Drug Development, Advanced Imaging, Surgical Experience Fuel Unrivaled Care

At UAB’s Level IV comprehensive epilepsy center — the highest designation given by the National Association of Epilepsy Centers — patients receive expert, broad-based care, support, and education for seizure conditions and related comorbidities, as well as the socioeconomic issues so often associated with epilepsy, says Professor and Director R. Edward Faught Jr, MD.

The UAB Epilepsy Center began as an Epilepsy Foundation-sponsored clinic in 1980. In 1983 the medical center added an inpatient seizure monitoring unit and in 1985 established the epilepsy surgical treatment program. A year later the epilepsy program grew into a multidisciplinary center drawing on faculty from the departments of neurology, pediatric neurology, neurosurgery, neuropsychology, and others. The center’s core faculty now includes five adult neurologists, four pediatric neurologists, two neurosurgeons, two doctors of pharmacy, and a large staff of research nurses and research assistants.

“We have the necessary technology and treatment techniques to provide our patients with state-of-the-art care. As a comprehensive epilepsy center, our mission also is to address the full scope our patients’ needs, which can include psychosocial issues,” Faught says. “People with epilepsy often have trouble finding or holding a job, yet do not always qualify for Social Security disability benefits. Through connections with social services, the Epilepsy Foundation, and drug assistance programs, we can help patients find employment or seek disability and assist with obtaining medications, which many people with epilepsy cannot afford.”

Center physicians are adept at identifying conditions that coexist with epilepsy and provide treatment or specialist referral, Faught says. “We have, for example, a dedicated clinic for women with epilepsy to meet the special needs of patients of childbearing age. Women receive counseling and education about issues related to birth control, pregnancy, and child care.”

Drug Development
With one of the largest clinical trials programs in the Southeast, the UAB epilepsy program has been at the forefront of antiepileptic drug (AED) development since the 1980s, when the National Institutes of Health began emphasizing the need for novel, effective medications. “Prior to 1993 no drugs for epilepsy had been introduced for more than 20 years. Since then 15 new medications have become available,” Faught says. “UAB participated in trials of 12 of those medications and was the leading center for patient enrollment for 5 of the new drugs.”

AED development continues, and UAB currently has three medications in clinical trials. “The drugs under investigation are designed primarily for patients who have not achieved complete seizure control with other medications,” Faught says. “The latest generation of drugs can potentially offer benefits beyond seizure control. Many recently developed AEDs have other effects on the nervous system and have some efficacy for treating conditions such as migraine and mood disorders, both of which are common among epilepsy patients.”

Faught is principal investigator for UAB’s AED development trials, which include a multicenter randomized placebo-controlled trial of ganaxolone, one of a new class of anticonvulsants that modulate GABAA receptors.

Investigators are evaluating the drug’s efficacy and safety as an add-on therapy in patients of both genders with uncontrolled partial-onset seizures and in women with catamenial epilepsy — a condition in which seizure activity increases around the time of ovulation or menstruation. “Ganaxolone is chemically similar to progesterone, which suppresses seizures. The drug avoids the negative hormonal effects of progesterone and may be particularly useful in women whose seizure frequency is linked to their menstrual cycle.”

Faught notes the primary benefit of newer AEDs is fewer negative side effects. “We need more options,” he says, “as current drugs leave up to 30% of patients with inadequate seizure control.”

Patients with difficult-to-diagnose epilepsy or who have medically uncontrolled seizures undergo evaluation at UAB Hospital’s Penfield Epilepsy Service — the center’s inpatient monitoring unit. Epileptologists use the eight-bed unit for long-term (usually 3-5 days) electroencephalogram (EEG) recording of brain waves and videotaping of seizure activity.

“Inpatient evaluation helps us confirm diagnoses of epilepsy, classify individuals’ seizure type, and determine the site of seizure focus, which is crucial for epilepsy surgery evaluation,” Faught says. “Intensive studies help us direct patients to the most appropriate treatments.”

The service evaluates about 50 adult patients per month. Epileptologists assess younger patients at Children’s Hospital of Alabama’s four-bed inpatient unit.

Neuroimaging
UAB has a long history of investing in emerging imaging tools and was well positioned to take advantage of the technological boom that began in the 1990s and continues today, says Epilepsy Center Co-Director Robert C. Knowlton, MD, MSPH, who also directs the inpatient seizure monitoring unit and the Health Services Foundation Magnetoencephalography (MEG) Laboratory. UAB’s imaging capabilities are expanding as new technologies become available. Imaging tools currently include:
• MEG-based magnetic source imaging
• High-resolution magnetic resonance imaging (MRI), including two 3-Tesla MRI scanners
• Combined EEG and functional MRI (fMRI)
• Ictal single photon emission computed tomography
• Position emission tomography
Only a handful of US epilepsy centers offer all these capabilities, Knowlton says. “The EEG-fMRI is the latest advance in imaging, and we have begun studies to compare its efficacy in presurgical brain mapping with other technologies. EEG-fMRI simultaneously records and correlates scalp EEG events, which reflect electrical brain changes, with fMRI data that show associated hemodynamic changes,” he says. “EEG-fMRI identifies functional abnormal brain areas with high spatial resolution — information other noninvasive imaging tools cannot capture.”

Multiple, complementary imaging technologies allow epileptologists and neurosurgeons to better select surgical candidates. “Many imaging tools are so new that we are still studying their clinical impact,” Knowlton says. “It is clear, however, that advanced neuroimaging capabilities are increasing the pool of surgical candidates; these technologies allow us to locate seizure foci we could not identify in the past and give surgeons much more information to guide procedures.”

Faught notes, “Surgical treatment is the best chance for patients with intractable epilepsy to achieve complete seizure control. Both physicians and patients often view epilepsy surgery as a treatment of last resort, which is a major misconception. Surgery is an effective, standard treatment that has been available for half a century,” he says. “People with medically refractory epilepsy should be evaluated for surgery early, ideally when trials of no more than two medications have failed to completely control seizures. Too many epilepsy patients live with uncontrolled seizures. Earlier evaluation can mean decades of improved quality of life for patients who might otherwise try and fail multiple medications.”

Knowlton agrees. “I think there is sometimes a mistaken view that patients who are having limited seizures have achieved adequate control, but the bottom line is that epilepsy is not effectively treated until a person is seizure free.”

After a patient undergoes comprehensive evaluation of their seizure condition, all experts involved — neurologists, neurosurgeons, neuropsychologists, and nurses — discuss the case and provide a joint recommendation for optimal care. “Bringing together all data to make the best decision for the patient is one of the primary functions of a comprehensive epilepsy center,” Faught says.

Pediatric Epilepsy Surgery
Up to 40% of people with epilepsy will not achieve complete seizure control with medication, says UAB pediatric neurosurgeon Jeffrey P. Blount, MD. “These individuals tend to be patients with structural abnormalities in the brain, and children are disproportionately represented in this group.”

Functional imaging advances allow surgeons to precisely map seizure foci and remove these areas with low risk to the patient, Blount says. “Cortical dysplasias, the most common congenital brain abnormality, are the major cause of medically refractile pediatric epilepsy.” He notes cortical dysplasias — malformations of cortical development that lead to disorganization of the cerebral cortex — went unrecognized as distinct pathological entities until the 1980s and are still widely missed outside of epilepsy centers.

Temporal lobectomy is the most common surgical intervention among adults with epilepsy. Children with seizure conditions are much less likely to undergo lobectomy, Blount says, as cortical dysplasias arise in the neocortex. “Cortical dysplasias can look and act like normal tissue and require refined invasive monitoring to identify accurately,” he says.

“Localization of the seizure focus and determination of surgical candidacy rests on mapping the semiology of the seizure and on test concordance, which is achieved when different modalities implicate the same region and spread pattern in the brain,” says Blount.

Once epileptologists and neurosurgeons identify the most likely region of seizure origin, they perform a two-step procedure: Surgeons place grids directly on the brain surface, where they remain for several days and let surgeons observe electrical activity and seizure spread. Based on grid monitoring, surgeons can better define the chances of ending or attenuating seizures with surgery. If substantial improvement through surgery is highly probable, the operation proceeds.

“If grid findings show seizures involve eloquent areas, we must carefully consider the risks of introducing neurological deficits,” he says. “This is an individualized, prolonged decision-making process involving the family, the surgeon, and the epileptologist. Surgery is only considered when it could provide sufficient seizure control to warrant the possible introduction of a neurological deficit. Families whose children have severe, frequent seizures sometimes are willing to trade the unpredictability of epilepsy for a fixed deficit.”

A significant number of pediatric patients at UAB and Children’s Hospital undergo functional hemispherectomies. “We no longer remove half the brain as was done with anatomical hemispherectomy,” he says. “Advanced techniques allow us to leave a larger portion of tissue in place, which maintains spinal fluid dynamics and avoids hemosiderosis — the major complication of anatomical hemispherectomy.”

Blount also performs corpus callosotomy for children who have tonic or atonic drop events. “Sectioning the major fiber tract that links the left and right brain decreases spread of epileptic discharge,” he says. “This is not a curative operation but is highly effective for eliminating drop events, which cause serious injuries.”

Implantable vagus nerve stimulators also are an option for children who have drop events and for those with medically refractile multifocal epilepsy.

Virtually all epilepsy surgical series show that between 70% and 80% of people with epilepsy had seizures begin in childhood, Blount says, noting that after a child has failed two medications, it is time to consider surgical evaluation.

Although seizure freedom is the ideal goal for all pediatric surgeries, Blount says that improved seizure control can make substantial, favorable differences in children’s lives. Frequent seizures significantly impair children’s cognitive development, limiting their potential to grow into productive adults. Eliminating or reducing seizures also improves learning ability and can dramatically increase self-esteem and social skills.

“Carefully designed surgical intervention can make a tremendous difference in the lives of children who may be seizing 50 to 100 times a day with devastating effects,” he says. “Reducing seizure frequency can change the lives of these children and their families, but surgery is still grossly underutilized in the pediatric population. The overwhelming majority of our pediatric surgery patients experience significant improvements. Surgery should be considered very early in the course of treatment — not years later when cognitive deficits are irreversible.”

Adult Epilepsy Surgery
All adults with epilepsy who are not seizure free with medical therapy should be assessed for surgery, says UAB neurosurgeon Kristen Riley, MD. “The average time for referral for surgical evaluation is 14 years. Although only 10% to 15% of adults with medically refractile epilepsy are surgical candidates, a significant number with localized epilepsy could have been seizure free years ago through surgery,” she says, noting that adults with temporal lobe epilepsy whose imaging studies show concordant data indicating a well-localized seizure focus have an 85% chance of achieving seizure freedom with surgery.

“If there were an anticonvulsant with an 85% cure rate, it would be widely used,” she says. “The only way to identify surgical candidates is through an evaluation including inpatient EEG monitoring, noninvasive imaging studies, and occasionally invasive monitoring. Invasive monitoring with grids is becoming more common as imaging techniques improve,” says Riley. “We want to work with referring physicians to evaluate their epilepsy patients for surgery as early as possible in the course of their condition.”

Genetics of Epilepsy
UAB is 1 of 13 centers in the nation that will participate in the Epilepsy Phenome/Genome Project (EPGP), a 5-year, $15 million study investigating the complex genetic factors that underlie both common and rare forms of epilepsy. The EPGP, which is funded by the National Institute of Neurological Disorders and Stroke, is recruiting more than 3700 epilepsy patients and 3000 controls, including 1500 sibling pairs with epilepsy and 750 patients with rare epilepsies and their families.

“During the first phase project investigators will collect information about phenotypic features in a rigorous, consistent fashion,” explains Knowlton, who is principal investigator for the UAB site of the EPGP. Family and medical histories, EEGs, imaging studies, treatment response information, and blood or saliva samples will be amassed and archived in a central data repository. Later phases will involve whole genome scans of genetic material and investigation of potential connections between participants’ DNA sequences and phenotypic characteristics.

UAB, one of the initial four epilepsy centers that began recruitment this fall (others begin activities in 2008), will enroll 300 patients. Candidates are individuals aged 4 weeks to 50 years with generalized or localized epilepsy who have a sibling who can participate and patients with infantile spasms, Lennox-Gastaut syndrome, polymicrogyria, and periventricular heterotopia who have parents who can donate DNA.

“The project’s ultimate goal is to identify new molecular targets for drug development, individualize therapy by revealing mechanisms of treatment response, and eventually, prevent the disease in people at risk,” Knowlton says.

For more information:
Dr. Edward Faught
Dr. Robert Knowlton
Dr. Jeffrey Blount
Dr. Kristen Riley
1.800.UAB.MIST
mist@uabmc.edu
1.800.UAB.MIST
mist@uabmc.edu