Metronidazole central nervous system toxicity

Metronidazole, which is used to treat a wide variety of bacterial and protozoal infections can, in exceedingly rare cases, lead to central nervous system toxicity.

Epidemiology

In a review of the case literature ¹, affected patients range widely in age, with the peak incidence occurring in the fifth and sixth decades. The most common indication for metronidazole treatment among affected cases was abscess (48%). 

The mean duration of metronidazole treatment was 54 days, although 26% of the patients had taken the drug for less than a week. The average daily dose was 719 mg and the average cumulative dose of metronidazole was 93.4 grams.

Clinical presentation

It presents as cerebellar dysfunction (75% of cases), altered mental state (33%) and/or seizures (13%) ¹. The potential for neurotoxicity of metronidazole has been recognized for some time ².

Among patients with cerebellar dysfunction, dysarthria (66%) and ataxia (56%) are common; dysmetria (33%) nystagmus (8%) less so. Altered mental state (33%) and/or seizures (13%) are also encountered ¹. 

Pathology

Pathophysiological mechanisms of metronidazole neurotoxicity remain unclear. 

Radiographic features

MRI

Nearly all cases show lesions in the cerebellum (93-100%) ^1,3, particularly of the cerebellar dentate nuclei. There is slightly less frequent involvement of corpus callosum, midbrain, pons, and/or medulla. 

A majority of cases (86%) show a characteristic pattern of bilateral symmetric involvement of the dentate nuclei, vestibular nuclei, and a focal area of the tegmentum and the superior olivary nucleus ³.

• T2: bilateral, symmetric, hyperintense signal
• T1 C+ (Gd): non-enhancing  
• DWI: variable, from hyperintense to isointense to normal white matter in lesions of the dentate nucleus, midbrain, medulla, and pons
• ADC: ADC values of lesions of the dentate nucleus, midbrain, medulla, and pons are similar or higher than those of normal white matter, whilst corpus callosum lesions can show lower values than in normal white matter ³

Treatment and prognosis

After discontinuation of metronidazole the majority of cases either improve (29%) or have complete resolution of symptoms (65%). A very small minority (3%) experience permanent cognitive impairment. Cases with cerebellar dysfunction seem slightly less likely to experience complete resolution than those with mental status changes or seizures (RR, 0.67; 95% CI, 0.49-0.92) ¹.

Differential diagnosis

Possible imaging differential considerations include

• acute Wernicke encephalopathy