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Management of cyclic vomiting syndrome in adults is limited by the small number of effective medications for maintenance therapy. The clinical response to treatment with 2 newer antiepileptic drugs was evaluated retrospectively to see whether they might have a prophylactic role in this syndrome.Outpatient records from 20 adult patients with cyclic vomiting syndrome attending a university-based practice were reviewed. Each had received zonisamide (median dose, 400 mg/d) or levetiracetam (median dose, 1000 mg/d) because tricyclic antidepressants alone were unsatisfactory as maintenance medications. Outcome was graded from chart review and directed interview; characteristics of the vomiting episodes were compared before and after initiation of antiepileptic drug therapy.At least moderate clinical response was described by 15 (75.0%) subjects, and 4 of these (20.0% of the total) reported symptomatic remission during 9.5 ± 1.8 months of follow-up. Rate of vomiting episodes decreased from 1.3 ± 0.3 to 0.5 ± 0.2 per month (P = .01). Tricyclic antidepressants were discontinued in 11 (61.1%) of the 18 subjects who were still taking the medications when antiepileptic drug therapy was initiated. Moderate or severe side effects were reported by 45.0%, but by switching drugs, intolerance to antiepileptic drug therapy occurred in only 1 subject.Newer antiepileptic drugs, specifically zonisamide and levetiracetam, appeared beneficial as maintenance medications for nearly three fourths of adults with cyclic vomiting syndrome in this uncontrolled clinical experience. Although side effects occur in a large proportion of subjects, newer antiepileptic drugs might offer an alternative for patients who fail conventional treatment.