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Clinical outcome of cotransplantation of peripheral nerve and adrenal medulla in patients with Parkinson's disease

Juan J. López-Lozano, Gonzalo Bravo, Javier Abascal, Begoña Brera, Isabel Millan, and Clínica Puerta de Hierro Neural Transplantation Group

Object. Transplants of adrenal medulla (AM) and fetal ventral mesencephalon (FVM) are currently being tested as therapeutic alternatives in patients with Parkinson's disease (PD). At the Clínica Puerta de Hierro in Madrid, a controlled clinical trial is underway to establish which donor tissue, if any, is the best for open surgical implantation in patients with PD.

Methods. Since 1987, varying degrees of clinical improvement have been achieved in Grade IV and V parkinsonian patients by implanting perfused AM and FVM into the right caudate nucleus. To investigate further whether implantation of different types of donor tissues results in qualitatively and quantitatively different degrees of recovery, four patients with Grade IV or V PD received implants of pre-coincubated autologous AM and intercostal nerve in the caudate nucleus. Four nonsurgically treated patients served as a control group. Three years posttransplantation, longer on phases (46.2% ± 10.4% of the day presurgery to 87.5% ± 10.4% of the day 36 months postsurgery) and improved symptoms in on and off phases persist in all four cases, with reduced dyskinesias (67.1% ± 9.2% of the day in on phases presurgery to 17% ± 13.8% of the day in on phases 36 months postsurgery). Progress appears to be stepwise, starting within weeks of tranplantation and becoming clinically significant in the 2nd and 3rd months (similar to our AM- and sooner than in our FVM-implanted patients), followed by a period of stability and, after a second wave of improvement 12 to 18 months posttransplantation (similar to FVM implants), has continued (87.5 ± 7 points presurgery to 46 ± 5.6 points 36 months postsurgery). In the experimental group, doses of levodopa have been reduced by more than 60% and dopamine agonist use has not resumed. In contrast, there have been no significant clinical changes in the control group.

Conclusions. Implantation of tissue other than fetal tissue can promote a long-term improvement in the clinical symptomatology of seriously disabled parkinsonian patients. This finding is supported by the autopsy report of a patient with PD who had undergone grafting of AM plus peripheral nerve in which it was demonstrated that a large number of tyrosine hydroxylase—positive cells survive 1 year after implantation. In addition, there was a dense network of host dopaminergic fibers around the graft.

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Grafting of perfused adrenal medullary tissue into the caudate nucleus of patients with Parkinson's disease

Juan J. López-Lozano, Gonzalo Bravo, Javier Abascal, and the Clinica Puerta de Hierro Neural Transplantation Group

✓ The authors report results obtained in 20 severely affected patients with Parkinson's disease (Grade IV or V) who received an autotransplant of perfused adrenal medullary tissue. This study seems to indicate that these autoimplants can improve the parkinsonian symptomatology and induce amelioration in the patients' performance of routine activities. All the symptoms analyzed showed improvement, although it differed in intensity and time of onset. Moreover, this improvement was accompanied by a reduction in the daily intake of L-dopa, with discontinuance of dopamine agonists and amantadine.

A number of medical complications were encountered, including three deaths, probably related to performing abdominal surgery in seriously affected parkinsonian patients who were unable to tolerate the discontinuance of their medication. The transient psychiatric disorders observed appeared to be related to the postoperative dose of L-dopa and/or anticholinergic agents administered, and diminished or disappeared when the doses were reduced.

The reasons for improvement, which was bilateral, remain unknown, although one cause may be the surgical trauma (minicaudotomy) together with the implantation of adrenal medullary tissue, which may promote the sprouting of surviving dopaminergic fibers. Moreover, in this series, perfusion of adrenal medulla increased the capacity for revascularization of the tissue and may have reduced the damaging effects of warm ischemia on the cells. This, together with the existence of fenestrated vessels, could hypothetically have served as an access point for drugs, and if the implanted cells were viable, they might have served to store and manufacture different factors and/or transmitters. These results as well as those of other groups justify the development of a controlled international clinical trial.

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Preparation of adrenal medullary tissue for transplantation in Parkinson's disease: a new procedure

Technical note

Juan J. López-Lozano, Begoña Brera, Javier Abascal, and Gonzalo Bravo

✓ The authors describe a technique by which adrenal medullary tissue can be easily dissected from the adrenal cortex. The method involves perfusion with Locke's modified buffer, dissection of adrenal gland in buffer free of calcium or magnesium, and storage in a culture medium before implantation into the caudate nucleus of patients with Parkinson's disease. This method seems to increase the viability and purity of adrenal medullary tissue. The results obtained in 15 parkinsonian patients implanted with perfused adrenal medulla indicate the potential value of this technique.