A wide variety of evidence, including the observation that mutations in the same genes can cause migraine or epilepsy and sometimes both, suggests that the two disorders are closely related and may share common molecular therapeutic targets.
OJAI, CA—Similarities between migraine and epilepsy suggest that the two disorders share a common pathogenesis and that certain therapeutic approaches may be effective in both conditions, according to Michael A. Rogawski, MD, PhD.
Dr. Rogawski, Chair of the Department of Neurology at the University of California, Davis, presented his findings at the Fourth Annual Meeting of the Headache Cooperative of the Pacific. “Migraine and epilepsy really aren’t so different,” he said. “Our communities ought to be spending a lot more time talking to one another, because we’re basically dealing with a very similar kind of phenomenology and underlying pathophysiology.”
A Rare Condition
Dr. Rogawski noted that migralepsy, according to the International Headache Society classification, occurs when an epileptic seizure is experienced during or within one hour after an attack of migraine with aura. “True migralepsy is probably extremely rare,” he said. “Many of the cases in the literature likely represent occipital seizures imitating migraine aura.”
He pointed out that it is often difficult to make a distinction between occipital epilepsy and migraine with visual aura, and he raised the question of whether it is really possible to make a sharp distinction between the two conditions.
“It is difficult to make the distinction between occipital epilepsy and migraine,” Dr. Rogawski stated. “And that leads to the question, ‘How different really are migraine and epilepsy?’”
Shared Pathophysiologic Mechanisms
“There is fundamentally a shared pathophysiology of both conditions,” said Dr. Rogawski. Epilepsy and migraine are episodic disorders—a migraine attack or epileptic seizure interrupts a patient’s life, but then it is resolved and the patient returns to normalcy.
“There may be antecedent symptoms in both situations,” he continued. “We use the same term—aura—to describe what happens before a migraine attack and what happens before an epileptic seizure.”
Epidemiologic studies have found that epilepsy and migraine are comorbid conditions. The prevalence of migraine in patients with epilepsy is estimated at 8% to 24%, so the risk of migraine is twice that of the normal population.
The prevalence of epilepsy in persons with migraine is estimated at 6%, compared with 0.5% to 1%, in the general population, according to Dr. Rogawski.
Common triggers for epilepsy and migraine include stress, photic stimulation, hormonal changes, and alcohol. “Migraine rarely triggers seizures, but seizures can certainly trigger headache that, in some cases, may have migraine-like features,” he added.
Cortical Hyperresponsiveness and Neuronal Hyperexcitability
Dr. Rogawski proposed that, in addition to sharing common triggers and characteristics, epilepsy and migraine are both associated with cortical hyperresponsiveness and that hyperexcitability underlies both conditions. “Fundamentally, there is a neuronal hyperexcitability phenomenon that occurs in both situations,” he said, which, in the case of migraine, transitions into cortical spreading depression, a state of markedly reduced excitability, and activation of cranial pain mechanisms.
“In epilepsy, localized hyperexcitability representing hypersynchronous neuronal firing underlies seizure aura,” Dr. Rogawski stated. “When this hypersynchronous activity spreads to encompass larger areas of the cortex, a full-blown seizure occurs.
“In the case of migraine, that hyperexcitability leads to the spreading depression phenomenon, which moves at a slower rate than often occurs in epilepsy,” he continued. A wave of depolarization and electrical silence associated with ionic shifts spreads along the cortex.
“Perhaps the strongest evidence for a commonality between migraine and epilepsy comes from familial hemiplegic migraine, an autosomal dominant syndrome characterized by severe migraine that arises as a result of mutations in genes for membrane ion transport proteins,” Dr. Rogawski stated.
“Mutations in the same genes that cause hemiplegic migraine can cause generalized, and in some cases, focal epilepsy,” he explained. “Some mutations result in hemiplegic migraine and epilepsy in the same family members. In a few cases, individuals with hemiplegic migraine have had seizures during migraine attacks, so these people truly have migralepsy.”
New Molecular Targets for Migraine Therapy
“Even though electrical silence is the hallmark of cortical spreading depression, the preliminary trigger is hyperexcitability, and that, presumably, is due to excessive release of the neurotransmitter glutamate,” Dr. Rogawski commented. “We know that glutamate is the key excitatory neurotransmitter in the brain. Ergo, glutamate receptor antagonists may be useful in migraine prophylaxis and therapy.”
One type of ionotropic glutamate receptor—the NMDA receptor—is critical for triggering cortical spreading depression, he noted. Antagonists of NMDA receptors, such as the drug memantine (which is currently marketed to treat the symptoms of Alzheimer’s disease), have been shown to inhibit cortical spreading depression. Antiepileptic agents topiramate and valproate are also approved for migraine prophylaxis; the mechanisms of these drugs are different, but both influence excitability mechanisms.