Intractable Epilepsy: When Medicine Can't Stop Seizures

An estimated 2 million Americans of all ages have epilepsy, and most of them are successfully treated with medications that keep their seizures well controlled. But as many as 35% of epileptic patients are termed drug-resistant, experiencing frequent, sometimes disabling seizures. For them, procedures being offered at the Medical College of Wisconsin and other leading research facilities in the nation are offering patients the hope of freedom from seizures.

One of those leading the effort at the Medical College of Wisconsin's Comprehensive Epilepsy Program is Manoj Raghavan, MD, PhD, Assistant Professor of Neurology and Neurosurgery. He is the director of the Adult Comprehensive Epilepsy Program based at Froedtert Hospital. The pediatric component of this program, the Pediatric Comprehensive Epilepsy Program, is based at the Children's Hospital of Wisconsin, and is directed by Mary L. Zupanc, MD, Associate Professor of Pediatric Neurology and Chief of the Division of Pediatric Neurology.

Epilepsy is the second most common serious neurological condition in the United States after stroke. According to the National Institute of Neurological Disorders and Stroke, which is a division of the National Institutes of Health, about 125,000 new patients develop epilepsy each year.

For both children and adults, alternative treatments are available when medications fail, Dr. Raghavan says. "For some patients, surgery to remove the part of the brain where seizures originate may be the best treatment option, and it offers a potential cure. The success of epilepsy surgery depends on the accuracy with which we can locate the seizure-generating areas, and careful testing to ensure that surgical removal of this area does not affect critical brain functions such as language, memory or motor abilities," Dr. Raghavan says.

"For patients who are not good candidates for epilepsy surgery, vagus nerve stimulation - the delivery of electrical pulses to the vagus nerve in the neck using a pacemaker-like device - offers another treatment option. For children with drug-resistant epilepsy, a high-fat diet with no carbohydrates - called a ketogenic diet - may reduce seizures, but it is a regimen that is hard to sustain in adults."

Identifying Type and Source of Seizures
The goal of these evaluations is to determine that the seizures being reported are indeed epileptic in nature, and if so, to classify them according to epilepsy type. Treatment options differ for different seizure types.

According to Dr. Raghavan, "while a 30 minute brain-wave recording, also called an electroencephalogram, or EEG, may be sufficient to establish seizure type in some patients, it often becomes necessary to observe a patient's seizures using simultaneous EEG and video monitoring." Such video-EEG studies are typically done in the Epilepsy Monitoring Unit at the Comprehensive Epilepsy Center.

During these studies, seizure medications might be withdrawn or reduced to provoke seizures. "Analysis of the brain's electrical activity and the patient's behavior during seizures allows us to classify seizure types in most patients, and locate their source," Dr. Raghavan says. "Seizures arising from a localized brain region, often referred to as 'partial epilepsy,' are the ones we can hope to eliminate using surgery," he says. Patients with so-called 'generalized epilepsy' - where seizures start simultaneously across the whole brain - cannot be offered epilepsy surgery. "It is also not uncommon that video-EEG monitoring often reveals that the condition the patient has is not epilepsy at all," Dr. Raghavan says.

Evaluating Patients for Epilepsy Surgery
For patients who are being evaluated for epilepsy surgery, further tests are often used to pinpoint the location of the seizure-generating brain areas, and also identify what functions that region of the brain might be involved. "It is in our ability to image and visualize areas of both brain dysfunction and function that some of the biggest strides are being made in refining epilepsy surgery," Dr. Raghavan notes. An essential test to visualize structural abnormalities in the brain that are often the basis of epilepsy is high-resolution MRI.

"In some cases," he says, "we use a brain imaging test called Single Photon Emission CT, or SPECT, to measure the relative blood flow in various regions of the brain during seizures. When patients begin to experience seizures, they are injected with a radioactive tracer (similar to that used in diagnostic tests for heart disease, for example). They subsequently undergo a brain scan. The brighter areas can indicate the area of brain in which the seizure began. SPECT studies between seizures may show areas of lower than normal brightness in these same areas.

"The changes may be subtle sometimes, but computing tools available at the Medical College allow us to compare quantitatively the differences being those scans acquired during and those between seizures. These differences often reveal the areas involved in seizures," he says.

Patients also undergo comprehensive neuropsychological evaluations, and often need a procedure called the Wada test to determine memory and language functions in the two halves of the brain. The Wada test involves positioning a fine catheter in the arteries on either side of the neck and injecting a short-acting medication to suppress the functioning of one hemisphere of the brain. By suppressing each hemisphere of the brain in turn, the neuropsychologist and neurologist can assess language and memory functions of each hemisphere and determine the safety of proceeding with surgery.

Positron Emission Tomography (PET) is another brain imaging tool available at the Medical College. It is often useful for locating seizure-generating regions of the brain, especially when other tools do not clearly identify the region.

Surgical Procedures
When the area causing seizures is far removed from areas that have important brain functions, the surgical procedure is not unlike other kinds of brain surgery. However, if language, motor or visual areas are located close to the surgical target, the neurosurgeon may choose to wake up the patient during surgery and electrically map out the region to avoid damaging critical functions. This kind of "awake surgery" lessens the risk of neurological deficits from the surgery, Dr. Raghavan says.

In some patients, accurate identification of the areas producing seizures may require the recording of electrical activity directly from the surface of the brain. In these instances a two-stage epilepsy surgery is often undertaken. During the first stage of the surgery electrical contacts embedded in sheets or strips of thin plastic are placed over the brain surface, and the surgical wound is closed over. The patient undergoes EEG monitoring using the electrodes placed on the brain, and this technique is usually able to pinpoint the tissue that needs to be targeted for surgery. The same electrical contacts are often used to electrically map out important functions in the vicinity. In the second stage of surgery, the areas triggering seizures are removed while avoiding critical areas.

Surgery has the potential to relieve seizure activity in more than 80% of patients with epilepsy arising from the temporal lobes. But, Dr. Raghavan notes, after five to 10 years, "a significant number of patients - estimated at around 45% to 50% - may relapse. This failure of surgery is the subject of intense research. Recent data suggests that the biggest predictor of relapse is the number of years for which a patient experienced uncontrolled seizures before undergoing surgery. I think we are learning that surgery should not be put off as a last resort - for some patients it may be best to pursue this option as soon as it is evident that medications are not likely to control seizures."

For patients who are not candidates for surgery, or those who opt for alternatives to epilepsy surgery, vagus nerve stimulator (VNS) implants may provide significant relief. These devices, which have been used at the Medical College for the past decade, help prevent seizures by sending regular, mild pulses of electrical energy to the brain via the vagus nerve, somewhat the way a pacemaker stimulates the heart. Like a pacemaker, the device is placed under the skin on the chest wall.

Advanced Diagnostic and Treatment Techniques Under Development
The faculty at the Comprehensive Epilepsy program, in collaboration with other researchers at the Medical College and elsewhere in the country, are actively exploring newer techniques for the diagnosis and treatment of epilepsy.

Researchers at the Medical College pioneered the development of functional Magnetic Resonance Imaging, or fMRI, beginning in 1992, and they remain international leaders in the field. "The Medical College is one of the leading centers that have developed fMRI as a tool for mapping language and memory function before epilepsy surgery," Dr. Raghavan says. This effort is lead by Jeffrey R. Binder, MD, Professor of Neurology at the Medical College, and is supported by a grant from the National Institutes of Health. "Locating the regions of brain dysfunction can often provide strong clues to the location of epileptic areas that can be targeted surgically," Dr. Raghavan says, adding that the techniques pioneered by Dr. Binder's group may eventually replace invasive procedures such as the Wada test.

More recently, Medical College researchers and epilepsy specialists have been exploring newer MRI brain imaging technologies to assist in the planning of epilepsy surgery. These include Tensor Diffusion Imaging, which allows visualization of "white matter" bundles of the brain in detailed, 3-dimensional views to accurately locate surface features of the brain before surgery; and electrical "source imaging" which helps identify the generators of epileptic activity within in the brain based on EEG recordings.

Dr. Raghavan notes that "the networks in the brain that produce seizures may be more extensive than previously believed, and may gradually expand over the many years that a patient has uncontrolled epilepsy." Unfortunately, he adds, "there are currently no good tools for imaging the full extent of these epileptic networks. One of our hopes is that fMRI and electrical imaging tools will prove useful in this effort." Some of his own research focuses on this area.

"We are also currently developing experimental treatment protocols to use novel brain stimulation techniques to treat epilepsy patients who are not candidates for conventional surgery," he says.

For additional information, patients may call the Comprehensive Epilepsy Center at 414-805-5206.

Barbara Abel
HealthLink Contributing Writer

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.