Status of Fetal Tissue Transplantation for the Treatment of Advanced Parkinson Disease

Paul E. Greene, M.D., Stanley Fahn, M.D.

Disclosures

Neurosurg Focus. 2002;13(5) 

In This Article

Questions Raised by the Fetal Tissue Implant Study

We would like to address in detail several of the questions raised by this study.

Why was no Improvement Seen in Medication-Related Motor Fluctuations Despite Reports of Such Improvement in Open-Label Studies?

The patients in our study were chosen because they experienced a significant response to levodopa but troublesome motor fluctuations that defied management by current methods. The most common problem was disabling dyskinesias even in patients receiving doses of medication sufficient to provide a reasonable duration of acceptable motor functioning, although some patients also suffered off-medication freezing, off-medication anxiety, and a variety of other problems. Even in the subgroup of younger patients, improvement in scores while off medication, in the absence of levodopa, was not sufficient to produce an improvement in the quality of life for the group as a whole. Some individual patients did appear to exhibit improvement in motor fluctuations. This will not be helpful in the clinical setting, however, unless such patients can be identified in advance. We should note that, at initiation of the study, ropinirole and entacapone were not commercially available in the United States. It is possible that these medications might have affected recruitment, but it is unlikely that they would have affected the outcome in a major way. The absence of improvement in time on medication or time on medication with dyskinesias is a major limitation of fetal tissue transplantation in our study. It is possible that an increase in the amount of surviving dopaminergic tissue might overcome this limitation; however, this might also predispose patients to runaway dyskinesias (see following section). Some authors have argued that deficiencies in our technique accounted for the lack of improvement of motor fluctuations in this study. At least six groups have reported improvement in motor fluctuations after fetal tissue implantation in open-label studies.[1,5,6,7,8,11] There is no way to know, however, whether improvements reported by those groups was due to placebo effect. Only additional placebo-controlled studies can settle this question.

Why was Clinical Improvement Absent in Older Patients Despite Improved PET Results?

We do not know why graft survival, as gauged by fluorodopa PET, did not correlate with clinical improvement in the off-medication state. It is disappointing that clinical improvement on average did not occur in patients in the typical age range for PD, (age > 60 years) despite apparent graft survival and dopamine production. Once again, this has been attributed to peculiarities in tissue processing or surgical technique in this study (tissue was cultured prior to implantation; no immunosuppression was used, and a novel anterior-posterior surgical approach was used instead of the more common coronal approach). Although it is easy to generate plausible hypotheses, it remains to be shown why these technical variances should affect younger and older patients differently. Examination of the open-label literature does not clearly indicate whether other investigators found similar problems. It remains for the authors of future controlled, agestratified studies to determine whether this problem is associated with other techniques of fetal tissue processing and implantation.

Did Runaway Dyskinesias Result From Focal Excess Dopamine Production?

Five of our patients developed dyskinesias and dystonia that persisted in the absence or near absence of levodopa and other antiparkinsonian medications (some patients were unable to stop medications completely because of residual parkinsonian symptoms). These involuntary movements were disabling in four patients, in whom the best fetal tissue transplantation-induced outcomes were achieved, making these dyskinesias a significant concern despite the relatively small number of patients involved. These patients all experienced substantial clinical improvement, and fluorodopa PET revealed a larger increase in signal than in those in whom runaway dyskinesias did not develop.[9] This suggests that the dyskinesias resulted from excess graft-related dopamine production. Although no larger than normal concentrations of dopamine for an entire putamen occurred in any transplant-treated patient, it is likely, based on autopsy and PET studies, that regions within the putamen may have received large concentrations of dopamine.[3,9] There is one other report, of off-medication dyskinesias in 14 transplanted patients, in which the authors concluded that excess dopamine was not likely the cause of dyskinesias[4] In that study patients were included if dyskinesias were present in the morning before taking their usual dosage of medications. Dyskinesias seemed to correlate with the severity of preoperative dopamine deficit demonstrated on fluorodopa PET scans, suggesting that striatal denervation, not graft dopamine production, was the major factor producing off-medication dyskinesias. Clinically troublesome dyskinesias, however, were present in only one patient, and they persisted for at least 9 weeks off levodopa and dopamine agonists. It is not known in most of those cases if the dyskinesias persisted in the absence of antiparkinsonian medications. Thus, these cases are not comparable with our cases with runaway dyskinesias. If graft tissue-produced dopamine does cause runaway dyskinesias, attempts to increase graft-produced dopamine (for example, by using trophic factors) may induce even more runaway dyskinesias. In addition, this raises the possibility that treatment of PD by stem cell implant procedures, in which it is easier to implant larger number of cells, may also suffer from the problem of runaway dyskinesias.

Was it Ethical to Use Sham Surgery Rather Than Compare Surgery With Best Medical Therapy?

At the time our study was proposed, there was public discussion about the ethical implication of involving patients in a sham surgery procedure. In our study, the sham procedure consisted of twist drill holes made in the forehead without needle passes through the dura into the brain. We argued that the risks of sham surgery had to be weighed against the greater risks of performing a procedure that was mistakenly believed to be useful because of placebo effects. If not for concern about placebo effects, it would be reasonable to rely on comparisons between patients randomized to surgery or best medical therapy. We believe that sham surgery is ethical if the placebo effect (1 year after transplantation) is sufficient to affect the out-come of the study. In fact, there was no mean change in UPDRS score in sham-treated patients. This does not, however, mean that placebo effect did not influence the outcome of the study. The mean improvement in implant-treated patients was 32% in the off-medication motor UPDRS score. There were four placebo-treated patients who experienced comparable improvements in off-medication motor UPDRS scores, ranging from 25 to 31%, and another patient with a 23% improvement in off-medication motor UPDRS score. Thus, the placebo effect does increase the variability in outcome, which influences statistical comparison between transplant-and sham-treated groups. The placebo-induced improvement in our study was measured 1 year after sham surgery and thus was very long lasting. Additionally, relatively little is known about the factors that influence the magnitude of the placebo effect. It is not surprising, therefore, that the authors of another placebo-controlled study of tissue implants (using porcine fetal mesencephalic tissue) did find a statistically significant improvement in the placebo-treated group.[10]

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