41
CHAPTER
Epilepsy and Headaches
Timothy A. Collins
Epilepsy and migraine have been discussed as having possible links since the late 1800s. In 1906, Gowers gave a series of lectures titled “On the Borderland of Epilepsy,” with the third lecture devoted to migraine. He expressed the belief that there was some association between migraine, with some patients having migraines earlier in life, transitioning to epileptic fits later in life. He was one of the earliest neurologists to note that aura was a cortically based process, and could be differentiated from “Jacksonian Epilepsy” by the clinical symptoms (1). Since then, various studies and expert opinion have found an association between migraine and epilepsy or have noted a lack of association, depending on the clinical trial.
EPIDEMIOLOGY
Migraine headache is a common disorder. Lifetime prevalence in women is 12%, and as many as 25% of women have migraine during the reproductive years. In men, the prevalence remains about 6% in all age groups (2). Migraine with aura is seen in a subset of patients with migraine, ranging from 10% to 30% (3).
ASSOCIATION OF EPILEPSY AND MIGRAINE
In the last 20 years, a number of surveys have attempted to evaluate the association between seizures and migraine. In 1994, a large study using structured phone interviews (3,000 people with epilepsy and their family members) found the incidence of migraine was twice as high in the index family member with epilepsy compared to family members without epilepsy (4). In 1996, a second study by the same authors of adults with epilepsy did not find an association between epilepsy and migraine (5). Migraine has been found to have a higher prevalence in children with epilepsy, with the increased prevalence occurring after the onset of seizures. Other studies have suggested a shared genetic risk for migraine and epilepsy.
Migraine onset appears to occur after onset of seizure in children. Overall patients with idiopathic epilepsy appear to have about twice the risk for migraine compared to the general population. Conversely, the prevalence of seizures appears to be higher in people with migraine at about 5.9% (range 1%–17%) compared to non-migraine patients. The prevalence of epilepsy in the general population is about 0.5% to 1% (6). Other authors note that the reported prevalence of migraine in patients overlaps the ranges reported in the general population when evaluated by age and gender.
TERMINOLOGY
The IHS classification of headache disorders (ICHD-II) recognizes two seizure related headache disorders: hemicrania epileptica, and post ictal headache. Hemicrania epileptica is defined as a headache lasting seconds to minutes, with features of migraine, occurring during a partial epileptic seizure. The headache develops synchronously with the seizure, and is ipsilateral to the ictal discharge, and the headache resolves immediately with the seizure. Postictal headache is defined as a headache with features of tension or migraine, developing within 3 hours following the seizure, and resolves within 72 hours. Migralepsy is an older term for a seizure evolving from a typical migraine aura.
The International League Against Epilepsy describes ictal headache as a manifestation of an autonomic seizure. The term “ictal epileptic headache” (IEH) has been used with increasing frequency. IEH is a headache as the only manifestation of an epileptic seizures (7). There are a number of single case reports with onset of headache co-incident with the onset of seizure activity by EEG monitoring. The reported cases typical also have other subtle symptoms including tachycardia and swallowing movements. In a series of 11 patients with headache as the sole manifestation of non-convulsive status, headaches lasted for a prolonged period of time, did not resolve when the seizure activity resolved, and would not meet the ICHD-II criteria for “hemicrania epileptica” (8).
PATHOPHYSIOLOGY
The pain of migraine headache is a disorder of altered function in the trigeminal sensory nucleus, and the associated cranial vascular structures (often referred to as the trigeminal–vascular system). Output from the trigeminal nucleus results in release of proinflammatory peptides in the perivascular space in the scalp and meninges including substance P, bradykinin, and calcitonin gene-related peptide (CGRP). This results in plasma protein extravasation from the vessels, a sterile inflammatory response, and sensitization of the surrounding nociceptors. Sensory stimuli result in increased pain perception, followed by central sensitization. The aura of migraine has been linked to spreading cortical depression. In migraine, there is a wave of cortical discharge and increased metabolic activity. This is associated with a slowly propagating wave of sustained strong neuronal depolarization that generates transient intense spike activity. The neuronal suppression following this wave is associated with decreased cerebral blood flow, based on decreased metabolic demand.
From a functional viewpoint, increased glutamate release (as seen in mutations associated with familial hemiplegic migraine) facilitates cortical spreading depression, likely due to disruption of the excitatory/inhibitory balance. Increased excitatory amino acids (or decreased reuptake) have been associated with seizures as well (9). Cortical spreading depression moves much slower than propagating seizure activity, suggesting that it spreads through unmyelinated fibers or even cell to cell.
GENETICS
A number of genes have been associated with familial migraine syndromes, primarily hemiplegic migraine and mitochondrial disorders. Several of the genes associated with familial epilepsy have been found to locate in the same gene as migraine disorders.
CACNA1A Gene
The CACNA1A gene codes for a P/Q type voltage-gated calcium channel. Mutations with gain of function are associated with familial hemiplegic migraine type 1 (FHM1). Patients with hemiplegic migraine have prolonged episodes of migraine headache associated with hemiplegia. Families with FHM1 also have episodic ataxia, and some families have episodic confusion or seizures (9). Episodic ataxia type 2 (EA2) is associated with a mutation in the same sequence as FHM1, and about 50% of patients with episodic ataxia have migraine headaches. Epilepsy is more common in EA2 than in the general population, with an approximate sevenfold increase risk of seizure. Compared to FHM1, the mutation in EA2+epilepsy appears to be a loss of function mutation (10). Other mutations in the CACNA1A sequence have been associated with developmental delay, seizures, and hemiplegic migraine. In at least one case, seizures preceded the development of hemiplegic migraine (11).
ATP1A2 Gene
The ATP1A2 gene codes for a subunit of the sodium–potassium ATPase. A loss of function mutation causes familial hemiplegic migraine type 2 (FHM2). In a survey of 30 patients with “sporadic” hemiplegic migraine, 11 patients had de novo mutations in the ATP1A2 gene. Five of these patients had seizures (11). FHM2 associated with ATP1A2 mutations have also been associated with familial epilepsy (12).
SCN1A Gene
The SCN1A gene codes for a voltage-gated potassium channel and is associated with FHM. It has been associated with an increased risk for epilepsy (12) and has been associated with myoclonic epilepsy (13).
SLC1A3 Gene
The SLC1A3 gene codes for an excitatory amino acid reuptake transporter and results in lower rates of glutamate reuptake. Mutations in the SLC1A3 gene are associated with episodic ataxia type 6 (EA6). This is associated with episodic ataxia, alternating hemiplegia, and migraine headaches (14).
Mitochondrial Mutations (15)
Maternally Inherited Diabetes and Deafness
Maternally inherited diabetes and deafness (MIDD) is due most often to a mutation in tRNA(Leu) or tRNA(Lys) mitochondrial genes. Patients with this condition may also have seizures and migraine headaches.
Neurogenic Weakness, Ataxia, and Retinitis Pigmentosa
Neurogenic weakness, ataxia and retinitis pigmentosa (NARP) is due to a heteroplasmic transversion m9993T-C in the ATP6 gene. This is a multisystem disease with ophthalmoplegia, retinitis pigmentosa, ataxia, seizures, and migraine. Electromyography may show evidence of neuropathy and myopathic features but no ragged red fibers (RRF) on biopsy.
Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes
In mitochondrial encephalopathy, lactic acidosis and stroke like episodes (MELAS) initial symptoms are often migraines, vomiting, and seizures. Muscle biopsy shows RRF and increased number of mitochondria. Eighty percent of patients have m3245A > G mutation in the tRNA(Leu) gene.
Progressive External Ophthalmoplegia
Progressive external ophthalmoplegia (PEO) can be sporadic, autosomal recessive (AR) or dominant (AD). Sporadic PEO is associated with a large mtDNA deletion that is often found only in muscle tissue. AR and AD forms of PEO are associated with four mutations. POLG1 (catalytic subunit of mtDNA specific polymerase gamma), PEO1 (encodes mtDNA helicase “twinkle”), SLC25A4 (muscle heart specific mitochondrial adenine nucleotide translocator 1 [ANT1]), and ECGF1 encoding thymidine polphorylase. POLG1 mutations are the most common causes of familial PEO. Clinically, patients with PEO have ophthalmoplegia, and may have neuropathy (axonal) migraine headaches, seizures, and movement disorders including ataxia and parkinsonism.
TREATMENT
Episodic migraine is expected to occur in patients with seizure disorders, based on gender specific incidence of migraine discussed earlier. It can be treated with similar medications used for patients without a seizure disorder.
Acute Migraine Therapy
The triptans (see Table 41.1) have been standard therapy for acute migraine for 20 years, and are not associated with an appreciable risk for triggering seizures. Nonsteroidal anti-inflamatory drugs (NSAIDs) are effective for acute migraine therapy, with a preference for NSAIDs with longer duration of action (naproxen preferred over ibuprofen, for example). Older medications containing ergotamines remain effective, but cannot be combined with triptans due the increased risk of vasospasm. Butalbital-containing products should be avoided in patients with seizure disorder. Butalbital as a barbiturate may result in drug interactions with older anticonvulsants, and abrupt withdrawal of butalbital can trigger seizures or delirium.
