Vigabatrin and epilepsy: Further lessons in early childhood

To the Editors: Levetiracetam (LEV) is considered a new antiepileptic drug with proven efficacy primarily as add-on treatment in adult patients with intractable partial seizures (Klitgard, 2001). In our ongoing uncontrolled, prospective open-ended clinical trial of LEV on patients with refractory epilepsy, we noticed a paradoxical increase in seizure frequency on LEV administration in 23.3%. We introduced LEV in 30 patients with difficult to treat epilepsy (25 partial seizures, 4 generalized seizures, 1 Lennox–Gastaut syndrome). The etiology of seizures was established in 13. Mean duration of epilepsy was 11.2 ± 7.2 years with mean duration of treatment as 6.3 ± 5.7 years. LEV was introduced in adults as 500 mg/day after 3 months of baseline period, and the dose was escalated by 500 mg/month. Mean seizure frequency (MSF) per month was recorded at each visit. The follow-up ranged from 2 to 20 months. MSF was reduced in 21 patients (>50% reduction in 18) and was unchanged in 2. Seven patients recorded a paradoxical increase in seizure frequency. All of them had complex partial seizures with long duration of epilepsy (>15 years in five, >10 years in two). Barring one, all were adults (mean age 32 ± 12.5 years) with four males. No specific EEG abnormality was noted. The etiology of epilepsy could be established in all but one (neurocysticercosis in three, focal cortical gliosis in two, left cerebral hemiatrophy in one). The increase in MSF ranged from 50% to several hundred times. The daily LEV dose at escalation was <1,000 mg in four, <2,000 mg in two, and >2,000 mg in one. Paradoxical increase was noted after 2–12 months of LEV introduction (<6 months in four). The escalated seizures were complex partial seizures in all but one, with generalized tonic–clonic seizures. None developed status epilepticus. The commonest concomitant AED was carbamazepine/oxcarbazepine. The paradoxical worsening was accompanied with adverse reactions like sedation in four and vertigo in two. Reduction in LEV doses resulted in decrease in seizures in 7–15 days. It reached below baseline frequency in four patients, returned to baseline in two, but persisted above it in one. The sedation and vertigo also disappeared on reduction of dose. In one patient with neurocysticercosis, the paradoxical increase was reported at a daily dose of 2,000 mg. On further escalation to 2,500 mg, seizure frequency increased by >1,000%. LEV dose was reduced to 1,000 mg with marked reduction in seizure frequency (150% of baseline). Addition of 250 mg LEV led to further aggravation of seizure by 200%, with reduction of seizures on cutting the dose back to 1,000 mg. The paradoxical exacerbation of seizures by LEV has been reported (Nakken et al. 2003). Exacerbation of seizures on reintroduction of LEV dose with decreased frequency on reducing the dose in one of our patients implies LEV as the aggravating factor and argues well against natural fluctuation of disease. Detailed pharmacokinetic studies with serum LEV level and clinical response are desirable to establish cause and effect.