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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 11  |  Issue : 4  |  Page : 220-222

Nitroimidazole-induced reversible neurotoxicity


Department of Neurology, SAMC and PGI, Indore, Madhya Pradesh, India

Date of Submission24-Jun-2020
Date of Decision19-Jul-2020
Date of Acceptance21-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Dr. Dinesh Chouksey
A2, Flat 204, Maple Woods, Piplya Kumar, Nipania Main Road, Indore - 452 010, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/INJMS.INJMS_69_20

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  Abstract 


The nitroimidazole group of drugs is commonly used in India and worldwide for diarrhea and other indications. People are taking it over the counter for their subsequent problems without consultation, and this is harmful to them on chronic use. Similarly, many indications such as amoebic liver abscess need long-duration therapy of these drugs which may present with its toxic effects. We report two cases of metronidazole and ornidazole overuse presented as central and peripheral nervous system toxicity. The magnetic resonance imaging changes similar to nitroimidazole drug toxicity can be seen in many other diseases, and it needs to correlate with a good history for the diagnosis to avoid unnecessary workup burden to the patient.

Keywords: Dentate hyperintensity, metronidazole-induced encephalopathy, metronidazole peripheral neuropathy, metronidazole toxicity, ornidazole toxicity


How to cite this article:
Chouksey D, Singh A, Goyal N, Sodani AK. Nitroimidazole-induced reversible neurotoxicity. Indian J Med Spec 2020;11:220-2

How to cite this URL:
Chouksey D, Singh A, Goyal N, Sodani AK. Nitroimidazole-induced reversible neurotoxicity. Indian J Med Spec [serial online] 2020 [cited 2021 Mar 6];11:220-2. Available from: http://www.ijms.in/text.asp?2020/11/4/220/295489




  Introduction Top


Nitroimidazoles are an antibacterial and antiprotozoal group of drugs; metronidazole and ornidazole are the two commonly used and over-the-counter available drugs of this class and are generally well tolerated. Neurological toxicity is relatively common with these drugs like headache, seizure, encephalopathy, ataxia, and peripheral neuropathy.[1] We report two cases of reversible central nervous system toxicity and bilateral dentate nucleus hyperintensities on magnetic resonance imaging (MRI) brain.


  Case Reports Top


Case 1

A 45-year-old female patient was treated for an amoebic liver abscess with metronidazole for 6 weeks (2.4 g/day and the total cumulative dose was 103.2 g). She was on oral metronidazole presented to us with subacute onset giddiness, inability to walk, and tingling and burning sensation in both feet and legs for 2–3 days. On examination, horizontal bidirectional nystagmus was seen; appendicular and truncal ataxia was present in both upper and lower limbs. MRI brain revealed symmetrical T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensity without restricted diffusion in the bilateral dentate nucleus, the splenium of the corpus callosum, and dorsal midbrain [Figure 1]. Routine nerve conduction study was normal, and skin sympathetic response was abnormal, suggestive of small fiber neuropathy. In view of metronidazole-induced central and peripheral nervous system toxicity, the drug was stopped. The patient received symptomatic treatment with pregabalin and amitriptyline. Within 6–7 days of drug withdrawal, her gait ataxia was improving, and tingling and burning sensation was improved. Repeat MRI brain was not done due to financial constraints of the patient.
Figure 1: (a and b) T2 hyperintensity at dentate nucleus and the splenium of corpus callosum, respectively, (c and d) fluid-attenuated inversion recovery hypeintensity at dorsal midbrain and dentate nucleus

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Case 2

A 34-year-old female patient was having the tendency to take ornidazole drug for even 1–2 episodes of loose stools for 3–4 years, i.e., ornidazole overuse for chronic diarrhea. She was admitted with complaints of walking difficulty, slurring of speech, and aggressive abusive behavior for 1 month. On examination, dysarthria (scanning speech), appendicular, truncal, and gait ataxia were seen; MRI brain showed bilateral dentate nucleus and the splenium of corpus callosum T2/FLAIR hyperintensities, and MRI spine was normal [Figure 2]. The possibility of demyelinating disease was kept, and intravenous methylprednisolone pulse therapy for 5 days was given, but there was no improvement in symptoms. She presented to us after 1 year with the above complaints without progression in symptoms and not on any drug other than self-use of ornidazole for loose stools. We made a clinical diagnosis of drug-induced neurotoxicity and did MRI brain, which shows hyperintense signals in bilateral dentate nucleus and corpus callosum. Her cerebrospinal fluid (CSF) studies were normal; Visual Evoked Potential (VEP) was normal and serum angiotensin-converting enzyme level was also normal. She was advised to not take ornidazole tablets, and sertraline was given. After 2 months, her behavior and gait ataxia were improved and MRI changes disappeared.
Figure 2: (a and b) T2 hyperintensity at dentate nucleus and splenium of corpus callosum, respectively, (c and d) fluid-attenuated inversion recovery hyperintensity at dentate nucleus and splenium of corpus callosum, respectively

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  Discussion Top


The metronidazole-induced encephalopathy (MIE) usually presents with cerebellar dysfunction (75%), altered mental status (33%), and seizures (13%) in affected patients.[2] The peripheral neuropathy is the most common adverse effect, and rare ones are movement disorders such as chorea, myoclonus, and sensori-neural hearing loss.[1] Metronidazole is a lipophilic drug that can easily penetrate blood–brain barriers, and serum to CSF ratio is 1.0, and its toxic cumulative dose ranges from 13.2 to 228 g.[1],[2] There are several proposed mechanisms of MIE such as free radical injury, mitochondrial toxicity, and interference with GABAergic neurotransmission in the cerebellum and brain stem that lead to localized axonal swelling with increased water content.[4] The MIE-specific MRI changes are bilateral symmetrical T2, FLAIR hyperintense cerebellar dentate and inferior colliculus lesions, and other frequently affected areas are splenium of the corpus callosum, midbrain, inferior olivary nucleus, and cerebral white matter.[5] The differential diagnosis of these MRI changes could be Wernicke's encephalopathy, osmotic demyelination, methyl bromide intoxication, maple syrup urine disease, enterovirus encephalopathy, Marchiafava–Bignami disease, and acute toxic encephalopathy (methotrexate and 5-fluorouracil).[5] Sudan et al. reported MIE in a young boy having a history of a short course of metronidazole intake and his MRI of the brain revealed symmetrical T2 hyperintense and T1 hypointense lesions involving the optic tracts, dorsal midbrain, periaqueductal white matter, superior and inferior colliculi, superior cerebellar peduncle, dentate nuclei, and medulla oblongata extending up to the cervicomedullary junction (confluent nonenhancing intramedullary long segment T2 hyperintense lesion was seen in the cervical spinal cord extending from the cervicomedullary junction up to C6–C7 level).[6]

The ornidazole-induced encephalopathy is rarely described in the literature, and only two cases from India have been reported yet. One case is a 61-year-old female who had a history of chronic intake of ornidazole for diarrhea presented with ataxia and her MRI shows additional bilateral basal ganglia T2, FLAIR hyperintensity.[7] Another case is a 51-year-old female who presented with dysarthria, tremor, and gait ataxia. Her MRI brain shows T2, FLAIR hyperintensities involving bilateral symmetrical dentate nucleus, splenium of corpus callosum, and dorsal pons. The exact mechanism is not yet clear, but a possible hypothesis is axonal swelling due to vasogenic edema or reversible ischemia due to vasospasm. The MRI changes are reversible over days or weeks after discontinuation of drug.[8] Our cases are showing a unique clinicoradiological presentation of nitroimidazole group of drugs' neurotoxicity and reversibility.


  Conclusion Top


The brain lesions on MR images in these patients were always bilateral symmetrical and were typically located at the cerebellar dentate nuclei, the splenium of the corpus callosum, and dorsal brain stem without diffusion restriction, and detailed drug history is very important to make such clinical diagnosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Vaithiyam V, Jadon RS, Ray A, Manchanda S, Meena VP, Ranjan P, et al. Metronidazole induced encephalopathy: A rare side effect with a common drug. Indian J Radiol Imaging 2019;29:431-4.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Kuriyama A, Jackson JL, Doi A, Kamiya T. Metronidazoleinduced central nervous system toxicity: A systematic review. Clin Neuropharmacol 2011;34:241-7.  Back to cited text no. 2
    
3.
Nau R, Sorgel F, Eiffert H. Penetration of drugs through the bloodcerebrospinal fluid/bloodbrain barrier for treatment of central nervous system infections. Clin Microbiol Rev 2010;23:858-83.  Back to cited text no. 3
    
4.
Mittal GK, Sureshbabu S, Peter S, Khanna L. Dentate hyperintensities-the imaging signature of metronidazole induced encephalopathy. J Neurosci Rural Pract 2017;8:272-3.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Kim E, Na DG, Kim EY, Kim JH, Son KR, Chang KH. MR Imaging of MetronidazoleInduced Encephalopathy: Lesion distribution and diffusionweighted imaging findings. Am J Neuroradiol 2007;28:1652-8.  Back to cited text no. 5
    
6.
Sudan YS, Garg A, Gupta R, Bansal AR. Headphone sign: Metronidazole-induced encephalopathy. Neurol India 2016;64:1374-6.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Gopinath KG, Wilson BP, Viggeswarpu S, Mathews PK, Mani S. Ornidazole-induced ataxia in an Indian woman: A case report. SAGE Open Med Case Rep 2015;3:2050313X15621857.  Back to cited text no. 7
    
8.
Shekhar KS, Praveen SM, Sarvana KS, Malathi V. A Rare Case of Ornidazole-Induced Encephalopathy. Available from: http://www.eurorad.org/case/12507. [Last accessed on 2020 Jul 21].  Back to cited text no. 8
    


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