Metronidazole induced cerebellar ataxia.

Metronidazole is a widely used antimicrobial usually prescribed by many specialist doctors for a short duration of 10-15 days. Prolonged use of metronidazole is rare. The present case is of a patient who used the drug for 4 months and developed peripheral neuropathy, convulsions, and cerebellar ataxia. He was treated with diazepam and levetiracetam. The patient recovered completely following discontinuation of metronidazole.

Introduction

Metronidazole is a nitroimidazole antiprotozoal drug used in different indications. General practitioners use the drug for control of amoebiasis, giardiasis, and trichomonas infection. Surgeons, gynecologists, dental surgeons, and physicians use it to control anaerobic organisms. Neurologists use metronidazole in amoebic infections of nervous system and also in treating meningitis. It is also used controlling pseudomembranous colitis caused by clostridium difficile and for control of Helicobacter pylori causing gastric ulcer. The gel preparation is use in the treatment of dermatological conditions such as, rosacea and fungating tumor. It is used as a radiosensitizer by oncologists while treating malignancies.[1] Often the use of metronidazole is not associated with any serious adverse effects except mild change in taste, nausea, and occasional hypersensitivity reactions following intravenous use. The drug can interact with alcohol leading to severe reactions and sometimes sudden death.[2] It also interacts with some antidepressant drugs, especially, selective serotonin reuptake inhibitors leading to “serotonin syndrome.”[3] Prolonged use can result in peripheral neuropathy. We report a case of prolonged metronidazole administration resulting in seizures and cerebellar ataxia.

Case Report

A 31-year-old male patient, carpenter by occupation was admitted to the hospital on 25-01-2012 for instability of gait since 1 month duration. There was also slurring of speech since then. There was a history of tingling and numbness of both lower limbs, which had gradually ascended up to the knees for the past 1 month. The footwear used to slip off his feet while walking. Because of the numbness of the feet and the in coordination he was dependent on the family members for most of his daily activities. He experienced clumsiness while buttoning his shirt and mixing the food was also observed. Tremulous and overshooting of hand while eating, food was observed.

The patient had a generalized tonic-clonic seizure in the hospital, on the day of admission. There was a past history of 3 seizures 3 weeks earlier, on 15-12-2011 however, he was not evaluated at that time and was not on any antiepileptic medication at the time of admission. He was not a known epileptic before starting the anti-amoebic medication.

There was a history of weight loss of 11 kg in the past 4 months. He was admitted to the gastroenterology unit of the hospital 4 months ago, where he was diagnosed to be suffering amoebic liver abscess. The liver abscess was drained twice in 15 days’ time and he was administered metronidazole infusion in the hospital at that time and he was asked to stop alcohol. As the abscess was resolving, he was advised to continue metronidazole tablets 400 mg 5 tablets daily for a long period for another 2 weeks. Patient came for review after nearly 3 months with diarrhea. The patient was taking metronidazole for nearly 4 months before admission. In the last 1 month, Ornidazole 250 mg + Diloxanidee furoate 200 mg twice daily were added for control of diarrhea (without the knowledge that he was also taking metronidazole), The latter combination was taken for 3 weeks and discontinued, thereafter since the patient could not afford it.

On examination, he was alert and co-operative; there were no cranial nerve deficits. Speech was slurred with a scanning character. There was hypotonia in all 4 limbs. The muscle power on medical research council (MRC) grading scale was normal except minimal weakness of toe extensors bilaterally. The plantar reflexer were flexor, deep tendon reflexes were normal. There was intention tremor, dysmetria, dysdiadochokinesia in both upper limbs. In-coordination was noted in both upper and lower limbs. He was unable to stand on a narrow base. The gait was ataxic and he was unable to walk tandem. There was impairment of all modalities of sensation in both lower limbs below the knees.

The patient was investigated for his complaints. The laboratory work-up showed total leucocyte count of 8600/Cu mm with normal differential count. Platelets were adequate on smear and the count was 230,000/Cu mm. Random blood glucose was 143 mg/dl, blood urea was 37 mg/dl, and serum creatinine was 1.2 mg/dl. Liver function tests were normal. An ultrasound examination of the abdomen was normal, and the abscess had resolved. Nerve conduction study of the limbs suggested a length dependent axonal sensorimotor neuropathy. X-ray chest and electrocardiogram ruled out any cardiac involvement. Magnetic resonance imaging (MRI) scanning of the brain showed faint hyper-intense signals on T2 and FLAIR imaging from the dentate nucleus bilaterally more prominent on the left side [Figures 1-3]. There was also hyper-intense signal in the splenium of corpus callosum.

Figure 1

FLAIR magnetic resonance imaging images showing hyper-intense lesion in the dentate nucleus (white arrow)

Figure 3

Faint T2-hyper-intense lesions in dentate nuclei of cerebellum axial view and sagittal view

Axial view

On the day of admission, the seizures were controlled with diazepam. He was started on an anti-epileptic drug, levetiracetam. A diagnosis of post-infectious immune mediated disease like acute disseminated encephalomyelitis (ADEM) was considered initially as the seizures and ataxia followed a diarrheal illness. He was given one bolus of high-dose methylprednisolone as part of treatment for ADEM. When the MRI did not reveal typical lesions of ADEM, the history and clinical findings were reviewed. Metronidazole was suspected to cause the adverse reaction and was discontinued.

The patient was discharged after 7 days and followed-up after 10 days. Dysarthria and ataxia had resolved. There were no more seizures. Levetiracetam was also discontinued. The sensory symptoms in the lower limbs were persisting; however, he was able to walk independently.

Discussion

Prolonged use of metronidazole 4 months is rare. It is the drug of choice for amoebic liver abscess. In endemic areas prolonged treatment may be necessary, but never for more than 3 weeks. in vivo resistance to metronidazole has not been reported. Secnidazole or Ornidazole may be substituted for metronidazole however, there is no indication for use of two drugs together. A luminal amoebicidal like diloxanide furoate agent may be administered to eradicate the intestinal carriage after the amebic liver abscess has been treated with one of the above tissue amebicides.

Alcohol as a cause of the cerebellar ataxia in the present case was also considered but was excluded as the patient had discontinued alcohol nearly 3-4 months before the onset of ataxia. The clinical scenario, imaging appearances of hyper-intense signal in the cerebellar dentate nuclei and splenium of the corpus callosum, and rapid resolution of dysarthria and ataxia following discontinuation of the offending drug suggest that metronidazole is the cause of the adverse drug reaction.

Usual adverse effects of metronidazole include nausea, headache, and metallic taste. Abdominal cramps, vomiting, diarrhea, and dizziness also may occur. Dark urine may occur from one of the metabolites of the drug.

The most serious side effects of metronidazole involve the nervous system. There can be acute encephalopathy, seizures, headache, dizziness, syncope, ataxia, dysarthria, hallucinations, agitation, disorientation, and insomnia. Aseptic meningitis and optic neuropathy are also described. Reversible optic neuropathy was described after 8 months use of metronidazole by McGrath et al.[4] Prolonged oral administration of metronidazole has been associated with peripheral neuropathy, which probably is related to the dose and duration of therapy. Mostly a dose of 1000-2400 mg/day for at least 30 days or a total dose of 50 g can result in neuropathy. Patients taking large doses in a short time for acute infection may also develop such neuropathy. Axonal degeneration of both myelinated and unmyelinated fibers can occur, with slow improvement after the agent is stopped. The mechanism may involve deoxyribonucleic acid binding.[5] It is a length dependent neuropathy generally seen in the lower limbs first. Neuropathy may persist even after the drug is discontinued, for a few more weeks.

Harati Y et al and Mulcahy et al. described patients with dysarthria and ataxia who were shown to be having MRI abnormalities in the form of increased signal intensity in the dentate nuclei of the cerebellum bilaterally on T2-weighted and FLAIR images. Gadolinium contrast did not show any enhancement in these lesions and the lesions resolved several weeks after discontinuing metronidazole.[67]

An analysis of the case report suggests that the present case is an uncommon Adverse drug reaction (ADR) (Type 3 variety of adverse drug reaction) that occurs on long term exposure of the drug and is dose related. Causality analysis using Naranjo's scale showed that metronidazole is the probable cause of the adverse reaction (score = 8).

Thus, metronidazole when judiciously used is useful in management of amebiasis, both hepatic and intestinal forms. However, when inadvertently administered for longer periods can lead to neurotoxicity. There can be seizures, cerebellar ataxia or length dependent peripheral neuropathy. The neuropathy worsens as the total dose consumed increases the recovery may be incomplete even after discontinuation of the offending drug.