Correspondence

Reversible Metronidazole-Induced Lesions of the Cerebellar Dentate Nuclei

N Engl J Med 2002; 346:68-69January 3, 2002

Article

To the Editor:

The toxic effects of metronidazole include ataxia, peripheral neuropathy, and seizures.1 There have been two reported cases in which abnormalities of the dentate nucleus on magnetic resonance imaging (MRI) were associated with metronidazole treatment.2,3 We describe two additional cases of new-onset ataxia and dysarthria associated with the use of metronidazole. We also document the reversibility of both the clinical symptoms and the MRI abnormalities after discontinuation of the drug.

Ataxia and dysarthria developed approximately one month after the initiation of antibiotic therapy in a 62-year-old man with multiple epidural abscesses. He had been treated with metronidazole (500 mg given orally four times a day) and cefepime (2 g given intravenously twice a day). The results of liver-function tests were only mildly abnormal. MRI studies of the head showed prominently increased signal intensity in the dentate nuclei bilaterally on T₂-weighted images obtained with fluid-attenuated inversion recovery (FLAIR). The ataxia and dysarthria resolved within five weeks after the discontinuation of treatment with metronidazole, in parallel with the resolution of the abnormalities in the dentate nuclei on MRI (Figure 1Figure 1MRI Scans in a 62-Year-Old Man with Dysarthria and Ataxia.).

A 74-year-old man with metastatic carcinoid tumor and intraabdominal abscesses that had been treated with percutaneous drainage had ataxia and dysarthria four weeks after the initiation of antibiotic therapy for the abscesses. His antimicrobial regimen consisted of levofloxacin (500 mg given orally once a day) and metronidazole (500 mg given orally three times a day). MRI studies of the head showed findings that were identical to those in the first patient — increased signal intensity confined to both dentate nuclei on T₂-weighted FLAIR sequences. Discontinuation of the metronidazole resulted in the improvement of the dysarthria and ataxia over a period of approximately two weeks. A repeated MRI scan showed that the lesions had resolved.

In one of the two previous case reports of ataxia, dysarthria, and MRI abnormalities associated with metronidazole therapy, the serum concentration of metronidazole was at a toxic level, but in our two cases, the administered dose was within the recommended range. The patients were not taking other drugs that could have reduced the metabolism of metronidazole. Studies of metronidazole in rats have shown sharply demarcated, symmetric lesions in the brain stem and cerebellar nuclei.4 The apparent preferential involvement of the dentate nucleus remains puzzling. However, this cerebellar structure, which is part of the principal cerebellar connections, appears to be particularly susceptible to injury, since it is frequently involved in neurodegenerative, ischemic, and metabolic disorders.5 Physicians need to be aware of this subacute cerebellar syndrome, given the wide use of metronidazole. Resolution of the abnormalities may take a number of weeks.

Bryan K. Woodruff, M.D.
Eelco F.M. Wijdicks, M.D.
William F. Marshall, M.D.
Mayo Clinic, Rochester, MN 55905
wijde@mayo.edu

5 References

1. 1

   Frytak S, Moertel CH, Childs DS. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med 1978;88:361-362
   Web of Science | Medline

2. 2

   Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology 1995;45:588-589
   Web of Science | Medline

3. 3

   Horlen CK, Seifert CF, Malouf CS. Toxic metronidazole-induced MRI changes. Ann Pharmacother 2000;34:1273-1275
   CrossRef | Web of Science | Medline

4. 4

   Von Rogulja P, Kovac W, Schmid H. Metronidazol-Encephalopathie der Ratte. Acta Neuropathol (Berl) 1973;25:36-45
   CrossRef | Medline

5. 5

   Greenfield JG. Greenfield's neuropathology. 6th ed. New York: Oxford University Press, 1997.
   

Citing Articles (14)

Citing Articles

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   Akira Kuriyama, Jeffrey L. Jackson, Asako Doi, Toru Kamiya. (2011) Metronidazole-Induced Central Nervous System Toxicity. Clinical Neuropharmacology1
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   Yoochang Bahn, Eunyoung Kim, Chongoon Park, Hyung-Chun Park. (2010) Metronidazole Induced Encephalopathy in a Patient with Brain Abscess. Journal of Korean Neurosurgical Society 48:3, 301
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   Tracey D. Graves, Marie Condon, Marina Loucaidou, Richard J. Perry. (2009) Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient. Journal of the Neurological Sciences 285:1-2, 238-240
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   Marcelo Galvez, Javier Brahm, Marcelo Miranda. (2009) Movement disorders as a manifestation of metronidazole-induced encephalopathy in a patient with chronic liver disease. Movement Disorders 24:12, 1864-1866
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   Seong Soo Lee, Sang-Hoon Cha, Seung Young Lee, Chang June Song. (2009) Reversible Inferior Colliculus Lesion in Metronidazole-Induced Encephalopathy. Journal of Computer Assisted Tomography 33:2, 305-308
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   Kalpeshkumar Patel, Israel Green-Hopkins, Stanley Lu, Allan R. Tunkel. (2008) Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. International Journal of Infectious Diseases 12:6, e111-e114
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   E. Kim, D.G. Na, E.Y. Kim, J.H. Kim, K.R. Son, K.H. Chang. (2007) MR Imaging of Metronidazole-Induced Encephalopathy: Lesion Distribution and Diffusion-Weighted Imaging Findings. American Journal of Neuroradiology 28:9, 1652-1658
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   Hirono Ito, Michiyuki Maruyama, Naoko Ogura, Toshiki Fujioka, Yasuo Iwasaki, Atsushi Aikawa, Akira Hasegawa. (2004) Reversible Cerebellar Lesions Induced by Metronidazole Therapy for Helicobacter Pylori. Journal of Neuroimaging 14:4, 369-371
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   Dong Wook Kim, Jong-Moo Park, Byung-Woo Yoon, Min Jae Baek, Jung Eun Kim, SangYun Kim. (2004) Metronidazole-induced encephalopathy. Journal of the Neurological Sciences 224:1-2, 107-111
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    Mario Savoiardo, Laura Farina. (2003) Reversible MR Imaging and MR Spectroscopy Abnormalities in Association with Metronidazole Therapy. Journal of Computer Assisted Tomography 27:4, 552
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    Hendrikus G.J Krouwer, Eelco F.M Wijdicks. (2003) Neurologic complications of bone marrow transplantation. Neurologic Clinics 21:1, 319-352
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    Kim M. Cecil, Mark J. Halsted, Mark Schapiro, Argirios Dinopoulos, Blaise V. Jones. (2002) Reversible MR Imaging and MR Spectroscopy Abnormalities in Association with Metronidazole Therapy. Journal of Computer Assisted Tomography 26:6, 948-951
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    (2002) Current Awareness. Pharmacoepidemiology and Drug Safety 11:4, 345-360
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14. 14

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