Shared Genetic Link Found in Epilepsy, Migraine With Aura

Pauline Anderson

January 28, 2013

For the first time, researchers have demonstrated a shared genetic susceptibility to epilepsy and migraine with aura in a large cohort of patients with generalized epilepsy (GE) or nonacquired focal epilepsy (NAFE).

In their new study, migraine with aura was more than twice as likely in patients with epilepsy who had 3 or more first-degree relatives with a seizure disorder.

The findings are "potentially transformational," said lead author Melodie R. Winawer, MD, MS, assistant professor of neurology, Columbia University, New York.

The study results represent "a major step in our understanding that epilepsy does not stand alone as a disorder," Dr. Winawer told Medscape Medical News. "We should start to consider intersecting combinations of disorders as clinical entities to be treated."

The study was published online January 7 in Epilepsia, a journal of the International League Against Epilepsy.

Assessing Migraine

The analysis included 730 participants aged 12 years or older from 501 families who were enrolled in an arm of the Epilepsy Phenome/Genome Project (EPGP) that included sibling pairs or parent-child pairs with well-characterized GE or NAFE. The EPGP is an ongoing study that includes detailed phenotyping and collection of DNA from participants with epilepsy at 27 clinical centers in the United States, Canada, Argentina, Australia, and New Zealand.

Dr. Melodie R. Winawer

To be classified with NAFE, neuroimaging findings had to be normal or demonstrate mesial temporal sclerosis or focal cortical dysplasia, and patients had to have focal electroencephalographic abnormalities or clinical semiology consistent with focal seizures. To be classified as having GE, participants had to have generalized-onset seizures, normal results on neuroimaging (if done), and an electroencephalogram showing generalized epileptiform activity with a normal posterior dominant rhythm for age.

Researchers assessed migraine using a standardized and validated interview. Migraine with aura or migraine without aura was diagnosed according to criteria of the International Classification of Headache Disorders (2004). Data on history of seizure disorders in other family members were collected through a single interview question.

The researchers found that the prevalence of any migraine and migraine with aura in enrolled participants increased when 2 or more first-degree relatives, in addition to the enrolled pair, were reported to have seizure disorders (adjusted odds ratio [OR] for any migraine, 2.0; 95% confidence interval [CI], 0.99 - 3.85; adjusted OR for migraine with aura, 2.5; 95% CI, 1.13 - 5.46).

The prevalence of migraine without aura did not increase with 2 or more additional relatives with seizure disorders (OR, 1.1; 95% CI, 0.50 - 2.38).

It has already been established that some genetic mutations — for example, in the CACNAIA and SCNIA genes — occur in certain types of epilepsy and a specific rare form of migraine called familial hemiplegic migraine. However, a shared genetic effect on common forms of epilepsy and commonly occurring migraine has not been previously demonstrated.

This new research should have a huge influence on the conception of disease boundaries and therefore on understanding of the causes of disease, said Dr. Winawer. "It really changes prevention; it changes prediction; and it changes the way in which patients are viewed as being at risk."

Serotonin Role?

Asked to comment on this study, Andres Kanner, MD, director of the Comprehensive Epilepsy Center, University of Miami Miller School of Medicine, Florida, said the findings "proved a point."

Previous research had observed only "interesting associations" between migraine with aura and epilepsy. For example, a history of migraine with aura in those with epilepsy predicted a worse course of epilepsy, he told Medscape Medical News.

One of the more interesting findings to date came from a 2007 Icelandic study showing that the co-occurrence of migraine with aura with major depression or suicide attempt increased the risk of developing unprovoked seizures more than did these conditions alone, Dr. Kanner said (Epilepsy Res. 2007;75:220-223).

These kinds of findings have helped convince Dr. Kanner that the neurotransmitter serotonin may play a role not only in depression but also in epilepsy and migraine with aura.

"This study we're looking at [by Winawer et al] showed a common genetic mechanism. We now want to go a step further and ask what could these genes be doing at a neurochemical or neurophysiological level. This is speculation, but one possible common pathogenic mechanism is serotonin."

An investigation in animal models of epilepsy has shown that selective serotonin reuptake inhibitors (SSRIs) improved seizure activity, and open trials had similar findings. Now, a study funded by the National Institutes of Health is examining whether a serotonin agonist that increases synaptic concentrations of serotonin improves seizures. Dr. Kanner's own research group is planning a study that will look into treating seizures with an SSRI.

Dr. Winawer agrees that serotonin may represent a "tremendous advance" in therapy.

"If we could understand the cause and pinpoint a very specific pathophysiology, then that would lead to the development of novel therapies that are directed at novel targets, and therefore we could open a whole new avenue of treatment," she said. "Serotonin may very well be one such avenue."

The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Winawer has disclosed no relevant financial relationships. Dr. Kanner is a member of the editorial advisory board for Medscape Neurology; he has disclosed no relevant financial relationships.

Epilepsia. Published online January 7, 2013. Abstract