In the Grip of the Unknown

"It's OK, they know. I came home intoxicated the other night at 5 a.m."

Thus begins another skirmish in Devinsky's long-standing war on the fecklessness of youth, their natural tendency to forget their medication, stay up all night working on a term paper and propel themselves into a hypernormal state by swilling vodka or cough medicine. The human brain, for all its marvels, has one glaring fault, the tendency to discount future losses—such as the risk of a fatal seizure—relative to present pleasure, if that's the right word for how 15 Benadryls makes you feel. This psychological quirk has cost the lives of more than 150 of his patients, mostly in their teens and 20s. "I had a patient who hadn't had a seizure in two years," Devinsky tells her. "Last fall I got a call. He went off to college, stayed up late one night at a party and never got up the next morning.

"Do you want to be the mother of two children wondering when your next seizure is coming?"

Striking the right balance of medication is especially important in children as they pass through the critical years for learning. Devinsky raises this with the father of a fourth-grade girl who suffers from brief absence seizures, just five seconds at a time, a few times a day. She has already been on Topamax, Keppra and Zarontin, and is now being treated with Lamictal. Devinsky is hesitant to give her more drugs, but he worries that the absence seizures, which seem so benign, might be causing subtle damage to her learning and behavior. "It's like you're trying to read something," he says, "and I keep tapping you on the arm, like this. For an adult it might not be such a big deal. But if you have this constant distraction during a critical learning window, you miss out, and you don't ever get that back." After talking it over with her father, he decides to up the dosage of Lamictal, and asks the father to let him know of any changes.

Devinsky doesn't disdain technology, but he has a keen sense of its limits. He has all the latest scanners and imagers at his disposal, but knows that most of the time whatever is causing a seizure won't show up on them, at least not definitively. The most important tool in his lab is the EEG machine, which monitors brain activity through electrodes on the scalp, a technology that was invented in 1929.

There are, at this time, only a few ways to treat epilepsy, and applying them is still an art as much as it is a science. What works for one patient often has no benefit for another with identical symptoms. Researchers still don't understand, 80 years after it was discovered, why some children can control seizures with a ketogenic diet, high in fat but so low in carbohydrates that even the amount of sugar in toothpaste can be too much. Nor do they know why two thirds of patients can control their seizures with drugs, but not the rest. Since the 1960s about 30 different compounds have been approved to treat epilepsy, although most neurologists, says Devinsky, have a stable of around 10 that they generally rely on. New ones are being developed and put into use regularly, but that progress is deceptive, says Michael Rogawski, a neurologist at University of California, Davis, who studies epilepsy therapies. The new drugs may have fewer side effects or less toxicity than older ones, but by and large they work only for the same percentage of patients who were already being helped; the number of refractory cases hasn't changed much over the years. And it's still impossible to know in advance which patients will benefit, and from which drugs. "I can look at a person, do all the testing, even see their seizure, and I can't tell which drug they'll respond to," says Carl Bazil, who heads Columbia's Comprehensive Epilepsy Center. "There must be something about their action in the brain, but we don't know what it is." Many researchers believe that the next important breakthrough won't be a new drug at all, but the development of a subcutaneous pump that can deliver medication directly to the right spot in the brain, bypassing both the organs of the rest of the body, and a delivery mechanism that relies on a teenager late for the school bus to remember where he left the bottle.

Devinsky tries not to use more than two different drugs on a patient at a time, but even so, the number of ways to combine different dosages of two drugs from among 10 is infinite, especially compared to the time he has to get someone's seizures under control before they fry their synapses beyond repair. When he first treated Wheeless he was on Depakote, which was making him lethargic and fat; Devinsky substituted Felbatol in combination with Lamictal. When that didn't work well, Devinsky switched him to Felbatol with Keppra. The improvement was dramatic—so much so that he kept Wheeless on Felbatol even after reports appeared of deaths from liver failure and aplastic anemia. For the relief Wheeless received, the risks seemed small enough to Devinsky, and manageable as long as he closely monitored his blood chemistry. Up till now, he's been right, but if the Felbatol-Keppra combo is losing its effectiveness, he will have to consider increasing the dosage, or switching him to another medication. He wants to improve Wheeless's sleep schedule and control his mood. Depression works synergistically with epilepsy; it can promote seizures, and seizures, of course, can make you depressed. And if those don't work … well, he'll think of something.

The complexity of managing epilepsy this way has led patients and their parents to agitate for research on a cure. Although "cure" is in the name of the foundation Devinsky founded, he uses the term sparingly, especially around patients; just hearing it can encourage them to stop taking their medications, and after a while they show up back in his office with new seizures. Cures do happen, except they're most often spontaneous and random; about half of all children with epilepsy outgrow their seizures and can be taken off meds after several years. In theory, gene therapy could someday cure some cases of generalized epilepsy. The first step would be to identify the mutations that cause the condition, and thousands of patients are being recruited for a study aimed at doing that. And, also in theory, and sometimes in practice, partial epilepsy can be cured by removing the part of the brain where the seizure originates—although most patients continue to take anti-seizure drugs afterward as a precaution.