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Calming the storm

The University launches new era in epilepsy

To the ancients, it was a sign of connection with the spirit world. To Napoleon, Handel, Kierkegaard, Socrates, and Dostoevsky, it was an unwelcome intruder, bursting unannounced into their brains at unexpected and unexplained times. To 50 million people today, it’s a disruptive disease that injects their lives with uncertainty and stigma.

To three new faculty members at the University of Minnesota, epilepsy is a problem they aim to solve. Bolstering the U’s growing emphasis on the brain, Aviva Abosch, M.D., Ph.D.; Thomas Henry, M.D.; and Steven Rothman, M.D., are exploring a variety of innovative approaches to treating and curing the disorder.

Abosch, assistant professor and director of epilepsy and functional neurosurgery in the Department of Neurosurgery, came here in 2005, offering the option of surgery to individuals whose epilepsy cannot be controlled adequately by medication. Henry, director of the Medical School’s Epilepsy Care and Research Program and a professor of neurology with clinical expertise and research interests in neuroimaging and epilepsy diagnosis, joined her last summer. Rothman, who joined the University as director of the Division of Pediatric Clinical Neuroscience in July, focuses his clinical attention on childhood epilepsy, which can have different causes and symptoms than adult epilepsy. He also is exploring new technologies that may stop or prevent seizures.

Together, the three are not only bringing new dimensions to patient care but are also conducting translational research ranging from enhancing the effectiveness of conventional drug therapies to venturing deep within the brain in novel ways.

“We have some new, interesting faces at the University of Minnesota in epilepsy,” says David Anderson, M.D., head of the Department of Neurology. “This is a new era.”

Brain storm

Most of the time, our brains behave like orderly—though unfathomably complex—electrical circuits. Impulses travel from one cell to another, transmitting messages that allow us to interact with the rest of world in an organized, integrated way.

But for one out of a hundred of us, that’s not always the case. Intermittently, and often unpredictably, the circuits in some brains erupt in a brief but riotous storm of electrical activity known as an epileptic seizure. Sometimes seizures can be linked to a specific cause, such as a head injury or brain cancer. But more commonly, they are just there—threatening to temporarily disrupt functions that affect every aspect of life.

“Epilepsy is much more complicated than the average person recognizes,” says neurologist Ilo Leppik, M.D., professor and head of the College of Pharmacy’s Epilepsy Research and Education Program. For three decades, Leppik has been helping people with epilepsy regain control by regulating their seizures with medications.

That approach works for many individuals with the disorder. But not all. Because epilepsy is not a single problem with a single cause, there is no single treatment that works for everyone—and in some cases, no treatment that works, period.

Thomas Henry, M.D., who directs the Medical School’s Epilepsy Care and Research Program, uses neuroimaging to help find better treatment options for people with epilepsy.

“If you look at all patients with epilepsy, about a third of them have seizures that are quickly controlled with standard medications with few or no side effects,” Henry says. “Perhaps another third have seizures that are fully controlled or almost controlled, but they experience significant side effects from their medications. Then about a third don’t get any seizure control at all.”

Henry uses EEG monitoring to visualize the electrical characteristics of seizures. He then evaluates the results to distinguish seizures caused by epilepsy from seizures resulting from other causes. The patients he sees are the ones for whom diagnosis is difficult.

A candidate for surgery

Some patients who have epileptic seizures that are not controlled by medication can be cured through brain surgery. If imaging shows that the seizure arises in a certain area of the brain—the hippocampal region of the temporal lobe—Abosch may be able to calm the storm within by removing the offending portion.

When medications failed to relieve the epileptic seizures Norys Andrea had experienced for 30 years, she underwent brain surgery at the University. Now seizure-free, she feels like “the new Norys.”

Norys Andrea was what Abosch calls a “pretty characteristic” candidate for such surgery. A native of Venezuela, Andrea has been experiencing epileptic seizures since she was four years old, she suspects as a result of a high fever. As a young adult, she began an exciting career as a pharmaceutical sales representative. She loved the part she played in helping people get the medical care they needed. But her condition worsened with the job stress, forcing her to give it up. Uncontrolled seizures meant no driving, and that meant no sales.

“We tried all the treatments on the market,” she says, “and they didn’t work.”

When Andrea moved to Minnesota three years ago, she was experiencing one or two seizures a month, and her medications provided no relief. Fortunately, her physician back home had referred her to Miguel Fiol, M.D., associate professor of neurology at the University of Minnesota. Fiol told Andrea that her seizures originated in a part of her brain that might make her a good candidate for surgery. He referred her to Abosch, who sent her through a battery of tests that confirmed Fiol’s suspicions and indicated that the proposed surgery would not impair Andrea’s quality of life.

“Everything lined up with respect to her history, preoperative imaging, neuropsychological testing, and EEG analysis,” Abosch says. “Once all of those things line up, you can proceed.”

Andrea didn’t hesitate. “Stay like I was, or change my life forever? This is not life. I cannot drive. I have to depend on other people,” she remembers thinking. “I was positive and confident I wanted to go through with the surgery.”

On June 12, 2007, in a six-hour operation, Abosch opened up the right side of Andrea’s skull, then used suction to remove a portion of her brain the size and shape of a person’s thumb. After four days in the hospital, Andrea was home again. She hasn’t had a seizure since.

“It was incredible,” Andrea says. “It let me start my life again.” Within three weeks, she was starting class at the University. In the fall, she began work as a teacher’s aide at a local elementary school.

On November 16—her 34th birthday—Andrea received the best news yet: Fiol gave her the okay to apply for a driver’s license. “It was the best birthday gift!” she says. “I feel ready to look for the job of my dreams again. I feel like I’m the new Norys.”

Deep in the brain

Surgery is not the answer, however, for everyone who experiences epileptic seizures that don’t respond adequately to drugs. To determine whether they are candidates for surgery, patients undergo brain imaging to find out what key structures and functions—if any—arise at the site of seizure onset.

Andrea was one of the lucky ones: Her seizures started in a part of her brain she could function without, and the imaging results were unambiguous. In some individuals, the seizures originate in a part of the brain that’s too close to brain tissue that controls critical functions, such as speech or movement. In others, the site of seizure onset cannot be clearly determined, making them unsuitable for surgery as well.

“What do you do with those people?” Abosch asks. “As a surgeon, I want to fix the problem.”

Neurosurgeon Aviva Abosch, M.D., Ph.D., is exploring the use of deep-brain stimulation to treat epilepsy.

One approach Abosch and Henry are exploring together is using high-resolution structural and functional imaging to identify locations in the brain—other than that in which the seizure originates—where surgery might make a difference.

“Mapping out areas of brain function is an important new research area,” Henry says. Such mapping, he hopes, will eventually allow doctors to perform surgery that stops seizures originating outside the temporal lobe—without disrupting critical brain function.

Mapping also plays a key role in another novel therapy Abosch and Henry are investigating: deep-brain stimulation, or DBS. This approach involves implanting an electrode in the brain, then delivering electrical current via a pacemaker-like device before or at the onset of a seizure.

Abosch already uses DBS to calm tremors in patients with Parkinson’s disease. Given a better understanding of the right place in the brain and the right timing and dose of electricity, she thinks it could make a difference for epilepsy patients, too. As a possible treatment for epilepsy, stimulation of a part of the brain known as the anterior nuclear group of the thalamus is currently being tested in clinical trials. Abosch and Henry are exploring whether DBS might work even better in other parts of the brain.

“We’re looking for something that is more obviously a home run,” Abosch says.

Other innovative approaches

Rothman, whose focus is translational research, is exploring new techniques for patients whose epilepsy is not amenable to drugs or conventional surgery, and he has found a surprising ally in the electronics industry.

Translational researcher Steven Rothman, M.D., is investigating the use of localized cooling devices and light to interrupt and prevent seizures.

One innovation attracting Rothman’s attention is a refrigerator the size of a watermelon seed that has been developed to help cool the central processing units of computers and other electronic components. Animal studies have repeatedly shown that rapid, localized cooling of the right spot in the brain can stop a seizure in its tracks. Why not, Rothman wonders, implant into the brains of people with epilepsy a miniature cooling device that can deliver a quick chill at the right place and time to do just that?

“This technology is very effective in our animal models,” he says. But there are plenty of details to refine: removing waste heat generated by the cooling process, cutting the amount of power needed, and figuring out how to anticipate or sense early seizure. In collaboration with Tay Netoff, Ph.D., assistant professor in the Department of Biomedical Engineering, Rothman hopes to begin testing inside-the-brain cooling devices within a couple of years.

Rothman is also looking into using light to help prevent or interrupt seizures. The idea, he says, is to insert a light-activated therapeutic drug, along with a light-emitting diode, into the part of the brain where the seizure is centered. The light could be turned on at the seizure onset, activating the drug and terminating the seizure.

As Rothman’s research progresses, both Henry and Abosch will be welcome partners. Implanting new devices depends on precisely pinpointing seizure centers and key functional parts of the brain—an endeavor in which Henry will prove an invaluable collaborator. If the devices Rothman is developing advance to the point of clinical trials, Abosch would be the one to place them.

Abosch, Henry, and Rothman aren’t alone in charting new territory. For example, in addition to testing new drugs, Fiol is studying the genetics of epilepsy in families with multiple affected individuals and exploring ways to enhance culturally sensitive epilepsy care in Native American Indian and immigrant populations. Among other work, Leppik has just completed a study of the safety and efficacy of deep-brain stimulation and is assessing the onset of epilepsy among nursing home patients as well as the care they receive.

Says Abosch, “It’s an exciting time and a very dynamic environment in which to be doing this work.”

By Mary Hoff

Photos By Scott Streble

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