Autologous Adrenal Medullary, Fetal Mesencephalic, and Fetal Adrenal Brain Transplantation in Parkinson's Disease: A Long-Term Postoperative Follow-Up

We report on the clinical status of 5 patients with Parkinson's disease (PD) 3 years after autologous adrenal medullary (AM)-to-caudate nucleus (CN) implanfion, and of 2 PD patients, 2 years after fetal ventral mesencephalon (VM)- and fetal adrenal (A)-to-CN homotransplantation. Current clinical evaluation of 4 of the AM grafted patients revealed sustained bilateral amelioration of their PD signs, most notably of rgidity, postural imbalance and gait disturbances, resulting in a substantial improvement in their quality of life. the disease-related dystonia of one of them disappeared only 2 years after surgery. The levodopa requirements of 2 of these patients and the anticholinergic therapy of another have been reduced. In agreement with the satisfactory clinical evaluation of these 4 patients, their neuropsychological and electrophysiological improvements, initially registered 3 months after surgery, have been maintained for 3 years. After 1 year of significant recovery, the 5th patient of this group has almost returned to her preoperative state. The 2 homotransplanted patients also showed sustained bilateral improvement of their PD signs. Two years after surgery, the most improved signs of the fetal VM case were rigidity, bradykinesia, postural imbalance, gait disturbances and facial expression. The fetal A case has only shown amelioration of rigidity and bradykinesia. Neither of them has shown significant neuropsychological changes. Their current levodopa requirements are less than before surgery. The improvements shown here by PD patients after brain tissue grafts go beyond those obtained using any other therapeutic approach, when levodopa fails. Although more studies and the development of these procedures are obviously required, these initial human trials appear to be resisting the test of time.

tients, 2 years after fetal ventral mesencephalon (VM)and fetal adrenal (A)-to-CN homotransplantation. Current clinical evaluation of 4 of the AM grafted patients revealed sustained bilateral amelioration of their PD signs, most notably of rigidity, postural imbalance and gait disturbances, resulting in a substantial improvement in their quality of life. The disease-related dystonia of one of them disappeared only 2 years after surgery. The levodopa requirements of 2 of these patients and the antichoHnergic therapy of another have been reduced. In agreement with the satisfactory clinical evaluation of these 4 patients, their neuropsychological and electrophysiological improvements, initially registered 3 months after surgery, have been maintained for 3 years. After 1 year of significant recovery, the 5th patient of this group has almost returned to her preoperative state.
The 2 homotransplanted patients also showed sustained bilateral improvement of their PD signs. Two years after surgery, the most improved signs of the fetal VM case were rigidity, bradykinesia, postural imbalance, gait disturbances and facial expression. The fetal A case has only shown amdioration of rigidity and bradykinesia. Neither of them has shown significant neuropsychological changes. Their current levodopa requirements are less than before surgery. The improvements shown here by PD patients after brain tissue grafts go beyond those obtained using any other therapeutic approach, when levodopa fails. Although more studies and the development of these procedures are obviously required, these initial human trials appear to be resisting the test of time. With the aim of providing a therapeutic alternative for these patients, wc turned to the use of dopaminc (DA)-rich brain grafts [adult adrenal medullary (AM), fetal ventral mcscnccphalon (VM) and fetal adrenal (A) tissues/ which, implanted in the striatum of animal models of the disease, improved their motor disturbances/2/. In 1987 wc reported/8/ on the short term beneficial effects of autologous DA-rich AM brain transplants to the caudatc nucleus (CN) of two patients suffering from PD.

INTRODUCTION PATIENTS AND METHODS
In 1988, wc presented the initial beneficial effects of fetal VM and fetal A implants to the first 2 homotransplantcd parkinsonians /17/. Because of the sustained amelioration of their PD signs, wc gradually extended our brain transplantation program, and have now autotransplanted a total of 67 patients (60 using our cavitation procedure/8,10,16/, 5 with a multiple site implantation technique/7/.and 2 with AMintercostal peripheral ncvc co-grafts), and a total of 7 parkinsonians have received human fetal tissue.
The therapeutic value of these ncurosurgical procedures in treating PD rests on the fact that they should produce long lasting beneficial effects. It has thus bccn our concern to monitor carefully our patients over time/9,11,13-16/, in order to establish the effectiveness of these surgical procedures. Hcrc wc present the followup of the 5 autotransplantcd parldnsonians who have reached 3 years after surgery, and the 2 year follow-up of the first 2 patients with fetal homotransplants.

Clinical data
The 5 autotransplanted patients included 3 males (JMC, farmer, with a grade school education; FPT, subway employee, with a grade school education; NAG, civil engineer), and 2 females (MSP, housewife, with a grade school education; MAO, assistant accountant), all of them unable to work. Their ages at surgery were 35, 47 and 33, and 51 and 59 years, respectively. The durations of their illness were 5, 8 and 10, and 5 and 5 years, respectively. Three of the patients were under chronic levodopa therapy.
FPT was receiving 1,000 mg/day, NAG 500 mg/day and MAO 1,750 mg/day. The other 2 could not tolerate levodopa. One of them (JMC) did not tolerate any medication, and the other (MSP) was being treated with an anticholinergic drug (biperiden) at a dose of 8 mg/day. Patients on levodopa therapy presented "on-off' phenomena, and dyskinesia during their "on" periods. MSP showed disease-related dystonia.
The patient who underwent fetal VM brain homotransplantation was a 50-year-old salesman, with a grade school education (MTM), who had had PD for 9 years, was receiving 1,000 mg/day of levodopa, and presented drug-induced dystonia and dyskinesia. The patient who received the fetal A graft was a 35-year-old housewife, with secretarial training (LBC), with a 5 year evolution of PD, and who was on 750 rag/day of levodopa.
Brain and adrenal gland computed tomography, brain magnetic resonance imagings (MRI), and brain scintigraphy /4/ were obtained at various times throughout the study. Fig. 1 shows the brain

Surgery
The brain transplantation method we designed to implant both freshly excised autologous AM fragments or human fetal tissue has been described in detail elsewhere/10,12,16/. Human fetal VM was dissected with a hands-free technique in order to ensure the intactness of the tissue/6/. Table 1 shows the UPRS scores of the 5 autotransplanted parkinsonians in their preoperative and postoperative conditions 1 and 3 years after surgery. One (JMC) had severe PD and 4 were moderate to severe cases. Three years after surgery, 4 of them have maintained the level of recovery seen at one year postsurgery, that is, have maintained a change on the UPRS of more than 30 points. Improvements were observed in the length and quality of the "on" periods, as well as in the reduced frequency of motor fluctuations. In fact, the 2 patients now on a reduced or suppressed levodopa therapy have stopped fluctuating. Patients' recovery has been bilateral and symmetric. The most improved signs have been rigidity, postural imbalance and gait disturbances.

AM autotransplants
Three of the AM transplanted patients improved progressively until they reached a steady state approximately 6 to 10 months posttransplant, which has remained stable now for 3 years. During this time, patients showed oscillations in the intensity of their PD signs, usually related to their depressive state, stress, and/or levodopa dosage adjustments. However, none of these patients has shown a sustained regression of symptoms, In one patient (MSP), the diseaserelated dystonia, which was manifest at her one year evaluation, notably disappeared 2 years after surgery. MAO, who showed a moderate response to surgery one year after brain grafting, has become worse over t/me, although in "on", she has not deteriorated to her preoperative state. AM patients' evaluations on the Hoehn and Yahr, Schwab and England, and on our performance scales were congruent with these results. Preoperatively all patients were occupationally impaired. After surgery, 3.of them (JMC, NAG, MSP) have been able to return to their original occupations, and one of them (FPT) is now a merchant. MAO has remained impaired.
The current postoperative levodopa therapy of the autotransplanted patients is indicated in Table 2. Of the 3 autotransplanted patients who were taking levodopa before surgery, the current postoperative dose of one of them (NAG) has been significantly reduced, and that of another '-LUME 2, NO. [3][4]1991  MSP showed frontal lobe-type deficits, with alterations in behavioral programming, leading to difficulties in the organization of motor sequences and alternating programs. Visuospatial and visuoperceptual tasks were also affected, showing loss of figure-ground perspective and fragmentation. Immediate memory was diminished, and there were marked difficulties in delayed memory. There was formal perseveration of reading and writing, although motor problems affected the quality of the written product. She could perform basic arithmetical operations, but had difficulty counting backwards from 100 in Higher scores reflect a greater number of errors than average and lower scores the opposite. M: months. 7's. MSP's postoperative evaluation, carried out 3 months after surgery, revealed an amelioration of frontal-lobe symptoms, and of visuospatial deficits, as well as the improved quality of her writing due to an important reduction in tremor. These improvements remained unchanged after 36 months. Of the 5 AM autotransplanted patients, 3 of them showed specific cognitive deficits in their preoperative neuropsyehologieal evaluations. The postoperative evaluations of 2 of these patients revealed an amelioration of :heir frontal-lobe type symptoms and visuospatial deficits that has been maintained for 36 months. In the ease of MAO, only minor neuropsyehologieal improvements were observed one year after surgery, and at her 36-month evaluation her neuropsyehologieal profile proved to be very similar to her preoperative state. FPT, who preoperatively showed a depressive symptomatology, has suffered recurrent depressive episodes after surgery that have been controlled pharmacologically.
Electrophysiologieal data, obtained from long latency auditory evoked potentials, have revealed a significant change in the amplitude of the P300 component and a shortening of the latency of the N100 component that have been sustained in 3 patients for 36 months postsurgery.

Fetal homotransplants
The postoperative UPRS courses in "on" and "off' of the 2 homotransplanted parkinsonians are shown in Fig. 4, together with the corresponding levodopa requirements. MTM with the VM homograft, 5 months after surgery, had significan amelioration of rigidity, bradykinesia, postural imbalance, gait disturbances and facial expression, but tremor was a remaining sign. At his 2 year evaluation, tremor has further decreased and, in general, his current clinical status is very good. Today, he leads a normal life, and has gone back to work. devoted to establish the best candidates for surgery and the best donor tissue, as well as the best implantation technique. We strongly believe that, with the current state of knowledge regarding brain transplantations, we cannot disregard the usefulness of any type of graft for the treatment of neurological 8. diseases. Though at this time fetal tissue seems to be the most useful graft, autotransplants, which do not require immunosuppression, as well as genetically modified cells, will in time 9. assume their place as implantation alternatives for each individual patient.