Metronidazole-Induced Central Nervous System Toxicity: A Systematic Review

Objective: To assess patient and medication factors that contribute to metronidazole toxicity. Data Sources: We searched PUBMED from 1965 through April 7, 2011, and performed a hand search of bibliographies. Study Selection: Case reports or case series reporting metronidazole-induced central nervous toxicity. Data Extraction: Two authors independently abstracted demographics, metronidazole indication, dose and duration, neurological manifestations, and outcomes as well as brain imaging findings. Data Synthesis: Among 64 patients, 48 (77%) had cerebellar dysfunction, 21 (33%) had altered mental status, and 8 (15%) had seizures. Patients' ages averaged 53.3 years (range, 12-87 years), and 64% were male. The median duration of metronidazole was 54 days, although 26% had taken it less than a week and 11% had taken it less than 72 hours. Among cases with outcome data, most patients either improved (n = 18 [29%]) or had complete resolution of their symptoms with discontinuation of metronidazole (n - 41 [65%]). There was no difference in resolution of symptom by age (P = 0.71) or sex (P = 0.34). The patients with cerebellar dysfunction were less likely to experience complete resolution than those with mental status changes or seizures (relative risk, 0.67; 95% confidence interval (CI), 0.49-0.92). Nearly all patients (n = 55 [86%]) underwent imaging of the brain: 44 (69%) underwent magnetic resonance imaging (MRI) and 12 (19%) underwent computed tomographic studies. All patients with cerebellar dysfunction had abnormalities on imaging: 93% (n = 39) had a cerebellar lesion, although numerous areas in the brain were affected. On follow-up MRIs, 25 patients (83%) had complete resolution of abnormalities. Conclusions: Metronidazole can rarely cause central nervous system toxicity; it does not seem to be a dose-or duration-related phenomenon. Most patients will have MRI abnormalities. Prognosis is excellent with metronidazole cessation.