Zonisamide in children and young adults with refractory epilepsy: An open label, multicenter Italian study

doi:10.1016/j.eplepsyres.2008.10.012

Epilepsy Research

Volume 83, Issues 2–3, February 2009, Pages 112-116

https://doi.org/10.1016/j.eplepsyres.2008.10.012 Get rights and content

Summary

Purpose

To report on the first multicenter Italian experience with zonisamide as an add-on drug for refractory generalised or partial epilepsy in children, adolescents and young adults.

Methods

The patients were enrolled in a prospective, add-on, open-label treatment study from eight Italian centres for children and adolescent epilepsy care. Eighty-two young patients (45 males, 37 females), aged between 3 and 34 years (mean 13.1 years), all affected by partial (47) or generalised (35) refractory epilepsy, were enrolled in the study.

ZNS was added to the baseline therapy at a starting dose of 1 mg/kg/day twice daily. This dose was increased by 2 mg/kg every 1–2 weeks over a period of up 3 months, according to the patient's response and tolerability, up to a maximum dose of 12 mg/kg. ZNS was given at the mean daily dose of 5.7/mg/kg/24 h (range 1–12 mg/kg).

Results

After a mean follow-up period of 11.9 months (range 2–64 months), 9 patients (10.9%) were seizure-free. The number of seizures decreased by 50–99% in 31 cases (37.8%), by 25–49% in 5 cases (6.1%), remained the same in 29 cases (35.4%) and increased in 8 cases (9.7%).

After 15 months of follow-up, 61 patients (74.4%) were still taking ZNS, while the remaining 21 (25.6%) had stopped. Twenty-two patients (26.8%) reported adverse effects while taking ZNS. They generally appeared during the first weeks of treatment, and were mild to moderate. The most frequent adverse effects were irritability and a reduced appetite.

Conclusion

ZNS effectively reduced seizure frequency in this pediatric population with both partial and generalised crypto/symptomatic refractory epilepsy. Its overall tolerability was good.

Introduction

The novel antiepileptic drug zonisamide (ZNS) is characterised by a broad range of pharmacological effects associated with multiple mechanisms of action. These include a voltage-sensitive sodium and T-type calcium channel blockade, a reduction in glutamate-mediated synaptic excitation and enhanced inhibitory effects mediated by gamma-aminobutyrric acid (Biton, 2004).

Zonisamide has recently been approved in Europe for the adjunctive treatment of refractory partial seizures in adults. It has been available in Japan since, 1989, with studies there having established that ZNS is effective and safe for use in children (Ohtahara, 2006). Information from other countries concerning its use in pediatric patients is still somewhat limited. There are, however, a growing number of studies reporting the clinical efficacy of ZNS, both as add-on therapy (Kim et al., 2005, Mandelbaum et al., 2005; Santos and Brotherton, 2005; Ohtahara, 2006, Kluger et al., 2008) and as monotherapy (Miura, 2004, Seki et al., 2004, Kim et al., 2005, Kothare et al., 2006) in pediatric generalised and partial seizures.

The aim of this paper is to report on the first multicentre Italian experience with ZNS as an add-on drug for the treatment of refractory generalised and partial epilepsy in children, adolescents and young adults.

Section snippets

Methods

Patients were recruited in a prospective add-on, open-label treatment study from eight Italian centres for pediatric and adolescent epilepsy care. The patients were selected according to the following criteria: (1) age one year and over; (2) partial or generalised epileptic seizures refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination; (3) more than 1 seizure per month in the last 6 months; (4) use of at least one other AED, but no more than two, at

Results

Eighty-two young patients (45 males, 37 females), aged between 3 and 34 years (<6 years: 20.7%; 7–12 years: 35.4%; 13–18 years: 23.2%; >19 years: 20.7%: mean age 13.1 years), all affected by refractory epilepsy, were enrolled in the study. Patient diagnoses were as follows: symptomatic (28) and cryptogenic (19) partial epilepsy; symptomatic (19) and cryptogenic (16) generalized epilepsy (including 2 with Lennox–Gastaut syndrome, 3 with myoclonic–astatic syndrome, 6 with severe myoclonic

Discussion

In this study, ZNS as add-on therapy significantly reduced seizure frequency in approximately half of our patients who had partial or generalised epilepsy that had proved resistant to at least three previous antiepileptic drugs.

Few patients (10.9%), all of whom were in the cryptogenic group, became seizure-free. In addition, ZNS proved to be somewhat more effective in the treatment of partial seizures.

The overall response to ZNS observed in our study is in keeping with that reported in Japanese

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Short-term efficacy and safety of zonisamide as adjunctive treatment for refractory partial seizures: A multicenter open-label single-arm trial in Korean patients
2012, Seizure
Citation Excerpt :
The efficacy and safety of ZNS in partial epilepsy have been demonstrated in several pre-registration, randomized, double-blind, placebo-controlled studies in which this drug was administered as adjunctive therapy in drug-resistant epileptic patients with partial epilepsy.6–9 Long-term open studies as well as double-blind, placebo-controlled studies have demonstrated that ZNS has a good efficacy and tolerability profile, supporting its use as an adjunctive therapy for adult epileptic patients.10–15 A long-term open-label study13 in 317 patients with refractory partial epilepsy who completed a fixed-dose, randomized, double-blind, add-on trial4 showed that patient retention rates at 1, 2, and 3 years were 65.3%, 44.5% and 28.8%, respectively, comparable to those reported for other AEDs.
To evaluate the efficacy and safety of adjunctive zonisamide (ZNS) therapy in Korean adults with uncontrolled partial epilepsy.
Study patients had an average of at least one seizure per 4-week (averaged over a 12-week historical baseline) despite the use of one to three antiepileptic drugs. The starting dose of ZNS was 100 mg/day, and was increased to 200 mg/day after 2 weeks. During the 12-week maintenance period, the dose of ZNS was adjusted to 200–400 mg/day based on the physicians’ discretion. The global evaluation scale (GES) and quality of life (QOLIE-31) were also evaluated.
A total of 121 patients were enrolled, of which 88 patients completed the study. The median percent reduction in weekly seizure frequency over the treatment period was 59.0%. The ≥50% and ≥75% responder rates were 57.3% and 38.5%, respectively. Seizure freedom over the treatment period was observed in 25 patients, but seizure freedom throughout the 16-week treatment period was attained in only 16 patients. On investigator's GES, 84 patients were considered improved, with 33 patients showing marked improvement. In QOLIE-31 scale, seizure worry improved significantly but emotional well-being deteriorated. Treatment-emergent adverse events (AEs) were reported in 80 patients. The most common AEs were dizziness (28.1%), somnolence (24.0%), anorexia (18.2%), headache (14.0%), nausea (13.2%), and weight loss (10.7%). Twenty-two patients discontinued the trial due to drug-related AEs.
Our results suggest that adjunctive ZNS therapy for the treatment of refractory partial epilepsy, though efficacious, is associated with significant tolerability problems.
Antiepileptic drugs
2011, Side Effects of Drugs Annual
Citation Excerpt :
There were adverse effects in 45, which led to drug withdrawal in 24. In a prospective, add-on, open study in 82 patients, aged 3–34 years, with partial (n = 47) or generalized (n = 35) refractory epilepsy, zonisamide was started in a dosage of 1 mg/kg/day and increased by 2 mg/kg every 1–2 weeks over a period of 3 months up to a maximum dose of 12 mg/kg/day [439c]. After 12 months the mean dosage was 5.7 mg/kg/day and nine patients were seizure-free.
This chapter presents the studies of the effects of antiepileptic drugs. Clinicians have only recently realized that chronic adverse effects of antiepileptic drugs, mainly those involving central nervous system, may be more disabling to the patient than the seizures themselves. Up to a few years ago, the historical belief that seizure frequency is the major determinant of health-related quality of life and that adverse reactions are merely a secondary end-point was the prevalent opinion. It has been shown that changes in seizure rate among patients with drug-resistant epilepsy are only modestly correlated with the quality of life, while adverse reactions and depression are critical determinants of subjective health status. In an attempt to define specific patterns of adverse reactions and their clinical relevance to subjective health status, 200 subjects with epilepsy completed validated self-report health assessments, including the adverse event profile and quality of life in epilepsy inventory. The mean number of adverse reactions per subject was 6.5.
Effectiveness and tolerability of zonisamide in children with epilepsy: A retrospective review
2010, Seizure
Citation Excerpt :
There are no published randomised clinical trials (RCT) of zonisamide use in children. There are several open-label adjunctive or ‘add-on’ studies reporting on children with mostly refractory seizures.10,11,16–21 The responder rates, defined as a reduction in seizure frequency of at least 50%, range from 15% to 48.7%10,16–20 but the time that these responses have been evaluated has not been standardised.
To evaluate the effectiveness and tolerability of zonisamide in children with epilepsy.
Retrospective case note review of young people (less than 19 years) with epilepsy from three UK tertiary centres who received treatment with zonisamide and were followed up for a minimum of 12 months.
Fifty-seven children were included, aged 1.5–18.5 (median, 12) years. Thirty-three (57.9%) patients had generalised epilepsy, 21 (36.8%) focal epilepsy, and three (5.3%) a mixed, generalised and focal, epilepsy. Fifty-six of the 57 patients had been refractory to at least three previous antiepileptic drugs. The maintenance dose of zonisamide was [range (median)] 0.7–14 (5) mg/kg/day. The median duration of treatment for all patients was 12 (range 0.25–35) months. After 2 months of treatment, 51 patients remained on zonisamide, 18 (35.3%) of whom demonstrated a ≥50% reduction in seizure frequency. At the end of the follow-up period, there was a loss of effect for some patients. Thirteen (25.5%) of the 51 patients continued to demonstrate a ≥50% reduction in seizure frequency whilst two who had become seizure-free started having seizures again. Six (11.8%) had <50% reduction, twenty-four (47%) had no change, and eight (15.7%) had increasing seizures. Twenty-five (43.9%) patients reported unwanted effects although this contributed to the withdrawal of zonisamide in only ten (17.6%) patients.
Zonisamide appeared to be a reasonably effective and generally well-tolerated antiepileptic drug in a heterogeneous group of 57 children with poorly controlled epilepsy and provides another treatment option for children with refractory seizures.
Bioequivalence of Different Formulations of Zonisamide Oral Suspensions: A Short Review
2023, Patient Preference and Adherence
Effectiveness of zonisamide in childhood refractory epilepsy
2022, Child's Nervous System
Long-term effects of zonisamide in adult patients with intellectual disability
2021, Acta Neurologica Scandinavica

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Zonisamide in children and young adults with refractory epilepsy: An open label, multicenter Italian study

Summary

Purpose

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Eur. J. Paediatr. Neurol.

Pediatr. Neurol.

Pediatr. Neurol.

Zonisamide: newer antiepileptic agent with multiple mechanisms of action

Expert Rev. Neurother.

L’epilepsie myoclonicque severe du nourisson

Clinical efficacy of zonisamide in childhood epilepsy after long-term treatment: a postmarketing, multi-institutional survey

Seizure

Proposal for revised clinical and electroencephalographic classification of epileptic seizures

Epilepsia