Parkinsonism during cyclosporine treatment in renal transplantation

Hyun Chul Kim1, Seung Yeup Han1, Sung Bae Park1 and Soo Jhi Suh2

1 Department of Internal Medicine, Dongsan Kidney Institute, 2 Department of Radiology, Keimyung University, Dongsan Medical Center, Taegu, Korea

Sir,

Cyclosporin (CyA), a lipophilic, cyclic oligopeptide that modulates T-cell function, is a potent immunosuppressive agent [12]. A variety of neurological complications have been associated with CyA, including seizures, headaches, encephalopathy, cortical blindness, visual hallucinations, and tremor [14]. Parkinsonism is not generally recognized as a nervous system complication of CyA. Recently Wasserstein and Honig [5] first reported two cases of parkinsonism during CyA treatment following allogenic bone marrow transplantation. To the best of our knowledge, there has been no reported case in the literature documenting the occurrence of parkinsonism during CyA therapy in renal transplantation. We report here a case of parkinsonism developed during CyA therapy in renal transplantation, which was improved after switching to tacrolimus.

Case.

A 41-year-old woman received a cadaveric renal transplantation on March 16, 2000, for end-stage renal disease due to chronic glomerulonephritis. Initial immunosuppression consisted of 300 mg of microemulsion form of CyA, mycophenolate mofetil 1 g bid, and methylprednisolone (later prednisone) 30 mg daily. There was delayed graft function after transplantation and the patient remained dialysis dependent for 15 days. The first allograft biopsy, taken on the 14th postoperative day, showed acute tubular necrosis. Soon after, the patient's graft function began to improve with marked diuresis. However, there was no further improvement in graft function. The nadir of serum creatinine remained elevated around 2.2–2.6 mg/dl (Figure 1Go). The second allograft biopsy, performed on April 11, revealed acute rejection. Steroid pulse therapy was given without success. OKT3 infusion 5 mg daily was administered for 10 days to reverse the refractory acute rejection. Renal function improved slowly with the OKT3 therapy. Five days after the start of OKT therapy (on the 36th hospital day) the patient first developed severe neuralgia, which was followed by dysarthria, and bradykinesia 2 days later, which progressed to akinesia several days later. She could not turn her body freely without the help of others. Examination showed decreased blinking rate, reduced facial expression, and reduced arm swing. Coordinated movements were slowed and muscle tone was increased, particularly in the upper extremities. MRI taken on day 47 showed bilateral high signal in basal ganglia, without any signs of hydrocephalus. This finding and the neurological symptoms were very consistent with parkinsonism. We reviewed medication history and found nothing particular except possibly OKT3 because her neurological symptoms and signs were aggravated during OKT3 therapy. The blood levels of CyA were within the therapeutic range (140–568 ng/ml). We thought that parkinsonism would be resolved with the stopping of OKT3, and Sinemet (300 mg levodopa/75 mg carbidopa/day) and Artane 4 mg were introduced but without improvement. She continued to have severe tremor and akinesia. On day 54 the patient complained of severe neuralgia, which required multiple injections of analgesics including Demerol. Carbamazepine was added to alleviate the neuralgic pain, but without response. On day 69 we finally suspected that CyA might cause the parkinsonism in this patient. CyA was stopped and tacrolimus was started. After being switched to tacrolimus the patient began to show a dramatic improvement of neuralgic pain and tremor. Two weeks after conversion to tacrolimus the patient showed marked improvement of dysarthria and muscle rigidity. Four weeks after conversion the neuralgic pain had subsided. The patient was discharged from the hospital in wheel chair state 3 months after renal transplantation. One month after discharge she was able to walk without the help of others or a cane. However, it took a further 3 months for her to be able to walk around the city freely without help. Follow-up brain CT showed almost complete clearing of the previous lesions noted in MRI.



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Fig. 1. Hospital course after renal transplantation.

 

Comment.

We describe here the first case of parkinsonism developed during CyA therapy in a renal transplant recipient. The patient had rest tremor, severe neuralgic pain, and bradykinesia to akinesia along with muscle rigidity. These symptoms developed after CyA was started, and during CyA administration the patient continued to have troublesome tremor and bradykinesia which deteriorated further. MRI findings taken in this patient were highly consistent with the diagnosis of parkinsonism. Wasserstein and Honig [5] first described two cases of parkinsonism in patients who received CyA following allogenic bone marrow transplantation. In their paper one patient improved markedly with Sinemet and concomitant reduction of CyA dosage, while the other improved with a decrease in CyA dosage. The mechanism of this CyA neurotoxicity is unclear. The drug is highly lipophilic and thus is expected to pass through the blood-brain barrier. Possible mechanisms for reversible CNS injury include drug-induced brain microangiopathy (a syndrome akin to haemolytic uraemic syndrome) or direct drug effects on neurotransmitter function, neuroglial cell phosphorylation pathways, transcription factors, or other cell functions. The haemolytic uraemic syndrome is a well known complication of CyA use in kidney transplantation. The relationship between OKT3 and haemolytic uraemic syndrome has been documented in several reports [67]. However, the persistence of neurological signs even long after cessation of OKT3 use rules out the possibility of this drug as a cause of parkinsonism in this patient. In our case haemolytic uraemic syndrome was noted in view of thrombocytopenia, haemolytic anaemia, and mild renal failure when the patient first developed neuralgic pain. Since the parkinsonian symptoms described here and in Wasserstein and Honig's cases were reversible, it seems likely that they were the result of a functional rather than a structural effect. The severity and clinical course of neurological deficits were more severe and protracted in our case than in those of Wasserstein and Honig. Prolonged use of CyA in our case might explain these differences.

In conclusion, although CyA-induced parkinsonism is an extremely rare side effect, this complication may be reversible as shown in the present renal transplant patient.

References

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