Zonisamide add‐on for drug‐resistant partial epilepsy
Abstract
Background
The majority of people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding zonisamide, when used as an add‐on treatment for drug‐resistant partial epilepsy.
Objectives
To evaluate the efficacy and tolerability of zonisamide when used as an add‐on treatment for people with drug‐resistant partial epilepsy.
Search methods
We searched the Cochrane Epilepsy Group Specialized Register (12 February 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1) (January 2013), MEDLINE (Ovid, 1946 to 12 February 2013), SCOPUS (13 February 2013), ClinicalTrials.gov (12 February 2013) and the WHO International Clinical Trials Registry Platform ICTRP (13 February 2013). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing/unpublished studies.
Selection criteria
Randomised, placebo‐controlled, add‐on trials of zonisamide in people with drug‐resistant partial epilepsy.
Data collection and analysis
Two review authors independently selected trials for inclusion and extracted data. Outcomes were: (1) 50% or greater reduction in total seizure frequency; (2) treatment withdrawal; (3) adverse effects. Primary analyses were intention‐to‐treat. We estimated summary risk ratios (RRs) for each outcome. All studies were assessed for risk of bias using the Cochrane risk of bias tool and the quality of evidence was assessed using the GRADE approach and presented in a summary of findings table.
Main results
Five trials (949 participants) were included. The overall RR with 95% confidence interval (CI) for 50% reduction in seizure frequency compared to placebo for 300 to 500 mg/day of zonisamide was 2.00 (95% CI 1.58 to 2.54). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 to 500 mg per day) was 1.92 (95% CI 1.52 to 2.42). The number needed to treat (NNT) was 6 for this outcome. Two trials provide evidence of a dose response relationship for this outcome. The RR for treatment withdrawal for 300 to 500 mg/day of zonisamide compared to placebo was 1.64 (95% CI 1.20 to 2.25) and for 100 to 500 mg per day was 1.47 (95% CI 1.07 to 2.01). NNT for this outcome was 21. The CIs of the following adverse effects indicate that they are significantly associated with zonisamide: ataxia 3.77 (99% CI 1.28 to 11.11); somnolence 1.83 (99% CI 1.08 to 3.11); agitation 2.35 (99% CI 1.05 to 5.27) and anorexia 2.71 (99% CI 1.29 to 5.69). Across the 5 studies, risk of bias domains were rated as low is bias or unclear. None of the evidence for outcomes was downgraded for quality.
Authors' conclusions
Zonisamide has efficacy as an add‐on treatment in people with drug‐resistant partial epilepsy. In this review minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of a maximum stable‐dose phase of 18 weeks in duration and results cannot be used to confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.
PICOs
Plain language summary
Zonisamide add‐on for drug‐resistant partial epilepsy
Zonisamide in combination with another antiepileptic drug can reduce seizures, but with some adverse effects.
Around 70% of epileptic patients can become seizure‐free with antiepileptic drug treatment. The remaining 30% of people with epilepsy may be resistant to antiepileptic drugs and still experience seizures. Older drugs do not prevent seizures for everyone and they have adverse effects. New drugs have been developed to try to treat those people who are resistant to the old drugs and to try to limit the adverse effects. These newer drugs are taken as well as the patient's existing medication, as an 'add‐on' treatment. Zonisamide is used as an add‐on treatment.
A search of databases was carried out on 12/02/2013. Five trials were found which included 949 people with partial epilepsy. These trials were all randomised controlled trials which compared the antiepileptic drug Zonisamide to a placebo drug for a period of 12 weeks. Taking all the evidence of the trials into account, the review found that seizure frequency was significantly reduced for people with drug‐resistant partial epilepsy if zonisamide is added to their usual treatment. Patients treated with 300 to 500 mg/day of zonisamide were twice as likely as people given placebo tablets in addition to their usual treatment to experience at least a 50% reduction in the frequency of their seizures. However, adding zonisamide to the usual treatment is associated with an increase in adverse effects such as problems with co‐ordination (ataxia), drowsiness (somnolence), agitation and anorexia.
The trials were assessed with regards to bias and quality and overall, the quality of the evidence was rated as high quality. However more research is need which concentrates on examining the dose of zonisamide.
