Abstract and Introduction
Abstract
We evaluated our clinical experience with zonisamide, a broad-spectrum antiepileptic drug, in a group of children with predominantly medically refractory epilepsy. A retrospective chart review was conducted on patients at our tertiary referral center following Institutional Review Board approval. Observers documented reports of seizure frequency, and seizure types were identified either clinically or by prior video-electroencephalography monitoring. We identified 68 patients (age range 1.9-18.1 years [median 6.9 years]; male to female ratio 1.3:1) treated with zonisamide for 0.7 to 28.9 months; at the last visit, 22% and 78% were on monotherapy and adjunctive therapy, respectively. The median duration of treatment and maintenance dose at the end of the follow-up were 11.2 months and 8.0 mg/kg/day, respectively. Seizure types included generalized (primary generalized tonic-clonic, myoclonic, tonic, atonic, absence) and partial (simple, complex, and secondarily generalized tonic-clonic seizures); 10 (15%) patients had both partial and generalized seizures. Sixteen (25.8%) patients were seizure free, although five of them were already in remission prior to starting zonisamide. Thirteen (21.0%) patients had a = 50% seizure reduction, 10 (16.1%) patients had a < 50% seizure reduction, 14 (22.6%) had no improvement in baseline seizures, and 9 (14.5%) reported having increased seizures. The latter were mostly associated with dosage alterations in concomitant antiepileptic drugs. Common side effects were central nervous system related, including behavioral or psychiatric (23.5%), cognitive dysfunction (12.0%), and sedation (10.3%). Eleven (16.2%) patients ultimately discontinued zonisamide, but only five were strictly due to side effects. Zonisamide is clinically effective against multiple seizure types in a significant proportion of children with epilepsy across a broad age range. Drug discontinuation as a result of side effects is uncommon.
Introduction
Zonisamide (3-sulfamoylmethyl-1,2-benzisoxazole) is an antiepileptic drug recently approved in the United States for adjunctive use against partial seizures in adults. It is chemically distinct from other conventional antiepileptic drugs. Zonisamide possesses a broad spectrum of mechanistic actions that, in part, overlap the actions of phenytoin, carbamazepine, and valproate.
In vitro studies have demonstrated that zonisamide inhibits sustained repetitive action potentials in spinal cord neurons, enhances Na-channel inactivation in Myxicola giant axons, and blocks T-type Ca channels in rat cortical neurons. Although zonisamide also binds to the ?-aminobutyric acid (GABAA)-benzodiazepine receptor complex and inhibits carbonic anhydrase, these actions might not contribute significantly to its anticonvulsant effect.
This mechanistic profile of zonisamide predicts broad efficacy in animal models of epilepsy. Zonisamide suppresses both interictal cortical spikes and cortical seizure propagation. It exerts a depressant effect on kainic acid-induced and kindled limbic seizures. Zonisamide also blocks seizures induced by maximal electroshock and has variable effects on pentylenetetrazole-induced seizures.
Consistent with predictions from these in vitro and in vivo studies, zonisamide appears to ameliorate a broad range of seizure types in humans. Its efficacy in controlling partial seizures with or without secondary generalization was demonstrated by two multicenter, randomized, controlled, adjunctive treatment trials in adults.
There are limited data from systematic studies regarding zonisamide use in pediatric patients. Children possess a broad range of epilepsies and underlying etiologies, many of which are distinct from those in adults and fail to respond to first-generation antiepileptic drugs. In addition, use of antiepileptic drugs in children is confounded by age-dependent pharmacokinetic variables. Therefore, there is a need to determine the safety, efficacy, and tolerability of newer antiepileptic drugs (such as zonisamide) in children of varying ages. These issues initially can be explored using retrospective observational studies as a prelude to more costly, systematic, randomized controlled trials. We present our clinical experience with the use of zonisamide in the treatment of pediatric patients with epilepsy at a tertiary care referral center.