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Neurologic Complications of Metronidazole

Published online by Cambridge University Press:  23 September 2014

Justyna R. Sarna ,
Sarah Furtado  and
A. Keith W. Brownell
Justyna R. Sarna*
Affiliation:
Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
Sarah Furtado
Affiliation:
Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
A. Keith W. Brownell
Affiliation:
Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
*
Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. Email: [email protected].
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Abstract

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Metronidazole (Flagyl®) is an antimicrobial agent commonly used in clinical practice. Although it is generally well tolerated with minimal side effects, there are a host of still under-recognized neurologic complications of metronidazole treatment. The following review is aimed at summarizing current literature pertaining to metronidazole-induced neurotoxicity including clinical syndromes, neuroradiological findings, prognosis and proposed pathophysiology. Recognition of the neurotoxic effects of metronidazole is critical as prompt discontinuation is generally associated with full clinical recovery and radiological resolution.

Résumé

RÉSUMÉ

Le métronidazole (Flagyl®) est un agent antimicrobien utilisé couramment en pratique clinique. Bien qu'il soit généralement bien toléré et que ses effets secondaires soient minimes, il existe une myriade de complications neurologiques du traitement par le métronidazole qui ne sont pas toujours reconnues. Le but de cette revue constitue un sommaire de la littérature actuelle concernant la neurotoxicité induite par le métronidazole dont les syndromes cliniques, les constatations neuroradiologiques, le pronostic et l'hypothèse physiopathologique expliquant cette neurotoxicité. Il est important d'identifier ces effets neurotoxiques du métronidazole étant donné que l'arrêt immédiat du traitement est généralement associé à une guérison clinique complète et à la disparition des signes radiologiques.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 40 , Issue 6 , November 2013 , pp. 768 - 776
Copyright
Copyright © The Canadian Journal of Neurological 2013

References

1. Finegold, SM. Metronidazole. Ann Intern Med. 1980 Oct;93(4):585–7.Google Scholar
2. Ralph, ED. Clinical pharmacokinetics of metronidazole. Clin Pharmacokinet. 1983 Jan-Feb;8(1):43–62.Google Scholar
3. Ralph, ED, Clarke, JT, Libke, RD, Luthy, RP, Kirby, WM. Pharmacokinetics of metronidazole as determined by bioassay. Antimicrob Agents Chemother. 1974 Dec;6(6):691–6.Google Scholar
4. Jokipii, AM, Myllyla, VV, Hokkanen, E, Jokipii, L. Penetration of the blood brain barrier by metronidazole and tinidazole. J Antimicrob Chemother. 1977 May;3(3):239–45.Google Scholar
5. Phongsamran, PV, Kim, JW, Cupo Abbott, J, Rosenblatt, A. Pharmacotherapy for hepatic encephalopathy. Drugs. 2010 Jun 18;70(9):1131–48.Google Scholar
6. Perencevich, M, Burakoff, R. Use of antibiotics in the treatment of inflammatory bowel disease. Inflamm Bowel Dis. 2006 Jul;12 (7):651–64.CrossRefGoogle ScholarPubMed
7. Eyre, HJ, Ohlsen, JD, Frank, J, et al. Randomized trial of radiotherapy versus radiotherapy plus metronidazole for the treatment metastatic cancer to brain. A Southwest Oncology Group study. J Neurooncol. 1984;2(4):325–30.Google Scholar
8. Aiken, R, Leavengood, JM, Kim, JH, Deck, MD, Thaler, HT, Posner, JB. Metronidazole in the treatment of metastatic brain tumors. Results of a controlled clinical trial. J Neurooncol. 1984;2(2):105–11.Google Scholar
9. Sarna, JR, Brownell, AK, Furtado, S. Cases: Reversible cerebellar syndrome caused by metronidazole.. CMAJ. 2009 Oct 27;181(9):611–3.Google Scholar
10. Kusumi, RK, Plouffe, JF, Wyatt, RH, Fass, RJ. Central nervous system toxicity associated with metronidazole therapy. Ann Intern Med. 1980 Jul;93(1):59–60.Google Scholar
11. Ahmed, A, Loes, DJ, Bressler, EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology. 1995 Mar;45(3 Pt 1):588–9.Google Scholar
12. Alvarez, RS, Richardson, DA, Bent, AE, Ostergard, DR. Central nervous system toxicity related to prolonged metronidazole therapy. Am J Obstet Gynecol. 1983 Mar 1;145(5):640–1.Google Scholar
13. Bonkowsky, JL, Sondrup, C, Benedict, SL. Acute reversible cerebellar lesions associated with metronidazole therapy. Neurology. 2007 Jan 16;68(3):180.Google Scholar
14. Chatzkel, JA, Vossough, A. Metronidazole-induced cerebellar toxicity. Pediatr Radiol. 2010 Aug;40(8):1453.CrossRefGoogle ScholarPubMed
15. De Bleecker, JL, Leroy, BP, Meire, VI. Reversible visual deficit and Corpus callosum lesions due to metronidazole toxicity. Eur Neurol. 2005;53(2):93–5.CrossRefGoogle ScholarPubMed
16. Deenadayalu, VP, Orinion, EJ, Chalasani, NP, Yoo, HY. Abnormal enhancing lesion of dentate nuclei causing neurologic symptoms induced by metronidazole toxicity. Clin Gastroenterol Hepatol. 2005 Mar;3(3):xxix.Google Scholar
17. Galvez, M, Brahm, J, Miranda, M. Movement disorders as a manifestation of metronidazole-induced encephalopathy in a patient with chronic liver disease. Mov Disord. 2009 Sep 15;24(12):1864–6.Google Scholar
18. Graves, TD, Condon, M, Loucaidou, M, Perry, RJ. Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient. J Neurol Sci. 2009 Oct 15;285(1–2):238–40.CrossRefGoogle Scholar
19. Gupta, AK, Agarwal, MP, Avasthi, R, Bhadoria, DP, Rohatgi, N. Metrondazole-induced neurotoxicity. J Assoc Physicians India. 2003 Jun;51:617–8.Google Scholar
20. Heaney, CJ, Campeau, NG, Lindell, EP. MR imaging and diffusion-weighted imaging changes in metronidazole (Flagyl)-induced cerebellar toxicity. AJNR Am J Neuroradiol. 2003 Sep;24(8):1615–7.Google Scholar
21. Horlen, CK, Seifert, CF, Malouf, CS. Toxic metronidazole-induced MRI changes. Ann Pharmacother. 2000 Nov;34(11):1273–5.Google Scholar
22. Ito, H, Maruyama, M, Ogura, N, et al. Reversible cerebellar lesions induced by metronidazole therapy for helicobacter pylori. J Neuroimaging. 2004 Oct;14(4):369–71.Google Scholar
23. Kalia, V, Vibhuti, Saggar K. Case report: MRI of the brain in metronidazole toxicity. Indian J Radiol Imaging. 2010 Aug;20 (3):195–7.Google Scholar
24. Lawford, R, Sorrell, TC. Amebic abscess of the spleen complicated by metronidazole-induced neurotoxicity: case report. Clin Infect Dis. 1994 Aug;19(2):346–8.Google Scholar
25. Moosa, AN, Perkins, D. Neurological picture. MRI of metronidazole induced cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2010 Jul;81(7):754–5.Google Scholar
26. Patel, K, Green-Hopkins, I, Lu, S, Tunkel, AR. Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. Int J Infect Dis. 2008 Nov;12(6):e111–4.Google Scholar
27. Takase, K, Santa, Y, Ohta, S, Yoshimura, T. [MRI and SPECT findings in a case of metronidazole-induced reversible acute cerebellar ataxia]. Rinsho Shinkeigaku. 2005 May;45(5):386–9.Google Scholar
28. Toumi, S, Hammouda, M, Essid, A, Medimagh, L, Slamia, LB, Laouani-Kechrid, C. [Metronidazole-induced reversible cerebellar lesions and peripheral neuropathy]. Med Mal Infect. 2009 Dec;39(12):906–8.Google Scholar
29. Woodruff, BK, Wijdicks, EF, Marshall, WF. Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. N Engl J Med. 2002 Jan 3;346(1):68–9.Google Scholar
30. Loft, S, Sonne, J, Dossing, M, Andreasen, PB. Metronidazole pharmacokinetics in patients with hepatic encephalopathy. Scand J Gastroenterol. 1987 Jan;22(1):117–23.Google Scholar
31. Cheong, HC, Jeong, TG, Cho, YB, et al. Metronidazole-induced encephalopathy in a patient with liver cirrhosis. Korean J Hepatol. 2011 Jun;17(2):157–60.Google Scholar
32. Groothoff, MV, Hofmeijer, J, Sikma, MA, Meulenbelt, J. Irreversible encephalopathy after treatment with high-dose intravenous metronidazole. Clin Ther. 2010 Jan;32(1):60–4.Google Scholar
33. Kim, DW, Park, JM, Yoon, BW, Baek, MJ, Kim, JE, Kim, S. Metronidazole-induced encephalopathy. J Neurol Sci. 2004 Sep 15;224(1–2):107–11.Google Scholar
34. Bottenberg, MM, Hegge, KA, Eastman, DK, Kumar, R. Metronidazole-induced encephalopathy: a case report and review of the literature. J Clin Pharmacol. 2011 Jan;51(1):112–6.Google Scholar
35. Seok, JI, Yi, H, Song, YM, Lee, WY. Metronidazole-induced encephalopathy and inferior olivary hypertrophy: lesion analysis with diffusion-weighted imaging and apparent diffusion coefficient maps. Arch Neurol. 2003 Dec;60(12):1796–800.Google Scholar
36. Arik, N, Cengiz, N, Bilge, A. Metronidazole-induced encephalopathy in a uremic patient: a case report. Nephron. 2001 Sep;89(1):108–9.CrossRefGoogle Scholar
37. Cazals, X, Omoumi, P, Agnard, P, et al. [Reversible metronidazole-induced encephalopathy and hypertrophic olivary degeneration]. J Radiol. 2010 Mar;91(3 Pt 1):304–6.Google Scholar
38. Desai, JA, Dobson, J, Melanson, M, Pari, G, Jin, AY. Metronidazole-induced encephalopathy: case report and review of MRI findings. Can J Neurol Sci. 2011 May;38(3):512–3.Google Scholar
39. Hammami, N, Drissi, C, Sebai, R, et al. Reversible metronidazole-induced encephalopathy. J Neuroradiol. 2007 May;34(2):133–6.Google Scholar
40. Kim, E, Na, DG, Kim, EY, Kim, JH, Son, KR, Chang, KH. MR imaging of metronidazole-induced encephalopathy: lesion distribution and diffusion-weighted imaging findings. AJNR Am J Neuroradiol. 2007 Oct;28(9):1652–8.CrossRefGoogle ScholarPubMed
41. Kim, H, Kim, YW, Kim, SR, Park, IS, Jo, KW. Metronidazole-induced encephalopathy in a patient with infectious colitis: a case report. J Med Case Reports. 2011;5:63.Google Scholar
42. Lee, SS, Cha, SH, Lee, SY, Song, CJ. Reversible inferior colliculus lesion in metronidazole-induced encephalopathy: magnetic resonance findings on diffusion-weighted and fluid attenuated inversion recovery imaging. J Comput Assist Tomogr. 2009 Mar–Apr;33(2):305–8.Google Scholar
43. Omotoso, AB, Opadijo, OG. Acute encephalopathy associated with metronidazole therapy. Afr J Med Med Sci. 1997 Mar-Jun;26(1–2):97–8.Google Scholar
44. Park, KI, Chung, JM, Kim, JY. Metronidazole neurotoxicity: sequential neuroaxis involvement. Neurol India. 2011 Jan–Feb;59(1):104–7.Google Scholar
45. Wienbren, M, Perinpanayagam, RM, Camba, L, Lee, CA. Convulsions and encephalopathy in a patient with leukemia after treatment with metronidazole. J Clin Pathol. 1985 Sep;38(9):1076.Google Scholar
46. Beloosesky, Y, Grosman, B, Marmelstein, V, Grinblat, J. Convulsions induced by metronidazole treatment for Clostridium difficile-associated disease in chronic renal failure. Am J Med Sci. 2000 May;319(5):338–9.Google Scholar
47. Frytak, S, Moertel, CH, Childs, DS. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med. 1978 Mar;88(3):361–2.CrossRefGoogle ScholarPubMed
48. George, WL, Kirby, BD, Sutter, VL, Wheeler, LA, Mulligan, ME, Finegold, SM. Intravenous metronidazole for treatment of infections involving anaerobic bacteria. Antimicrob Agents Chemother. 1982 Mar;21(3):441–9.CrossRefGoogle ScholarPubMed
49. Halloran, TJ. Convulsions associated with high cumulative doses of metronidazole. Drug Intell Clin Pharm. 1982 May;16(5):409.Google Scholar
50. Herreman, G, Krainik, F, Betous, F, Nicolas, MO, Mundler, B. [Convulsive seizures and polyneuritis in a patient with lupus treated with metronidazole (author's transl)]. Ann Med Interne (Paris). 1981;132(6):398–403.Google Scholar
51. Cecil, KM, Halsted, MJ, Schapiro, M, Dinopoulos, A, Jones, BV. Reversible MR imaging and MR spectroscopy abnormalities in association with metronidazole therapy. J Comput Assist Tomogr. 2002 Nov–Dec;26(6):948–51.Google Scholar
52. McGrath, NM, Kent-Smith, B, Sharp, DM. Reversible optic neuropathy due to metronidazole. Clin Experiment Ophthalmol. 2007 Aug;35(6):585–6.Google Scholar
53. Putnam, D, Fraunfelder, FT, Dreis, M. Metronidazole and optic neuritis. Am J Ophthalmol. 1991 Dec 15;112(6):737.Google Scholar
54. Hobson-Webb, LD, Roach, ES, Donofrio, PD. Metronidazole: newly recognized cause of autonomic neuropathy. J Child Neurol. 2006 May;21(5):429–31.Google Scholar
55. Bradley, WG, Karlsson, IJ, Rassol, CG. Metronidazole neuropathy. Br Med J. 1977 Sep 3;2(6087):610–1.Google Scholar
56. Coxon, A, Pallis, CA. Metronidazole neuropathy. J Neurol Neurosurg Psychiatry. 1976 Apr;39(4):403–5.Google Scholar
57. Gupta, BS, Baldwa, S, Verma, S, Gupta, JB, Singhal, A. Metronidazole induced neuropathy. Neurol India. 2000 Jun;48(2):192–3.Google Scholar
58. Ramsay, ID. Endocrine ophthalmopathy. Br Med J. 1968 Dec 14;4 (5632):706.Google Scholar
59. Sarma, GR, Kamath, V. Acute painful peripheral neuropathy due to metronidazole. Neurol India. 2005 Sep;53(3):372–3.Google Scholar
60. Takeuchi, H, Yamada, A, Touge, T, Miki, H, Nishioka, M, Hashimoto, S. Metronidazole neuropathy: a case report. Jpn J Psychiatry Neurol. 1988 Jun;42(2):291–5.Google Scholar
61. Tan, CH, Chen, YF, Chen, CC, Chao, CC, Liou, HH, Hsieh, ST. Painful neuropathy due to skin denervation after metronidazole-induced neurotoxicity. J Neurol Neurosurg Psychiatry. 2011 Apr;82(4):462–5.Google Scholar
62. Zivkovic, SA, Lacomis, D, Giuliani, MJ. Sensory neuropathy associated with metronidazole: report of four cases and review of the literature. J Clin Neuromuscul Dis. 2001 Sep;3(1):8–12.Google Scholar
63. Said, G, Goasguen, J, Laverdant, C. [Neuropathy in long term treatment with metronidazole (author's transl)]. Rev Neurol (Paris). 1978 Aug–Sep;134(8–9):515–21.Google Scholar
64. Caylor, KB, Cassimatis, MK. Metronidazole neurotoxicosis in two cats. J Am Anim Hosp Assoc. 2001 May–Jun;37(3):258–62.Google Scholar
65. Dow, SW, LeCouteur, RA, Poss, ML, Beadleston, D. Central nervous system toxicosis associated with metronidazole treatment of dogs: five cases (1984–1987). J Am Vet Med Assoc. 1989 Aug 1;195(3):365–8.Google Scholar
66. Olson, EJ, Morales, SC, McVey, AS, Hayden, DW. Putative metronidazole neurotoxicosis in a cat. Vet Pathol. 2005 Sep;42(5):665–9.Google Scholar
67. Scharer, K. [Selective alterations of Purkinje cells in the dog after oral administration of high doses of nitroimidazole derivatives (author's transl)]. Verh Dtsch Ges Pathol. 1972;56:407–10.Google Scholar
68. Placidi, GF, Masuoka, D, Alcaraz, A, Taylor, JA, Earle, R. Distribution and metabolism of 14C-metronidazole in mice. Arch Int Pharmacodyn Ther. 1970 Nov;188(1):168–79.Google ScholarPubMed
69. von Rogulja, P, Kovac, W, Schmid, H. [Metronidazol encephalopathy in rats]. Acta Neuropathol. 1973 Jun 26;25(1):36–45.Google Scholar
70. Loft, S, Poulsen, HE. Metabolism of metronidazole and antipyrine in hepatocytes isolated from mouse and rat. Xenobiotica. 1990 Feb; 20(2):185–91.Google Scholar
71. Rao, DN, Harman, L, Motten, A, Schreiber, J, Mason, RP. Generation of radical anions of nitrofurantoin, misonidazole, and metronidazole by ascorbate. Arch Biochem Biophys. 1987 Jun;255(2):419–27.Google Scholar
72. Alston, TA. Neurotoxicity of metronidazole. Ann Intern Med. 1985 Jul;103(1):161.Google Scholar
73. Taskapilioglu, O, Seferoglu, M, Kaygili, E, Hakyemez, B, Zarifoglu, M. Reversible cerebellar toxicity during treatment with ornidazole: the first case report. J Neurol Neurosurg Psychiatry. 2010 Mar;81(3):349–50.Google Scholar
74. Chacko, J, Pramod, K, Sinha, S, et al. Clinical, neuroimaging and pathological features of 5-nitroimidazole-induced encephalo-neuropathy in two patients: Insights into possible pathogenesis. Neurol India. 2011 Sep–Oct;59(5):743–7.Google Scholar
75. Ludwig, E, Csiba, A, Magyar, T, Szocs, G, Graber, H. Age-associated pharmacokinetic changes of metronidazole. Int J Clin Pharmacol Ther Toxicol. 1983 Feb;21(2):87–91.Google Scholar
76. Loft, S, Egsmose, C, Sonne, J, Poulsen, HE, Dossing, M, Andreasen, PB. Metronidazole elimination is preserved in the elderly. Hum Exp Toxicol. 1990 May;9(3):155–9.Google Scholar
77. Houghton, GW, Dennis, MJ, Gabriel, R. Pharmacokinetics of metronidazole in patients with varying degrees of renal failure. Br J Clin Pharmacol. 1985 Feb;19(2):203–9.Google Scholar
78. Kuriyama, A, Jackson, JL, Doi, A, Kamiya, T. Metronidazole-induced central nervous system toxicity: a systematic review. Clin Neuropharmacol. 2011 Nov–Dec;34(6):241–7.Google Scholar