Like many people with epilepsy, Richard Shane, 56, has some problems with memory. But he can easily recall his first seizure, 34 years ago. “I was on the phone with my father, and I noticed that I started moaning, and I lost some level of consciousness,” Shane says. After experiencing a similar episode three weeks later, he went to a doctor and learned he had epilepsy, a neurological disorder caused by abnormal electrical activity in the brain. The first medication he was prescribed, Dilantin (phenytoin), failed to stop or even reduce his seizures. So did the second and the third. His epilepsy, it turned out, was drug-resistant.

Over the next 22 years Shane suffered two to five or more seizures a week. He and his doctors tried every new antiseizure drug that came along, but none worked. Finally, in 2004, as a last resort, a neurosurgeon removed a small part of Shane's brain where his seizures originated. “It was a matter of what sucks less,” Shane says, “having brain surgery or having epilepsy.” Shane has been seizure-free ever since.

As many as three million people in the U.S. live with epilepsy, and more than 30 percent of them receive inadequate relief from medication, a number that persists despite the introduction of more than a dozen new antiepileptic drugs since 1990. Although surgery has helped some patients such as Shane, uncontrollable epilepsy remains a living nightmare for patients and an intractable foe for clinicians and researchers. “I hate to say it, but we do not know why” some people respond to medications and others do not, says neurologist Michael Rogawski, who studies epilepsy treatments at the University of California, Davis. And yet if the central conundrum continues, so does the determined quest for new and different approaches to treating the toughest cases.

Faulty Treatments

Epilepsy has been baffling humans ever since it was first described in Babylonian texts more than 3,000 years ago. Over the centuries sages have attributed its seizures to everything from the presence of excess phlegm in the brain (per the ancient Greeks) to possession by evil spirits (during the Middle Ages). Past treatments included drilling holes in the skull, animal sacrifice and exorcism.

The first effective drug for epilepsy, potassium bromide, was introduced in the 1850s and works by inhibiting the excitability of neurons. The compound, since supplanted by phenobarbital and other treatments with fewer side effects, stopped seizures in about a quarter of those who took it and lessened them in another 43 percent of patients. As Rogawski points out, about 50 percent of current patients become seizure-free with the first drug they try, and another 20 percent will be able to control most of their seizures with their second or third drug. Thus, in some respects, “we have not made much of an improvement,” he says.

Which leaves roughly one million people with epilepsy for whom the more than 20 available agents are about as helpful as a handful of jelly beans. Rogawski and others in the field believe that more people could benefit from surgery than are receiving it. Around 60 percent of surgery patients remain seizure-free after 10 years. Less than a quarter of drug-resistant patients, however, meet the medical criteria for the procedures, the main one being a distinct site of origin in the brain for their seizures (confirmed with brain scans and electroencephalography) that does not overlap with regions involved in essential functions, such as language. Studies have found that most surgical candidates, like Shane, typically live with their condition for 20 to 25 years before choosing to undergo the knife. Many people may delay the decision because they fear potential complications, which include infections of the brain and permanent paralysis.

For Orrin Devinsky, director of the Comprehensive Epilepsy Center at N.Y.U.'s Langone Medical Center, the ongoing mystery of intractable epilepsy carries a certain irony. “I went into epilepsy [research] 25 years ago, paradoxically, because it was one of the few things in neurology that you could treat,” he says. The fact that nearly a third of his patients do not respond to medication is only made worse by the long-term effects of uncontrolled epilepsy. “People who keep having seizures, especially convulsive seizures, may suffer progressive impairment of cognitive functions [as well as personality changes],” Devinsky says. He attributes those complications to the chronic disruption of brain function by seizures and medications, among other things. Other problems include anxiety, depression, migraine and sleep disorders.

Epilepsy can also be fatal—either on its own or as the cause of an accident. “I would estimate that epilepsy kills at least 6,000 people a year in the U.S.,” Devinsky says. About half those deaths occur for reasons that cannot be determined, whereas the rest are the result of seizure-related drownings, traffic accidents, falls, burns, and the like.

New Approaches

The first challenge in treating any patient with epilepsy is figuring out what kind he or she has. The disorder falls into two broad categories: generalized epilepsy, in which seizures begin simultaneously in all parts of the brain, and focal epilepsy, in which seizures begin in a particular region of the brain, such as the temporal lobe. These types are further broken down into subtypes, including a rare genetic condition, known as Dravet syndrome, which usually shows up in affected children in the first 12 months after birth. There are also many different kinds of seizures — among them tonic-clonic seizures, in which a person loses consciousness and experiences whole-body spasms, and absence seizures, brief spells in which a person spaces out for five to 10 seconds on average and is unaware of his or her surroundings.

Epilepsy specialists such as Devinsky decide which of the many drugs to prescribe for patients based on the type of seizure they are experiencing, their medical history, and other details such as age, gender and body weight. The drugs act on multiple molecular targets in the brain, including specialized molecules located in neurons that help them communicate with other neurons by transferring sodium, calcium and potassium ions in and out of the cells.

Unfortunately, for people who do not respond to existing drugs, new ones that might help will not be coming soon. “There aren't any major drugs in the pipeline at the moment,” Rogawski says. A 2013 joint report from epilepsy research organizations explained that “because the marketplace is already awash with [antiseizure drugs], many pharmaceutical companies now refrain from the expensive enterprise of developing new compounds.”

Faced with this roadblock, many patients and families have opted to conduct their own experiments. In recent years, for example, as marijuana was approved for medical uses in Colorado and other states, parents of children with Dravet syndrome have started giving their sons and daughters doses of cannabidiol, a nonpsychoactive component of the plant, prepared as an oil. In anecdotal reports online and in the media, some families described a dramatic reduction in seizures. Since then, a few clinical studies of cannabidiol have also supported its potential as an effective treatment for some forms of epilepsy.

In 2014 GW Pharmaceuticals, a British drug company, received special permission from the U.S. Food and Drug Administration to test its pharmaceutical version of cannabidiol, called Epidiolex. In a recent trial of 225 patients, completed in September 2016, participants who took the drug (along with their other epilepsy medications) reduced their nonstop seizures by 42 percent, compared with 17 percent for those taking a placebo.

Other groups have taken a page from history to develop a nutritional approach to treating epilepsy. A so-called ketogenic diet (high in fats and low in carbohydrates) was widely used in the 1920s to lessen seizures, particularly in children. Recent studies have confirmed that it offers some antiseizure benefits, although 90 percent of children in one study found the diet so unpalatable that they eventually dropped it.

Given how long it is likely to take for new medications against epilepsy to be tested and approved, some experts argue that more patients with relentless epilepsy could benefit from recent advances in surgical techniques and various methods for stimulating neurons in ways that make them behave less erratically. Devinsky estimates that up to 20 percent of such patients are candidates for surgery because they have focal seizures that can be traced to a specific and surgically approachable site in the brain.

Another option that has been around for two decades consists of a kind of pacemaker for the brain. The idea is to prevent seizures by stimulating the vagus nerve in the neck, via electrodes attached to a battery pack implanted in the chest. A programmed pattern of mild electric current overrides and calms the abnormal activity in the brain. A 2011 meta-analysis of 74 clinical trials involving more than 3,300 subjects found that vagus nerve stimulation reduced seizures by more than half in 50 percent of the patients.

A newer device, NeuroPace's RNS System, approved by the FDA in 2013, has a neurostimulator that is implanted in the skull, under the scalp. When it detects unusual electrical activity in the brain, it sends a charge through two electrodes to stop or even prevent a seizure. According to Devinsky, 10 to 15 percent of patients with otherwise unmanageable epilepsy are potential candidates for the treatment; clinical trials have shown that the implants reduce seizures in the treated group by an average of as much as 66 percent after three to six years of follow-up.

In the laboratory, meanwhile, researchers are working with mice, fruit flies, worms and computers to develop new and better models of epilepsy in animals, in an effort to speed drug discovery. In 2016, for example, scientists at Florida Atlantic University and the Scripps Research Institute for the first time induced seizures in nematodes, microscopic worms with just 302 brain cells. They then successfully treated the creatures with existing antiepileptic drugs, suggesting the worms could potentially serve as fast and efficient tools for testing new medicines.

As for Richard Shane, who now owns his own travel company, epilepsy is still part of his life. He no longer has seizures, but there is something else that nags at him: “I wonder sometimes who I would have been if I never had all this electrical activity in my brain. How did it change who I am?”

It is a question without an answer, another unknown in the swirl of unknowns around drug-resistant epilepsy. But doctors such as Gregory Bergey, director of the Johns Hopkins Epilepsy Center, try to offer encouragement as they confront the disorder's myriad riddles: “I always tell my patients, we never give up.”