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Metronidazole-induced encephalopathy
Journal of the Neurological Sciences 224 (2004) 107 – 111 www.elsevier.com/locate/jns
Short communication
Metronidazole-induced encephalopathy Dong Wook Kima,b, Jong-Moo Parkc, Byung-Woo Yoona,b, Min Jae Baeka,b, Jung Eun Kima,b, SangYun Kima,b,* a
Clinical Neuroscience Center, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 464-707, South Korea b Department of Neurology, Seoul National University College of Medicine, Seoul, South Korea c Department of Neurology, Eulji General Hospital Eulji University, School of Medicine, Seoul, South Korea Received 31 December 2003; received in revised form 15 June 2004; accepted 16 June 2004 Available online 24 August 2004
Abstract We report the clinical, neuropsychological, and neuroimaging findings of two patients of diffuse encephalopathy associated with the use of metronidazole. Both patients showed characteristic abnormalities on magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) and recovered incompletely after the discontinuation of metronidazole. We also suggest that MRI with DWI may be useful in the diagnosis of metronidazole-induced encephalopathy, and that they have a role in the prediction of prognosis. D 2004 Elsevier B.V. All rights reserved. Keywords: Metronidazole; Encephalopathy; Magnetic resonance imaging
1. Introduction
2. Cases report
Metronidazole is a synthetic 5-nitroimidazole that exhibits antiprotozoal and antibacterial activity. Metronidazole is fairly well tolerated, but it can produce several adverse neurologic effects including peripheral neuropathy, cerebellopathy, encephalopathy, and seizure [1]. Reversible high signal intensity by magnetic resonance imaging (MRI) of the cerebellar dentate nuclei has often been reported in several cerebellopathy cases [2–5]. Recently, we encountered two cases of metronidazoleinduced encephalopathy with incomplete recovery. Both patients showed abnormalities on MRI, with diffusionweighted imaging (DWI), which have not been previously described.
2.1. Case 1
* Corresponding author. Department of Neurology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 464-707, South Korea. Tel.: +82-31-787-7462; fax: +82-31719-6815. E-mail address: [email protected] (S.Y. Kim). 0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2004.06.012
A 31-year-old man, who had been diagnosed as having Crohn disease 14 years previously and who had been treated with prednisolone, sulfasalazine, and metronidazole was admitted for altered consciousness. From 1 week before admission, he suffered from aggravated diarrhea and took metronidazole and prednisolone at over three times the usual dose. One day before admission, he became drowsy and showed a slow response to verbal commands, and he was determined to be confused on the day of admission. On neurologic examination, he did not follow verbal commands well and spoke incomprehensibly. However, pupillary response to light was normal, and there was no gloss limitation on extraocular muscle movement. Motor power was symmetrically normal to painful stimuli. Deep tendon reflexes were normoactive, and toe signs were bilaterally flexor. Laboratory findings including blood, urine, and CSF tests were all normal. Electrocardiography (ECG), and brain
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computed tomography (CT) did not show any specific abnormality, and electroencephalography showed continuous diffuse theta slowing. T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI (Fig. 1a–d) performed on the second day of hospitalization showed diffuse high signal intensity in the bilateral subcortical white matter and in cerebellar dentate nuclei. On DWI, performed on the same day, hemispheric lesions of high signal intensity with low apparent diffusion coefficient (ADC) were observed in the corresponding areas (3.45–5.3210 4 mm2/s), but no abnormality was evident in the dentate nuclei (Fig. 1e,f). After the discontinuation of all medication, his level of consciousness improved slowly. On the 7th day of hospitalization, he could answer simple questions, but a global impairment of cognitive function was still noted (Korean version of Mini-Mental State Examination [K-MMSE]: 10/ 30; education: 18 years). Two months later, he could perform activities required for daily living and showed a markedly improved cognitive function (K-MMSE: 26/30). Therefore, he underwent more detailed neuropsychological testing. The results of the neuropsychological tests are presented in Table 1. The overall results showed dysfunctions of attention, visuo-perceptive ability, visuo-analytic
ability, visuo-constructive ability, learning and memory (verbal and visual), and frontal lobe function. Follow-up brain T2-weighted MRI images (Fig. 1g,h) showed a reduction in the high signal intensity in the subcortical white matter and a resolution of the dentate nuclei lesions. Follow-up DWI (Fig. 1i) showed the resolution of high signal intensity in the subcortical white matter. Subsequently, his neurologic status has not changed significantly during 10 months of follow-up. 2.2. Case 2 A 46-year-old man was referred to the neurology department for altered consciousness. He had a past medical history of total gastrectomy and segmental bowel resection for advanced gastric cancer and a subsequent intestinal hernia with infarction 7 years previously. He was on prolonged parenteral nutrition through a central venous catheter due to short bowel syndrome. One week before examination, he developed acute cholangitis and was treated with the intravenous cefotaxime with metronidazole, but his gastrointestinal symptoms did not show significant improvement. Six days later he suddenly became comatose.
Fig. 1. Magnetic resonance imaging findings in case 1. T2-weighted and fluid-attenuated inversion recovery images showing high signal intensities in the subcortical white matter (a, b) and cerebellar dentate nuclei (arrows) (c, d). Diffusion-weighted images showing high signal intensities only in the subcortical white matter (e, f). On follow-up images, T2-weighted images (g, h) and diffusion-weighted image (i) showed lesions resolution two months after discontinuing metronidazole.
D.W. Kim et al. / Journal of the Neurological Sciences 224 (2004) 107–111 Table 1 Results of neuropsychological testing
significantly, and he has remained in a persistent vegetative state over the six months of follow-up. Further neuropsychological evaluation was impossible.
Neuropsychologic test Attention Digit span: Forward/backward Letter cancellation Language and related functions Fluency Auditory comprehension Repetition Naming (K-BNT) Reading/writing Calculation Finger naming Right–left orientation Praxis: pantomiming gestures Visuospatial functions Interlocking pentagon Copy of Rey-CFT Memory Orientation: Time/Place (5/5) Remote memory: naming the presidents (5) 3 words registration/recall K-CVLT: Free recall: 1st+2nd+3rd+4th+5th=total/delayed recall Recognition: True positive–false positive Rey Figure Immediate recall/delayed recall Recognition: True positive–false positive Frontal/executive function Contrasting program Go/no-go test Fist-edge-palm Alternating hand movement Alternating square and triangle Luria loop Semantic word fluency: Animals/supermarket items Phonemic word fluency (Korean alphabet: !/,/*) Stroop test: Word reading: correct/incorrect Color reading: correct/incorrect K-MMSE
109
4/3 Normal Fluent Normal Normal 55/60(63%ile) Normal/Normal Abnormal Borderline Borderline Normal Normal 26/36(=1%ile) 4/5 5 3/2
6+8+8+10+6=38/5 16–3 5/5.5 11/4 Normal Normal Abnormal Abnormal Normal Normal 6/6 7/5/7 71/0 11/6 26/30
K-BNT; Korean version of the Boston Naming Test, K-CVLT; KoreanCalifornia Verbal Learning Test, K-MMSE; Korean version of the MiniMental Status Examination, Rey-CFT; Rey-Complex Figure Test.
Laboratory findings including blood, urine, and CSF tests showed no significant abnormality except mildly elevated liver enzymes with high bilirubin. T2-weighted MRI showed diffuse high signal intensity in the bilateral subcortical white matter and in the cerebellar dentate nuclei (Fig. 2a,b). On DWI, the hemispheric lesions also showed as high signal intensity with low ADC in the corresponding areas (2.75– 3.8110 4 mm2/s), but the dentate nucleus lesions did not show abnormality (Fig. 2c,d). His mental status showed a slight improvement with the discontinuation of the metronidazole. He opened his eyes spontaneously and slowed sleep–wake cycle one week later. However, since then his neurologic status has not changed
3. Discussion Neurotoxicity is one of the most important adverse effects of metronidazole therapy. While reversible cerebellopathy [2–5] and peripheral neuropathy [6,7] have been frequently reported, other neurotoxicities such as encephalopathy, seizure, and mental confusion have also been documented [2,8–13]. However, permanent encephalopathy, has not been reported, thus it is necessary to differentiate other conditions such as demyelinating and metabolic diseases. Multiple sclerosis or acute disseminated encephalomyelopathy could produce diffuse encephalopathy, but normal CSF, low ADC, and the selective involvement of cerebellar dentate nuclei make these diagnoses less likely [14]. The possibility of Wernicke encephalopathy is also slight because it tends to show a predilection for the midbrain and diencephalon, and high signal intensities on DWI with low ADC in the these areas [15,16]. Both of our patients developed encephalopathy following the initiation or overuse of metronidazole and showed partial improvement after discontinuation. This temporal relationship also supports the diagnosis of metronidazole-induced encephalopathy. DWI is a technique that detects the diffusion of water molecules. It is most commonly used in acute stroke where water diffusion is highly restricted due to a shift of fluid into the intracellular compartment leading to cytotoxic edema. The ADC of brain tissue is significantly reduced in cytotoxic edema. Regions of vasogenic edema demonstrate increased ADC because the diffusion of water in the extracellular compartment is lower than that of free water, but nonetheless significantly higher than in the extracellular compartment [17]. Recently, DWI with ADC has been recognized to be important in the evaluation of metabolic encephalopathy. High signal in DWI with high ADC, suggesting the presence of vasogenic edema, is more frequently described [18–21], and high signal in DWI with low ADC has also been detected in some metabolic encephalopathies, such as, Wernicke encephalopathy [15,16], Canavan disease [22], and maple syrup urine disease [23]. Although explanations of the restricted diffusion edema pattern in this kind of metabolic encephalopathy are yet unsatisfactory, it would be logical to assume that the signal increase on DWI with low ADC would result from intracellular (cytotoxic) edema caused by disease states other than ischemia. Unlike an initial report that accounted for the MRI finding as axonal swelling with increased water content resulting in T2 prolongation [2], our cases suggest that while vasogenic edema may be evident in the cerebellopathy, it may be not be an important component in the encephalopathy at least in severe cases.
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Fig. 2. Magnetic resonance imaging findings in case 2. T2-weighted images show high signal intensities in the subcortical white matter and cerebellar dentate nuclei (arrow) (a, b). Diffusion-weighted images show high signal intensity only in the subcortical white matter (c, d).
Since the previously documented metronidazole-induced encephalopathy cases followed a favorable prognosis, it is an unusual finding that our patients showed persistent neurologic abnormalities for more than several months. The clinical situation may explain in part its severity in our patients; one had been chronically exposed to metronidazole and then overdosed, and the other was under chronic parenteral nutrition. Poor prognosis may be associated with the low ADC. In an experimental ischemia model [24], a lower ADC was associated with a poor prognosis, and certain ADC value (4.5010 4 to 5.5010 4 mm2/s) was suggested as a threshold to irreversible damage. Although the prognostic predictive role of ADC in metabolic encephalopathy has not been studied, our findings suggest that there may be a similar threshold to irreversible damage in metronidazole encephalopathy, and that the prognosis difference in our patients may be explained by ADC differences (the ADC of case 1 [3.45–5.3210 4 mm2/s] was higher than that of case 2 [2.75–3.8110 4 mm2/s]). In conclusion, our cases illustrate that metronidazole can cause irreversible neurotoxicity to the supratentorial white matter, and that the mechanism of encephalopathy may differ from that of cerebellopathy. In addition, it can be inferred that MRI including DWI may have a role in diagnosis and in the prediction of the prognosis of metronidazole-induced encephalopathy.
References [1] Finegold SM. Metronidazole. Ann Intern Med 1980;93:585 – 7. [2] Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology 1995;45:588 – 9. [3] Kim DS, Jung JW, Kim JY, Kim JH, Kim EG, Kim SE. Reversible MRI findings in metronidazole-induced cerebellar dysfunction. J Korean Neurol Assoc 1999;17:904 – 7. [4] Horlen CK, Seifert CF, Malouf CS. Toxic metronidazole-induced MRI changes. Ann Pharmacother 2000;34:1273 – 5. [5] Woodruff BK, Wijdicks EF, Marshall WF. Reversible metronidazoleinduced lesions of the cerebellar dentate nuclei. N Engl J Med 2002;346:68 – 9. [6] Coxon A, Pallis CA. Metronidazole neuropathy. J Neurol Neurosurg Psychiatry 1976;39:403 – 5. [7] Bradley WG, Karlsson IJ, Rassol CG. Metronidazole neuropathy. Br Med J 1977;2:610 – 2. [8] Frytak S, Moertel CG, Childs DS. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med 1978;88:361 – 2. [9] 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;26:948 – 51. [10] Kusumi RK, Plouffe JF, Wyatt RH, Fass RJ. Central nervous system toxicity associated with metronidazole therapy. Ann Intern Med 1980;93:59 – 60. [11] 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;391: 338 – 9.
D.W. Kim et al. / Journal of the Neurological Sciences 224 (2004) 107–111 [12] Mahl TC, Ummadi S. Metronidazole and mental confusion. J Clin Gastroenterol 2003;36:373 – 4. [13] Arik N, Cengiz N, Bilge A. Metronidazole-induced encephalopathy in a uremic patient: a case report. Nephron 2001;89:108 – 9. [14] Horsfield MA, Lai M, Webb SL, Barker GJ, Tofts PS, Turner R, Rudge P, Miller DH. Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance. Magn Reson Med 1996;36:393 – 400. [15] Chu K, Kang DW, Kim HJ, Lee YS, Park SH. Diffusion-weighted imaging abnormalities in Wernicke Encephalopathy: reversible cytotoxic edema? Arch Neurol 2002;59:123 – 7. [16] Halavaara J, Brander A, Lyytinen J, Setala K, Kallela M. Wernicke’s encephalopathy: is diffusion-weighted MRI useful? Neuroradiology 2003;45:519 – 23. [17] Schaefer PW, Grant PE, Gonzalez RG. Diffusion-weighted MR imaging of the brain. Radiology 2000;217:331 – 45. [18] Debaere C, Stadnik T, De Maeseneer M, Osteaux M. Diffusionweighted MRI in cyclosporin A neurotoxicity for the classification of cerebral edema. Eur Radiol 1999;9:1916 – 8. [19] Furukawa M, Terae S, Chu BC, Kanelvo K, Kamada H, Miyasalva K. MRI in seven cases of tacrolimus (FK-506) encephalopathy: utility of
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[22]
[23]
[24]
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FLAIR and diffusion-weighted imaging. Neuroradiology 2001;43: 615 – 21. Yen PS, Chen CJ, Lui CC, Wai YY, Wan WL. Diffusion-weighted magnetic resonance imaging of porphyric encephalopathy: a case report. Eur Neurol 2002;48:119 – 21. Gelal F, Calli C, Apaydin M, Erdem G. Van der Knaap’s leukoencephalopathy: report of five new cases with emphasis on diffusionweighted MRI findings. Neuroradiology 2002;44:625 – 30. Engelbrecht V, Scherer A, Rassek M, Witsack HJ, Modder U. Diffusion-weighted MR imaging in the brain in children: findings in the normal brain and in the brain with white matter diseases. Radiology 2002;222:410 – 8. Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM. MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 2003;45:393 – 9. Dardzinski BJ, Sotak CH, Fisher M, Hasegawa Y, Li L, Minematsu K. Apparent diffusion coefficient mapping of experimental focal cerebral ischemia using diffusion-weighted echo-planar imaging. Magn Reson Med 1993;30:318 – 25.
Short communication
Metronidazole-induced encephalopathy Dong Wook Kima,b, Jong-Moo Parkc, Byung-Woo Yoona,b, Min Jae Baeka,b, Jung Eun Kima,b, SangYun Kima,b,* a
Clinical Neuroscience Center, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 464-707, South Korea b Department of Neurology, Seoul National University College of Medicine, Seoul, South Korea c Department of Neurology, Eulji General Hospital Eulji University, School of Medicine, Seoul, South Korea Received 31 December 2003; received in revised form 15 June 2004; accepted 16 June 2004 Available online 24 August 2004
Abstract We report the clinical, neuropsychological, and neuroimaging findings of two patients of diffuse encephalopathy associated with the use of metronidazole. Both patients showed characteristic abnormalities on magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) and recovered incompletely after the discontinuation of metronidazole. We also suggest that MRI with DWI may be useful in the diagnosis of metronidazole-induced encephalopathy, and that they have a role in the prediction of prognosis. D 2004 Elsevier B.V. All rights reserved. Keywords: Metronidazole; Encephalopathy; Magnetic resonance imaging
1. Introduction
2. Cases report
Metronidazole is a synthetic 5-nitroimidazole that exhibits antiprotozoal and antibacterial activity. Metronidazole is fairly well tolerated, but it can produce several adverse neurologic effects including peripheral neuropathy, cerebellopathy, encephalopathy, and seizure [1]. Reversible high signal intensity by magnetic resonance imaging (MRI) of the cerebellar dentate nuclei has often been reported in several cerebellopathy cases [2–5]. Recently, we encountered two cases of metronidazoleinduced encephalopathy with incomplete recovery. Both patients showed abnormalities on MRI, with diffusionweighted imaging (DWI), which have not been previously described.
2.1. Case 1
* Corresponding author. Department of Neurology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 464-707, South Korea. Tel.: +82-31-787-7462; fax: +82-31719-6815. E-mail address: [email protected] (S.Y. Kim). 0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2004.06.012
A 31-year-old man, who had been diagnosed as having Crohn disease 14 years previously and who had been treated with prednisolone, sulfasalazine, and metronidazole was admitted for altered consciousness. From 1 week before admission, he suffered from aggravated diarrhea and took metronidazole and prednisolone at over three times the usual dose. One day before admission, he became drowsy and showed a slow response to verbal commands, and he was determined to be confused on the day of admission. On neurologic examination, he did not follow verbal commands well and spoke incomprehensibly. However, pupillary response to light was normal, and there was no gloss limitation on extraocular muscle movement. Motor power was symmetrically normal to painful stimuli. Deep tendon reflexes were normoactive, and toe signs were bilaterally flexor. Laboratory findings including blood, urine, and CSF tests were all normal. Electrocardiography (ECG), and brain
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D.W. Kim et al. / Journal of the Neurological Sciences 224 (2004) 107–111
computed tomography (CT) did not show any specific abnormality, and electroencephalography showed continuous diffuse theta slowing. T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI (Fig. 1a–d) performed on the second day of hospitalization showed diffuse high signal intensity in the bilateral subcortical white matter and in cerebellar dentate nuclei. On DWI, performed on the same day, hemispheric lesions of high signal intensity with low apparent diffusion coefficient (ADC) were observed in the corresponding areas (3.45–5.3210 4 mm2/s), but no abnormality was evident in the dentate nuclei (Fig. 1e,f). After the discontinuation of all medication, his level of consciousness improved slowly. On the 7th day of hospitalization, he could answer simple questions, but a global impairment of cognitive function was still noted (Korean version of Mini-Mental State Examination [K-MMSE]: 10/ 30; education: 18 years). Two months later, he could perform activities required for daily living and showed a markedly improved cognitive function (K-MMSE: 26/30). Therefore, he underwent more detailed neuropsychological testing. The results of the neuropsychological tests are presented in Table 1. The overall results showed dysfunctions of attention, visuo-perceptive ability, visuo-analytic
ability, visuo-constructive ability, learning and memory (verbal and visual), and frontal lobe function. Follow-up brain T2-weighted MRI images (Fig. 1g,h) showed a reduction in the high signal intensity in the subcortical white matter and a resolution of the dentate nuclei lesions. Follow-up DWI (Fig. 1i) showed the resolution of high signal intensity in the subcortical white matter. Subsequently, his neurologic status has not changed significantly during 10 months of follow-up. 2.2. Case 2 A 46-year-old man was referred to the neurology department for altered consciousness. He had a past medical history of total gastrectomy and segmental bowel resection for advanced gastric cancer and a subsequent intestinal hernia with infarction 7 years previously. He was on prolonged parenteral nutrition through a central venous catheter due to short bowel syndrome. One week before examination, he developed acute cholangitis and was treated with the intravenous cefotaxime with metronidazole, but his gastrointestinal symptoms did not show significant improvement. Six days later he suddenly became comatose.
Fig. 1. Magnetic resonance imaging findings in case 1. T2-weighted and fluid-attenuated inversion recovery images showing high signal intensities in the subcortical white matter (a, b) and cerebellar dentate nuclei (arrows) (c, d). Diffusion-weighted images showing high signal intensities only in the subcortical white matter (e, f). On follow-up images, T2-weighted images (g, h) and diffusion-weighted image (i) showed lesions resolution two months after discontinuing metronidazole.
D.W. Kim et al. / Journal of the Neurological Sciences 224 (2004) 107–111 Table 1 Results of neuropsychological testing
significantly, and he has remained in a persistent vegetative state over the six months of follow-up. Further neuropsychological evaluation was impossible.
Neuropsychologic test Attention Digit span: Forward/backward Letter cancellation Language and related functions Fluency Auditory comprehension Repetition Naming (K-BNT) Reading/writing Calculation Finger naming Right–left orientation Praxis: pantomiming gestures Visuospatial functions Interlocking pentagon Copy of Rey-CFT Memory Orientation: Time/Place (5/5) Remote memory: naming the presidents (5) 3 words registration/recall K-CVLT: Free recall: 1st+2nd+3rd+4th+5th=total/delayed recall Recognition: True positive–false positive Rey Figure Immediate recall/delayed recall Recognition: True positive–false positive Frontal/executive function Contrasting program Go/no-go test Fist-edge-palm Alternating hand movement Alternating square and triangle Luria loop Semantic word fluency: Animals/supermarket items Phonemic word fluency (Korean alphabet: !/,/*) Stroop test: Word reading: correct/incorrect Color reading: correct/incorrect K-MMSE
109
4/3 Normal Fluent Normal Normal 55/60(63%ile) Normal/Normal Abnormal Borderline Borderline Normal Normal 26/36(=1%ile) 4/5 5 3/2
6+8+8+10+6=38/5 16–3 5/5.5 11/4 Normal Normal Abnormal Abnormal Normal Normal 6/6 7/5/7 71/0 11/6 26/30
K-BNT; Korean version of the Boston Naming Test, K-CVLT; KoreanCalifornia Verbal Learning Test, K-MMSE; Korean version of the MiniMental Status Examination, Rey-CFT; Rey-Complex Figure Test.
Laboratory findings including blood, urine, and CSF tests showed no significant abnormality except mildly elevated liver enzymes with high bilirubin. T2-weighted MRI showed diffuse high signal intensity in the bilateral subcortical white matter and in the cerebellar dentate nuclei (Fig. 2a,b). On DWI, the hemispheric lesions also showed as high signal intensity with low ADC in the corresponding areas (2.75– 3.8110 4 mm2/s), but the dentate nucleus lesions did not show abnormality (Fig. 2c,d). His mental status showed a slight improvement with the discontinuation of the metronidazole. He opened his eyes spontaneously and slowed sleep–wake cycle one week later. However, since then his neurologic status has not changed
3. Discussion Neurotoxicity is one of the most important adverse effects of metronidazole therapy. While reversible cerebellopathy [2–5] and peripheral neuropathy [6,7] have been frequently reported, other neurotoxicities such as encephalopathy, seizure, and mental confusion have also been documented [2,8–13]. However, permanent encephalopathy, has not been reported, thus it is necessary to differentiate other conditions such as demyelinating and metabolic diseases. Multiple sclerosis or acute disseminated encephalomyelopathy could produce diffuse encephalopathy, but normal CSF, low ADC, and the selective involvement of cerebellar dentate nuclei make these diagnoses less likely [14]. The possibility of Wernicke encephalopathy is also slight because it tends to show a predilection for the midbrain and diencephalon, and high signal intensities on DWI with low ADC in the these areas [15,16]. Both of our patients developed encephalopathy following the initiation or overuse of metronidazole and showed partial improvement after discontinuation. This temporal relationship also supports the diagnosis of metronidazole-induced encephalopathy. DWI is a technique that detects the diffusion of water molecules. It is most commonly used in acute stroke where water diffusion is highly restricted due to a shift of fluid into the intracellular compartment leading to cytotoxic edema. The ADC of brain tissue is significantly reduced in cytotoxic edema. Regions of vasogenic edema demonstrate increased ADC because the diffusion of water in the extracellular compartment is lower than that of free water, but nonetheless significantly higher than in the extracellular compartment [17]. Recently, DWI with ADC has been recognized to be important in the evaluation of metabolic encephalopathy. High signal in DWI with high ADC, suggesting the presence of vasogenic edema, is more frequently described [18–21], and high signal in DWI with low ADC has also been detected in some metabolic encephalopathies, such as, Wernicke encephalopathy [15,16], Canavan disease [22], and maple syrup urine disease [23]. Although explanations of the restricted diffusion edema pattern in this kind of metabolic encephalopathy are yet unsatisfactory, it would be logical to assume that the signal increase on DWI with low ADC would result from intracellular (cytotoxic) edema caused by disease states other than ischemia. Unlike an initial report that accounted for the MRI finding as axonal swelling with increased water content resulting in T2 prolongation [2], our cases suggest that while vasogenic edema may be evident in the cerebellopathy, it may be not be an important component in the encephalopathy at least in severe cases.
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D.W. Kim et al. / Journal of the Neurological Sciences 224 (2004) 107–111
Fig. 2. Magnetic resonance imaging findings in case 2. T2-weighted images show high signal intensities in the subcortical white matter and cerebellar dentate nuclei (arrow) (a, b). Diffusion-weighted images show high signal intensity only in the subcortical white matter (c, d).
Since the previously documented metronidazole-induced encephalopathy cases followed a favorable prognosis, it is an unusual finding that our patients showed persistent neurologic abnormalities for more than several months. The clinical situation may explain in part its severity in our patients; one had been chronically exposed to metronidazole and then overdosed, and the other was under chronic parenteral nutrition. Poor prognosis may be associated with the low ADC. In an experimental ischemia model [24], a lower ADC was associated with a poor prognosis, and certain ADC value (4.5010 4 to 5.5010 4 mm2/s) was suggested as a threshold to irreversible damage. Although the prognostic predictive role of ADC in metabolic encephalopathy has not been studied, our findings suggest that there may be a similar threshold to irreversible damage in metronidazole encephalopathy, and that the prognosis difference in our patients may be explained by ADC differences (the ADC of case 1 [3.45–5.3210 4 mm2/s] was higher than that of case 2 [2.75–3.8110 4 mm2/s]). In conclusion, our cases illustrate that metronidazole can cause irreversible neurotoxicity to the supratentorial white matter, and that the mechanism of encephalopathy may differ from that of cerebellopathy. In addition, it can be inferred that MRI including DWI may have a role in diagnosis and in the prediction of the prognosis of metronidazole-induced encephalopathy.
References [1] Finegold SM. Metronidazole. Ann Intern Med 1980;93:585 – 7. [2] Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology 1995;45:588 – 9. [3] Kim DS, Jung JW, Kim JY, Kim JH, Kim EG, Kim SE. Reversible MRI findings in metronidazole-induced cerebellar dysfunction. J Korean Neurol Assoc 1999;17:904 – 7. [4] Horlen CK, Seifert CF, Malouf CS. Toxic metronidazole-induced MRI changes. Ann Pharmacother 2000;34:1273 – 5. [5] Woodruff BK, Wijdicks EF, Marshall WF. Reversible metronidazoleinduced lesions of the cerebellar dentate nuclei. N Engl J Med 2002;346:68 – 9. [6] Coxon A, Pallis CA. Metronidazole neuropathy. J Neurol Neurosurg Psychiatry 1976;39:403 – 5. [7] Bradley WG, Karlsson IJ, Rassol CG. Metronidazole neuropathy. Br Med J 1977;2:610 – 2. [8] Frytak S, Moertel CG, Childs DS. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med 1978;88:361 – 2. [9] 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;26:948 – 51. [10] Kusumi RK, Plouffe JF, Wyatt RH, Fass RJ. Central nervous system toxicity associated with metronidazole therapy. Ann Intern Med 1980;93:59 – 60. [11] 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;391: 338 – 9.
D.W. Kim et al. / Journal of the Neurological Sciences 224 (2004) 107–111 [12] Mahl TC, Ummadi S. Metronidazole and mental confusion. J Clin Gastroenterol 2003;36:373 – 4. [13] Arik N, Cengiz N, Bilge A. Metronidazole-induced encephalopathy in a uremic patient: a case report. Nephron 2001;89:108 – 9. [14] Horsfield MA, Lai M, Webb SL, Barker GJ, Tofts PS, Turner R, Rudge P, Miller DH. Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance. Magn Reson Med 1996;36:393 – 400. [15] Chu K, Kang DW, Kim HJ, Lee YS, Park SH. Diffusion-weighted imaging abnormalities in Wernicke Encephalopathy: reversible cytotoxic edema? Arch Neurol 2002;59:123 – 7. [16] Halavaara J, Brander A, Lyytinen J, Setala K, Kallela M. Wernicke’s encephalopathy: is diffusion-weighted MRI useful? Neuroradiology 2003;45:519 – 23. [17] Schaefer PW, Grant PE, Gonzalez RG. Diffusion-weighted MR imaging of the brain. Radiology 2000;217:331 – 45. [18] Debaere C, Stadnik T, De Maeseneer M, Osteaux M. Diffusionweighted MRI in cyclosporin A neurotoxicity for the classification of cerebral edema. Eur Radiol 1999;9:1916 – 8. [19] Furukawa M, Terae S, Chu BC, Kanelvo K, Kamada H, Miyasalva K. MRI in seven cases of tacrolimus (FK-506) encephalopathy: utility of
[20]
[21]
[22]
[23]
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