Gene Linked to Drug-Resistant Epilepsy

It may block needed medication from entering brain

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By
HealthDay Reporter

WEDNESDAY, April 9, 2003 (HealthDayNews) -- Scientists have found a gene that may explain why as many as one-third of epilepsy patients don't respond to medications.

The discovery could one day point the way to new drugs but, more imminently, may lead to a test to identify individuals who are drug-resistant.

"This is very important stuff, although translating it into clinical practice is not going to happen tomorrow," says Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at New York University Medical Center.

The ability to identify this group of patients, he adds, means "we know not to prescribe those drugs and not to put that patient through five years of med adjustment and failed drugs."

The study appears in the April 10 issue of The New England Journal of Medicine.

Epilepsy is a chronic medical condition produced by "temporary changes in the electrical function of the brain, causing seizures which affect awareness, movement, or sensation," the Epilepsy Foundation says.

According to the study authors, more than 30 percent of people with epilepsy continue to have seizures even when they are taking various drugs, alone or in combination. These individuals, usually considered to have "intractable" or "refractory" epilepsy, are at a higher risk of death from the disease, not to mention memory loss, decreased school performance, depression and impaired psychosocial skills, the researchers say.

The phenomenon is made even more mysterious by the fact that different anti-epileptic drugs work through different mechanisms and, yet, some people are resistant to them all.

Some of these drug-resistant people are candidates for surgery, in which the portion of the brain that is responsible for the seizures is removed. If the seizures come from multiple regions of the brain or from a wide area, surgery is no longer an option. Many of these people have to live with their disorder, although some may benefit from Vagus Nerve Stimulation, which delivers regular pulses of electrical energy to the brain.

Needless to say, scientists have been searching for an explanation for the large proportion of those with epilepsy who are drug-resistant. The London-based authors of the new study hypothesized that the answer lay in a certain gene, and looked at the DNA of 315 patients with epilepsy. Two hundred were drug-resistant and 115 responded to medication. An additional 200 people with neurological conditions, but not epilepsy, acted as controls.

As it turned out, patients with drug-resistant epilepsy were more likely to have a mutation in the ABCB1 3435 gene. That basically means there may be a glitch in the mechanism by which drugs are transported into the brain, say the study authors, from the University College London.

Not all substances can enter the brain, which is "a very 'privileged' space," Devinsky explains. Because the wrong compound could disrupt the organ's electrical and chemical balance, the "blood-brain barrier" exists to exclude certain molecules. Apparently, in the case of drug-resistant epilepsy sufferers, drugs can't cross this barrier.

"Most of us would have a protein that allows us to bind certain molecules and bring them into the brain at a certain concentration. In people with these multiple drug resistances, those proteins are altered and they do not absorb the medications in the normal way," Devinsky says.

The blood-brain barrier is working to block the very molecules that would bring relief, he explains.

More information

To learn more about epilepsy, visit the Epilepsy Foundation or the National Institute of Neurological Disorders and Stroke.

SOURCES: Orrin Devinsky, M.D., director, Comprehensive Epilepsy Center, New York University Medical Center, and professor, neurology, neurosurgery and psychiatry, New York University School of Medicine, both in New York City; April 10, 2003, The New England Journal of Medicine

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