Neurosurgical intervention for Parkinson’s disease: an update

Scientific Update

Neurosurgical Intervention for Parkinson’s Disease: An Update Alexander Kolchinsky, Ph.D. Health Front Line, Ltd., Champaign, Illinois

Kolchinsky A. Neurosurgical intervention for Parkinson’s disease: an update. Surg Neurol 2001;56:277– 81.

For patients with advanced Parkinson’s disease who do not respond to levodopa anymore, neurosurgical intervention is the only option. Cell transplantation has not met expectations as yet. Deep brain stimulation is gaining ground and currently seems to be the most efficient, flexible, and safe procedure. © 2001 by Elsevier Science Inc. KEY WORDS

Parkinson’s disease, transplantation, DBS (deep brain stimulation), pallidotomy, thalamotomy, cell transplantation.

he occurrence of Parkinson’s disease (PD), a major neurodegenerative disorder, is ever growing because of the aging population. The prevalence of PD increases from 0.3% between 55 to 64 years to 4.3% after age 85. In the US alone, between half a million and a million and a half people are affected at any one time. Ironically, bad habits correlate with lower incidence of PD: heavy smoking and drinking lowers the chances of acquiring the disease by roughly 50%. The mechanism of this effect remains largely unknown. The cause of PD is selective loss of dopaminergic neurons in the substantia nigra. According to a simplified scheme, dopamine secreted by these neurons controls the activity of GABA-ergic neurons that run from the substantia nigra and contain large amounts of dopamine receptors [20]. These GABA-ergic neurons extend to the globus pallidus and corpus striatum and ensure the fine balance of excitatory and inhibitory activity in the major loops of GABA-ergic and glutaminergic neurons that control voluntary movements. The discovery of dopamine deficiency in PD led to radical advances in treatment as a result of the introduction of levodopa. Although levodopa dramatically improves the condition of patients, it

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Address reprint requests to: Dr. Alexander Kolchinsky, Health Front Line, Ltd., 1506 Country Lake Drive, Champaign, IL 61821. Received August 9, 2000; accepted March 20, 2001. © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

does not alleviate all symptoms equally well and cannot stop the progression of the disease, that is, further loss of neurons. Some reports have suggested that levodopa might be neurotoxic in vitro and in model animals; its neurotoxicity has not been compellingly demonstrated in humans. A number of prospective neuroprotective drugs have undergone clinical trials in the recent years. One of the most promising of them, selegiline, provided significant symptomatic improvements, but failed to either decrease mortality or delay the adverse effects of levodopa. According to the authors of one of the largest clinical trials of selegiline, “neuroprotective therapy remains an elusive goal for the experimental therapeutics of Parkinson’s disease” [19]. In any event, the positive effect of levodopa tapers off within 5 to 15 years, and the patient is left with few options for treatment. In particular, patients often experience severe levodopa-induced dyskinesias during “on-periods” and profound tremor, rigidity, and akinesia during the “offperiods.” Currently, more patients reach the stage of the disease when the effect of levodopa becomes too incoherent, and surgical intervention acquires growing popularity. There are three major surgical treatments for PD patients: restorative (cell transplantation); ablative (thalamotomy or pallidotomy); and electrophysiological (deep brain stimulation, DBS) [9]. It has to be stressed that the placebo effect of sham brain surgeries in PD patients is very significant; therefore, isolated examples of spectacular success are most often followed by disappointment when larger double-blinded series are used.

Cell Transplantation Although first attempts to replace lost neurons in PD patients by transplantation date back almost 20 years, this approach is still in an experimental, pre0090-3019/01/$–see front matter PII S0090-3019(01)00578-X

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liminary stage. The first problem to be resolved is the origin of the material to be transplanted. Four major sources of dopamine-producing cells are being considered. HUMAN FETAL NEURAL CELLS One type of transplant is dopamine-producing neurons or their precursors from human fetal tissue. Fetal transplants work best in animal models of PD in terms of cell survival and limited resolution of neurological deficits. However, the use of human fetuses as a source of “spare parts” remains an extremely controversial proposition, and an existing moratorium on such experiments is likely to prevent further research in this direction. Besides moral reservations, it is difficult to collect the tissue from several fetuses at the same stage of development that is necessary to perform just one operation. In 1993, the ban on the use of fetal tissue in the USA was partially lifted, and the NIH sponsored the first double-blind placebo-controlled trial of fetal graft transplantation for advanced PD in 40 patients who were still levodopa-responsive [4,6,10]. The results varied widely among patients. After 1 year, significant improvements in rigidity and bradykinesia were observed in younger patients. At the same time, no changes were seen in freezing gait. The authors suggested that dopa-responsive freezing gait is not directly related to decreased dopaminergic activity in the putamen. Autopsies of two treated patients showed large numbers of tyrosine hydroxylase-positive (dopamine-producing) cells along the needle tracks, with long cell processes extending into the surrounding putamen. Usually, improvements in younger patients lasted for 2 to 3 years only. After the treatment, all patients still needed levodopa, although in some patients the doses could be reduced. Interestingly, significant placebo effects were reported in patients who underwent sham surgeries. Currently, there is one NIH-sponsored trial of fetal transplantation in the USA (principal investigator—C.W. Olanow). It is closed to new patients, and its results have not been published. ES CELLS Another source of transplants is a culture of the so-called embryonic stem cells (ES cells). By manipulating the composition of their medium, ES cells can be indefinitely propagated in culture in undifferentiated form and then induced to differentiate; in particular, they may become dopamineproducing neurons. Although initially the ES cells must be obtained from developing human embryos,

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this is a one-time event, and the concept is more acceptable from the moral standpoint than the use of aborted fetuses. Publicly funded research on ES cells has been recently approved in Great Britain and in the USA [21]. It may take years before this research, together with ongoing privately funded studies, will result in clinical applications. ADULT CELLS One of the most puzzling questions in brain research is whether neuronal precursor cells persist in adult human brain. Some researchers claim to be able to isolate such precursors from animals, and a major newspaper called it the scientific discovery of the decade [2]. However, the results in the human brain are more ambiguous, and reliable material for PD transplants is unlikely to become available in the near future. In some early attempts to transplant cells for PD treatment, adrenal tissue was used because of its ability to secrete dopamine; the results were widely publicized, but eventually disappointing. XENOTRANSPLANTATION The most promising approach from the viewpoint of cell availability is xenotransplantation. The main concern here is potential transfer of unknown pathogens; this issue was discussed in an official document issued by FDA that established cautious guidelines [5]. The company Alexion Pharmaceuticals, together with neurosurgeons from Massachusetts and Florida, reported the first successful transplantation of porcine embryonic mesencephalic cells to PD patients [17]. Besides providing scrupulous control of viral infections, Alexion researchers designed three lines of defense against immune rejection of the transplanted cells. First, the source animals were genetically transformed so that their cells carried a human-like coat of sugar moieties. Second, dopamine-producing cells expressed a human complement inhibitor on the surface. Third, the patients were treated with a proprietary inhibitor C5, a potent anti-complement and anti-inflammatory monoclonal antibody. Preliminary neurological results of these trials are encouraging. Generally, critical reviewers note that there are inherent problems in the transplantation of dopaminergic cells that were not circumvented despite many years of intensive research. First, the survival of newly transplanted cells is very low, on the order of 10⫺1 to 10⫺2. Second, they remain within millimeters from the injection site and do not integrate well with the existing neural circuitry, thus limiting the efficiency of the procedure. Third, they tend to

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lose their ability to secrete dopamine, whether it occurred naturally or was conferred by genetic manipulations. Last, but not least, the transplantation procedure is technically very complicated, and its results vary among different institutions. For this reason, the proponents of transplantation deem that multicenter trials dilute positive outcomes achieved by the best surgical teams. There are attempts to improve the survival of transplanted cells by gene therapy by introducing genes for growth factors and other cytokines. Although this approach seems to be promising in animal models, it is not clear what cytokines are responsible for long-term survival of the transplanted cells; in addition, the expression of genes transferred into cells by gene therapy manipulations tends to go down in time. Two major obstacles hamper the implementation of cell transplantation as routine Parkinson’s disease treatment: technical difficulty and insufficient understanding of the biology of both brain damage and transplanted cells.

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authors concluded that for a subset of severely affected patients, pallidotomy remains the treatment of choice. Another experimental procedure was described at the meeting of American Neurological Association in October 1999 by Dr Alvarez from Cuba. He reported improvement in PD patients after subthalamic nucleus (STN) ablation. The advantages of this approach are that it is easier to perform than pallidotomy, it is cheaper than DBS because it does not require a stimulator, and it can be efficiently performed bilaterally. Meanwhile, noninvasive stereotactic radiosurgery is showing promise as an alternative to invasive ablation. At last year’s meeting of the Radiological Society of North America, researchers from Thomas Jefferson University Hospital (Philadelphia, PA) presented the results of a 12-patient study using radiosurgery to destroy selected portions of the GPi or the thalamus in PD patients. The short-term outcome was comparable to traditional surgical intervention. These studies are in the investigational stage and are actively promoted by the manufacturers of expensive radiosurgical equipment.

Ablative Treatments Before the introduction of levodopa, the treatment of severe PD by selective destruction of basal ganglia was the only option available. There is no comprehensive theory behind this approach; it was discovered by chance, and targeting of specific areas of brain is still mostly empirical [3]. Although ablative treatments, as well as DBS, are not curative, their success rate in improving PD symptoms is usually reported in the range of 40 to 90%, depending on specific treatment and observation period. Pallidotomy is most useful for the treatment of peak-dose dyskinesias and for dystonia that occurs at the end of a dose. It may also improve bradykinesia and, to a lesser extent, contralateral tremor. It is most effective in patients under age 70. Thalamotomy is effective primarily for the treatment of tremor; it may also alleviate rigidity and peak-dose dyskinesia. However, the risks of thalamotomy are increased by the proximity of sensitive brain structures and the potential for worsening of some PD symptoms, including gait and speech difficulties. For these reasons, thalamotomy is not as widely used as it once was. Phase II nonblinded clinical trials of pallidotomy in a limited number of patients showed modest improvements [1]. In another recent report, longterm results of pallidotomy in 20 patients were analyzed [8]. Some symptoms of the on-periods stayed improved for 5 years and longer, and the

Deep Brain Stimulation Initially, DBS for the treatment of PD was applied to the thalamus; later, surgeons began to apply DBS to the STN and globus pallidus (GPi) in advanced cases [12]. DBS of subcortical structures is being developed based on the progress of stereotactic precision and functional mapping of the brain. The stimulation system delivers high frequency impulses to suppress the firing activity of select ganglia; the neurostimulator is placed subcutaneously in the pectoral area. Similarly to ablative procedures, DBS of the thalamus is primarily used to treat disabling tremor, especially unilateral tremor: it works in about two thirds of patients. Successful thalamic stimulation allows patients to resume activities inhibited by tremor, such as handwriting and self-feeding. Successful procedures result in immediate relief of symptoms even during the testing of equipment in the OR. DBS of the GPi is useful in treatment of dyskinesias. DBS of the STN may have an effect on most motor features of PD, and preliminary clinical data are encouraging [13]. For unknown reasons, unilateral procedures are much more effective than bilateral treatments, both ablative and DBS. In fact, in the United States, only unilateral thalamic implants are approved by the Food and Drug Administration. However, unilateral

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DBS may be performed on a person who has already had pallidotomy or thalamotomy on the opposite side. According to a recent review, DBS is displacing ablative procedures for the treatment of severe movement disorders [15]. The only NIH-sponsored clinical trial of DBS is performed at Mount Sinai Hospital (New York). After encouraging preliminary results [14], 15 patients with severe dystonia will be treated in a phase II/III trial. In the past, clinical trials of DBS devices were sponsored by Medtronic Inc., the manufacturer of the stimulators. Another firm, Sofamor Danek Group (Memphis, TN) plans to market its stimulators together with a stereotactic technology platform “StealthStation”. The Sixth International Congress of Parkinson’s Disease and Movement Disorders (Barcelona, 2000) included a round table discussion of surgical approaches to the treatment of Parkinson’s disease [11], in which it was concluded that, while ablative treatments and DBS were considered highly efficient, clinically proven treatments, especially when tailored to the needs of individual patients, cell transplantation remained a highly experimental approach with limited clinical data to support its potential value.

Progress in Basic Research PD research has traditionally focused on environmental risk factors such as viral infection or neurotoxins. Correspondingly, animal models have been based on selective killing of dopaminergic neurons by chemicals administered systemically or locally [22], which fail to reproduce the human condition in all its complexity. The absence of adequate animal models of PD hindered preclinical development of new treatments. More recently, a positive family history was perceived to be a risk factor, and genes were eventually identified which, if mutated, result in early onset familial PD. Although such patients constitute a minor proportion of affected individuals, identification of the mutated genes has great value in the deciphering the mechanism of the disease. In particular, these findings will lead to the creation of new genetic animal models of PD. Analysis of one set of affected families led researchers to the discovery of the first gene of early PD. This gene encodes the protein alpha-synuclein, a major component of both Lewy bodies, the pathological hallmark of PD, and of senile plaques characteristic of Alzheimer’s disease [16]. Mutations in this gene result in abnormal accumulation of

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synuclein in brain tissue and neuronal death. Targeted mutations of synuclein in experimental animals result in a condition very similar to PD and constitute a more adequate model than the chemically lesioned animals used so far [14]. Amazingly, expression of mutant human alpha-synuclein in the fruit fly results in a condition similar to PD, including locomotor dysfunction, neuronal loss, and formation of Lewy bodies [7]. In a different set of families affected by early onset PD, another protein called parkin is mutated. The function of parkin was recently identified as a major element in the protein degradation machinery, which has been known previously as the major culprit in a wide variety of neurodegenerative diseases [18]. A defect in protein degradation may result in the slow-down of synuclein turnover and its subsequent accumulation in Lewy bodies, similar to mutations in the synuclein gene itself. REFERENCES 1. Baron MS, Vitek JL, Bakay RA, Green J, McDonald WM, Cole SA, DeLong MR. Treatment of advanced Parkinson’s disease by unilateral posterior GPi pallidotomy: 4-year results of a pilot study. Mov Disord 2000;15: 230 –7. 2. Blakeslee S. A decade of discovery yields a shock about the brain. New York Times, January 4, 2000. 3. Cosgrove GR, Eskandar E. Thalamotomy and pallidotomy. http://neurosurgery.mgh.harvard.edu/ pallidt.htm Accessed: January 22, 2001. 4. Dhawan V, Akamura T, Margouleff C, Freed CR, Breeze RE, Fahn S, Greene PE, Tsai WY, Kao R, Eidelberg D. Double-blind controlled trial of human embryonic dopamine tissue transplants in advanced Parkinson’s disease: fluorodopa PET imaging. Neurology 1999; 52(Suppl. 2):A405– 6. 5. Draft Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation; Notice. Federal Register 1996;61:49919 –32. 6. Fahn S, Greene PE, Tsai WY, Eidelberg D, Winfield H, Dillon S, Kao R, Winfield L, Breeze RE, Freed CR. Double-blind controlled trial of human embryonic dopamine tissue transplants in advanced Parkinson’s disease: Clinical outcomes. Neurology 1999;52(Suppl. 2):A405. 7. Feany MB, Bender WW. A Drosophila model of Parkinson’s disease. Nature 2000;404:394 – 8. 8. Fine J, Duff J, Chen R, Chir B, Hutchison W, Lozano AM, Lang AE. Long-term follow-up of unilateral pallidotomy in advanced Parkinson’s disease. N Engl J Med 2000;342:1708 –14. 9. Follett KA. The surgical treatment of Parkinson’s disease. Annu Rev Med 2000;51:135– 47. 10. Freed CR, Breeze RE, Greene PE, Tsai WY, Eidelberg D, Trojanowski JQ, Rosenst ein JM, Fahn S. Doubleblind controlled trial of human embryonic dopamine cell transplants in advanced Parkinson’s disease: study design, surgical strategy, patient demographics, and pathological outcome. Neurology 1999; 52(Suppl. 2):A272–3.

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11. Gatsos L. Surgical approaches to Parkinson’s disease. http://www.medscape.com/CPG/ClinReviews/2000/ v10.n05/c1005.02.gats/c1005.02.gats-01.html Accessed: January 23, 2001. 12. Gross RE, Lozano AM. Advances in neurostimulation for movement disorders. Neurol Res 2000;22:247–58. 13. Levesque MF, Taylor S, Rogers R, Le MT, Swope D. Subthalamic stimulation in Parkinson’s disease: preliminary results. Stereotact Funct Neurosurg 1999;72: 170 –3. 14. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000;287:1265–9. 15. Morrison CE, Borod JC, Brin MF, Raskin SA, Germano IM, Weisz DJ, Olanow CW. A program for neuropsychological investigation of deep brain stimulation (PNIDBS) in movement disorder patients: development, feasibility, and preliminary data. Neuropsychiatry Neuropsychol Behav Neurol 2000;13:204 –19. 16. Polymeropoulos MH. Autosomal dominant Parkinson’s disease and alpha-synuclein. Ann Neurol 1998; 44(3 Suppl. 1):S63– 4.

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17. Schumacher JM, Ellias SA, Palmer EP, Kott HS, Dinsmore J, Dempsey PK, Fischman AJ, Thomas C, Feldman RG, Kassissieh S, Raineri R, Manhart C, Penney D, Fink JS, Isacson O. Transplantation of embryonic porcine mesencephalic tissue in patients with Parkinson’s disease. Neurology 2000;54:1042–50. 18. Shimura H, Hattori N, Kubo Si, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T. Familial parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000; 25:302–5. 19. Shoulson I. DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group. Deprenyl and tocopherol antioxidative therapy of Parkinsonism. Ann Neurol 1998;44(3 Suppl. 1):S160 – 6. 20. Smith CUM. Elements of molecular neurobiology, 2nd ed. Chichester: John Wiley and Sons, 1996:457– 459. 21. Stephenson J. Green light for federally funded research on embryonic stem cells. JAMA 2000;284(14): 1773– 4. 22. Tolwani RJ, Jakowec MW, Petzinger GM, Green S, Waggie K. Experimental models of Parkinson’s disease: insights from many models. Lab Anim Sci 1999; 49:363–71.

lmost 30 percent of all doctors 39 or younger target 65 as time [to retire].

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—Brad Burg, “Young doctors face a steep climb” “Medical Economics,” August 20, 2001