Metronidazole-induced reversible cerebellar dysfunction

Discussion

Metronidazole is a 5-nitroimidazole compound that is widely used as an antibiotic against anaerobic and parasitic infections. The nitro radical of metronidazole acts as an electron sink that competes with biological electron acceptors of the anaerobic organism in the pyruvate:ferredoxin oxidoreductase pathway. It is considered to be an effective and safe drug. The common adverse effect encountered while using this drug include unpleasant metallic taste, nausea and abdominal pain. Rarely, one may encounter more serious adverse effects, such as the one mentioned in the present case report.

Both central and peripheral nervous system syndromes as a result of therapy with metronidazole have been described.1 The peripheral nervous system involvement consists of a painful, slowly progressive, symmetric distal sensory neuropathy with predominant small fibre involvement.2 The central nervous system involvement consists of distinctive syndrome of cerebellar dysfunction characterised by dysarthria, ataxia, dysmetria and nystagmus accompanied by dendate nuclei abnormalities on imaging.3 This syndrome is called MIE and appears to be more common among the two.

MIE was first reported in 1977, in a young woman who developed disorientation and memory loss after treatment for Trichomonas infection.4 The most common clinical manifestations are dysarthria, limb dyscoordination, gait instability and altered consciousness.5 Seizures, extrapyramidal features, chorea and myoclonus have also been reported.3 Presentations can mimic acute ischaemic stroke as well.6 Hyperintense lesions on T2-weighted and FLAIR sequences in the dentate nuclei are the most common MRI features seen. However, other features such as signal changes in the mid-brain, corpus callosum, periventricular and subcortical white matter, medulla, and basal ganglia may also be seen.7 MRI findings may rarely be assymetrical.8

Electroencephalogram findings in MIE are not specific. Sharp theta activity with a progressive anteroposterior diffusion may be suggestive of MIE.9 However, more studies are required before association can be conclusively made.

The differential diagnoses include demyelination, Wenicke’s encephalopathy, Marchiafava-Bignami disease, closed head injury, space occupying lesion, vascular events, postictal state, central nervous system tuberculosis, syphilis, HIV infection, substance abuse or withdrawal, other antibiotic associated encephalopathies (penicillin, cephalosporins, sulfonamides, fluoroquinolones and macrolides) primary central nervous system lymphoma and progressive multifocal leukoencephalopathy.5 Inborn errors of metabolism, lysosomal storage diseases and mitochondrial diseases can present with similar clinicoradiological features, but can be differentiated from MIE by their presentation in childhood and slow progression. MIE is a clinicoradiological diagnosis of exclusion. After excluding common differential diagnosis, if temporal association of the development of signs and symptoms, changes in MRI, and reversal of the same with cessation of metronidazole are observed, it can be taken as sufficient evidence of MIE.

The pathogenesis of MIE is unclear. The similarities between clinical and radiological features of MIE and chronic methyl bromide intoxication have lead to the hypothesis that the pathogenesis may include methylation of intracellular proteins and lipids and thereby disruption of essential metabolic processes.10 Another hypothesis states that metronidazole disrupts energy metabolism and explains the predilection of cerebellum, brainstem and periventricular areas by their vulnerability to disruption of energy-metabolic pathways.11 Inhibition of protein synthesis and vasospasm induced by the binding of metronidazole metabolites to DNA or RNA in neural cells are other proposed mechanisms.12 At present, it is not clear if MIE is dose dependant or idiosyncratic. However, there is some evidence to suggest that neurotoxicity is more common at cumulative doses higher than 42 g or for treatment duration more than 4 weeks.13 14 Other risk factors for MIE appear to be severe hepatic or renal disease, advanced cancer and organ failure.5 In most cases, the symptoms and signs resolved after cessation of metronidazole. However, there are instances of persistent neurological deficits and death as a result of MIE. It is possible that these deaths occurred as a result of other events, and not directly due to MIE.5 Li et al have reported a case of MIE that worsened after drug cessation, and was treated successfully with methylprednisolone, thiamine and vitamin B₁₂.15 Overall, about 65%–70% of patients seem to have a complete recovery, about 30% have partial recovery and a minority experience severe residual deficits.16 If therapy with a 5-nitroimidazole is necessary, tinidazole or ornidazole can be substituted for metronidazole. It must be noted that a similar presentation may be seen with these drugs as well.17 18

In conclusion, metronidazole, although widely considered to be a relatively safe drug, can be associated with rare adverse effects involving both the central and peripheral nervous system. MIE can manifest with cerebellar dysfunction characterised by dysarthria, ataxia, dysmetria and nystagmus accompanied by MRI signal changes predominantly in the dendate nuclei. The diagnosis is made clinically after excluding other causes and, in a majority of cases, seems to be reversible by stopping the drug. However, in some patients, this complication may result in residual deficits or death. MIE is an uncommon adverse effect of a commonly used drug that clinicians must be aware of.