Original Article
Bilateral Fetal Mesencephalic Grafting in Two Patients with Parkinsonism Induced by 1-Methyl-4-Phenyl-L,2,3,6-Tetrahydropyridine (MPTP)
N Engl J Med 1992; 327:1556-1563November 26, 1992
- Abstract
- Abstract
Background.
Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism.
Methods.
We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation.
Results.
Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications.
Conclusions.
Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease. (N Engl J Med 1992;327:1556–63.)
Article Activity
- Article
THE drug l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin that produces parkinsonism in humans1 and monkeys2 , 3 and induces a condition that closely resembles idiopathic Parkinson's disease.1 , 4 Transplantation of fetal dopamine-rich neuronal tissue can ameliorate symptoms in experimental parkinsonism in rodents5 6 7 8 9 and in monkeys with MPTP-induced lesions.10 11 12 13 14 15 16
This study was designed to analyze the therapeutic potential of the intracerebral implantation of fetal mesencephalic tissue in patients with MPTP-induced parkinsonism. Such patients represent a unique bridge between experimental work in monkeys with MPTP-induced parkinsonism and work in humans with the idiopathic disease. Although studies in patients with Parkinson's disease indicate that fetal dopaminergic neurons can survive transplantation and exert functional effects,17 18 19 20 patients with MPTP-induced parkinsonism may be better candidates for neural grafting for several reasons. First, the causative agent may still be present in the idiopathic disease, but not in patients with MPTP-induced parkinsonism.4 Second, the effects of neural grafting are less likely to be confounded by the progression of the disease. Third, MPTP induces a lesion largely limited to the nigrostriatal dopaminergic system, providing an opportunity to assess the effects of intrastriatal grafting in a pure hypodopaminergic state. Finally, experimental studies using the MPTP model suggest that grafting of fetal neurons may benefit severely incapacitated patients who no longer benefit from anti-parkinsonism medications. This report also describes an attempt at bilateral grafting of fetal mesencephalic tissue in humans to treat parkinsonism.
Methods
Patients were selected from a group of seven well-characterized patients with MPTP-induced parkinsonism.4 The terms used follow those applied by the Core Assessment Program for Intracerebral Transplantation, with "on" denoting periods in which medication has a beneficial effect, "off" periods in which parkinsonian symptoms return, and "practically defined off" periods in which the patient has been without anti-parkinsonism medication for 12 hours and has been awake for at least 1 hour.21
Patient 1
Severe parkinsonism requiring anti-parkinsonism medication developed in a 43-year-old man after intravenous self-injection of MPTP in 1982.1 , 4 Since then his condition has deteriorated, partly because of the increasing side effects of levodopa, including visual hallucinations and generalized severe dyskinesias. Repeated attempts to decrease the dose of levodopa led to intolerable bradykinesia and rigidity. Before the patient underwent a preoperative evaluation in 1988, his medication was adjusted to an optimal dose of 50 mg of levodopa and 5 mg of carbidopa five times daily.
Patient 2
Severe parkinsonism requiring anti-parkinsonism medication developed in a 30-year-old woman after self-injection of MPTP in 1982.1 , 4 Repeated attempts to decrease her dose of levodopa led to profound rigidity and bradykinesia. Her optimal regimen, before she began a preoperative evaluation in 1988, was 100 mg of levodopa and 25 mg of carbidopa five times daily.
Scales and Tests
The following clinical rating scales were used: the Unified Parkinson's Disease Rating Scale (UPDRS),22 version 3.0; the Hoehn—Yahr staging system22; Schwab—England Activities of Daily Living (ADL)22 scale; the Abnormal Involuntary Movement Scale (AIMS),23 items 1 through 7; and the rigidity scale17 for the wrist, elbow, and knee. For timed tests of motor performance, movements were classified according to the periods in which they were measured — practically defined off periods and the best, or optimal, on periods.17 , 21 Three such tests were used: the pronation—supination test, in which the number of full turns of the wrist that Patient 1 completed during a 30-second period was counted or the length of time it took Patient 2 to turn 20 times was measured; the walking test, in which the length of time and number of steps needed to walk 14 m, with a turn at 7 m, were recorded; and the movement-velocity test, in which the mean velocity (expressed in centimeters per second) the patient reached while moving a pen-shaped contact between two points 25 cm apart on a digital pad 30 consecutive times was measured.
For the single-dose levodopa test, levodopa was given during a practically defined off period after an overnight fast.17 , 21 Patient 1 received 50 mg of levodopa and 5 mg of carbidopa. Patient 2 was given a dose of 100 mg of levodopa and 25 mg of carbidopa during all tests, but 12, 15, and 22 months postoperatively she was also tested with a dose of 50 mg of levodopa and 12.5 mg of carbidopa. The AIMS and rigidity scoring and the three timed tests were undertaken every 20 minutes until the effects of the medication wore off.
Positron-Emission Tomography
Positron-emission tomography with [18F]fluorodopa was performed once preoperatively and on three occasions postoperatively.24 [18F]Fluorodopa (2.0 to 3.5 mCi) was given intravenously at the start of scanning, one hour after a 100-mg oral dose of carbidopa. The degree of radioactivity in the blood was corrected for the rate at which fluorodopa is metabolized to determine the true input function.25 A 12-cm2 region of interest was placed over the striatum on each slice, where it was visible with the aid of previously obtained magnetic resonance images. For each slice, the value for the region of interest was added and values measured from posterior parietal regions of interest were subtracted to determine the mean striatal radioactivity. The rate constant for the steady-state uptake of fluorodopa by the whole striatum was calculated by a graphic method.26
Times of Assessment
The patients were completely evaluated every 3 months, from 18 months preoperatively to 15 months postoperatively and at 22 and 24 months. Patient 1 was also assessed during a practically defined off period with timed tests, AIMS scoring, and rigidity scoring every second week from 3 months preoperatively to 15 months postoperatively and then monthly through 24 months. The movement-velocity test was administered in conjunction with positron-emission tomography scanning.
Informed Consent
The research protocol was approved by the appropriate institutional review boards at the University of Lund, Lund, Sweden; the California Institute of Medical Research, San Jose; and the University of British Columbia, Vancouver, Canada. Informed consent for the donation of fetal tissue was given by women seeking abortions.
Donor-Tissue Preparation
Fetal tissue (obtained six to eight weeks after conception; crown-to-rump length measured by ultrasound, 14 to 25 mm) was collected from routine suction abortions. The women were screened for antibodies against human immunodeficiency virus, hepatitis B virus, cytomegalovirus, and herpes simplex virus types 1 and 2. The ventral mesencephalon was dissected and dissociated in 100 μl of Hanks' balanced salt solution into a suspension.17 , 18 Tissue from three to four fetuses was used for each hemisphere. At the end of surgery, 72 to 80 percent of the cells were viable and approximately 10 to 15 percent of the cells were positive for tyrosine hydroxylase. Bacterial cultures from the remaining suspensions were negative.
Implantation Technique
Fresh donor tissue was implanted bilaterally into the caudate and putamen within four hours after abortion, the right side followed by the left side. The surgery was performed in two sessions separated by a two-week interval.17 18 19 Through a 1.0-mm (outer diameter) cannula, eight 2.5-μl aliquots were deposited over a distance of 10 to 14 mm along each cannula track. Three implants were placed in the putamen on either side in both patients, and one implant was placed in each caudate nucleus in Patient 1. Patient 2 did not receive an implant in the left caudate. Metronidazole and cefuroxime were given perioperatively for three days. Immunosuppressive treatment with azathioprine, cyclosporine, and prednisolone was administered.17 18 19 Since no further transplantations were planned and because of practical problems in monitoring the patients' immunosuppressive treatment, cyclosporine was gradually withdrawn after 12 months and azathioprine after 18 months. The dose of prednisolone was reduced to a maintenance level of 10 mg per day.
Results
Patient 1
General Functioning
The dose of anti-parkinsonism medication was held constant for Patient 1 throughout the study. He was treated for depression with amitriptyline between 18 and 24 months postoperatively. His symptoms during the 18-month preoperative phase were stable; the score on the motor section of the UPDRS ranged from 31 to 39. The patient needed extensive help with eating, dressing, and personal hygiene. He had at least six off periods per day; only 25 to 50 percent of the day was composed of on periods. He was rated as Hoehn—Yahr stage 4, and occasionally 5, during practically defined off periods.
Patient 1 had no serious postoperative complications. At the most recent follow-up, 24 months after surgery, the patient was much more independent. He could dress and feed himself, visit the bathroom without help, and make trips outside his home. His on periods made up to 50 to 75 percent of the day. He was rated as Hoehn—Yahr stage 3 during practically defined off periods. As shown in Table 1Table 1
Scores of Clinical Rating Scales and Timed Tests for Patient 1 during Practically Defined Off Periods and Best On Periods., beginning approximately six months after surgery there was a gradual decrease in the total UPDRS score of 50 to 70 percent (during practically defined off periods and his best on periods), mainly in the motor section of this scale, and a gradual increase in the Schwab—England ADL score.Functional Status during Practically Defined Off Periods
The patient's preoperative problems included pronounced hypokinesia and muscular rigidity, early fatiguing when walking, a shuffling gait with no arm swings, and a tendency to walk on the toes with propulsion. He had frequent falls and "freezing" episodes. There were prolonged periods of eyelid apraxia during which he could not open his eyelids without help. He drooled constantly and choked frequently. His speech was difficult to understand, and he was able to speak only in short sentences.
By 24 months after surgery, muscular rigidity had virtually disappeared (Fig. 1Figure 1
Median Rigidity-Scale Scores during Practically Defined Off Periods.). He could initiate movement at any time, and the freezing episodes almost completely disappeared. His gait was smooth, with strides taken on the whole sole of the foot. Spontaneous bilateral arm swing had returned, but he still lacked axial rotation during turning and hesitated and took small steps when going through narrow passages. There were no falls after the ninth postoperative month. The right arm was better than the left, but both arms could be used without preference. The patient could overcome levator inhibition by touching his eyelids, and the drooling was less bothersome.Functional Status during On Periods
Preoperatively, the patient had peak-dose visual hallucinations, generalized dyskinesias, frequent episodes of tongue protrusion, and dystonia of the back muscles. His speech was difficult to understand. His gait was smooth with associated arm swing, but there was early fatiguing, and he managed to walk well only for about 50 m, after which he began to use smaller, shuffling steps.
Twenty-four months after surgery, the peak-dose hallucinations had decreased and levodopa-induced dyskinesias had almost completely disappeared (Table 2Table 2
Integrated AIMS Score for the Two Patients during the Single-Dose Levodopa Test.*). The patient's speech was improved, and he could be understood over the telephone. He could walk several hundred meters without difficulty. On the basis of the single-dose levodopa test, the latent period preceding an on period and the mean duration of the on period were unchanged postoperatively. The transition from an off period to an on period was less pronounced from nine months onward.Timed Tests of Motor Performance
The patient's pronation—supination test markedly improved postoperatively, with an increase of approximately sevenfold in the number of turns on the left and of approximately threefold on the right during practically defined off periods; during his best on periods, there was an increase of about threefold on the left and of about fourfold on the right (Table 1). The walking-test scores improved by 60 percent during practically defined off periods and by 40 percent during his best on periods (Table 1 ). Movement velocity increased by a factor of 6.4 on the left side and 5.5 on the right side (Fig. 2Figure 2
Results of the Movement-Velocity Test during Practically Defined Off Periods, Showing the Mean Velocity of 30 Averaged Alternating Movements.).Positron-Emission Tomography
Preoperatively, the mean rate constant for the striatal uptake of fluorodopa was 0.220. This value is about one third the normal mean and is in the lower range of values for patients with idiopathic Parkinson's disease. The rate constant was unaltered 5 months postoperatively, but had increased 1.5-fold at 13 months and 1.6-fold at 24 months (Fig. 3Figure 3
Steady-State [18F]Fluorodopa Concentration during the Last 60 Minutes of Positron-Emission Tomography in Patient 1 (Panels A and C) and Patient 2 (Panels B and D). and 4Figure 4
Steady-State Rate Constant for the Uptake of [18F]Fluorodopa by the Striatum during Positron-Emission Tomography in Patient 1 (Circles) and Patient 2 (Squares).).Patient 2
General Functioning
The dose of medications given to Patient 2 was held constant during the 18-month preoperative period, and symptoms in this phase were stable; the score on the motor section of the UPDRS ranged from 25 to 38. The patient had on periods 50 to 75 percent of the day but had continuous dyskinesias that were almost completely incapacitating, requiring a dose of up to 20 to 30 mg of diazepam per day to make them tolerable. There were five to six off periods during the day. During practically defined off periods, the patient was rated as Hoehn—Yahr stage 4. There was little difference preoperatively in the Schwab—England ADL scores during on and off periods. The patient managed poorly during off periods, and during on periods she had difficulties with the activities of daily living because of dyskinesias and a lack of fine motor skill. She required extensive help with eating, dressing, and personal hygiene. Micturition was impossible during on periods, and during off periods she was unable to have a bowel movement.
After the first implantation procedure the patient had bronchitis, which responded to treatment with antibiotics. There were no other postoperative complications.
Her motor performance gradually improved postoperatively. Because of increasing and intolerable dyskinesias it was necessary to reduce the dose of levodopa three times. After 18 months it had been reduced by 70 percent, to a dose of 30 mg five times daily. Diazepam was withdrawn after nine months. Twenty-two months after surgery the patient was much more independent. Dyskinesias were dramatically reduced (Table 2); on periods lasted more than 50 percent of the day without dyskinesias. The patient could perform most chores without help, although she needed assistance with some activities, such as combing her hair and tying her shoelaces. She could eat and feed herself without any problems and could micturate and have a bowel movement at any time. She was rated as Hoehn—Yahr stage 2.5 to 3 during practically defined off periods. Beginning in the third postoperative month, the UPDRS score gradually decreased — eventually decreasing by 40 percent during her best on periods and by 50 percent during practically defined off periods — whereas the Schwab—England ADL score gradually increased (Table 3Table 3
Scores of Clinical Rating Scales and Timed Tests for Patient 2 during Practically Defined Off Periods and Best On Periods.).Functional Status during Practically Defined Off Periods
Preoperatively the patient had global bradykinesia, with early arrests during almost all activities. Rigidity was present in all limbs, but was slightly more pronounced in the arms. Episodes of freezing were rare, but finger movements were clumsy and difficult to initiate, and the patient was often unable to perform them. She was seldom able to get out of a chair unassisted. She had a shuffling gait, no arm swing, and difficulty turning. Her balance was poor, and she had frequent falls. Her speech was weak, with poor articulation and intonation. She was unable to eat during off periods because of an inability to chew.
Twenty-two months after surgery she could perform any movement, including those requiring fine motor skills. She could get out of a chair without help and walked with a long stride and spontaneous bilateral arm swings. Her balance improved, and she had not fallen for six months. There was axial rotation when she turned. Her speech improved, with better articulation and decreased slurring. Muscle rigidity had virtually disappeared by the ninth postoperative month (Fig. 1).
Functional Status during On Periods
Before grafting, the patient's voluntary movements were jerky, and there was easy fatiguing. Levodopa-induced dyskinesias appeared in all limbs both randomly and when she performed specific movements. She was unstable while seated because of the dyskinesias, and when she walked, overshooting of the legs resulted in an awkward, high-stepping gait. At the end of on periods there was a sudden decrease in muscle tone.
Twenty-two months after surgery, the patient's gait pattern was nearly normal and she could readily manage tasks requiring fine motor skills. There was no fatiguing, and her movements were smooth. Muscle tone remained normal throughout the day, and the only sign that the medication was wearing off was a tightening of facial muscles. The most striking postoperative change was the dramatic reduction in dyskinesias. When present, they were mainly confined to the legs. On the basis of the single-dose levodopa test, the latent period preceding an on period and the duration of the on period remained the same postoperatively, but the transition from an off period to an on period was more gradual and difficult to detect. The overall postoperative integrated AIMS score was reduced by 50 percent from the preoperative value (Table 2). This degree of dyskinesia after a 100-mg dose of levodopa was higher than the degree of dyskinesia actually experienced by the patient once her daily dose of medication had been reduced. When the test was performed 12 to 22 months postoperatively with 50 mg of levodopa, the integrated AIMS score was 75 to 80 percent lower than the preoperative mean (Table 2).
Timed Tests of Motor Performance
Approximately six months postoperatively, the patient began to perform the pronation—supination test more quickly, and at 22 months the time had decreased by about 35 percent during practically defined off periods and by 25 percent during her best on periods (Table 3). The results of the walking test also improved gradually by 50 to 60 percent during practically defined off periods; at 22 months during her best on periods, the walking speed approached values recorded in normal subjects (Table 3). The movement velocity of both arms increased by approximately six-fold to sevenfold during practically defined off periods (Fig. 2).
Discussion
These results provide evidence that grafts of human fetal dopaminergic neurons can improve the functional status of patients with MPTP-induced parkinsonism. Several postoperative changes have been beneficial with respect to our patients' ability to perform activities of daily living. Patient 1 has had a marked decrease in rigidity and akinesia and complete resolution of freezing episodes, and he can now initiate any desired movement. In Patient 2, the reduction of bradykinesia and rigidity and the virtual disappearance of dyskinesias have greatly improved daily function. The fluctuations in motor performance have been much less evident. Scores for timed tests of motor performance and for walking tests have greatly improved. The intensity and duration of dyskinesias on the single-dose levodopa test have decreased by over 90 percent in Patient 1, despite the fact that his medication regimen was not changed, and by at least 70 percent in Patient 2, raising the possibility that the grafts have increased the striatal buffering capacity of levodopa. Finally, positron-emission tomography showed a bilateral doubling of the striatal uptake of fluorodopa in both patients. This increase in uptake was maintained, and the patients' clinical condition continued to improve during the second postoperative year, despite the withdrawal of immunosuppressive treatment (cyclosporine and azathioprine).
There are several possible explanations for the postoperative improvement other than a graft effect, including spontaneous remission, change in medication, and leakage of levodopa across the blood–brain barrier. Spontaneous remission seems unlikely, since both patients had been severely affected without improvement for seven years. A decrease in the levodopa dosage might have helped the second patient, but before the operation whenever her dose was reduced enough to alleviate the dyskinesias, severe parkinsonian symptoms developed. Leakage of levodopa across the blood–brain barrier is an unlikely explanation, since the first postoperative tomographic scans (at six months) showed no increase in the uptake of fluorodopa. Furthermore, the course of the clinical improvement was delayed and protracted.
Although the clinical improvement was most probably graft-induced, the mechanism responsible is less certain. Trophic effects on spared host neurons, perhaps induced by the release of growth-stimulating substances or by the inflammatory responses provoked by the transplant or surgery, cannot be excluded. On the other hand, although increased striatal uptake of fluorodopa could theoretically be due to a pronounced graft-induced sprouting response of spared host dopaminergic fibers, the magnitude and time course of the functional recovery and the protracted changes in the striatal uptake of fluorodopa suggest progressive reinnervation of the host striatum by growing fetal neurons. This interpretation is supported by studies of fetal mesencephalic grafts in monkeys with MPTP-induced lesions, in which survival of grafted dopamine neurons and increased levels of dopamine and tyrosine hydroxylase—positive innervation in the host striatum were associated with a reversal of rigidity and akinesia and increased movement speed in severely impaired animals.10 11 12 13 14 15 16 Taylor et al.12 reported that the graft-induced effects developed gradually, with the principal improvement occurring three to eight months after transplantation.
The degree of improvement in our two patients appears to have been more extensive than in many if not all of the 55 patients with idiopathic Parkinson's disease who have undergone grafting of fetal mesencephalic tissue to date.17 18 19 , 27 28 29 30 31 The approach reported here is the most complete striatal engraftment attempted so far. These patients received bilateral transplants, and the amount of tissue used (obtained from seven to eight mesencephalic dissections) was larger than in other trials. It is also possible that humans with MPTP-induced parkinsonism may be more responsive to neural grafting, perhaps because their lesion is limited to the substantia nigra, whereas in the idiopathic disease there is involvement of multiple extranigral sites that are not affected by the transplant procedure.
Clinical improvement occurred slowly. The first effects appeared three to four months after transplantation and were still occurring more than six months postoperatively. Patient 1 was still improving during the second postoperative year. In contrast, in our previous patients with idiopathic Parkinson's disease, the effects plateaued four to five months after transplantation and remained stable thereafter.17 18 19 In these patients with idiopathic disease, sequential positron-emission tomography has shown increased fluorodopa uptake by the grafted putaminal site but a progressive decrease in uptake by nongrafted striatal regions — a difference that probably reflects ongoing degeneration of the patient's own substantia nigra.20 It seems possible that progression of the underlying disorder in idiopathic Parkinson's disease may counteract the functional improvement and increased fluorodopa levels induced by the transplanted cells.
The improvement in these patients was clearly incomplete. It may be that the volume of dopamine reinnervation in the caudate and putamen obtained with the use of three to four implantation sites on each side is still insufficient. A wider distribution of the same amount of tissue may also help increase the functional response. An increased survival rate of the grafted dopamine neurons (currently estimated at 5 to 10 percent) may also improve the functional effects. Further development of the implantation technique is therefore necessary before it can be offered as a therapeutic choice.
Supported by grants from the County of Malmohus, the Swedish Medical Research Council (14X-8666), the Segerfalk and Westerstrom Foundations, the California Parkinson's Foundation, the Parkinson's Disease Foundation, and the Dystonia Research Foundation of Canada.
We are indebted to Ingrid Ahlesten, Sandra Cooper, Helene Edvall, Julie Holt, Paula Lewis, Mary Lee, Lene Mangalanayagam, Sara Marshall, Bengt Mattsson, Deborah McTaggert, Deborah Savoini, Cornelia Scofield, Alberta St. Pierre, and David Rosner for providing expert technical skills and patient care and to Jerome Kutner, Ph.D., San Jose, California, Robert Taylor, M.D., Havre, Montana, Wayne R. Martin, M.D., Edmonton, Alberta, Donald B. Calne, M.D., Vancouver, British Columbia, Jan Andersson, M.D., Ph.D., Stockholm, Sweden, and Barbro Johansson, M.D., Ph.D., Lund, Sweden, for support and advice.
Source Information
From the Restorative Neurology Unit of the Department of Neurology (H.W., P.B., O.L.), the Department of Neurosurgery (S.R.), and the Department of Obstetrics and Gynecology (B.G.), University Hospital, Lund, Sweden; the Department of Clinical Immunology, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden (H.W.); the California Parkinson's Foundation, San Jose (J.T., J.W.L.); the Division of Neurology, University of British Columbia, Vancouver (B.S.); and the Department of Medical Cell Research, University of Lund, Lund, Sweden (P.B., A.B.). Address reprint requests to Dr. Widner at the Restorative Neurology Unit, Dept. of Neurology, University Hospital, S-221 85 Lund, Sweden.
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