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May 01, 1996; 46 (5) Articles

Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts

Rebecca D. Folkerth, Raymon Durso
First published May 1, 1996, DOI: https://doi.org/10.1212/WNL.46.5.1219
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Abstract

Background: Since 1985, treatment of idiopathic Parkinson's disease (PD) by surgical transfer of adult or fetal chromaffin tissue or of fetal central neural tissue to the brains of afflicted patients has been attempted, with variable clinical results. Neuropathologic studies of the status of these transplants are few and show wide variation in degree of graft survival.

Methods: We report the case of a 52-year-old man, who, 23 months earlier, received both intrastriatal implantation and intraventricular infusion of tissues derived from fetuses of 15 to 16 weeks and 5 to 6 weeks gestational age. Clinical improvement, as measured by increased amounts of “on” time with reduced levodopa requirements, seemed to occur over the subsequent months. He died suddenly at home after a several-hours interval of progressive lethargy and breathing difficulties.

Results: At autopsy, the diagnosis of PD was confirmed. Intrastriatal graft sites were identified, but contained no viable neurons; astrogliosis, focal microgliosis, and mixed inflammatory response, suggesting allograft rejection, were present. Surprisingly, the intraventricular tissues survived and showed ectodermal and mesenchymal, but no neural, differentiation, as well as cellular response; the left lateral and fourth ventricles were filled completely by this proliferated tissue.

Conclusions: By intraventricular infusion, tissues from early-gestation sources can engraft successfully, grow, and survive for at least 23 months in the brain of a PD patient. However, contamination by, or differentiation into, nonneural tissues can occur, can lead to proliferation of tissues within ventricular spaces, and may result in ventricular obstruction. Grafts, whether intraventricular or intraparenchymal, are capable of inciting host responses, which in turn may limit their long-term survival. Finally, post-transplant clinical improvement in symptoms of PD may be unrelated to survival of engrafted neurons.

Since 1985, scores of patients have undergone adrenal medullary autografts, fetal adrenal allografts, or fetal mesencephalic allografts at centers in the United States and abroad. 1–12 Unfortunately, most of these studies were performed prior to the development of the Core Assessment Program for Intracranial Transplantation (CAPIT) in 1992, 13 and suffer from the lack of standardized protocols with regard to selection criteria, operative techniques, pre- and postoperative neurologic evaluations, and drug regimens. As a result, the objective assessment of clinical outcomes is difficult, l4,15 and there is no clear consensus of the clinical value of the procedure, which carries morbidity and mortality as does any surgical operation, 16,17 and has, in the case of fetal allografts, certain ethical concerns. 18–21 The transition from rodent studies to human clinical trials without extensive prior nonhuman primate research has contributed to the controversy surrounding the rationale and methodology of neural transplantation. 15,22–26 Indeed, correlation of postoperative clinical status with graft viability and interaction with the host brain has been addressed in only a small number of nonhuman primate studies, many of which have followed reports of clinical trials in human subjects, and which used a variety of surgical methods and tissue sources. 24,26–31 Detailed histopathologic evaluations of grafts in patients are, therefore, especially valuable, and to date comprise four cases of adrenal medullary autograft 32–35 and only two fetal mesencephalic allograft. 36,37 We now present the clinical course and unique autopsy findings of a third patient with PD treated by allograft of fetal mesodiencephalic tissues.

Case Report

Clinical course

This 52-year-old man had initial symptoms of tremor and rigidity in 1985. His condition deteriorated over the ensuing years to one of severe “on-off phenomena with frequent freezing spells and severe disability in the “off state (Hoehn and Yahr score IV-V). These problems persisted despite a medication regimen of carbidopdevodopa (CD/LD) 25 mg/250 mg six to eight times daily, amantadine 100 mg twice daily, and bromocriptine 5 mg twice daily. In April 1989, he traveled to China and underwent stereotactic implantation of ventral mesencephalic tissue fragments from two 16-week gestation fetuses into right caudate and left putamen, and infusion of dissociated diencephalic/mesodiencephalic region cells from a 16-mm (5 to 6 weeks gestation) embryo into the CSF of the ventricular system via an Ommaya reservoir, using a now-published surgical technique. 38 In brief, the protocol entailed stereotactic placement of polyethylene catheters into the basal ganglionic sites, with closure of the scalp. Between 2 and 11 days afterward, the latergestation fetal tissues were dissected into 0.5 to 1.5-mm fragments, with part introduced as a suspension into the head of the right caudate (in contact with the ventricular surface), and the remainder loaded into an Apuzzo insertion coil inplanted in the left putamen; the stereotactic catheters to these sites were removed. A suspension of similarly prepared tissues from the area of the pontine flexure of the earlier gestation source was injected into the ventricle through an indwelling Ommaya reservoir. Cyclosporine 10 mg/kg/day and prednisone 60 mglday were administered from 48 hours before the operation and continuously until his death.

During the first 6 postoperative weeks, 38 the CD/LD dosage was reduced intentionally to 25/250 three times daily. The patient's parkinsonism was noted to be worse than preoperatively. However, at 6 weeks, there was improved facial expression, followed by improved speech, swallowing, and gait stability. Between 6 and 14 months postsurgery, a significant improvement was noted by the patient and family, characterized by an increase in both duration and quality of response to CDLD. He seldom experienced freezing spells and was able to ambulate easily during his “on” states. During this same period, he had adjustments to his medication regimen (i.e., an increase of CD/LD from three to four tablets per day and the addition of deprenyl 5 mg twice daily) that made the source of his improvement difficult to interpret. Ventricular CSF samples had been drawn from the Ommaya reservoir periodically (0, 3, 6, 10, and 13 months postsurgery). They were analyzed for homovanillic acid (HVA) using high-performance liquid chromatography with electrochemical detection. 39 The HVA levels were found to be 343, 325, 303, 373, and 330 ng/ml at 0, 3, 6, 10, and 13 postoperative months. At 15 months, positron-emission tomography, using [18F]-labeled L-dopa (FD), was performed and compared with images of normal volunteers and other (presumably unimplanted) PD patients. It detected “an area of uptake just lateral and posterior to the left caudate nucleus[,]… in the posterior portion of the left putamen, and on the left side of the pons. There was no specific uptake of FD in the ventricles. 38 These findings were interpreted as supporting graft survival and function as the mechanism underlying the patient's decrease in symptoms; “however, nongraft of non-dopaminergic mechanisms [sic]” could not be excluded. 38 During the second postoperative year, the patient elected to see a number of different physicians throughout the country, including one of us (R.D.). The patient and his wife maintained that the improvement noted in the first months following surgery was persistent. The patient's final medical evaluation, performed about 22.5 months post-transplant, was notable for mild peripheral edema, but without cardiopulmonary abnormalities on physical examination. He exhibited mild chronic renal failure (BUN 30 mg/dl), which was thought to be related to ongoing cyclosporine treatment. At 23 months, he died suddenly. His wife related that he woke up in the morning feeling very tired. Within hours, he fell back asleep and his wife noticed “funny halted breathing.” She sent for an ambulance and he was pronounced dead.

Autopsy findings

Permission for postmortem examination, performed approximately 8 hours after death, was limited to the head. The unfured brain weighed 1,430 g, and had slight diffuse swelling, but no stigmata of herniation. An Ommaya reservoir communicated to the left lateral ventricle via catheter (figure 1). Coronal sections of the cerebral hemispheres revealed the graft sites in the head of the right caudate nucleus (figure 1), and in the left putamen, where the silver metal coil tissue carrier was visible (figure 2). The floor of the left lateral ventricle was studded with bosselated, gray-white, glistening nodules, measuring up to 0.6 cm in greatest dimension (figure 2). The glomus of the choroid plexus was also studded with nodules. The occipital horn of the left lateral ventricle was completely obliterated by nodules, which, at this level, were accompanied by soft, yellow, keratinous material (figure 3). The frontal horn of the left lateral ventricle, and the right lateral and third ventricles, were not involved in this process, nor were they enlarged.

Figure

Figure 1. Discoloration and cavitation (arrow) are found in the head of the right caudate nucleus (R, right). The tip of an indwelling catheter is visible in the frontal horn of the left lateral ventricle (arrowhead).

Figure

Figure 2. The metal coil tissue carrier is in place in the left putamen (arrow). The floor of the left lateral ventricle (arrowhead) is studded with gray-white, glistening nodules, measuring up to 0.6 cm in greatest dimension.

Figure

Figure 3. The occipital horn of the left lateral ventricle is obliterated by gray-white nodules, accompanied by soft keratinous material.

Axial sections of the brainstem and cerebellum en bloc disclosed marked pallor of the substantia nigra bilaterally. There was obliteration of the fourth ventricle by nodules and keratinous debris (figure 4), which persisted caudally to the level of the open medulla.

Figure

Figure 4. The fourth ventricle is occluded by gray-white nodules and keratinous debris containing hair shafts. There is compression and discoloration of the roof of the fourth ventricle, including the cerebellar vermis, as well as the middle cerebellar peduncles and the pontine tegmentum.

Microscopic examination of formalin-fixed, paraffinembedded tissues, cut at 8 μm and stained with hematoxylin and eosin (H-E), confirmed the clinical diagnosis of PD. At the graft sites, only astroglial and connective tissue scars, associated with variable numbers of lymphocytes, plasma cells, foamy and pigmented macrophages, and microglial cells, were seen (figure 5). The infiltrating lymphocytes were primarily B-cells, with a minority of T-cells, as identified by immunohistochemistry performed on paraffin sections using standard protocols (Vectastain Avidin-Biotin-peroxidase Complex kit; Vector Laboratories, Burlingame CA Antisera: antibodies to leukocyte-common antigen, lysozyme, alpha-1-antichymotrypsin, UCHL-1, L-26, and keratins AEI-AEXII [Dakopattsl). At none of the graft sites were viable neurons or myelinated axons detected. Multiple attempts at immunohistochemical localization of tyrosine hydroxylase activity in graft sites and in residual neurons of the substantia nigra, using two different antibodies (kindly provided by Drs. C. Biswas and A. Tischler) on paraffin sections, were unsuccessful, presumably due to prolonged postmortem interval; parallel-run sections of well-preserved fetal organ of Zuckerkandl were positive.

Figure

Figure 5. Sections of the graft site (bounded by arrows) in the left putamen disclose only scar (H-E, bar = 980 μm) and infiltrates of mononuclear cells (inset, H-E, bar = 56 μm).

The nodules in the ventricular system were composed of mature hyaline cartilage (figure 6A), bone, and squamous epithelium, with keratinous debris and hair shafts (figure 6B); no neural elements were identified. At the points of implantation on the ventricular surfaces, the ependyma was absent, and there was marked lymphoplasmacytic response. Focal foreign-body giant cell reaction to keratin and hair was most striking around the fourth ventricular implants (figure 6B). Rosenthal fibers and astrogliosis, suggesting a longstanding process, were also found surrounding the fourth ventricle, including the pontine tegmentum. Ependymal surfaces throughout the ventricular system showed healed ventriculitis.

Figure

Figure 6. The grossly visible gray-white nodules in both the left lateral (A) and fourth ventricles consist of hyaline cartilage (H-E, bar = 700 μm), accompanied by squamous epithelium, dermal appendages, and keratin (not shown). The scattered mononuclear inflammatory cells and astrogliosis around hair shafts, extending from the fourth uentricular implants into the cerebellar peduncle (B) (H-E, bar = 56 μm), suggest a longstanding process.

The cerebral cortex and white matter and the cerebellum were grossly and microscopically normal.

Based on our findings in this limited autopsy, we felt the cause of death may have been related to the striking fourth ventricular obliteration by proliferated graft tissues, which could have resulted in progressive brainstem compression. However, we cannot exclude another mechanism, such as pulmonary embolism or myocardial infarction.

Discussion

We report the case of a severely disabled parkinsonian patient who enjoyed modest clinical improvement following transplantation of fetal tissues into the basal ganglia and ventricular system. Whether the transplant itself was responsible for this improvement is uncertain, since there were changes in his antiparkinsonian medication regimen postoperatively. The postmortem findings raise important questions concerning the selection of graft tissues and anatomic implantation sites, as well as the role of host immunity in graft viability.

Our autopsy findings echo prior observation 36,37,40 that early gestation sources (less than 11 weeks) survive better (i.e., longer) than later ones. They also are convent with animal studies showing that tissues in communication with the ventricles and CSF survive more readily than entirely intraparenchymal grafts. 41,42 Our case also demonstrates that intraventricular cell infusions can proliferate in an unregulated manner, leading to obliteration of ventricular spaces. In a primate implanted with very early gestational-age tissue (comparable to a human gestational age of 7 weeks), in contact with the lateral ventricle, occlusion and distortion of the ventricle by viable neural graft tissue was found 56 days post-transplant; the finding may have contributed to the death of the animal 28 Presumably, the neural grafts in our patient were contaminated, at the time of harvest from the embryonic and fetal cadavers, by branchial arch tissues that proliferated in the same manner as in the experimental animal.

An alternative possibility is that the donor tissue was contaminated by host tissues during the transplantation procedure, in a manner analogous to the development of intrathecal dermoid cysts following lumbar puncture. 43 Such a mechanism would not account, however, for the cartilage. In an even more unlikely scenario, perhaps the donor tissues indeed originated completely from the primitive nervous system, but followed a divergent developmental pathway after dissection and implantation into the host brain. “Regression” of neural tissue, followed by reorganization and maturation, has occurred in ganglion transplants in the rat ventricular system.44 However, to our knowledge, there is no such documented phenomenon of differentiation into a nonneural phenotype. Whether our case is an example of the feared neoplastic (i.e., growth-unregulated) transformation of grafts discussed by some researchers, 38,45 though usually in reference to implants of immortalized cell lines or virus-transfected models, is unknown.

Host immune surveillance in the CNS may play an important role in graft failure. In our case, the detection of T-cell reaction at all transplant sites supports the contention that graft rejection was occurring in spite of immunosuppressive therapy, even nearly 2 years post-transplant. Recent animal studies have shown that disruption of the host blood-brain barrier during the implantation procedure facilitates the travel of graft antigens to lymphoid tissues in the periphery, stimulating lymphocyte proliferation, activation, and migration to the graft site. Associated host tissue damage leads, via classical inflammatory mediators, to local activation of astrocytes and attraction of microglia. Grafted tissues develop increased major histocompatibility complex expression, as do native glial cells and ends thelia. 46 Once inflammation is established, killer T-cells begin graft cell lysis. 47,48 Variation in the rate of these steps depends on accessibility of grafted cells to vasculaure and of immune cells to the graft, and leads to variation in the timing and degree of histologically observed inflammation and graft viability. 49 In our case, the indwelling ventricular catheter, as well as the foreign-body type reaction in the fourth ventricle, may have served as constant sources of inflammatory mediators propagating the graft rejection.

Myriad other factors influence the graft-host immune interaction. Embryonic grafts can develop MHC antigen expression, leading to their rejection. 50,51 The degree of mismatch between the donor and the host may affect the timing and degree of graft rejeetion, 46 although tissue typing generally is not performed prior to transplantation. The role of cyclosporine A in the promotion of graft survival is controversial. 37,52,54 In nonhuman primates, rejection occurs in animals receiving, at intervals, grafts from more than one donor, suggesting that an immune response was engendered by the first transplant, leading to rejection of the subsequent grafts. 41,53,55,56 The minimum interval between sequential grafts that is capable of causing this immunization is not known.

Regardless of whether true rejection was occurring in our case at the time of death, we are unable to judge if any survival of engrafted neural tissue ever took place in the 23-month interval postoperatively. This inability to assess adequately in vivo the degree of graft viability and function remains a major limitation of fetal neural grafting. In contrast, solid organ transplants can be evaluated readily on the basis of serum studies, diagnostic imaging, and even allograft biopsy. Although function can be inferred on the basis of relief of parkinsonian symptoms, specific supportive evidence in the form of increased CSF HVA levels 1,6,8 and 18F-DOPA uptake at grafted sites by PET imaging B. 8,9,11,12,52,57,58 has not correlated consistently. Furthermore, a nonspecific regenerative response to surgical damage, with sprouting of dopaminergic nerve terminals, 29,53,59 possibly due to the release of trophic factors from injured tissues, 60,61 is known to occur. In animal models of PD, such changes have followed sham operatiodo and implantation of fetal amnion cells 62 and have accounted for transient symptomatic improvement. In our patient, multiple ventricular CSF samples analyzed for HVA over a 13-month period showed no consistent pattern of elevation. A single PET study was performed 15 months postoperatively 38 and seemed to indicate function not only in the left putaminal graft site, but also in the left side of the pons. Given the histopathologic findings of glial scar in the former and of nonneural tissue abutting the latter, albeit after an interval of 18 months, the ability of PET imaging to distinguish graft survival from host sprouting in a nonspecific response to injury must be questioned.

Finally, we want to emphasize the differences in our postmortem findings from those of Redmond et al. 36 and Kordower et al., 37 the only other illustrated histologic studies of fetal mesencephalic transplants known to us. Some of these differences may be related to variations in the gestational ages of the donors and the form and method of introduction of grafted tissues into the host brain. Problems with the means of assessing graft function, considered above, also contribute to the difficulty in comparing these cases. In the report by Redmond et al., 36 the patient had intraparenchymal implantation of cryopreserved material (whether solid or cell suspension not stated) from an 11-week gestation source, without real clinical improvement. Autopsy 4 months later revealed viable, synapse-forming graft neurons (though without tyrosine hydroxylase staining). CSF HVA levels or results of PET imaging were not mentioned. They describe reactive glia and macrophages at the graft site, while stating that “there were no signs of immune rejection”; the letter format of the report did not specify the basis upon which such a conclusion was drawn. 36 The patient's immune status was not stated. In the very thorough study of Kordower et al., 37 intraparenchymal engraftment of 6.5 to 9-week gestational-age neurons (whether solid or cell suspension not stated) resulted in 18 months' graft survival, as well as tyrosine hydroxylase-immunoreactive innervation of striatal graft sites, not thought to be due to host fiber sprouting. Their findings correlated well with clinical improvement as assessed by CAPIT guidelines13 and with serial PET imaging performed pre-and postoperatively according to established technical protocols allowing quantitative evaluation. The apparent absence of graft rejection, despite the lack of immunosuppression over the year prior to death, is in further stark contrast to the robust cellular response associated with all graft sites in our case, even after 23 months and ongoing cyclosporine treatment.

In summary, the results of autopsy evaluation and correlation with clinical course in our patient with PD following fetal neural implantation hint that early gestation sources, especially introduced as cell suspensions into the ventricular system, may survive better than intraparenchymally placed grafts. We must conclude also that, occasional examples to the contrary, host cellular immune response can occur and continue for almost 2 years postimplant, and may participate in destruction of the graft despite immunosuppressive treatment. This immune mechanism may play a greater role when later-gestation material is placed within brain parenchyma. The clinical improvement our patient enjoyed cannot be proven to have resulted from neural cell engraftment or from nonspecific host regenerative factors. Finally, the bizarre overgrowth of nonneural tissue in our patient's brain illustrates the risk of adverse outcomes of this controversial technique, especially with direct introduction of pluripotent or contaminated tissues into the cerebral ventricles as cell suspensions. In fact, although we cannot exclude completely other mechanisms of death in our case, we believe that the intraventricular tissue growths could have compromised brainstem function, leading to central cardiorespiratory failure. Clearly, additional postmortem analyses of fetal implant cases will be needed to appreciate the full spectrum of associated pathologic changes, and to allow correlation with clinical progress evaluated in standardized fashion. We emphasize the ever-important need for caution and vigilance in initiation of new (and still experimental 63) therapies such as fetal neural implantation.

Acknowledgments

We thank Dr. Robert Iacono and Mrs. M. Truex for information about this patient's care. We are indebted to Drs. Arthur S. Tischler, Ina Bhan, and Chitra Biswas, Tufts University School of Medicine and New England Medical Center, Boston MA, for assistance in performing and interpreting the immunohistochemical studies. We thank Ms. Lisa Loftus-Smith for secretarial support. Drs. Martin A. Samuels and Matthew P. Frosch provided helpful comments.

Footnotes

  • Received October 9, 1995. Accepted in final form December 7, 1995.

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