Update on Epilepsy Treatment
This report was reviewed for medical and scientific accuracy by Douglas S. Stuart , Peachtree Neurological Clinic, Atlanta, Georgia.
Scientists from many parts of the world shared their research at this year's American Academy of Neurology (AAN) Meeting in San Diego, CA. Over 120 presentations featured information on different aspects of epilepsy. Topics included new antiepileptic drugs (AEDs), epilepsy in the elderly, metabolic bone disease and epilepsy, cost-effective management of prolonged or repetitive seizures, and vagus nerve stimulation (VNS).
New Antiepileptic Drugs
Dr. Richard Mattson, Professor of Neurology at Yale University School of Medicine, summarized the indications, efficacy, and side effects of the eight new antiepileptic drugs (AEDs) that have become available since 1993; felbamate (Felbatol®), gabapentin (Neurontin®), lamotrigine (Lamictal®), levetiracetam (Keppra®), oxcarbazepine (Trileptal®), tiagabine (Gabitril®), topiramate (Topamax®), and zonisamide (Zonegran®). He noted that even the older drugs such as carbamazepine (Tegretol®), divalproex sodium (Depakote®), phenobarbital, and phenytoin (Dilantin®) will control 70 percent of patients. With combinations of two or three drugs, more patients are able to achieve seizure control. However, approximately 20-25 percent of people with epilepsy continue to have seizures. In addition, there are patients who achieve seizure control, but at the price of intolerable side effects from the medication.
Dr. Mattson instructed the physicians in the audience to "personalize and individualize the drugs to the patient's needs." With respect to the new AEDs, he commented, "some of them seem to be considerably safer. Many of them are very well tolerated." However, he emphasized that there is no clear superiority among the group of new drugs. Regarding a drug of choice, "there isn't one."
Dr. Susan Spencer, also a Professor of Neurology at Yale, recommended that physicians not give up hope even on patients who have had seizures for many years. She encouraged physicians to continue to work with their patients to find a drug that eliminates their seizures. "Refractory epilepsy can become controlled after having been medically intractable for many years."
Dr. Karsten Krakow and colleagues from the United Kingdom and Belgium presented the results of clinical trials of levetiracetam (Keppra®), a new antiepileptic drug approved this year by the Food and Drug Administration (FDA). Eleven percent became seizure free, while 19 percent of patients had a 75 percent seizure reduction and 38 percent of patients had at least a 50 percent decrease in seizures.
Side effects were mostly mild, including dizziness, fatigue, and sleepiness. Researchers have not yet learned the drug's mechanism of action. Levetiracetam is manufactured by UCB Pharma, a Belgian company.
Dr. Kazuichi Yagi, Dr. Shizuoka-Shi, and Dr. Michael Privitera authored an abstract on zonisamide (Zonegran®). Manufactured by Elan Pharmaceuticals in San Francisco and marketed in Japan since 1989, zonisamide was approved by the FDA for the adjunctive treatment of partial seizures in adults with epilepsy in March of this year. Zonegran® is a sulfonamide and chemically unrelated to other AEDs. It appears to control seizures by blocking sodium and calcium channels.
In their post marketing study performed in Japan, the authors found that zonisamide monotherapy controlled seizures in 79 percent of newly diagnosed patients with temporal lobe epilepsy, and 84 percent of 243 patients with nontemporal lobe epilepsy.
In clinical trials, the most common adverse effects were somnolence, dizziness, anorexia, headache, nausea, and agitation/irritability. According to Dr. Maureen Li, Chief Resident in Neurology at the University of Cincinnati, who worked with Dr. Privitera on the study, zonisamide also has two side effects similar to topiramate (Topamax®)-weight loss and kidney stones.
Based on promising results from animal studies, Parke-Davis Pharmaceutical Research is investigating pregabalin for the treatment of epilepsy. Pregabalin, like gabapentin (Neurontin®), another Parke-Davis drug, has a chemical structure that resembles the brain neurotransmitter, gamma-aminobutyric acid (GABA). Pregabalin has not yet been approved by the FDA and does not have a brand name.
Dr. Bockbrader, from Ann Arbor, Michigan, presented the results of two phase I studies in 86 healthy volunteers. The volunteers tolerated the drug well for the most part, although some developed dizziness and sleepiness. Most of the pregabalin was excreted and remained unchanged in the urine. Parke-Davis will present more research results on pregabalin at the upcoming American Epilepsy Society Meeting in December of 2000.
Seizures in the Elderly
Dr. Flavia Pryor and the VA Cooperative 428 Study Group assessed the efficacy and tolerability of carbamazepine (Tegretol®), gabapentin (Neurontin®), and lamotrigine (Lamictal®) in 280 patients over age 60. Patients had seizures due to strokes (35.1 percent), cerebral arteriosclerosis (7.3 percent), and head trauma (7.3 percent). The cause of seizures in the remaining patients was unknown.
Many of the patients experienced side effects. Forty-seven percent had weight gain, 26 percent gastrointestinal problems, 21 percent weight loss, 38 percent sedation, 27 percent dizziness, 25 percent difficulty thinking, and 25 percent difficulty walking. Fifty-five percent of the patients stopped taking their medication because of side effects. At one year, about two-thirds of the patients who stayed on medications were seizure free.
The authors concluded that older patients are more susceptible to medication side effects than other patients. However, older patients have a good chance of controlling their seizures when they take AEDs. (Many older people do better when they begin their AEDs at lower doses and increase the doses more slowly than younger patients.)
Bone Disease in Epilepsy
Researchers from Michael Sperling's laboratory in Philadelphia, PA, evaluated the advantages of screening for osteoporosis and osteomalacia in epilepsy patients. Almost half of the patients they evaluated with a DEXA scan had abnormal results. Seizure frequency did not correlate with bone density, but a long duration of epilepsy did.
The reasons for this increase in bone disease are unclear, but may be related to AED therapy, epilepsy related hormonal changes, or activity levels. The authors recommend that physicians screen adults with epilepsy for metabolic bone disease.
Cost Savings in Epilepsy Treatment
Dr. Frank Ritter and colleagues, from St. Paul, Minnesota presented a cost analysis of 30 young children (5 years old or younger) who had been prescribed rectal diazepam gel (Diastat®). The FDA has approved Diastat® for the treatment of acute repetitive seizures.
Dr. Ritter's chart review revealed that home treatment with rectal diazepam was effective in treating prolonged and acute repetitive seizures in 96 percent of patients. Although each dose cost $81, the home treatment avoided many expensive visits to the emergency room ($1,303/trip), resulting in significant cost savings. Parents and caregivers also felt less helpless because they could administer the treatment themselves.
Vagus Nerve Stimulation
Research continues on the vagus nerve stimulator (VNS). The FDA approved the VNS in 1997 as adjunctive treatment for refractory partial onset seizures in adults and adolescents over twelve years of age. Manufactured by Cyberonics, the VNS has been used in over 6,000 patients worldwide. Dr. Christopher DeGiorgio and the E05 group studied 195 patients with intractable epilepsy and VNS and found that the device resulted in a 45 percent median reduction of seizures after one year.
Another group of researchers tried the VNS for nine patients who had essential tremor of both hands. Although the patients tolerated the VNS, objective evaluation of their tremors by videotape at the beginning and end of the trial did not show improvement. The investigators concluded that VNS does not significantly help essential tremor.