- Email: [email protected]
Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient
Journal of the Neurological Sciences 285 (2009) 238–240
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient Tracey D. Graves a, Marie Condon b, Marina Loucaidou b, Richard J. Perry a,⁎ a b
Department of Neurology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, Du Cane Road, London W12 0NS, United Kingdom Renal Medicine, Imperial College Healthcare NHS Trust, Hammersmith Hospital, Du Cane Road, London W12 0NS, United Kingdom
a r t i c l e
i n f o
Article history: Received 8 February 2009 Accepted 8 June 2009 Available online 27 June 2009 Keywords: Metronidazole Ataxia Dentate nucleus
a b s t r a c t Metronidazole-induced central nervous system (CNS) toxicity causes a spectrum of neurological symptoms including ataxia, encephalopathy and peripheral neuropathy. It is associated with characteristic MRI changes of high signal intensity in the dentate nuclei. Given the increasing use of metronidazole, it is import to recognise this drug as a cause of ataxia, as it is entirely reversible on drug withdrawal. © 2009 Elsevier B.V. All rights reserved.
1. Introduction 1.1. Case report A 61 year old man was admitted for treatment of a wound infection. He had long-standing type 1 diabetes leading to end stage renal failure in 1997, when he commenced haemodialysis. He then received a cadaveric renal and pancreatic transplant in 1998, with a good functional outcome, however the pancreas failed after four years and he recommenced insulin treatment. Subsequently, he received another cadaveric pancreatic transplant in 2006, again rendering him insulin-independent. His original immunosuppressive regimen included tacrolimus, mycophenylate mofetil and prednisolone was added at the time of the second transplant. Standard post-transplant infection prophylaxis was with cotrimoxazole, doxycycline, valganciclovir and nystatin. Unfortunately, the pancreatic transplant wound became infected and despite treatment with oral antibiotics the wound eventually dehisced and he was admitted for intravenous antibiotics. The causative organism was found to be a resistant Klebsiella species. He was initially treated with meropenem 500 mg IV BD and linezolid 600 mg PO BD. The linezolid was continued from his oral regimen, as he had grown a Vanomycin resistant Enterococcus from the wound. It was discontinued on day eight as he developed thrombocytopenia. As a gas containing collection was found in the subcutaneous tissues on a CT abdomen, metronidazole 400 mg PO TDS was commenced for anaerobic cover. The patient completed 4 weeks of meropenem and had a good CRP response, however the CT findings did not improve. In view of the borderline sensitivity to meropenem this was substituted for amikacin 150 mg IV BD. Trough levels were ⁎ Corresponding author. Tel.: +44 8383 3291. E-mail address: [email protected] (R.J. Perry). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.06.011
within the recommended range. In total he received a six week course of amikacin and eleven weeks of oral metronidazole. Towards the end of his admission he noted a sudden onset of imbalance and gait disturbance. He felt very unsteady when walking and had several falls. By the end of the same day he was unable to walk unaided. He had not noticed any upper limb incoordination, dysarthria or dysphagia. There was no weakness, sensory loss or cognitive impairment and sphincter function was intact. On examination there were marked bilateral upper and lower limb cerebellar signs, with finger nose ataxia, dysdiadochokinesis and pastpointing. He had a severe truncal and gait ataxia. There was a full range of pursuit eye movements with normal saccades and no nystagmus. There was no dysarthria and the remaining cranial nerves were normal. There was no sensory disturbance or weakness in the limbs. Reflexes were present and symmetrical and the plantar responses were flexor. A CT brain performed within 24 h of the onset of symptoms was entirely normal. An MRI brain showed increased T2-signal intensity in the dentate nuclei bilaterally, more noticeable on the fluid-attenuated inversion recovery (FLAIR) sequences (see Fig. 1). There was no change in his biochemical or haematological indices. A metronidazole level was not performed. Within 24 h of the discontinuation of metronidazole, the symptoms were noticeably improved, in that the patient was able to mobilise with a frame. A planned CSF examination was not performed, due to his rapid recovery. He was discharged home six days after the onset of ataxia and three days after the discontinuation of metronidazole. There was a mild residual gait ataxia but he was able to walk with the aid of a stick. On review eight weeks later all cerebellar signs had resolved. 2. Discussion Metronidazole has long been known to cause neurological side effects at both toxic [1] and therapeutic levels [2]. Seventeen previous
T.D. Graves et al. / Journal of the Neurological Sciences 285 (2009) 238–240
Fig. 1. MRI FLAIR image at the level of the pons, showing abnormal signal intensity within the dentate nuclei bilaterally.
cases of reversible metronidazole-induced CNS disturbance have been reported in the English language literature (see Table 1) [1–15]. It appears to be associated with specific MRI changes of increased signal intensity of the dentate nuclei bilaterally, most notably seen on FLAIR sequences. The predominant symptom is ataxia but the co-occurrence
239
of encephalopathy and/or peripheral neuropathy associated with more extensive MRI abnormalities seems to be more common than the pure cerebellar syndrome. The duration of metronidazole therapy required to induce symptoms is variable but is usually prolonged and/or at high doses. The average daily dose of reported cases was 1.6 g (median 1.5 g) with an average duration of 79 days (median 28 days). Our patient was taking 1.2 g daily for 77 days. Of the seventeen reported cases, three had toxic levels [1,8,14] or were taking large dosages [10]. In addition, three patients had cancer, two had severe liver disease and one was on total parenteral nutrition, perhaps rendering them more susceptible to toxicity. Interestingly, one of the reported cases was in a renal transplant recipient receiving H. pylori eradication [7]. In the case of an isolated cerebellar syndrome, truncal and limb ataxia was associated with dysarthria in 3/4 cases [9,11,13]. This was not seen in our patient. All showed reversibility of both the MRI changes (where performed) and the symptoms and signs of ataxia within days to weeks of cessation of treatment (average 20 days). Those with more extensive disease also showed reversibility of symptoms and imaging findings. However, two cases with isolated encephalopathy had only a partial recovery [10]. In those with extra-cerebellar symptoms and signs recovery was slower, when compared to those with isolated ataxia — patients were completely asymptomatic by an average of 37 days (median 21), however this difference was not statistically significant. The clinical, radiological and laboratory features of the reported cases are summarised in the table. The proposed mechanism of the ataxia and MRI changes is vasogenic oedema [3], which is supported by the rapidity of recovery following drug cessation and the diffusion weighted imaging findings [7]. Why there is predilection for the dentate nuclei is currently unclear, but this phenomenon has been shown in experimental animal models and in other metabolic disorders, suggesting a shared pathophysiology [13]. Metronidazole-induced ataxia is a rare reversible cause of cerebellar ataxia that specifically affects the dentate nuclei, from which a full recovery can be expected upon drug withdrawal.
Table 1 Summary of reported cases. Clinical features
Metronidazole
Ataxia Encephalopathy Peripheral Additional neuropathy
Daily dose (g)/route
Duration (days)
+ + +
2 PO 1.5 PO 1.5 IV
30 28 14
1 PO 1.5 PO 3 times usual dose PO
60 5 6 (on top of chronic therapy of unknown duration) 6 18 14 56 180
Tinnitus, vertigo. Symptoms recurred on re-exposure
+ + +
+ + + +
+ + + + +
+ + +
+
+ + +
+ + +
+ + +
+ + +
Visual disturbance, tremor Visual disturbance Deafness, tinnitus
Rigidity
IV ?dose 1.5 IV PO ?dose 1.5 PO 1.5 PO 1.5 PO 2 PO 2.25 PO then 0.75 PO 3 PO 1 IV then PO 1 PO
Time to recovery (days)
Reference
5 Unknown
14 35 30
[13] [13] [11]
12 Unknown 8
7 [9] 14 [14] 60 [10] (incomplete)
Investigations Levels
Toxic Likely toxic
730 42 21 28 56 180
CSF
MRI
MRI resolved (weeks)
+ +
N N N
+ + + SWM
N
+ SWM
Protein 0.8 g/L N
+ pons and medulla + SWM − CC, basal ganglia, red nucleus + CC + + SWM, CC
N Toxic Toxic
N N
+ + SWM basal ganglia, inferior olives
6 8 12 32 6
16
NA 7 21 14 90
[10] [2] [4] [7] [5]
25 4 42
[6] [15] [3]
6 14 120
[1] [8] [12]
+ denotes present, NA not applicable, for MRI + denotes described changes of increased signal intensity within the dentate nuclei, − denate changes absent, SWM subcortical white matter, CC corpus callosum.
240
T.D. Graves et al. / Journal of the Neurological Sciences 285 (2009) 238–240
References [1] Kusumi RK, Plouffe JF, Wyatt RH, Fass RJ. Central nervous system toxicity associated with metronidazole therapy. Ann Intern Med 1980;93:59–60. [2] Alvarez RS, Richardson DA, Bent AE, Ostergard DR. Central nervous system toxicity related to prolonged metronidazole therapy. Am J Obstet Gynecol 1983;145:640–1. [3] Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology 1995;45:588–9. [4] Bonkowsky JL, Sondrup C, Benedict SL. Acute reversible cerebellar lesions associated with metronidazole therapy. Neurology 2007;68:180. [5] Cecil KM, Halsted MJ, Schapiro M, et al. Reversible MR imaging and MR spectroscopy abnormalities in association with metronidazole therapy. J Comput Assist Tomogr 2002;26:948–51. [6] De Bleecker JL, Leroy BP, Meire VI. Reversible visual deficit and corpus callosum lesions due to metronidazole toxicity. Eur Neurol 2005;53:93–5. [7] 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.
[8] Horlen CK, Seifert CF, Malouf CS. Toxic metronidazole-induced MRI changes. Ann Pharmacother 2000;34:1273–5. [9] Ito H, Maruyama M, Ogura N, et al. Reversible cerebellar lesions induced by metronidazole therapy for Helicobacter pylori. J Neuroimaging 2004;14:369–71. [10] Kim DW, Park JM, Yoon BW, et al. Metronidazole-induced encephalopathy. J Neurol Sci 2004;224:107–11. [11] Lawford R, Sorrell TC. Amebic abscess of the spleen complicated by metronidazoleinduced neurotoxicity: case report. Clin Infect Dis 1994;19:346–8. [12] 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;60:1796–800. [13] Woodruff BK, Wijdicks EF, Marshall WF. Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. N Engl J Med 2002;346:68–9. [14] 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;3:xxix. [15] 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;12:e111–114.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient Tracey D. Graves a, Marie Condon b, Marina Loucaidou b, Richard J. Perry a,⁎ a b
Department of Neurology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, Du Cane Road, London W12 0NS, United Kingdom Renal Medicine, Imperial College Healthcare NHS Trust, Hammersmith Hospital, Du Cane Road, London W12 0NS, United Kingdom
a r t i c l e
i n f o
Article history: Received 8 February 2009 Accepted 8 June 2009 Available online 27 June 2009 Keywords: Metronidazole Ataxia Dentate nucleus
a b s t r a c t Metronidazole-induced central nervous system (CNS) toxicity causes a spectrum of neurological symptoms including ataxia, encephalopathy and peripheral neuropathy. It is associated with characteristic MRI changes of high signal intensity in the dentate nuclei. Given the increasing use of metronidazole, it is import to recognise this drug as a cause of ataxia, as it is entirely reversible on drug withdrawal. © 2009 Elsevier B.V. All rights reserved.
1. Introduction 1.1. Case report A 61 year old man was admitted for treatment of a wound infection. He had long-standing type 1 diabetes leading to end stage renal failure in 1997, when he commenced haemodialysis. He then received a cadaveric renal and pancreatic transplant in 1998, with a good functional outcome, however the pancreas failed after four years and he recommenced insulin treatment. Subsequently, he received another cadaveric pancreatic transplant in 2006, again rendering him insulin-independent. His original immunosuppressive regimen included tacrolimus, mycophenylate mofetil and prednisolone was added at the time of the second transplant. Standard post-transplant infection prophylaxis was with cotrimoxazole, doxycycline, valganciclovir and nystatin. Unfortunately, the pancreatic transplant wound became infected and despite treatment with oral antibiotics the wound eventually dehisced and he was admitted for intravenous antibiotics. The causative organism was found to be a resistant Klebsiella species. He was initially treated with meropenem 500 mg IV BD and linezolid 600 mg PO BD. The linezolid was continued from his oral regimen, as he had grown a Vanomycin resistant Enterococcus from the wound. It was discontinued on day eight as he developed thrombocytopenia. As a gas containing collection was found in the subcutaneous tissues on a CT abdomen, metronidazole 400 mg PO TDS was commenced for anaerobic cover. The patient completed 4 weeks of meropenem and had a good CRP response, however the CT findings did not improve. In view of the borderline sensitivity to meropenem this was substituted for amikacin 150 mg IV BD. Trough levels were ⁎ Corresponding author. Tel.: +44 8383 3291. E-mail address: [email protected] (R.J. Perry). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.06.011
within the recommended range. In total he received a six week course of amikacin and eleven weeks of oral metronidazole. Towards the end of his admission he noted a sudden onset of imbalance and gait disturbance. He felt very unsteady when walking and had several falls. By the end of the same day he was unable to walk unaided. He had not noticed any upper limb incoordination, dysarthria or dysphagia. There was no weakness, sensory loss or cognitive impairment and sphincter function was intact. On examination there were marked bilateral upper and lower limb cerebellar signs, with finger nose ataxia, dysdiadochokinesis and pastpointing. He had a severe truncal and gait ataxia. There was a full range of pursuit eye movements with normal saccades and no nystagmus. There was no dysarthria and the remaining cranial nerves were normal. There was no sensory disturbance or weakness in the limbs. Reflexes were present and symmetrical and the plantar responses were flexor. A CT brain performed within 24 h of the onset of symptoms was entirely normal. An MRI brain showed increased T2-signal intensity in the dentate nuclei bilaterally, more noticeable on the fluid-attenuated inversion recovery (FLAIR) sequences (see Fig. 1). There was no change in his biochemical or haematological indices. A metronidazole level was not performed. Within 24 h of the discontinuation of metronidazole, the symptoms were noticeably improved, in that the patient was able to mobilise with a frame. A planned CSF examination was not performed, due to his rapid recovery. He was discharged home six days after the onset of ataxia and three days after the discontinuation of metronidazole. There was a mild residual gait ataxia but he was able to walk with the aid of a stick. On review eight weeks later all cerebellar signs had resolved. 2. Discussion Metronidazole has long been known to cause neurological side effects at both toxic [1] and therapeutic levels [2]. Seventeen previous
T.D. Graves et al. / Journal of the Neurological Sciences 285 (2009) 238–240
Fig. 1. MRI FLAIR image at the level of the pons, showing abnormal signal intensity within the dentate nuclei bilaterally.
cases of reversible metronidazole-induced CNS disturbance have been reported in the English language literature (see Table 1) [1–15]. It appears to be associated with specific MRI changes of increased signal intensity of the dentate nuclei bilaterally, most notably seen on FLAIR sequences. The predominant symptom is ataxia but the co-occurrence
239
of encephalopathy and/or peripheral neuropathy associated with more extensive MRI abnormalities seems to be more common than the pure cerebellar syndrome. The duration of metronidazole therapy required to induce symptoms is variable but is usually prolonged and/or at high doses. The average daily dose of reported cases was 1.6 g (median 1.5 g) with an average duration of 79 days (median 28 days). Our patient was taking 1.2 g daily for 77 days. Of the seventeen reported cases, three had toxic levels [1,8,14] or were taking large dosages [10]. In addition, three patients had cancer, two had severe liver disease and one was on total parenteral nutrition, perhaps rendering them more susceptible to toxicity. Interestingly, one of the reported cases was in a renal transplant recipient receiving H. pylori eradication [7]. In the case of an isolated cerebellar syndrome, truncal and limb ataxia was associated with dysarthria in 3/4 cases [9,11,13]. This was not seen in our patient. All showed reversibility of both the MRI changes (where performed) and the symptoms and signs of ataxia within days to weeks of cessation of treatment (average 20 days). Those with more extensive disease also showed reversibility of symptoms and imaging findings. However, two cases with isolated encephalopathy had only a partial recovery [10]. In those with extra-cerebellar symptoms and signs recovery was slower, when compared to those with isolated ataxia — patients were completely asymptomatic by an average of 37 days (median 21), however this difference was not statistically significant. The clinical, radiological and laboratory features of the reported cases are summarised in the table. The proposed mechanism of the ataxia and MRI changes is vasogenic oedema [3], which is supported by the rapidity of recovery following drug cessation and the diffusion weighted imaging findings [7]. Why there is predilection for the dentate nuclei is currently unclear, but this phenomenon has been shown in experimental animal models and in other metabolic disorders, suggesting a shared pathophysiology [13]. Metronidazole-induced ataxia is a rare reversible cause of cerebellar ataxia that specifically affects the dentate nuclei, from which a full recovery can be expected upon drug withdrawal.
Table 1 Summary of reported cases. Clinical features
Metronidazole
Ataxia Encephalopathy Peripheral Additional neuropathy
Daily dose (g)/route
Duration (days)
+ + +
2 PO 1.5 PO 1.5 IV
30 28 14
1 PO 1.5 PO 3 times usual dose PO
60 5 6 (on top of chronic therapy of unknown duration) 6 18 14 56 180
Tinnitus, vertigo. Symptoms recurred on re-exposure
+ + +
+ + + +
+ + + + +
+ + +
+
+ + +
+ + +
+ + +
+ + +
Visual disturbance, tremor Visual disturbance Deafness, tinnitus
Rigidity
IV ?dose 1.5 IV PO ?dose 1.5 PO 1.5 PO 1.5 PO 2 PO 2.25 PO then 0.75 PO 3 PO 1 IV then PO 1 PO
Time to recovery (days)
Reference
5 Unknown
14 35 30
[13] [13] [11]
12 Unknown 8
7 [9] 14 [14] 60 [10] (incomplete)
Investigations Levels
Toxic Likely toxic
730 42 21 28 56 180
CSF
MRI
MRI resolved (weeks)
+ +
N N N
+ + + SWM
N
+ SWM
Protein 0.8 g/L N
+ pons and medulla + SWM − CC, basal ganglia, red nucleus + CC + + SWM, CC
N Toxic Toxic
N N
+ + SWM basal ganglia, inferior olives
6 8 12 32 6
16
NA 7 21 14 90
[10] [2] [4] [7] [5]
25 4 42
[6] [15] [3]
6 14 120
[1] [8] [12]
+ denotes present, NA not applicable, for MRI + denotes described changes of increased signal intensity within the dentate nuclei, − denate changes absent, SWM subcortical white matter, CC corpus callosum.
240
T.D. Graves et al. / Journal of the Neurological Sciences 285 (2009) 238–240
References [1] Kusumi RK, Plouffe JF, Wyatt RH, Fass RJ. Central nervous system toxicity associated with metronidazole therapy. Ann Intern Med 1980;93:59–60. [2] Alvarez RS, Richardson DA, Bent AE, Ostergard DR. Central nervous system toxicity related to prolonged metronidazole therapy. Am J Obstet Gynecol 1983;145:640–1. [3] Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology 1995;45:588–9. [4] Bonkowsky JL, Sondrup C, Benedict SL. Acute reversible cerebellar lesions associated with metronidazole therapy. Neurology 2007;68:180. [5] Cecil KM, Halsted MJ, Schapiro M, et al. Reversible MR imaging and MR spectroscopy abnormalities in association with metronidazole therapy. J Comput Assist Tomogr 2002;26:948–51. [6] De Bleecker JL, Leroy BP, Meire VI. Reversible visual deficit and corpus callosum lesions due to metronidazole toxicity. Eur Neurol 2005;53:93–5. [7] 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.
[8] Horlen CK, Seifert CF, Malouf CS. Toxic metronidazole-induced MRI changes. Ann Pharmacother 2000;34:1273–5. [9] Ito H, Maruyama M, Ogura N, et al. Reversible cerebellar lesions induced by metronidazole therapy for Helicobacter pylori. J Neuroimaging 2004;14:369–71. [10] Kim DW, Park JM, Yoon BW, et al. Metronidazole-induced encephalopathy. J Neurol Sci 2004;224:107–11. [11] Lawford R, Sorrell TC. Amebic abscess of the spleen complicated by metronidazoleinduced neurotoxicity: case report. Clin Infect Dis 1994;19:346–8. [12] 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;60:1796–800. [13] Woodruff BK, Wijdicks EF, Marshall WF. Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. N Engl J Med 2002;346:68–9. [14] 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;3:xxix. [15] 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;12:e111–114.