Epilepsy: Life on the Frontlines

The worst thing about the epileptic seizure Dan Wheeless suffered on the first day of eighth grade wasn't dropping to the floor in the hallway and awakening with no memory of how he got there. It wasn't even being kicked to get up by his classmates, who thought his collapse and jerking were an act; like, say, piloting a fighter jet, being known as the class clown holds uncommon risk for people with a seizure disorder. The worst thing was how the drugs he took made his brain slow down, so that processing auditory information became painfully difficult. He had to write down what was said to him, break it into clauses and concentrate on the meaning of each one. "Sometimes my mom would have to say something to me five times before I could understand it," he recalls. Switching medications after several months improved his cognitive problems, but the new drugs caused lethargy and weight gain, which disappeared only when a new doctor, Orrin Devinsky of New York University, figured out the right regimen for him. "He saved my life," says Wheeless, who was back to see Devinsky recently at his office in Manhattan. Wheeless, a handsome, strapping 32-year-old, went on to graduate from the University of North Carolina, marry an actress and begin a career in the theater. It may be an overstatement that Devinsky saved his life, because doctors can't predict who will die from epilepsy—although Wheeless, who estimates he has had 50 major seizures in his life and countless smaller ones, was certainly a candidate. Devinsky couldn't even save Wheeless's front teeth, all of which had to be replaced after he broke them falling down with seizures. But it is safe to say that Devinsky saved his mind. (Article continued below...)

When Devinsky was in medical school in the early 1980s, he was attracted to studying the brain in all its magnificent complexity and subtlety. But he wasn't sure he wanted to be a neurologist, doctors with the reputation of not actually doing much for patients. "In neurology, you'd see strokes, MS, brain tumors and migraine," he recalls. "You pontificated about whether the problem was in the brain, but in those days there wasn't much you could do for them." Then he discovered epilepsy, a disease that provides "a window into the mind." The study of epilepsy drove many of the earliest discoveries about how the brain was organized. But just as important to him, it was a disease doctors could actually treat, and go home at the end of the day having made someone better. Since 1989 he has run one of the largest epilepsy centers in the country, at NYU Langone Medical Center; he is the author of the definitive guide for patients, "Epilepsy," a cofounder of the Web site epilepsy.com and of the Epilepsy Therapy Project and founder of an organization called FACES (Finding a Cure for Epilepsy and Seizures) that promotes research into new treatments.

Epilepsy is a uniquely human disorder, like psychosis, with which it used to be confused, or demonic possession, another now discredited diagnosis. Depending on the part of the brain affected, seizures can produce hallucinations, anxiety, feelings of religious ecstasy or bizarre psychological tics such as "hyperfamiliarity," a delusional sense that you're already acquainted with everyone you meet. Most often, though, they fall in a well-documented spectrum of mental and somatic anomalies, from the transient episodes of decreased awareness known as absence (formerly called "petit mal") to the tonic-clonic (or "grand mal") attack characterized by loss of consciousness, collapse and spasmodic stiffening and jerking. There is some debate about the long-term risk from repeated seizures; Devinsky maintains they can result in irreversible damage to the brain; some other researchers are less sure. But it's certain that uncontrolled seizures are associated with the risk of lasting memory problems, cognitive deficits, personality changes—and death.

Seizures can be triggered by a baffling array of stimuli, as blatant as a flashing strobe light or as subtle as, literally, thought. There are credible reports of people whose seizures were brought on by doing arithmetic, or by playing mah-jongg, or the sound of the TV personality Mary Hart's voice on television. The neurologist and author Oliver Sacks ("The Man Who Mistook His Wife for a Hat") described a woman, who was also a patient of Devinsky's, who would go into seizures at the sound of Neapolitan music. (Rx: Move to Sicily.) Patients sometimes use this knowledge to their advantage; one woman who never had more than one seizure a day induced one intentionally on the morning of her wedding day, so she could get through the ceremony on her feet. Alcohol, drugs, emotional stress and sleep deprivation are common triggers for seizures. Jet lag, a minor inconvenience for most people, can be catastrophic for someone with epilepsy. In earlier eras, people believed that seizures were influenced by the phases of the moon, something Devinsky doesn't dismiss out of hand. If the tides can feel the moon's gravity, why not the brain?

The brain, of course, is unique among the organs of the body both in its susceptibility to outside stimuli, and the variety of things that can go wrong with it. By contrast, a heart can fail in only so many ways. Conceptually, the job of the cardiologist is straightforward: he needs to restore a damaged heart to its normal rhythm. But epilepsy is the opposite. A normal brain is governed by chaos; neurons fire unpredictably, following laws no computer, let alone neurologist, could hope to understand, even if they can recognize it on an EEG. It is what we call consciousness, perhaps the most mathematically complex phenomenon in the universe. The definition of a seizure is the absence of chaos, supplanted by a simple rhythmic pattern that carries almost no information. It may arise locally (a "partial" seizure), perhaps at the site of an old injury, a tumor or a structural malformation. A network of neurons begin firing in unison, enlisting their fellows in a synchronous wave that ripples across the brain. Or it may begin everywhere at once ("generalized" epilepsy), with an imbalance of ions across the cell membrane, usually the result of an inherited mutation. At a chemical signal, whose origin is still a mystery, billions of neurons drop the mundane business of running the body and join in a primitive drumbeat, drowning out the murmur of consciousness. And so in contrast to the cardiologist, the epilepsy doctor must attempt to restore not order, but chaos.

Seizures can be fatal, especially the rare status epilepticus, a continuous convulsion lasting longer than 10 minutes. One of Devinsky's patients is a teenage boy who showed up at the hospital in December with status epilepticus of unknown origin, although Devinsky suspects a brain lesion from an undiagnosed infection. The only way to stop his convulsions was to induce a coma, and he has been in one ever since. Devinsky keeps looking for the right combination of drugs to save his life. Occasionally people with epilepsy will go to bed at night, apparently healthy, and die in their sleep; the autopsy may be inconclusive and the death is chalked up to SUDEP—Sudden Unexplained Death in Epilepsy. Among patients with refractory seizures—ones that can't be controlled with medication—the risk factor for SUDEP is a little less than 1 percent a year—small, but not negligible. Some of these patients may be candidates for surgery. But in general Devinsky spends more time thinking about the quality of a patient's life than the length of it. "Imagine you come to see me after a single seizure, just one," he says. "I examine you and do an EEG, an MRI and everything looks good, so I say, you're in luck, there's only a 20 percent chance you'll have another one." That is roughly the same risk a middle-aged man or woman runs of having a second heart attack within five years of the first. "But that could affect your life tremendously. Say you're a truckdriver, or a surgeon. Or if you're a commercial pilot—well, that's done." The biggest quality-of-life issue for most people with seizure disorders is driving; every state restricts, to varying degrees, the licenses of people who have had seizures. Most require them to be seizure-free for a certain number of months or years before restoring driving privileges—but only six require doctors to report seizures, so presumably a lot of people are getting away with it. "You say, 20 percent, that's terrible, I want you to tell me I won't have another one. And I can't. And then if you have two, your chance of a third goes up to 70 or 80 percent."

Epilepsy drugs are known for serious side effects, including lethargy, hyperactivity, weight gain, weight loss, dizziness, anemia, osteoporosis—and mental disturbances that may confoundingly mimic the symptoms of epilepsy themselves. Devinsky is continually balancing the unpleasantness of a seizure against the misery of throwing up. "You might have two staring spells a month lasting a couple of minutes, and you're on a high dose of medication," Devinsky says. "Now, I can put you on a second medication and get you down to one a month. So now you've got two extra minutes a month but in exchange it's affecting your quality of life for the 15 hours a day you're awake: it may make you tired, or dizzy, or cause mood changes or memory problems. So do you want to make that trade-off?"

Four days a week, Devinsky, who is 52, with a lean, athletic build and a brisk but friendly demeanor, takes a train from his home in New Jersey—he is married, with two teenage daughters and a dog, whom his patients faithfully inquire about—and arrives in New York by 6 a.m. He works out in the gym for an hour before starting his hospital rounds, and then heads to his office. On Thursdays, he sees patients at St. Barnabas Hospital in Livingston, N.J., where he runs another epilepsy center. In a tie and plaid sports jacket, he strides the narrow halls of his clinic, popping in and out of exam rooms where patients wait in varying degrees of anxiety. Even his adult patients usually come with a parent, or a spouse or sibling; almost no one comes alone.

Over the years Devinsky has found himself becoming deeply involved in the lives of his patients. He is close enough with Dan Wheeless to have been a guest at his wedding in 2006. Devinsky says he's been influenced in this way by Sacks, a close friend, who has an exceptional gift for entering into and describing the mental lives of his patients. "I do let patients into my life, and I let myself get into their lives," Devinsky says. "It's an important part of who I am as a doctor." He knows that Wheeless is discouraged because his seizures—which had disappeared entirely for years at a time—have resumed and are becoming more frequent, twice already since New Year's. Worse, they are happening with no obvious triggers under his control, such as drinking or missing a pill. Although Devinsky has patients from as far away as Italy lined up to see him, during a recent office visit he chats with Wheeless as if he had the whole morning for him. He increases the dosage of his antidepressant, suggests melatonin to help him sleep and schedules him for a home EEG—a brain-wave monitor that can be worn for a day while the patient goes about his routine. Wheeless smiles a wan smile, picks up his helmet—for bicycling, not to protect his head in a seizure—and heads out the door. Later, a reporter asks him how he feels about his seizures starting up again. "It's kind of heartbreaking," he says wearily. "I would love to not have epilepsy."

On the day he sees Wheeless, he also sees a college student who has had more than 100 seizures, the most recent one last fall. It happened, she says, after taking Benadryl, an over-the-counter allergy drug that can promote seizures in susceptible patients.

Devinsky nods sympathetically. "How many?" he asks.

"Fifteen," she mumbles. "It's like Robi-tripping."

Devinsky sighs. "I hate to give you the drugs-and-alcohol lecture in front of your parents."

"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.

The principles of epilepsy surgery have been known since the first operations took place more than a century ago: identify the area where the seizure begins and cut it out, as precisely as you can. Obviously this excludes most patients with generalized epilepsy, since you can't take out an entire brain (although in rare cases, you can remove half a brain; the patients sometimes compensate surprisingly well). Werner Doyle is one of two neurosurgeons at the NYU center; he does around 260 procedures a year, there and at St. Barnabas. In contrast to Devinsky's holistic approach to patient quality of life, Doyle's discipline requires an obsessive focus on brain stuff, on the paper-thin margin between diseased and healthy tissue. Sometimes, he says, he can feel the difference with his dissecting instruments, which cut easily through normal gray matter but meet resistance where the tissue is scarred from repeated seizure.

Like many surgeons, he is matter-of-fact about the manual dexterity he deploys inside the skull. The intellectual challenge for him is to find the focus of the seizure and trace the networks along which it spreads, while also mapping the boundaries of the unaffected areas. The basic tool for that is the EEG, but the standard device, with around 20 external leads, is a clumsy instrument for mapping a three-dimensional brain. That has led to the adoption of intracranial electrodes, which are inserted into the brain and can sample as many as 200 points. Inserting these requires opening the skull and takes as much of Doyle's skill and time—six or seven hours—as the subsequent operation itself. Patients may stay in the hospital for a week or more, trailing a Medusa-head of wires, under continuous monitoring both by EEG and video, while the doctors wait for the iconic seizure. Then Doyle goes to work.

In contrast to many types of neurosurgery—for tumors, notably—epilepsy surgery is generally performed on healthy people, and the risks are not that high. But Doyle believes, and hopes, that the future of his field lies not in the relatively blunt procedure of ablation, or cutting tissue, but in augmenting brain function through electronic devices. The first of these, the vagal nerve stimulator, has been in use since 1997, and more than 50,000 have been implanted. Its purpose is to disrupt an incipient seizure by sending an electrical signal to the brain through the vagus nerve in the neck. Again, no one knows exactly why it works, but it often does. Deep-brain stimulation, which has been successful in treating Parkinson's disease, is meant to do the same thing, by delivering a pulse directly to the brain itself, but clinical trials for its use in epilepsy so far have been disappointing. The VNS, though, is a primitive tool, which delivers a small current for a fixed duration at regular intervals of several minutes. Researchers now are working to develop a responsive device that could be implanted in the brain and "sense when a seizure is beginning, to release a small amount of medication or electrical stimulation where needed," says Harvard neurologist Steven Schachter, president of the American Epilepsy Society.

The key to such a device will be the computer algorithms that can predict a seizure, ideally in the "aura" stage that sets in before it even begins. We are accustomed to the idea that computers can process limitless amounts of data, but the brain, with its 100 billion neurons, each linked to as many as 10,000 others, is pushing the limits of information theory. The effort represents an audacious assault on a devastating disease, just what Devinsky was dreaming of in medical school. To conquer epilepsy we will have to outwit our own brains.