Letters to the Editor Related to New Topics Reversible Parkinsonism After Chronic Cyclosporin Treatment in Renal Transplantation

Cyclosporin A (CsA)-induced neurotoxicities are common, reported in up to 40% of transplant patients receiving CsA. Tremor is the most common abnormal movement, observed in 20% of patients receiving long-term CsA, Parkinsonism is very rare and only 3 cases have been reported. We describe a renal transplant patient who developed disabling parkinsonism after long-term CsA treatment, despite low trough therapeutic blood levels. Most of her symptoms were reversible after discontinuing CsA. A 59-year-old right-handed Thai woman presented with 18-month history of progressive bradykinesia, which had required assistance with walking and feeding during the past 4 months. Despite increasing the dose of levodopa (ldopa) up to 1 g daily, her Parkinsonism deteriorated. Within 10 months of symptom onset, she was stuporous and bedridden. At the age of 46 years, the patient was diagnosed with end-stage kidney disease in which the etiology remained inconclusive, later requiring cadaveric kidney transplantation. Immunosuppressive therapy consisted of CsA, mycophenolate mofetil, and prednisolone. Graft function was good and her serum creatinine levels were consistently normal. Her daily medications when transferred to our hopsital included L-dopa (1 g), levetiracetam (400 mg), quetiapine (25 mg), sertraline (50 mg), CsA (150 mg), mycophenolate mofetil (1 g), prednisolone (2.5 mg), clopidogrel, and folic acid. On the first day of hospital admission, she was apyrexial and normotensive. She only opened her eyes and withdrew limbs minimally in response to noxious stimuli. She was akinetic with severe generalized rigidity and tremor and myoclonus of the limbs. Mild cervical dystonia, consisting of anterocollis and right laterocollis was also present. Reflexes were brisk with bilateral flexor plantar response. Basic laboratory results were normal, except for borderline low magnesium level (Mg) (0.75; Ref: 0.75–1.05 mg/dL). Serum CsA level measured immediately before CsA intake (C0) was in the low therapeutic range, 61.3 ng/mL (<150 ng/mL). Magnetic resonance imaging (MRI) of the brain showed minimal T2-signal hyperintensities in the periventricular white matter. MR angiogram was normal. After excluding any potential metabolic or infectious causes, CsA was discontinued and tacrolimus was started on day 5 of hospital admission; all other medications remained unchanged (video). Within 4 days, her mental status and speech returned to normal. She experienced dramatic improvement in her Parkinsonism. Two weeks after stopping CsA, rigidity, and cervical dystonia resolved and she could walk independently with moderate ataxia. L-dopa was gradually discontinued. At a 5-month follow-up visit, tremor and myoclonus had completely resolved except for mild residual ataxia. Her renal function remained optimal. In view of the dramatic improvement of symptoms in close proximity to discontinuation of CsA, the diagnosis of CsA-induced Parkinsonism was made. We describe a renal transplant patient who developed rapidly progressive Parkinsonism in association with other abnormal movements after long-term CsA treatment. Her Parkinsonism was not responsive to L-dopa. Kim et al. reported the first renal-transplant patient who developed parkinsonism 6 weeks after taking CsA while the blood levels of CsA were normal. Similar to our patient, the symptoms were nonresponsive to L-dopa, but markedly improved after CsA was switched to tacrolimus. Our patient remained well in the first 4 years while taking CsA. Prolonged CsA therapy might have led to accumulation of CsA toxicities. Nevertheless, certain precipitating factors might have played a major role in crossing our patient over the symptom threshold, including hypomagnesemia and drug interaction. Other reported risk factors were fluid retention, hypertension, methylprednisolone, hypocholesterolemia, and aluminium overload. Hypomagnesemia can lead to vascularrelated adverse effects including vascular damage, acceleration of atherosclerosis, vasoconstriction, and thrombocyte aggregation, potentially resulting in cerebral vasospasm and endothelial dysfunction, which in turn increases CsA concentration in the brain. Serum CsA levels were normal in our patient. Similar findings were also reported in other cases of CsA-related neurotoxicities. Therefore, neurotoxicities could be caused by CsA metabolites. A trough CsA measurement, C0, may be a poor indicator of CsA exposure, whereas a 2-hour postdose, C2, and the area-under-the-curve of CsA profile are probably better. In addition to Parkinsonism, our patient also had action tremor, myoclonus, ataxia, and cervical dystonia. It seems that CsA neurotoxicities can induce a variety of movement disorders. Tremor induced by CsA is almost exclusively action tremor and is seen in 12 to 21% of patients, mostly during first 3 months of treatment and are generally mild. There were also other reports of transplanted patients with myoclonus, chorea, and ataxia with prolonged CsA therapy. Although mild in severity, our patient is the first reported case of cervical dystonia caused by CsA. Additional Supporting Information may be found in the online version of this article. Published online 15 July 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22530