Uncommon reaction to a common prescription

Abstract

In May, 2010, a 50 year-old man presented to us with a 10 day history of abdominal pain, fever, and shivering with elevated C reactive protein and leucocytes. He had a past history of congestive subvalvular aortic stenosis which had not required surgical treatment. He weighed 85 kg, had normal renal and hepatic function, and was not on any regular medication. CT of the abdomen suggested an abscess of the appendix. He was treated with intravenous cefotaxime 1 g three times a day and metro nidazole 1 g daily for 2 days and discharged with oral metronidazole 400 mg three times a day and cipro fl oxacin 500 mg twice a day. 5 days later, he returned with a complete loss of hearing, fatigue, dizziness, vomiting, impaired balance, ataxia and dysarthria. He was afebrile and CT of the brain was normal. We suspected an encephalopathy caused by an adverse eff ect of metro nidazole and/or ciprofl oxacin, and both drugs were discontinued. Within one hour after admission he became unconscious. He was transferred to the intensive care unit and was intubated. MRI of the brain showed bilateral and symmetric swellings of the cerebellar dentate nuclei, dorsal medulla, dorsal pons, midbrain, corpus callosum and increased signal intensity in the supratentorial periventricular white matter (fi gure A), which was in accordance with previously described cases of metro nidazole induced encephalopathy. Meropenem, aciclovir and betamethasone were started to cover possible meningitis and encephalitis. The electroencephalogram, lumbar puncture, infl ammatory markers, microbiological and viral testing, autoimmune markers, and thyroid function tests were all normal. Although the metronidazole concentration in plasma was not measured, an overdose was unlikely because our patient had only been prescribed one box containing 30 pills of 400 mg, and had followed the prescription accordingly. His symptoms and MRI fi nd ings were not found to correlate with earlier described cases of ciprofl oxacin-induced encephalopathy. Wernicke’s encepha lopathy may produce similar clinical symptoms, however without MRI lesions of cerebellar dentate nuclei. Furthermore, thiamine was not admin istered to our patient. Viral encephalitis and bacterial meningitis were ruled out. According to the Naranjo probability scale our patient’s symptoms were classifi ed as probably caused by metronidazole (Naranjo Score 5/13). The case was reported to and confi rmed by the Swedish adverse eff ect register institute “SWEDIS” as a probable case of metronidazoleinduced encephalopathy. His symptoms gradually resolved and an MRI two months later, showed a clear resolution of the earlier described signal changes (fi gure B and webappendix). At fi nal follow-up in September, 2010, he was well with only residual hearing impairment. Metronidazole has been used clinically for more than 30 years and is regarded as a safe antibiotic with few adverse reactions Encephalopathy is an extremely rare but serious, neurological side-eff ect. The pathophysiology of metronidazole encephalopathy is unknown, but an acute toxic insult producing axonal swelling may be responsible and the encephalopathy may be completely reversible. There are only twenty cases of metronidazole-induced encephalopathy currently reported in English medical literature. In these cases, neurological adverse eff ects of metronidazole occurred particularly with doses exceeding 2 g daily or when used for prolonged periods. Although MRI fi ndings are typical for this condition, ignorance of metronidazole-induced encephalopathy may result in clinical misjudgment and delay of the diagnosis.