Adrenal Medullary Transplantation Into the Brain for Treatment of Parkinson's Disease: Clinical Outcome and Neurochemical Studies

Ahlskog, J. Eric; Kelly, Patrick J.; Heerden, Jon A. van; Stoddard, Susan L.; Tyce, Gertrude M.; Windebank, Anthony J.; Bailey, Patricia A.; Bell, Gaye N.; Blexrud, Marceil D.; Carmichael, Stephen W.

doi:10.1016/s0025-6196(12)62532-4

Cited by 69 publications

(8 citation statements)

References 55 publications

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“…62,[66][67][68][69][70] There were 52 articles for adrenal medullary transplantation, but the review includes only the 9 that met criteria. [71][72][73][74][75][76][77][78][79] For human fetal mesencephalon transplantation, 19 papers were found and all were included. 13,75,[80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96] Once the evidence regarding all the articles reviewed was classified, each working group summarized all the collected data and indicated the quality of evidence of all citations contributing to their recommendations.…”

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Evaluation of surgery for Parkinson’s disease

Hallett¹,

Litvan²

1999

Neurology

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the Task Force on Surgery for Parkinson's Disease* PD is a common disorder affecting on average 100 per 100,000 population. Despite the large number of medications available for the treatment of early and moderately advanced PD, options specifically designed for the patient with advanced disease are limited. Surgery for PD dates from 1939-1940, when Bucy and Case 1 and Klemme 2 excised parts of the cerebral cortex to treat tremor and dystonia, but this type of surgery produced hemiparesis. Surgical basal ganglia lesions were introduced a few years later by Meyers, 3,4 who found that pallidotomy produced significant relief of tremor, rigidity, and dyskinesias, but with considerable mortality. Stereotaxic techniques to coagulate the globus pallidus in PD were introduced in the 1950s by Spiegel and Wycis, 5,6 and Cooper was an early advocate of pallidal surgery.7 Based on the anatomic connections between the pallidum and the thalamus, Hassler introduced the concept of surgery on the ventrolateral nucleus of the thalamus. 8,9Microelectrode recording allowed Narabayashi 10,11 to find that lesioning the ventral intermediate (Vim) nucleus of the thalamus was the most specific target to control the tremor in PD. Neurosurgery reached its peak in the 1960s, but declined after the introduction of levodopa.The recent resurgence of surgery was initiated by adrenal medullary transplantation. The premise of adrenal medullary transplants was that these cells, when transplanted into patients with advanced PD, would survive and function as a new source of dopamine. The theoretical advantages of adrenal tissue include that the tissue comes from the patient, eliminating the issue of immunologic rejection; dopamine is a normal intermediate compound made by the chromaffin cells; and chromaffin cells may have neuritic morphology when grown in culture. The disadvantages include the non-neuronal source and the rather modest survival rates of cells in laboratory transplantation studies. Isolated case reports of effective treatment of advanced PD with unilateral transplantation of adrenal medullary cells into the striatum in the 1980s led to several clinical trials testing the safety and efficacy of this procedure.Fetal mesencephalon transplantation was introduced subsequently and is based on several considerations. First, PD is associated with relatively selective degeneration of dopaminergic cells located in the substantia nigra, a portion of the mesencephalon. Second, replacement of dopaminergic activity by means of precursor drugs, receptor agonists, or inhibitors of dopamine catabolism improves the signs and symptoms of PD. Third, laboratory evidence in experimental animals has demonstrated that grafts of dopamine-containing neurons improve behavioral models of PD. Fourth, in these animal models, grafts reinnervate the striatum and form synaptic connections with host neurons. As a result, a small number of research teams have developed programs for human fetal mesencephalic cell grafts in PD patients. Several published reports exist,...

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confidence: 99%

Evaluation of surgery for Parkinson’s disease

Hallett¹,

Litvan²

1999

Neurology

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“…While initial clinical trials employing adrenal medullary implants were for the most part (Backlund et al, 1985;Lindvall et al, 1987), Madrazo and coworkers reported that intracaudate implantation of adrenal medulla resulted in a dramatic amelioration of parkinsonian symptoms (Madrazo et al, 1987a,b). These reports resulted in a flurry of clinical trials that were unable to replicate these dramatic findings (Penn et al, 1988;Allen et al, 1989;Goetz et al, 1989;Kelly et al, 1989;Ahlskog et al, 1990;Lopez-Lozano et al, 1990;Olanow et al, 1990).…”

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Robust survival of isolated bovine adrenal chromaffin cells following intrastriatal transplantation: a novel hypothesis of adrenal graft viability

et al. 1993

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Previous investigations have demonstrated that adrenal chromaffin cells survive poorly when grafted into the striatum of rodents, nonhuman primates, and patients with Parkinson's disease. This poor survival has been attributed to the low levels of endogenous NGF within the striatum. However, chromaffin cells isolated from the nonchromaffin constituents of the adrenal medulla (fibroblasts and endothelial cells) have recently been demonstrated to survive grafting into a number of CNS sites. The present study determined whether nonchromaffin constituents of the adrenal medulla may be responsible for poor graft survival. We compared the survival of intrastriatally grafted isolated bovine chromaffin cells with that observed following implantation of either perfused adrenal medullary suspensions containing all adrenal medullary cell types or isolated chromaffin cells that were then reseeded with autologous fibroblasts and endothelial cells. Implants of perfused adrenal medullary cells survived poorly and most graft sites were infiltrated with macrophages. The chromaffin cells in this group that did survive appeared to be in the process of degeneration. In contrast, large numbers of isolated chromaffin cells survived for up to 2 months following transplantation. These cells maintained their endocrine phenotype and stained for all enzymatic markers of catecholamine synthesis as well as chromogranin A. Morphologically, these cells resembled chromaffin cells seen in situ and the perigraft region was essentially devoid of macrophages. When isolated chromaffin cells were reseeded with autologous fibroblasts and endothelial cells, the implants degenerated and few, if any, surviving chromaffin cells were observed. Interestingly, these latter grafts induced a host- derived sprouting response of tyrosine hydroxylase-immunoreactive fibers. These data demonstrate that large numbers of adrenal chromaffin cells can survive intrastriatal implantation in the absence of exposure to exogenous NGF. Rather, the nonchromaffin cells of the adrenal medulla (fibroblasts and endothelial cells) appear to compromise the viability of grafted chromaffin cells. Once they are eliminated from the graft, robust survival of chromaffin cells occurs. If clinical trials employing adrenal medullary grafts are still to be considered for the treatment of Parkinson's disease, isolation of the chromaffin cells should be considered to enhance graft viability.

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“…However, an analysis of all cases of autologous transplantation of adrenal medulla alone was associated with minimal clinical improvements with very limited survival of grafts [20,21] and significant problems of morbidity and mortality.…”

Section: Adrenal Medullamentioning

confidence: 99%