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Cyclosporine A induced dystonia-parkinsonism
Journal of the Neurological Sciences 375 (2017) 68–70
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Cyclosporine A induced dystonia-parkinsonism Keywords: Parkinsonism Dystonia Cyclosporine A PRES
Dear Editor, Cyclosporine A (CsA) is an immunosuppressant drug widely used for prevention of organ rejection in transplant recipients. Neurological adverse effects of CsA include headache, encephalopathy, cortical blindness, visual hallucinations and seizures [1]. Movement disorders associated with CsA toxicity are rare, apart from action tremor [2]. Parkinsonism is uncommon complication of CsA treatment, while dystonia has not yet been described. Hitherto reported cases of CsA induced parkinsonism showed no evidence of structural involvement of basal ganglia (BG) on neuroimaging or autopsy and symptoms usually improved upon drug discontinuation [3–5]. We report two patients who underwent bone marrow transplantation (BMT) and developed acute dystonia-parkinsonism during CsA treatment, with clear evidence of basal ganglia involvement on serial brain MRIs. Despite treatment discontinuation, symptoms persisted in one patient, suggesting irreversible toxic effect of CsA on BG. Case 1. A 17-year-old boy with paroxysmal nocturnal hemoglobinuria and history of cerebral venous thrombosis (two years previously), underwent allogeneic bone BMT and was treated with CsA to prevent graft-versus-host disease (GVHD). The concentration of CsA was kept in the therapeutic range between 250 and 350 ng/ml. As a part of standard prophylaxis for GVHD he also received methotrexate, mycophenolate mofetil and tacrolimus (regimen is given in Supplementary file). On the day 19th his hands start to tremble and he had difficulties using the right arm. Neurological examination revealed hypomimia, hypophonia and right hand rest tremor, with bilateral rigidity and bradyhypokinesia more marked on the right. In addition, right upper limb dystonia was present (Fig. 1A and Supplementary Video Segment 1). Brain MRI revealed hyperintense signal on T2 and FLAIR sequences bilaterally in putamen and caudate nuclei (more pronounced in the left hemisphere) (Fig. 1B) and areas of restricted diffusion on DWI sequence, suggestive of cytotoxic edema (Supplementary Fig. 1). The MRI changes were consistent with atypical posterior reversible encephalopathy syndrome (PRES) [6]. Brain MRA was normal. CsA induced BG toxicity was suspected and the drug was discontinued. CSF analysis showed normal cells and proteins, extensive CSF work-up revealed no infectious cause (Supplementary file). The patient did not improve on L-Dopa (up to 300 mg), but showed mild improvement of both dystonia and parkinsonism with biperiden 5 mg/day. On dopamine transporter imaging
http://dx.doi.org/10.1016/j.jns.2017.01.043 0022-510X/© 2017 Elsevier B.V. All rights reserved.
(123I-Ioflupane SPECT) no evidence of presynaptic dopaminergic deficit was noticed (Supplementary Fig. 2). Four months later, he developed repetitive slow dystonic contractions affecting right side of the body (Supplementary Video Segment 2) which improved with increase of biperiden to 15 mg/day. The EEG was repeatedly normal. Repeated MRI revealed BG atrophy, but less pronounced signal changes (Supplementary Fig. 3). Brain FDG/PET-CT showed BG hypermetabolism bilaterally (Supplementary Fig. 4). The patient had been followed up for year and half and he continued to manifest mild dystonia and parkinsonism. He later developed GVHD with multiple organ failure and passed away. Case 2. A 51-year-old woman underwent allogeneic BMT for disseminated plasmacytoma and was treated with CsA. The concentration of CsA was kept in the therapeutic range. On day 47, she presented with decreased responsiveness and unusual movement of her right arm. Over the following 10 days she became encephalopatic manifesting agitation and confusion. Neurological examination revealed she was disoriented and was not able to cooperate in examination of vision. She was hypomimic, with bilateral postural arm tremor and bilateral rigidity and bradykinesia, more pronounced on the left. Marked dystonia of both hands was observed (Fig. 1C). The plantar responses were upgoing, while the rest of examination was normal. Her MRI showed increased signal on T2 and FLAIR sequences in the occipital lobe and the cerebellum bilaterally, consistent with CsA induced posterior reversible encephalopathy syndrome (PRES) (Supplementary Figs. 5 and 6). There was additional involvement of BG and thalamus bilaterally (Fig.1D), while brain MRA was normal. Extensive CSF work-up revealed no infectious cause (Supplementary File). CsA was stopped, however patient died soon after due to complications of necrotizing cholecystitis caused by gallstones.
Discussion Both patients developed acute dystonia-parkinsonism, as a probable complication of CsA treatment. In both patients there was clear temporal relationship between CsA treatment, development of symptoms and basal ganglia lesions on MRI. None of the patients received dopaminergic blocking agents or other medication that cause dystonia and parkinsonism. CNS infections and brain vasculitis were excluded. None had arterial hypertension, sepsis or renal failure, conditions that may predispose to typical or atypical PRES [6]. A new observation is that CsA induced neurological symptoms may persist after CsA withdrawal. This is presumably due to CsA induced permanent damage of BG, as evidenced by BG atrophy on the follow-up scans in the first patient. The further worsening of dystonia after withdrawal of CsA in the same patient is also consistent with permanent BG lesions. In secondary dystonia following vascular or traumatic brain injury, symptoms appear (or get worse) after a latency period, during which maladaptive plasticity changes take place [7].
Letter to the Editor
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Fig. 1. Patient 1 shows a dystonic posturing of the right hand (1A). His brain MRI (FLAIR sequence) shows hyperintense signal in ventral parts of both putamina and in the heads of both caudate nuclei, more pronounced on the left side (1B). Patient 2 demonstrates dystonic posturing of hands bilaterally (1C). Her MRI (FLAIR sequence) shows hyperintense signal in both thalami (predominantly pulvinar), heads of both caudate nuclei and in the corticosubcortical areas of the left occipital lobe and right occipitotemporal lobes (1D).
Investigations in our patients may provide some insight into possible mechanism of CsA induced BG toxicity. In the acute phase, increased signal on T2 and FLAIR with areas of restricted diffusion on DWI sequences in BG was indicative of cytotoxic edema, a premorbid cellular process that almost inevitably leads to cell death. Following the resolution of edema, BG atrophy was evident in the chronic phase in the first patient. Normal dopamine transporter imaging suggests that parkinsonism was not due to pre-synaptic but rather to post-synaptic impairment, consistent with observed BG changes on the MRI. The significance of increased metabolism in BG on FDG/PET-CT is unclear, but similar BG metabolic pattern was observed in another patient, who developed kinetic tremor on CsA treatment [8]. It remains unclear why patients only rarely develop parkinsonism and dystonia with CsA. PRES is known complication of CsA treatment and notably BG lesions, although asymptomatic, have been described in these patients [9]. This suggests that individual vulnerability of BG circuits and perhaps differences in compensatory abilities may play a role. It is also possible that CsA induced movement disorders are underreported, as both dystonia and parkinsonism may be difficult to recognize by non-neurologist.
Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2017.01.043. References [1] N.J. Serkova, U. Christians, L.Z. Benet, Biochemical mechanisms of cyclosporine neurotoxicity, Mol. Interv. 4 (2) (2004) 97–107. [2] R.P. Munhoz, et al., Movement disorders secondary to long-term treatment with cyclosporine A, Arq. Neuropsiquiatr. 63 (3A) (2005) 592–596. [3] M.A. Lima, S. Maradei, P. Maranhao Filho, Cyclosporine-induced Parkinsonism, J. Neurol. 256 (4) (2009) 674–675. [4] H.C. Kim, et al., Parkinsonism during cyclosporine treatment in renal transplantation, Nephrol. Dial. Transplant. 17 (2) (2002) 319–321. [5] P.H. Wasserstein, L.S. Honig, Parkinsonism during cyclosporine treatment, Bone Marrow Transplant. 18 (3) (1996) 649–650. [6] W.S. Bartynski, Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features, AJNR Am. J. Neuroradiol. 29 (6) (2008) 1036–1042. [7] C.D. Marsden, et al., The anatomical basis of symptomatic hemidystonia, Brain 108 (Pt 2) (1985) 463–483. [8] M.A. Meyer, Elevated basal ganglia glucose metabolism in cyclosporine neurotoxicity: a positron emission tomography imaging study, J. Neuroimaging 12 (1) (2002) 92–93. [9] A.M. McKinney, et al., Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings, AJR Am. J. Roentgenol. 189 (4) (2007) 904–912.
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Letter to the Editor
Petra Miklavčič Department of Neurology, University Medical Centre Ljubljana, Slovenia
Maja Trošt Department of Neurology, University Medical Centre Ljubljana, Slovenia
Simona Avčin Department of Pediatric Hematology and Oncology, Division of Pediatrics, University Medical Centre Ljubljana, Slovenia
Maja Kojović Department of Neurology, University Medical Centre Ljubljana, Slovenia Corresponding author at: Department of Neurology, University Medical Centre Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. E-mail address: [email protected]
Janez Jazbec Department of Pediatric Hematology and Oncology, Division of Pediatrics, University Medical Centre Ljubljana, Slovenia Tina Vipotnik Vesnaver Institute of Radiology, University Medical Centre Ljubljana, Slovenia Biljana Todorova Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana, Slovenia
9 November 2016
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Cyclosporine A induced dystonia-parkinsonism Keywords: Parkinsonism Dystonia Cyclosporine A PRES
Dear Editor, Cyclosporine A (CsA) is an immunosuppressant drug widely used for prevention of organ rejection in transplant recipients. Neurological adverse effects of CsA include headache, encephalopathy, cortical blindness, visual hallucinations and seizures [1]. Movement disorders associated with CsA toxicity are rare, apart from action tremor [2]. Parkinsonism is uncommon complication of CsA treatment, while dystonia has not yet been described. Hitherto reported cases of CsA induced parkinsonism showed no evidence of structural involvement of basal ganglia (BG) on neuroimaging or autopsy and symptoms usually improved upon drug discontinuation [3–5]. We report two patients who underwent bone marrow transplantation (BMT) and developed acute dystonia-parkinsonism during CsA treatment, with clear evidence of basal ganglia involvement on serial brain MRIs. Despite treatment discontinuation, symptoms persisted in one patient, suggesting irreversible toxic effect of CsA on BG. Case 1. A 17-year-old boy with paroxysmal nocturnal hemoglobinuria and history of cerebral venous thrombosis (two years previously), underwent allogeneic bone BMT and was treated with CsA to prevent graft-versus-host disease (GVHD). The concentration of CsA was kept in the therapeutic range between 250 and 350 ng/ml. As a part of standard prophylaxis for GVHD he also received methotrexate, mycophenolate mofetil and tacrolimus (regimen is given in Supplementary file). On the day 19th his hands start to tremble and he had difficulties using the right arm. Neurological examination revealed hypomimia, hypophonia and right hand rest tremor, with bilateral rigidity and bradyhypokinesia more marked on the right. In addition, right upper limb dystonia was present (Fig. 1A and Supplementary Video Segment 1). Brain MRI revealed hyperintense signal on T2 and FLAIR sequences bilaterally in putamen and caudate nuclei (more pronounced in the left hemisphere) (Fig. 1B) and areas of restricted diffusion on DWI sequence, suggestive of cytotoxic edema (Supplementary Fig. 1). The MRI changes were consistent with atypical posterior reversible encephalopathy syndrome (PRES) [6]. Brain MRA was normal. CsA induced BG toxicity was suspected and the drug was discontinued. CSF analysis showed normal cells and proteins, extensive CSF work-up revealed no infectious cause (Supplementary file). The patient did not improve on L-Dopa (up to 300 mg), but showed mild improvement of both dystonia and parkinsonism with biperiden 5 mg/day. On dopamine transporter imaging
http://dx.doi.org/10.1016/j.jns.2017.01.043 0022-510X/© 2017 Elsevier B.V. All rights reserved.
(123I-Ioflupane SPECT) no evidence of presynaptic dopaminergic deficit was noticed (Supplementary Fig. 2). Four months later, he developed repetitive slow dystonic contractions affecting right side of the body (Supplementary Video Segment 2) which improved with increase of biperiden to 15 mg/day. The EEG was repeatedly normal. Repeated MRI revealed BG atrophy, but less pronounced signal changes (Supplementary Fig. 3). Brain FDG/PET-CT showed BG hypermetabolism bilaterally (Supplementary Fig. 4). The patient had been followed up for year and half and he continued to manifest mild dystonia and parkinsonism. He later developed GVHD with multiple organ failure and passed away. Case 2. A 51-year-old woman underwent allogeneic BMT for disseminated plasmacytoma and was treated with CsA. The concentration of CsA was kept in the therapeutic range. On day 47, she presented with decreased responsiveness and unusual movement of her right arm. Over the following 10 days she became encephalopatic manifesting agitation and confusion. Neurological examination revealed she was disoriented and was not able to cooperate in examination of vision. She was hypomimic, with bilateral postural arm tremor and bilateral rigidity and bradykinesia, more pronounced on the left. Marked dystonia of both hands was observed (Fig. 1C). The plantar responses were upgoing, while the rest of examination was normal. Her MRI showed increased signal on T2 and FLAIR sequences in the occipital lobe and the cerebellum bilaterally, consistent with CsA induced posterior reversible encephalopathy syndrome (PRES) (Supplementary Figs. 5 and 6). There was additional involvement of BG and thalamus bilaterally (Fig.1D), while brain MRA was normal. Extensive CSF work-up revealed no infectious cause (Supplementary File). CsA was stopped, however patient died soon after due to complications of necrotizing cholecystitis caused by gallstones.
Discussion Both patients developed acute dystonia-parkinsonism, as a probable complication of CsA treatment. In both patients there was clear temporal relationship between CsA treatment, development of symptoms and basal ganglia lesions on MRI. None of the patients received dopaminergic blocking agents or other medication that cause dystonia and parkinsonism. CNS infections and brain vasculitis were excluded. None had arterial hypertension, sepsis or renal failure, conditions that may predispose to typical or atypical PRES [6]. A new observation is that CsA induced neurological symptoms may persist after CsA withdrawal. This is presumably due to CsA induced permanent damage of BG, as evidenced by BG atrophy on the follow-up scans in the first patient. The further worsening of dystonia after withdrawal of CsA in the same patient is also consistent with permanent BG lesions. In secondary dystonia following vascular or traumatic brain injury, symptoms appear (or get worse) after a latency period, during which maladaptive plasticity changes take place [7].
Letter to the Editor
69
Fig. 1. Patient 1 shows a dystonic posturing of the right hand (1A). His brain MRI (FLAIR sequence) shows hyperintense signal in ventral parts of both putamina and in the heads of both caudate nuclei, more pronounced on the left side (1B). Patient 2 demonstrates dystonic posturing of hands bilaterally (1C). Her MRI (FLAIR sequence) shows hyperintense signal in both thalami (predominantly pulvinar), heads of both caudate nuclei and in the corticosubcortical areas of the left occipital lobe and right occipitotemporal lobes (1D).
Investigations in our patients may provide some insight into possible mechanism of CsA induced BG toxicity. In the acute phase, increased signal on T2 and FLAIR with areas of restricted diffusion on DWI sequences in BG was indicative of cytotoxic edema, a premorbid cellular process that almost inevitably leads to cell death. Following the resolution of edema, BG atrophy was evident in the chronic phase in the first patient. Normal dopamine transporter imaging suggests that parkinsonism was not due to pre-synaptic but rather to post-synaptic impairment, consistent with observed BG changes on the MRI. The significance of increased metabolism in BG on FDG/PET-CT is unclear, but similar BG metabolic pattern was observed in another patient, who developed kinetic tremor on CsA treatment [8]. It remains unclear why patients only rarely develop parkinsonism and dystonia with CsA. PRES is known complication of CsA treatment and notably BG lesions, although asymptomatic, have been described in these patients [9]. This suggests that individual vulnerability of BG circuits and perhaps differences in compensatory abilities may play a role. It is also possible that CsA induced movement disorders are underreported, as both dystonia and parkinsonism may be difficult to recognize by non-neurologist.
Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2017.01.043. References [1] N.J. Serkova, U. Christians, L.Z. Benet, Biochemical mechanisms of cyclosporine neurotoxicity, Mol. Interv. 4 (2) (2004) 97–107. [2] R.P. Munhoz, et al., Movement disorders secondary to long-term treatment with cyclosporine A, Arq. Neuropsiquiatr. 63 (3A) (2005) 592–596. [3] M.A. Lima, S. Maradei, P. Maranhao Filho, Cyclosporine-induced Parkinsonism, J. Neurol. 256 (4) (2009) 674–675. [4] H.C. Kim, et al., Parkinsonism during cyclosporine treatment in renal transplantation, Nephrol. Dial. Transplant. 17 (2) (2002) 319–321. [5] P.H. Wasserstein, L.S. Honig, Parkinsonism during cyclosporine treatment, Bone Marrow Transplant. 18 (3) (1996) 649–650. [6] W.S. Bartynski, Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features, AJNR Am. J. Neuroradiol. 29 (6) (2008) 1036–1042. [7] C.D. Marsden, et al., The anatomical basis of symptomatic hemidystonia, Brain 108 (Pt 2) (1985) 463–483. [8] M.A. Meyer, Elevated basal ganglia glucose metabolism in cyclosporine neurotoxicity: a positron emission tomography imaging study, J. Neuroimaging 12 (1) (2002) 92–93. [9] A.M. McKinney, et al., Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings, AJR Am. J. Roentgenol. 189 (4) (2007) 904–912.
70
Letter to the Editor
Petra Miklavčič Department of Neurology, University Medical Centre Ljubljana, Slovenia
Maja Trošt Department of Neurology, University Medical Centre Ljubljana, Slovenia
Simona Avčin Department of Pediatric Hematology and Oncology, Division of Pediatrics, University Medical Centre Ljubljana, Slovenia
Maja Kojović Department of Neurology, University Medical Centre Ljubljana, Slovenia Corresponding author at: Department of Neurology, University Medical Centre Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. E-mail address: [email protected]
Janez Jazbec Department of Pediatric Hematology and Oncology, Division of Pediatrics, University Medical Centre Ljubljana, Slovenia Tina Vipotnik Vesnaver Institute of Radiology, University Medical Centre Ljubljana, Slovenia Biljana Todorova Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana, Slovenia
9 November 2016