Correspondence

Transplantation of Fetal Mesencephalic Tissue in Parkinson's Disease

N Engl J Med 1995; 333:730-731September 14, 1995

Article

To the Editor:

The report by Kordower et al. (April 27 issue)1 describes the remarkable survival of dopamine cells after neural transplantation in a patient with Parkinson's disease. These results provide a clear demonstration that the brains of patients with this disease can support embryonic cells, as predicted by the results of studies in animal models. Those of us who have been involved in human neural transplantation for many years have seen clinical improvement and findings on positron-emission tomography (PET) that are compatible with this outcome.2-4

The clinical methods chosen by this group reflect an amalgamation of techniques. Kordower et al. combined our surgical strategy of using closely spaced putaminal implants2,4 with the transplantation of tissue from a large number of embryos, as advocated by Widner et al.,3 and produced an excellent histologic outcome.

We have studied the value of immunosuppression after neurotransplantation. In our first 12 patients, we used immunosuppressive therapy with cyclosporine and prednisone in every other patient. The results showed no benefit from immunosuppression.5 Our first patient did not undergo immunosuppression and showed continued improvement in clinical status and in the results of fluorodopa PET scanning three to four years after the transplantation.2 In the patient described by Kordower et al., surviving dopamine neurons were found without any signs of tissue rejection many months after the discontinuation of cyclosporine, supporting the contention that long-term immunosuppression is not needed for transplant survival. This result is critically important because of the costs and complications of immunosuppressive regimens.

Kordower et al. noted only partial restoration of the patient's motor function, despite substantial evidence of cell survival at the time of his death 18 months after the transplantation. Since we have seen progressive improvement in humans for several years after transplantation, it is possible that further transplant outgrowth over time would have led to continuing improvement in the manifestations of the parkinsonian syndrome in their patient.

The objectives of neural transplantation in humans in the future are to improve cell survival and enhance neurite outgrowth. Kordower et al. found that only 5 percent of transplanted cells survived transplantation in their patient, a result similar to that seen in experiments in rats and primates. The fact that a single embryo contains enough dopamine cells to reinnervate all of the caudate and the putamen means that tissue from a single embryo may be adequate to replace the cells lost in the putamen if cell survival can be improved. The current availability of a number of growth factors that have been shown to promote dopamine-cell survival in animals may soon make neural transplantation a realistic treatment option for patients with advanced Parkinson's disease.

Curt R. Freed, M.D
Robert E. Breeze, M.D
Stuart A. Schneck, M.D
University of Colorado School of Medicine, Denver, CO 80262

5 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   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 | Medline

3. 3

   Widner H, Tetrud J, Rehncrona S, et al. Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992;327:1556-1563
   Full Text | Web of Science | Medline

4. 4

   Breeze RE, Wells TH Jr, Freed CR. Implantation of fetal tissue for the management of Parkinson's disease: a technical note. Neurosurgery 1995;36:1044-1048
   CrossRef | Web of Science | Medline

5. 5

   Freed CR, Breeze RE, Rosenberg NL, et al. Immunosuppression may be unnecessary for transplant success after human fetal dopamine cell implants in patients with Parkinson's disease. Abstr Soc Neurosci 1993;19:630-630
   

Author/Editor Response

The authors reply:

To the Editor: The patient we described with Parkinson's disease who received bilateral fetal nigral implants showed clinically relevant benefit and a progressive increase in striatal uptake of fluorodopa. These changes correlated with robust graft survival and extensive dopaminergic innervation at autopsy. Freed et al. contend that our methods consist of an amalgamation of techniques, combining their strategy of using closely spaced transplants with grafts from a large number of embryos, as advocated by Widner and colleagues. The procedures we followed differ from previous ones in specific, potentially critical, ways. We exclusively targeted the post-commissural putamen bilaterally, using higher concentrations of tissue to saturate this important region of the striatum.

Although we agree that needle tracts need to be closely spaced, the procedure we used is different from others' in that it separates graft deposits by no more than 5 mm in all three dimensions. The combination of bilateral transplantation, a limited target area, an increased concentration of tissue, and the close dispersion of grafted material may be critical in achieving the confluent putaminal innervation to produce the substantial clinical benefit we observed. We also limited donor age to a “window” that is critical for graft survival. Appreciating similarities and differences in techniques, even if they are subtle, is important to establish an optimal grafting procedure. However, establishing personal priority regarding a specific transplantation variable serves no useful purpose and potentially hinders progress.

Freed and coworkers also comment that our data, along with theirs, indicate that long-term immunosuppression is not required for fetal nigral transplantation. The effects in this patient were achieved with six months of immunosuppression. However, this is only one case, requiring cautious interpretation, and the need for long-term immunosuppression in humans has yet to be critically evaluated.

The goal of neural transplantation therapy in Parkinson's disease is to improve clinical function. We agree that cell survival and host innervation probably contribute to this goal. At present, clinical and basic research studies have begun to focus on those transplantation variables that enhance cell survival and host innervation, such as trophic factors, antioxidants, and genetic manipulation. Such studies are very exciting and will determine the ultimate value of neural grafting for patients with Parkinson's disease.

Jeffrey H. Kordower, Ph.D.
Thomas B. Freeman, M.D.
C. Warren Olanow, M.D.
Rush–Presbyterian–St. Luke's Medical Center, Chicago, IL 60612

Citing Articles (11)

Citing Articles

1. 1

   Jonathan Kimmelman, Katherine Duckworth, Tim Ramsay, Tiffini Voss, Bernard Ravina, Marina Elena Emborg. (2011) Risk of surgical delivery to deep nuclei: A meta-analysis. Movement Disorders 26:8, 1415-1421
   CrossRef

2. 2

   Eric Wexler. 2010. Emerging Applications of Gene and Somatic Cell Therapy in Geriatric Neuropsychiatry. , 330-341.
   CrossRef

3. 3

   Chrissa Sioka, Andreas Fotopoulos, Athanassios P. Kyritsis. (2010) Recent advances in PET imaging for evaluation of Parkinson’s disease. European Journal of Nuclear Medicine and Molecular Imaging 37:8, 1594-1603
   CrossRef

4. 4

   Mary B. Newman, Roy A. E. Bakay. (2008) Therapeutic potentials of human embryonic stem cells in Parkinson’s disease. Neurotherapeutics 5:2, 237-251
   CrossRef

5. 5

   Alan J. Fischman. (2005) Role of [18F]-dopa–PET imaging in assessing movement disorders. Radiologic Clinics of North America 43:1, 93-106
   CrossRef

6. 6

   Mei-Fang Cheng, Jing-Pian Peng, Gang Chen, Jeffrey P. Gardner, Edward M. Bonder. (2004) Functional restoration of acoustic units and adult-generated neurons after hypothalamic lesion. Journal of Neurobiology 60:2, 197-213
   CrossRef

7. 7

   S Polgar, M.E Morris, S Reilly, B Bilney, P.R Sanberg. (2003) Reconstructive neurosurgery for Parkinson’s disease: a systematic review and preliminary meta-analysis. Brain Research Bulletin 60:1-2, 1-24
   CrossRef

8. 8

   F. Cicchetti, W. Fodor, T. W. Deacon, C. van Horne, S. Rollins, W. Burton, L. C. Costantini, O. Isacson. (2003) Immune parameters relevant to neural xenograft survival in the primate brain. Xenotransplantation 10:1, 41-49
   CrossRef

9. 9

   Nina Törnqvist, Lars Björklund, Ingrid Strömberg. (2001) Evidence for Target-Specific Nerve Fiber Outgrowth from Subpopulations of Grafted Dopaminergic Neurons: A Retrograde Tracing Study Using in Oculo and Intracranial Grafting. Experimental Neurology 169:2, 329-339
   CrossRef

10. 10

    Yi Li, Michael Chopp, Jieli Chen, Lei Wang, Subhash C Gautam, Yong-Xian Xu, Zhenggang Zhang. (2000) Intrastriatal Transplantation of Bone Marrow Nonhematopoietic Cells Improves Functional Recovery After Stroke in Adult Mice. Journal of Cerebral Blood Flow & Metabolism 20:9, 1311-1319
    CrossRef

11. 11

    Alan J. Fischman, Ali A. Bonab, John W. Babich, E. Prather Palmer, Nathaniel M. Alpert, David R. Elmaleh, Ronald J. Callahan, Sandra A. Barrow, Wendy Graham, Peter C. Meltzer, Robert N. Hanson, Bertha K. Madras. (1998) Rapid detection of Parkinson's disease by SPECT with altropane: A selective ligand for dopamine transporters. Synapse 29:2, 128-141
    CrossRef