Correspondence
Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease
N Engl J Med 2001; 345:146-147July 12, 2001
- Article
To the Editor:
The study of the transplantation of embryonic dopamine neurons for severe Parkinson's disease reported by Freed et al. (March 8 issue)1 revealed no benefit as measured on the basis of the primary outcome variable. In addition, severe dyskinesias developed in some patients. We believe it is important to not rush to judgment in evaluating neuronal transplantation in Parkinson's disease on the basis of the results of a single study.
The outcome variable — a subjective global rating of the change in the severity of the disease — was assessed with the use of a scale that was not validated. The patients were evaluated one year after transplantation, possibly before the grafts had fully matured. In addition, the use of cells from a limited number of donors that had been cultured for up to a month before grafting, and the restricted distribution of the grafts in the brain of the recipients, may have contributed to the poor results. Better results may be achieved with the use of different transplantation protocols.2
The mechanism responsible for the reported dyskinesias is unknown, and there is no evidence that they were caused by an excess of graft-derived dopamine, as Freed et al. suggest. Indeed, previous findings in rats3 and in patients with Parkinson's disease4 and the findings on positron-emission tomography and postmortem examination in the study by Freed et al. do not support this hypothesis.
4 ReferencesC. Warren Olanow, M.D.
Mount Sinai School of Medicine, New York, NY 10029-6574
warren.olanow@mssm. edu Tom Freeman, M.D.
University of South Florida, Tampa, FL 33606Jeff Kordower, Ph.D.
Rush–Presbyterian–St. Luke's Medical Center, Chicago, IL 606121
Freed CR ,Greene PE ,Breeze RE , et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001;344:710-719
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Olanow CW ,Kordower JH ,Freeman TB . Fetal nigral transplantation as a therapy for Parkinson's disease. Trends Neurosci 1996;19:102-109
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Lee CS ,Cenci MA ,Schulzer M ,Bjorklund A . Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease. Brain 2000;123:1365-1379
CrossRef | Web of Science | Medline4
Kordower JH ,Freeman TB ,Snow BJ , et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med 1995;332:1118-1124
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To the Editor:
In 1994,1 leading transplantation scientists predicted the failure of the study by Freed et al. Moreover, the only controlled study in monkeys revealed that transplantation into the caudate had important antiparkinsonian effects but that transplantation into the putamen or sham procedures had no effect.2 In an earlier study in humans, Freed et al.3 found that the effect of neuronal transplantation was no greater than that of “optimal medication” in our control group of patients who did not undergo immediate transplantation.4 In the current study by Freed et al., the site of tissue placement in the putamen and the drug regimen may have led to dyskinesias. Thus, the failure of the study should not negate the results of many studies of neuronal transplantation in animals and humans that reported a benefit.
Since the methods used by Freed et al. were not well validated,5 the inclusion of a sham-surgery group was premature and unnecessary. The improvement from year 1 to year 3 in the transplantation group could represent a placebo effect, since blinding was discontinued at one year, or it could be seen as confirmation that the one-year outcome period was too short to reflect the known pattern of development of neuronal transplants. Unless the outcome of one study that evaluated one method leads us to give up research on cellular transplantation, treatments will surely emerge to cure degenerative, genetic, and traumatic damage to the brain and spinal cord.
5 ReferencesD. Eugene Redmond, Jr., M.D.
Yale University School of Medicine, New Haven, CT 06510
eugene.redmond@yale. edu John R. Sladek, Ph.D.
, North Chicago, IL 60064Dennis D. Spencer, M.D.
Yale University School of Medicine, New Haven, CT 065101
Cohen J . New fight over fetal tissue grafts. Science 1994;263:600-601
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Taylor JR ,Elsworth JD ,Sladek JR Jr ,Collier TJ ,Roth RH ,Redmond DE Jr . Sham surgery does not ameliorate MPTP-induced behavioral deficits in monkeys. Cell Transplant 1995;4:13-26
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Freed CR ,Breeze RE ,Rosenberg NL , et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 1992;327:1549-1555
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Spencer DD ,Robbins RJ ,Naftolin F , et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease. N Engl J Med 1992;327:1541-1548
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Macklin R . The ethical problems with sham surgery in clinical research. N Engl J Med 1999;341:992-996
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Author/Editor Response
The authors reply:
To the Editor: We agree with Olanow et al. and Redmond et al. that multiple studies of fetal-tissue transplantation for Parkinson's disease are needed. In our study, the transplants survived in 85 percent of patients, regardless of age and the absence of immunosuppression. On the basis of the Unified Parkinson's Disease Rating Scale motor score, obtained when a patient is “off medication” — a frequently used measure of transplantation outcome — we found an improvement of 18 percent (P=0.04) for the transplantation group as a whole and 34 percent for the group of patients who were 60 years of age or younger (P=0.005) during a blinded evaluation in the first year. These results provide definitive proof that the effects of transplantation are real. Scores on the subjective global rating scale were more variable and changed after the patients viewed preoperative videos.
Olanow et al. question the cause of the dyskinesias that persisted after a reduction in or cessation of dopamine-agonist drugs in 5 of the 33 transplant recipients. We think the dyskinesias were induced by dopamine, because a dopamine-synthesis inhibitor (metyrosine) reduced their severity. Transplants are known to grow over a period of years,1 and dyskinesias developed in years 2 and 3 in five patients who initially had excellent antibradykinetic responses. Three of the five patients have been treated successfully with implantation of stimulating electrodes into the internal pallidum.
Redmond et al. are critical of our transplantation methods even though postmortem examination of one of the patients in their study failed to show any surviving dopamine neurons with the techniques they used.2 They believe that implantation into the caudate is superior to transplantation into the putamen. We disagree. Caudate function is linked to eye movements and cognition, whereas the putamen controls movements of the limbs, trunk, and head. In Parkinson's disease, the extent of dopamine depletion is much more severe in the putamen than in the caudate.3 Because we found that older patients were less responsive to levodopa preoperatively, we have reexamined outcome data to correlate the preoperative response to levodopa with post-transplantation changes in motor function. We found that older patients with greater than 50 percent response to levodopa before surgery had significant improvement after the transplantation.
Olanow et al. suggest that we might have achieved a better result with a different transplantation technique. That is possible. The challenge for neurotransplantation is to produce greater clinical benefit with an acceptable level of side effects.
3 ReferencesCurt R. Freed, M.D.
Robert E. Breeze, M.D.
University of Colorado School of Medicine, Denver, CO 80262
curt.freed@uchsc. edu Stanley Fahn, M.D.
College of Physicians and Surgeons of Columbia University, New York, NY 100321
Freed CR ,Breeze RE ,Rosenberg NL , et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 1992;327:1549-1555
Full Text | Web of Science | Medline2
Redmond DE Jr ,Leranth C ,Spencer DD , et al. Fetal neural graft survival. Lancet 1990;336:820-822
CrossRef | Web of Science | Medline3
Kish SJ ,Shannak K ,Hornykiewicz O . Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease: pathophysiologic and clinical implications. N Engl J Med 1988;318:876-880
Full Text | Web of Science | Medline
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