Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease

Background: Parkinson disease (PD) is associated with a progressive loss of nigrostriatal dopamine neurons. Medication therapy provides adequate contr ol of symptoms for several years, but long-term treatment is complicated by progressive disability and the development of motor fluctuations and dyski nesias. In animal models of PD, fetal nigral transplants have been shown to survive grafting into the striatum, provide extensive striatal reinnervati on, and improve motor function. In patients with PD, cell survival and clin ical benefit have been observed following fetal nigral grafting, but result s have been inconsistent. Objective: To evaluate the safety and efficacy of bilateral fetal nigral tr ansplantation into the postcommissural putamen in patients with advanced PD complicated by motor fluctuations and dyskinesias. Patients and Methods: Six patients with advanced PD underwent bilateral fet al nigral transplantation. Each patient received solid grafts derived from donors aged 6 1/2 to 9 weeks after conception stereotactically implanted in to the postcommissural putamen using 3 to 4 donors per side. Cyclosporine w as administered for approximately 6 months to provide immune suppression. C linical evaluations included the Unified Parkinson's Disease Rating Scale ( UPDRS), Schwab-England Activities of Daily Living Scale, and timed tests of motor function conducted during both the "off" and "on" states at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation. Percen tage of time off and percentage of time on with and without dyskinesia were recorded at half-hour intervals using home diaries during the week prior t o each evaluation. F-18-fluorodopa positron emission tomographic scans were performed at baseline, and at 6 months and 1 year following transplantatio n. Results: Patients have been followed up for a mean +/- SD of 20.5 +/- 5.5 m onths. Complications related to surgery were mild and transient. Activities of daily living, motor, and total (activities of daily living plus motor) UPDRS scores during the off state improved significantly (P<.05, Wilcoxon s igned rank test) at final visit in comparison with baseline. Mean total UPD RS off score improved 32%, and each patient experienced at least a 19% impr ovement. Mean percentage of time on without dyskinesia during the waking da y improved from 22% to 60% (P<.05). Mean putamenal fluorodopa uptake on pos itron emission tomography increased significantly at 6 and 12 months in com parison with baseline (P<.001, 2-tailed t test). This increase correlated w ith clinical improvement. Two patients died 18 months after transplantation from causes unrelated to the surgical procedure. In both cases, histopatho logical examination showed robust survival of tyrosine hydroxylase immunore active cells and abundant reinnervation of the postcommissural putamen. Conclusions: Fetal nigral tissue can be transplanted into the postcommissur al putamen bilaterally in patients with advanced PD safely and with little morbidity. In this open-label pilot study we observed consistent long-term clinical benefit and increased fluorodopa uptake on positron emission tomog raphy. Clinical improvement appears to be related to the survival and funct ion of transplanted fetal tissue.