Epilepsy is a group of disorders of the brain characterized by recurring episodes of convulsive seizures, sensory disturbances, abnormal behaviour, loss of consciousness, or all of these. In all types of epilepsy, an uncontrolled electrical discharge from the nerve cells in the cerebral cortex of the brain is evident. While the cause of most types of epilepsy is unknown, it can be associated with head injury, infection, brain tumour, intoxication, or chemical imbalance.
Topiramate is a new drug that has shown promise in the treatment of epilepsy. Since preliminary evaluation has been encouraging, double-blind, placebo-controlled trials were established in an effort to better define the effectiveness, safety and appropriate dose range of topiramate for refractory partial epilepsy. The objective of this study was to evaluate a medium-to-high dose range consisting of daily dosages of 600, 800, and 1,000 mg of topiramate.
A total of 190 patients with epilepsy, aged from 18 to 68, were enrolled in the study. Over 90% of the patients had a history of complex partial seizures, and over 60% also had secondary generalized seizures. Patients were randomly assigned to one of four groups: placebo (47 patients), 600 (48 patients), 800 (48 patients), or 1,000 (47 patients) mg topiramate (Topamax) per day.
During the 18-week treatment period, the rate of reduction in average monthly seizure rates was 1% for placebo, 41% for 600 mg/day and 800 mg/day topiramate, and 38% for 1,000 mg/day topiramate. Patients who experienced a 50% or greater reduction in the frequency of seizures included 9% of those in the placebo group, 44% in the 600 mg/day topiramate group, 40% in the 800 mg/day topiramate group, and 38% in the 1,000 mg/day topiramate group. While none of the patients in the placebo group experienced improvement of 75% to 100% in the frequency of seizures, 20% of the patients given topiramate were improved to this extent. Topiramate therapy was discontinued in 16% of patients because of side effects, the most common of which were dizziness, headache, fatigue and confusion.
The results of this study indicate that topiramate is highly effective and generally well tolerated in the treatment of refractory partial epilepsy. Dosages of topiramate greater than 600 mg/day do not appear to result in significantly greater effectiveness and may result in more side effects. However, individuals who are able to tolerate higher dosages may receive additional benefit. The investigators suggest that future studies should be aimed at better characterization of the adverse effects of topiramate. Evaluations of the safety and effectiveness of smaller doses and smaller dosage increments are also indicated.
1. Would topiramate be effective in the treatment of other forms of epilepsy, or only refractory partial epilepsy?
The primary studies that have been completed and were submitted to the U.S. FDA for approval were conducted in patients with refractory partial epilepsy. Open-label studies of this medication included patients who had other types of epilepsy and anecdotal experience suggests the drug may be effective in other seizure types. There are currently ongoing studies looking at other seizure types such as generalized epilepsies and the Lennox-Gastaut Syndrome. The Lennox-Gastaut syndrome is a severe form of epilepsy typically seen in childhood and is considered one of the most difficult epileptic syndromes to treat. Results of these studies may be presented at national meetings in the next year or two.
2. Is topiramate synthetic or derived from a natural substance? How was it discovered?
Topiramate is a synthetic compound developed by the Johnson & Johnson Pharmaceutical Research Institute. Its effectiveness in epilepsy was discovered through the collaborative program of the National Institutes for Health Epilepsy Branch. The Epilepsy Branch program allows corporations to submit compounds that might be effective in epilepsy to be evaluated in a series of animal tests and compared to standard antiepileptic drugs. This program has screened thousands of compounds over the last two decades. Topiramate was one of the compounds found to be highly effective in animal models and so was moved on to testing in humans with epilepsy.
3. Are there any trials planned to compare the efficacy and safety of topiramate with other similar drugs?
Most experts in the field feel that such trials are definitely necessary in order to compare the efficacy and tolerability of these medications. Unfortunately, these comparative trials require large numbers of patients, a tremendous effort to organize, and are extremely costly. It is my understanding that several companies have preliminary plans for such comparative trials. At the present time I am not involved in any of these trials and do not believe that any comparative trials are ongoing in the United States.
4. What is known about the long-term effects of topiramate (Topamax)?
In the database submitted to the FDA consisting of approximately 3,000 patients, there did not seem to be any consistent abnormalities of the function of the liver or bone marrow as seen with some other medications. Some patients at the University of Cincinnati Epilepsy Treatment Center have been on the medication for over eight years without significant problems.
5. Has its safety in children been evaluated?
Trials evaluating topiramate’s safety and effectiveness in children are currently underway. Preliminary data are encouraging; however, we must wait for the final results of these efficacy and safety trials in order to fully determine its role in the treatment of children.