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Table of Contents
CASE REPORT
Year : 2018  |  Volume : 15  |  Issue : 4  |  Page : 190-192

Metronidazole-induced encephalopathy


1 Department of Neurology, Institute of Neurosciences/Internal Medicine, Indraprastha Apollo Hospitals, New Delhi, India
2 Department of Neurology, Institute of Neurosciences, Indraprastha Apollo Hospitals, New Delhi, India

Date of Web Publication5-Dec-2018

Correspondence Address:
Dinesh Mohan Chaudhari
L-428, Pocket L, Sarita Vihar, Near Mother Dairy, Mathura Road, New Delhi - 110 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_67_18

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  Abstract 


Metronidazole, an antiparasitic and antibacterial compound, is one of the world's most widely used drugs. Metronidazole is available for the treatment in anaerobic infections but may produce a number of neurologic side effects, particularly after prolonged use, such as cerebellar involvement, encephalopathy, seizures, autonomic neuropathy, optic neuropathy, and peripheral neuropathy. Symptoms of encephalopathy and neuropathy may recover completely or partially after discontinuation of metronidazole. The incidence of metronidazole-induced encephalopathy (MIE) is unknown. We report a case of a 31-year-old man with liver abscess and history of few weeks use of metronidazole therapy presenting with multiple episodes of seizures and altered sensorium. Magnetic resonance imaging brain revealed diffuse uniform extensive altered signals and restricted diffusion in body and genu of corpus callosum, suggestive of MIE.

Keywords: Brain, corpus callosum, encephalopathy, metronidazole


How to cite this article:
Chaudhari DM, Renjen PN, Ahmad K. Metronidazole-induced encephalopathy. Apollo Med 2018;15:190-2

How to cite this URL:
Chaudhari DM, Renjen PN, Ahmad K. Metronidazole-induced encephalopathy. Apollo Med [serial online] 2018 [cited 2018 Dec 15];15:190-2. Available from: http://www.apollomedicine.org/text.asp?2018/15/4/190/246894




  Background Top


Metronidazole, a 5-nitroimidazole, has bactericidal activity against most anaerobic and facultative anaerobic bacteria and protozoa. It is widely used for the treatment of anaerobic bacterial and protozoal infections. The drug has few common adverse reactions such as nausea, dry mouth, vomiting, and diarrhea. Neurotoxicity is uncommon, and it includes peripheral neuropathy, headache, dizziness, syncope, vertigo, and confusion.[1] Metronidazole-induced encephalopathy (MIE) is a rare toxic encephalopathy caused by prolonged use of the drug metronidazole. Metronidazole is believed to penetrate cerebrospinal fluid (CSF) and the central nervous system (CNS) easily.[2] The incidence of MIE is unknown.[1] Metronidazole toxicity can involve the CNS and peripheral nervous system, especially at dosages exceeding 2 g/day for prolonged periods.[1],[3]


  Case Report Top


A previously healthy, 31-year-old man with unremarkable medical history presented with fever, chills, and right upper abdominal pain of 8–10 days' duration. He was diagnosed at other hospital as a case of liver abscess, was treated with percutaneous pigtail catheter drainage of right lobe of liver along with oral as well as parenteral antibiotics, and was discharged after improvement in symptoms. He was treated with intravenous metronidazole in a dose of 800 ml three times a day for 5 days followed by 800 mg orally three times a day for 2 weeks as per available information. He presented to us with multiple episodes of generalized tonic–clonic seizures since 4 days and altered sensorium since 1 day. There was no history of consumption of alcohol or any substance abuse. There was no history of seizures in the past or relevant drug intake.

On general physical examination, the patient was febrile with temperature of 38.2°C. His blood pressure was 130/82 mmHg, pulse rate was 84/min, respiratory rate was 14/min, and there was no evidence of pallor, icterus, cyanosis, clubbing, edema feet, or lymphadenopathy. At the time of presentation, the patient was uncooperative, confused, drowsy, not oriented to time, place, and person. Rest of the CNS examination including fundus examination was normal; there was no neck rigidity and no signs of meningeal irritation. Abdominal examination revealed tender hepatomegaly and there was no ascites.

Investigations

Complete blood count, blood sugar levels, renal function test, serum electrolytes, and liver function tests were normal. Urine was examined for toxicology panel test (standard 10 drug panel screen) which was normal. Serum ammonia level was 31 μg/dl. Vitamin B12 and folate levels were normal. Thyroid function tests were within normal limits. HIV, HBsAg, and hepatitis C tests were negative. CSF analysis was done including wet mount for ameba and cultures, which were negative. Repeat abdominal ultrasound showed the presence of residual right lobe liver abscess, which was aspirated and found to be sterile on culture. Electroencephalogram was suggestive of generalized epileptiform discharges. In the presence of normal metabolic parameters and serum ammonia levels, possibility of hepatic encephalopathy was almost ruled out. Magnetic resonance imaging (MRI) brain done on the day of admission revealed diffuse uniform extensive altered signals and restricted diffusion in the body and genu of corpus callosum suggestive of metronidazole toxicity [Figure 1]. Metronidazole therapy was immediately discontinued.
Figure 1: Magnetic resonance imaging brain showing diffuse uniform extensive altered signals and restricted diffusion in body and genu of corpus callosum suggestive of metronidazole toxicity

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Treatment

After stopping metronidazole therapy, the patient was managed with supportive treatment and antiepileptic therapy. Subsequently, his agitation settled, but his sensorium remained same. Repeat MRI revealed decrease in lesions, but clinically, his sensorium was same. Follow-up ultrasonography revealed decrease in size of abscess. Further, he developed high-grade fever spikes and urine and blood cultures were sent and antibiotics upgraded accordingly.

Outcome and Follow-up

The patient responded to treatment and gradually patient's sensorium improved over the next 5 days. There was a considerable improvement in his sensorium, and he was able to walk with support in 4 days and without support in 10 days. Follow-up MRI after a week of discharge (after 4 weeks of initial presentation) revealed significantly reduced lesions in body and genu of corpus callosum [Figure 2].
Figure 2: Follow-up magnetic resonance imaging after a week of discharge (after 4 weeks of initial presentation) showing significantly reduced lesions in body and genu of corpus callosum

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  Discussion Top


The patient was treated with metronidazole for treatment of liver abscess. Metronidazole, an antiparasitic and antibacterial compound, is one of the world's most widely used drugs.[4] Liver abscesses are caused by bacterial, parasitic, or fungal infection.[5] Metronidazole is available for the treatment in anaerobic infections but may produce a number of neurologic side effects, particularly after prolonged use, such as cerebellar involvement, encephalopathy, seizures, autonomic neuropathy, optic neuropathy, and peripheral neuropathy. Symptoms of encephalopathy and neuropathy may recover completely or partially after discontinuation of metronidazole.[6] The incidence of MIE is unknown. The duration of treatment with metronidazole before appearance of CNS toxicity is variable (1 week to 6 months), and cumulative doses range from 25 g to 110 g.[7] Patients with severe hepatic dysfunction are at an increased risk of accumulation and may be at an increased risk of MIE, even with short-course therapy.[8] Ninety-five percent of uncomplicated amoebic abscesses resolve with metronidazole alone.[5] Hence, metronidazole is the mainstay of antibiotic treatment of liver abscesses. However, inappropriate use of metronidazole in excessive doses can give rise to neurological problems, such as ataxia, seizures, peripheral neuropathies, cerebellar signs and symptoms, and encephalopathy.[9]

MRI plays an important role in the diagnosis and follow-up of these cases. Increased signal intensity is observed on T2-weighted (T2W)/FLAIR sequences, as seen in our patient. It may also have a prognostic value in predicting the symptomatic improvement.[9]

MRI abnormalities have been described with metronidazole overdosage; however, it is not clear why only few patients develop these abnormalities and also with serum levels in the therapeutic range.[10] MRI brain lesions are hyperintense on T2W and FLAIR sequences with no mass effect. The lesions may show restricted diffusion and are nonenhancing on contrast administration. Characteristically, these lesions are mostly symmetric and bilateral involving cerebellar dentate nuclei, midbrain, dorsal pons (the vestibular nucleus, abducens nucleus, and superior olivary nucleus), splenium of the corpus callosum, and the dorsal medulla. Unusual sites are the inferior olivary nucleus and cerebellar white matter.[11],[12],[13],[14] Since our patient had few lesions without involvement of corpus callosum, he improved significantly within 5 days of cessation of metronidazole. The diagnosis of MIE is made by MRI findings in conjunction with clinical findings and treatment history of patient. With cessation of metronidazole treatment, the imaging findings and clinical symptoms usually resolve.[15]


  Take Home Messages Top


  • MIE and peripheral neuropathy should be considered in any patient who presents with seizures, cerebellar features, altered sensorium, and symptoms of distal pure sensory involvement and is receiving prolonged therapy with metronidazole
  • MRI should be performed for definitive diagnosis and reversibility of lesion in MRI should be looked for
  • MIE is a reversible condition; hence, high index of suspicion should be maintained for patients on prolonged metronidazole therapy.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/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.
Frytak S, Moertel CH, Childs DS. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med 1978;88:361-2.  Back to cited text no. 1
    
2.
Freeman CD, Klutman NE, Lamp KC. Metronidazole. A therapeutic review and update. Drugs 1997;54:679-708.  Back to cited text no. 2
    
3.
Kusumi RK, Plouffe JF, Wyatt RH, Fass RJ. Central nervous system toxicity associated with metronidazole therapy. Ann Intern Med 1980;93:59-60.  Back to cited text no. 3
    
4.
Khalil WK, Mahmoud MA, Zahran MM, Mahrous KF. A sub-acute study of metronidazole toxicity assessed in Egyptian Tilapia zillii. J Appl Toxicol 2007;27:380-90.  Back to cited text no. 4
    
5.
Krige JE, Beckingham IJ. Liver abscesses and hydatid disease. BMJ 2001;322:537-40.  Back to cited text no. 5
    
6.
Coxon A, Pallis CA. Metronidazole neuropathy. J Neurol Neurosurg Psychiatry 1976;39:403-5.  Back to cited text no. 6
    
7.
Puri V. Metronidazole neurotoxicity. Neurol India 2011;59:4-5.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Tracy JW, Webster LT. Drugs Used in the Chemotherapy of Protozoal Infections. Goodman Gillman's Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill-Co.; 2001. p. 1097-120.  Back to cited text no. 8
    
9.
Kalia V, Vibhuti, Saggar K. Case report: MRI of the brain in metronidazole toxicity. Indian J Radiol Imaging 2010;20:195-7.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Woodruff BK, Wijdicks EF, Marshall WF. Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. N Engl J Med 2002;346:68-9.  Back to cited text no. 10
    
11.
Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology 1995;45:588-9.  Back to cited text no. 11
    
12.
Horlen CK, Seifert CF, Malouf CS. Toxic metronidazole-induced MRI changes. Ann Pharmacother 2000;34:1273-5.  Back to cited text no. 12
    
13.
Heaney CJ, Campeau NG, Lindell EP. MR imaging and diffusion-weighted imaging changes in metronidazole (Flagyl)-induced cerebellar toxicity. AJNR Am J Neuroradiol 2003;24:1615-7.  Back to cited text no. 13
    
14.
Kim E, Na DG, Kim EY, Kim JH, Son KR, Chang KH, et al. MR imaging of metronidazole-induced encephalopathy: Lesion distribution and diffusion-weighted imaging findings. AJNR Am J Neuroradiol 2007;28:1652-8.  Back to cited text no. 14
    
15.
Reaven L, Reaven R, Kouo T, Shin R. Metronidazole Toxicity: A Case Series. Available from: http://www.neurology.org/cgi/content/meeting_abstract/78/1_MeetingAbstracts/0P04.15. [Last accessed on 2018 Oct 08].  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2]



 

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