of evidence from epidemiological, genetic, neurophysiological, and clinical research suggests a complex, bidirectional association between them. Migraine prevalence in epilepsy patients ranges from 8% to 23%, while the reverse is noted at 1%-17%. Both disorders are underpinned by cortical hyperexcitability, dysfunctional neurotransmission, and impaired ion homeostasis. Shared genetic mutations, particularly in genes encoding ion channel subunits such as CACNA1A, SCN1A, and ATP1A2, further support a common channelopathy model. Cortical spreading depression, the electrophysiological substrate of migraine aura, and paroxysmal depolarization shift, a hallmark of epileptic activity, share converging features, including neuronal depolarization, potassium accumulation, glutamate release, and eventual firing suppression. Glial dysfunction, glutamatergic excitotoxicity, and mitochondrial deficits are additional unifying elements. Clinically, the differential diagnosis between migraine with aura and focal seizures remains challenging due to overlapping sensory, visual, and autonomic symptoms. Rare phenomena including ictal epileptic headache, postictal headache, and migraine-triggered seizures further complicate the clinical spectrum. Additionally, certain epilepsy syndromes, such as childhood epilepsy, are strongly associated with migraine. Early recognition of comorbidity is crucial for appropriate management, as tailored treatment strategies may improve outcome. Several antiseizure medications, including topiramate, valproate, lamotrigine, and perampanel, also demonstrate efficacy in migraine prophylaxis. Moreover, non-pharmacological approaches such as ketogenic diet, vagus nerve stimulation, and transcranial magnetic stimulation provide further evidence of a shared neurobiological substrate. This review explores the epidemiological, pathophysiological, and clinical intersections between migraine and epilepsy, a frequent and clinically relevant dilemma. Accurate differentiation is urgently needed to avoid therapeutic delays or inappropriate interventions, given their phenotypic mimicry. In addition, it highlights therapeutic implications driven by overlapping molecular mechanisms. Ongoing research is needed to further elucidate this relationship.

Keywords: antiseizure medications; aura; headache; hemiplegic migraine; migralepsy; seizure.

FIGURE 1

Overview of the main purpose and key concepts of the review. The figure summarizes the complex relationship between epilepsy and migraine. It illustrates the key topics discussed, including epidemiological, pathophysiological, clinical, and therapeutic aspects. It also highlights the clinical impact and the remaining knowledge gaps that require further research.

FIGURE 2

Insight into the shared pathophysiological mechanism of epilepsy and migraine. (A) Cortical spreading depolarization (CSD) is the main neurophysiological mechanism underlying migraine. It consists of a slowly propagating wave across the cortical network, likely triggered by cortical hyperexcitability. CSD is associated with elevated concentrations of potassium ([K⁺]. Astrocytes play a key role in maintaining extracellular K⁺ and glutamate (GLU) homeostasis via Na⁺/K⁺-ATPase activity. Mutations impairing astrocytic K⁺ uptake, disrupting ionic buffering, and leading to defective K+ clearance, enhances excitatory neurotransmission. This results in excessive glutamate release from presynaptic terminals and overactivation of postsynaptic NMDA and AMPA receptors. (B) In epilepsy, increased GLU levels and reduced GABAergic inhibition led to neuronal hyperexcitability, sustained by paroxysmal depolarization shifts (PDS), which culminate in epileptic seizures. In migraine, elevated GLU relative to GABA promotes CSD, which activates the trigeminovascular system and triggers the release of calcitonin gene-related peptide (CGRP), resulting in headache. CDS underlies the clinical manifestation of migraine aura (most commonly visual). Genetic mutations affecting ion channels (i.e., CACNA1A, SCN1A, TRESK) contribute to excitatory/inhibitory imbalance. Postictal headache may occur after seizures, likely due to seizure-induced vascular or inflammatory changes. Excessive glutamatergic transmission represents a pathophysiological mechanism linking these two neurological disorders (Created with BioRender.com).