Neurosurgery for Parkinson’s Disease

Theresa A. Zesiewicz, M.D.1 and Robert A. Hauser, M.D.1,2

ABSTRACT

Medical therapy for Parkinson’s disease (PD) often becomes inadequate over several years. Disability increases despite maximal medical management and many patients develop motor fluctuations and dyskinesia. In addition, medications provide good control of tremor in only 50% of cases. In appropriately selected cases, surgical therapies for PD provide benefit for medically refractory symptoms. Recent advances have provided a greater array of surgical options. Unilateral thalamotomy and thalamic stimulation are considered safe and effective procedures to treat contralateral tremor. Pallidotomy and pallidal stimulation primarily reduce contralateral dyskinesia, with lesser effects on bradykinesia and rigidity. Studies indicate that subthalamic nucleus (STN) stimulation improves “off ” period function, decreases “off ” time, and lessens dyskinesia. Fetal cell transplantation remains experimental, and studies are underway to evaluate the safety and efficacy of porcine fetal cell and human retinal pigment epithelial cell transplantation. This chapter reviews the history of surgical procedures for PD, describes current procedures, and offers a look into the future of neurosurgical options for PD.
KEYWORDS: Parkinson’s disease, surgery, thalamotomy, thalamic stimulation,

pallidotomy, pallidal stimulation, subthalamic nucleus stimulation, fetal cell transplantation, porcine cell transplantation, human retinal pigment epithelial cell transplantation

Objectives: On completion of this article, the reader will be familiar with the application of lesioning, electrical stimulation, and cell transplantation as strategies for the treatment of Parkinson’s disease. Accreditation: The Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit: The Indiana University School of Medicine designates this educational activity for a maximum of 1.0 hours in category one credit toward the AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Disclosure: Statements have been obtained regarding the authors’ relationships with financial supporters of this activity. There is no apparent conflict of interest related to the context of participation of the authors of this article. Dr. Hauser has served on Medtronic advisory board. Dr. Hauser noted that Globus pallidus (GPi) and subthalamic nucleus (STN) stimulators are not approved by the FDA at this time.

urgical therapies are often sought when available medication treatments are inadequate. In Parkinson’s disease (PD), although current medications usually provide good benefit for bradykinesia and rigidity for

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several years, tremor is well controlled in only 50% of patients1 and clinical disability progresses over time. Many patients develop motor fluctuations and dyskinesia after a few years of medical treatment. Advances in

Seminars in Neurology, Volume 21, Number 1, 2001. Reprint requests: Dr. Hauser, Parkinson’s Disease and Movement Disorders Center, University of South Florida, 4 Columbia Drive, Suite 410, Tampa, FL 33606. 1Parkinson’s Disease and Movement Disorders Center, Department of Neurology and 2Department of Pharmacology and Experimental Therapeutics, University of South Florida, Tampa, Florida. Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 02718235,p;2001,21,01,091,102,ftx,en;sin00122x.

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and cell transplantation. Eighty-one percent of patients reported reduction in tremor. but tremor reduction came only at the expense of motor weakness. STEREOTACTIC SURGERY Stereotactic procedures employ a grid-coordinate system to target brain locations. Unfortunately. reporting results of 38 pallidotomies performed on hypokinetic PD patients. the hardware can be removed. If stimulation fails to provide benefit. sists of anatomical destruction of a target by electrical energy. chronic electrical stimulation.5 first noted that ablation of pallidofugal fibers originating from the medial globus pallidus improved tremor and rigidity. NUMBER 1 2001 our knowledge of the anatomy and physiology of the extrapyramidal motor circuits coupled with the development of more sophisticated neuroimaging and surgical techniques have renewed interest in neurosurgical treatments for PD. and there may be brain shift from the time of imaging. The patient experienced a reduction in tremor and rigidity without residual hemiparesis. rigidity. Electrophysiologic techniques. and implantation. Pallidotomy became a popular surgical procedure in the 1950s. and one patient experienced transient postoperative hemiparesis.9 Thalamotomy eventually replaced pallidotomy as the treatment of choice because of more consistent benefit in tremor reduction and lower rates of tremor recurrence. A wire beneath the skin connects the electrode to a stimulator placed in the chest wall.9 Laitenen et al16. when the limitations of levodopa therapy became apparent.13 Neurosurgical techniques were rarely performed following the introduction of levodopa therapy in the late 1960s. However. They lesioned the ansa lenticularis of four PD patients and noted improvement in rigidity and tremor without weakness. the resultant reduction of symptoms was often accompanied by neurologic deficits. noting that 65% experienced improvement in tremor. There may be individual variation of functional anatomy within MRIdefined structures.6 In 1952. Advances in neuroimaging have permitted more precise target localization using magnetic resonance imaging (MRI) and computerized localization. Irving S.9–12 However. Spiegel et al14 placed a ring fixed to a plaster of Paris cap on the heads of patients and used pneumoencephalography to outline the lateral ventricles to define the location of brain targets.15 Svennilson et al also utilized stereotactic lesioning of the posteroventral rather than the anterodorsal thalamus with good results. stimulation. interest in surgical procedures for PD was rekindled in the 1970s. HISTORY Major limitations in medical therapy for both PD and postencephalitic parkinsonism3 sparked interest in surgical treatments in the 1930s and 1940s. Lesioning. thereby decreasing cortical motor output (Fig. bradykinesia. The era of basal ganglia surgery for PD began when Meyers4. Early neurosurgical procedures focused on pyramidal tract lesions for tremor resolution. Cooper inadvertently nicked and then ligated the anterior choroidal artery during a cerebral pedunculotomy for postencephalitic parkinsonism. Chronic stimulation involves placing an electrode into a target site. including microelectrode recording. the operative mortality rate was approximately 10%.3. evaluates current procedures. help further define target location during surgery. Chronic stimulation has the advantage of adjustability and reversibility. The striatal dopamine deficiency in PD causes underactivity of the direct pathway (which is inhibitory) and overactivity of the indirect pathway (which is excita- .7. Implantation of cells into a target site attempts to replace neurons that have died from the disease process. Side effects of stimulation can be resolved by adjustment or discontinuation of stimulation. It was found that lesioning the posteroventral rather than the anterodorsal pallidum resulted in more satisfactory tremor suppression. there is increased inhibitory output from the internal segment of the globus pallidus (GPi) to thalamocortical neurons. and offers a look into the future. 92% of patients exhibited significant improvement in hypokinesia and rigidity. However.92 SEMINARS IN NEUROLOGY/VOLUME 21. Cooper concluded that symptom improvement was due to infarction of the anterior and lateral portions of the thalamus. First introduced in the 1940s. 1). and bilateral thalamotomy often resulted in dysarthria and neuropsychiatric complications.2 Surgical procedures currently fall into three categories: lesioning. Six patients suffered permanent partial homonymous hemianopsia. side effects of thalamotomy included motor deficits and dystonia. even these systems have limitations. and gait abnormalities.8 However. The stimulator is adjusted by external means to optimize symptom control and minimize side effects. He proceeded to perform anterior choroidal artery occlusion on approximately 50 patients. At 28 months after surgery. TYPES OF SURGERY Surgical options to treat PD include lesioning. This is expressed clinically as bradykinesia. the regions perfused by the anterior choroidal artery. stereotactic techniques have significantly reduced postoperative morbidity and mortality in PD. This article reviews the history of neurosurgical procedures for PD.” con- Pathophysiology In PD.17 reintroduced stereotactic surgery in the 1980s. or “ablation.

chronic stimulation is the procedure of choice to minimize the likelihood of permanent sequelae. thereby normalizing basal ganglia function.28 Linhares and Tasker29 performed 40 microelectrode-guided thalamotomies in PD patients and reported upper limb tremor reduction in 75% of patients at a mean of 35. rigidity. and timed tests of motor function improved 38. and improved neuroimaging led to a resurgence of the procedure in the 1990s. This leads to increased inhibitory output from the GPi to the thalamus. Osenbach and Burchiel31 performed unilateral ventral intermediate (VIM) nucleus thalamotomies without microelectrode recording in 57 PD patients and reported complete tremor relief in 79%. The amplitude of the tremor contralateral to surgery was significantly less than that on the ipsilateral side.5%. and dyskinesia in 38 patients.9 years after thalamotomy. Contralateral tremor was also significantly improved. weakness occurred in up to 26% of patients. and tremor were noted.35 Pallidotomy is very effective in reducing contralateral dyskinesias and.27 Less than 1. gait. indicating persistence of benefit. contralateral offperiod symptoms. Less striking improvements were also reported during on-periods. HAUSER 93 Figure 1 Decreased dopamine production by the SNc leads to overinhibition of the thalamocortical pathway.8 years in 44 patients who underwent unilateral thalamotomy. Lozano et al. bradykinesia.27 and are now rarely performed. Originally popular in the prelevodopa era (1950s and 1960s). but it is now rare with modern techniques. tory) to the GPi. THALAMOTOMY Thalamotomy effectively reduces contralateral tremor in PD and.NEUROSURGERY FOR PARKINSON’S DISEASE/ZESIEWICZ. off-period Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores were improved by 65%. Cell transplantation aims to correct the striatal dopamine deficiency. This model suggests that lesioning of the subthalamic nucleus (STN) or GPi should diminish the excessive inhibitory output from the GPi and improve bradykinesia.8 to 92% of cases. to a lesser extent. pallidotomy was largely replaced by thalamotomy because this procedure more consistently improved tremor. Fox et al30 performed 36 ventrolateral thalamotomies using microelectrode recording and reported persistent tremor abolition in 86% and improvement in an additional 5%.5%. to a much lesser extent.2% in the contralateral limb and 24. tients a mean of 10.3% of patients experience seizures. If a second thalamic surgery is required.32 Moriyama et al33 noted significant reduction of contralateral tremor and rigidity at a mean of 8.2% in the ipsilateral limb.18–27 Studies have documented good tremor reduction in approximately 80% of patients. Laitenen et al37 performed posteroventral pallidotomies and reported significant improvement in tremor.3 Based on discussions with Leksell. respectively. while rigidity is significantly reduced in 41 to 92%.21. Successful thalamotomies produce long-term tremor suppression. found total “off ” motor scores improved by 30% while dyskinesias were practically eliminated. Diedrich et al32 evaluated 17 pa- PALLIDOTOMY Pallidotomy refers to lesioning of the globus pallidus interna (Gpi). Patients were able to take more levodopa in light of diminished dyskinesia. At 12 months. Resolution of contralateral dyskinesia and improvement in bradykinesia. speech. rigidity. Long-term experience with thalamotomy indicates that the procedure improves contralateral tremor in roughly 45. The pallidum is a target for lesioning or chronic stimulation (which has a functional effect similar to that of lesioning). A better understanding of the anatomy of the basal ganglia motor circuit. rigidity. Historically. advances in stereotactic techniques. Dogali et al38 reported results of stereotactic pallidotomy using microelectrode recording in 18 patients with severe motor fluctuations. Pallidotomy was resurrected by Laitenen in the 1980s. whereas the STN is mostly a target for stimulation because of concern that lesioning might cause uncontrolled dyskinesia similar to chorea seen following an STN infarction. and gait disturbances and paresthesias were reported in 7.39 using blinded evaluations 6 months after pallidotomy.34 Bilateral thalamotomies are associated with a high incidence of dysarthria and swallowing difficulties13.24–27.22.27 Transient paresthesias of the fingers or mouth occur commonly but usually resolve within 1 year of surgery.19. Persistent hand ataxia occurred in 12. Thalamotomy-associated mortality is less than 1% and usually due to hemorrhage at the lesion site. Baron et al40 evaluated 15 advanced .5% and 27.8 months.

43 Pallidotomy improves bradykinesia as measured by movement and reaction time. However. postoperative confusion. noted 36% improvement in patients 60 years or younger and only 16% in patients older than 60 years. Lang et al36 followed advanced PD patients for up to 2 years following posteroventral medial pallidotomy and found significant reductions in contralateral dyskinesias. Several studies have identified greater improvement in younger patients than older patients. Once implanted.39. In one open-label series. ADLs.50 However.46.40.49 At least one open-label study also suggests that pallidotomy significantly improves quality of life in patients with advanced PD.01 to . Jankovic et al44 evaluated the effect of unilateral. and off-period parkinsonism. THALAMIC STIMULATION The main effect of thalamic DBS is to reduce contralateral tremor. microelectrode-guided posteroventral pallidotomy on bradykinesia in 41 moderately advanced PD patients.0001) and by 12% on the ipsilateral side (P < . movement time (MT) improved by 24% on the contralateral side (P < . emotions.50 Martinez-Martin et al reported that four areas of the PDQ-3939 (mobility. Mean on UPDRS motor scores improved by 24%.42.001) and choice reaction time (CRT) improved by 12. rigidity. an electrode is implanted into the target and attached by wire to a programmable stimulator placed under the skin in the chest wall. Onperiod scores were only transiently improved. On the contralateral side. and somnolence.30.2% (P < .46–48 One open-label study of 29 PD patients 3 and 6 months after pallidotomy failed to note a change in postural instability as measured by UPDRS.46 for example. and the subthalamic nucleus (STN). A number of additional series have been reported with similar results. potential complications from pallidotomy include visual field deficits and hemiparesis. At 3 months.46. stimulation of the VIM nucleus of the thalamus suppresses tremor. facial droop.16. especially dysarthria and swallowing difficulties. bradykinesia. although 9 patients (56%) who were able to stand prior to surgery had an improvement in the average stability score or a decrease in the number of falls after surgery. Targets of DBS for PD include the VIM nucleus of the thalamus. BILATERAL PALLIDOTOMY There is little information available regarding bilateral pallidotomy.1 kg 1 year after surgery. Improvements were noted in ipsilateral symptoms within the first year after surgery but did not persist.40. dysarthria.001).9%).57 Another case series evaluating gait 1 month prior to and 1 month following bilateral pallidotomy identified a twofold increase in walking speed.005) and on motor scores (P < .44 Although at least three studies have noted improvement in postural instability following pallidotomy. NUMBER 1 2001 patients and found significant improvement in off-period motor UPDRS scores at 3 months (24.94 SEMINARS IN NEUROLOGY/VOLUME 21. Baron et al40 found that total UPDRS scores improved by 52% in patients aged 38–52 years.38. dysphagia. Total activities of daily living (ADLs) and motor off UPDRS scores improved by about 30% at 6 months following surgery.63 but it offers the additional advantage that stimulation is ad- . simple reaction time (SRT) improved 14.59 DEEP BRAIN STIMULATION Deep brain stimulation (DBS) was developed in the 1970s as a nonablative procedure.54 Improvement in off motor scores (P < . Similarly. the stimulator is adjusted externally using a programmer with an electromagnetic head to optimize clinical response and minimize side effects.58.56 One study found that bilateral pallidotomy significantly reduced dyskinesia. bilateral pallidotomy is associated with an increased risk of complications including cognitive and bulbar symptoms.0002) in the contralateral arm but significant improvement did not occur in the ipsilateral arm.60–62 During DBS surgery. whereas patients aged 58–69 had only a 14% improvement. Purdue pegboard (PP) scores improved by 35.36 On-period dyskinesia in this series improved by more than 80% contralateral to the lesion and remained improved at 2 years following surgery.51 Lang et al.001). Kishore et al46. and bodily pain) were significantly improved following pallidotomy (P < . Additional potential adverse effects from pallidotomy include hemorrhage. Uitti et al41 reported that older patients responded as well as younger patients. the internal segment of the globus pallidus (GPi). Like thalamotomy.5% (P < .52 found a correlation between age and improvement in off motor scores in patients who received pallidotomy. Because the optic tract and internal capsule lie in close proximity to the globus pallidus. and mean UPDRS off motor scores were reduced by 20%.005).53 Weight gain following unilateral pallidotomy in PD has also been reported.0 4. Uitti et al41 noted significant improvement in both on and off UPDRS motor scores in 20 PD patients after pallidotomy. The clinical effects of chronic high-frequency stimulation mimic a lesion.45 several other studies have reported that balance remains unchanged.55. postpallidotomy patients were found to have gained a mean of 4.05) predicted weight gain. with benefit sustained at 2 years. Patients may turn the stimulator on and off themselves using a handheld magnet.5% (P < .

potentially. Benabid et al64 noted that resting and postural tremors were more frequently improved by VIM stimulation than action tremors. rigidity. Stimulation significantly improved UPDRS motor scores. Improvements were noted in UPDRS ADL. In another early study. Ghika et al72 followed six advanced PD patients who received bilateral pallidal stimulation for a period of at least 24 months. substantia nigra pars reticulata (SNr). The most commonly reported side effect was paresthesias at high stimulation intensities. Most side effects of thalamic DBS are mild. PD patients demonstrated a significant reduction in contralateral tremor (P < . UPDRS motor scores were significantly reduced at 3-month follow-up. disequilibrium (9%). dyskinesias.8%) at 12-month follow-up. microthalamotomy effect (one patient). highfrequency VIM stimulation in 24 PD patients with tremor. subjective tremor scores (P < . Complications related to surgery included lead dislodgment during surgery (one patient). battery replacement every several years.8 to 23.0001). Benabid et al64 followed 80 PD patients who underwent chronic thalamic stimulation and found that upper extremity tremor was completely or almost completely controlled in 92% of patients at 3-month followup and that in many cases the procedure’s effects lasted up to 8 years. Long-term efficacy of the procedure is not well defined.1 14. and total off scores (>50%). SUBTHALAMIC NUCLEUS STIMULATION The STN contains glutaminergic. Patients underwent blinded evaluations 3 months after DBS. ischemic changes on electrocardiogram (one patient). and rigidity at 3.5% experienced dysarthria. mean off time (>50%). gait. and disability scores (P < . Koller et al66 performed a multicenter trial to determine the safety and efficacy of unilateral. randomly assigned to stimulation on or off. dystonia. HAUSER 95 justable. contralateral akinesia. and dyskinesia.NEUROSURGERY FOR PARKINSON’S DISEASE/ZESIEWICZ. compared with 40% of patients who underwent unilateral thalamotomy with stimulation on the opposite side. excitatory output projections to the external and internal segments of the globus pallidus.2%) at 3 months.3%) had complete tremor resolution. Three patients reported gait ignition failure at 1 year. PALLIDAL STIMULATION Chronic high-frequency stimulation of the GPi has been shown to improve off symptoms. and substantia nigra pars compacta (SNc). Headache occurred in six patients (11. from 54.and 12-month follow-up. and 12 months. and only 1 patient (4. 19 patients (35. and withdrawal of consent in the operating room (one patient). Bilaterally stimulated patients also did not experience the neuropsychological deficits seen commonly with bilateral thalamotomy. VIM stimulation resulted in a significant decrease in contralateral tremor with stimulation on at all visits. Advantages of thalamic DBS over thalamotomy include reversibility of the procedure (the electrode can be explanted) and adjustability of stimulation parameters (to maximize symptom control and minimize side effects related to stimulation). side effects included paresthesias (9%).2%) experienced no benefit. subdural hemorrhage during burr hole placement (one patient).69 Disadvantages of chronic stimulation include expense. upper and lower extremity tremor was significantly reduced (P < . motor.64 Of bilaterally stimulated patients. Adverse events were mild and responded to parameter adjustment.4%) experienced disequilibrium 3 months after surgery.3%).and 12-month follow-up. intracranial hemorrhage (one patient). Blond et al65 followed 10 PD patients who underwent VIM stimulation and noted tremor suppression or reduction in all cases.8%) at 6 months. and. Six patients were not implanted. Ondo et al68 evaluated 19 PD patients who received unilateral thalamic DBS. Additional open-label evaluations were conducted at 6. Volkman et al71 performed an open-label prospective study in nine advanced PD patients who underwent bilateral stimulation of the internal pallidum. and generalized motor seizure postoperatively (one patient). There was no decline in clinical effectiveness at 12-month follow-up (n = 4). and 11 patients (20.01).0001). posture.2%) when stimulation was turned on. bradykinesia. and lesions in this region improve parkinsonian signs in . 27.6%). there was a trend toward loss of clinical efficacy at 1 year despite stimulation parameter adjustments.7 (44. and resolve with cessation of stimulation. 9. Fourteen of the 24 patients (58. However. potential hardware malfunction. Improvements were noted in tremor. Seventy-three PD patients who received thalamic stimulation were followed in a multicenter European study. Four of the six patients had no perceptible motor fluctuations and two other patients experienced only very mild motor fluctuations. a higher infection rate. and dyskinesia (65%).9 11. and this was their most troublesome deficit. and five patients (9. and motor fluctuations in a limited number of studies. In one large case series. dysarthria (19.001). Siegfried and Lippitz70 first reported improvement in three PD patients who underwent bilateral pallidal stimulation.73. Thalamotomy and thalamic stimulation appear to provide comparable efficacy to reduce contralateral tremor. Common side effects included transient paresthesias in 42 patients (79. and confusion.67 At 3.74 Dopamine deficiency in PD causes overactivity of the STN. Reasons for not implanting included lack of tremor suppression at surgery (two patients). Lower extremity tremor was also effectively reduced. and dystonia (5%). Side effects included dysarthria.

0002). In one study of 62 consecutive PD patients who received either pallidal or STN stimulation.3 0.05).9 to 1. and UPDRS ADLs improved by 52. Moro et al80 followed seven advanced PD patients who received bilateral STN stimulation for an average of 16. while unilateral stimulation improved symptoms by 23%. and bradykinesia. Both procedures produced good improvement in rigidity and tremor. The daily dose of antiparkinsonian medication was reduced by 61% (P < . there was greater improvement in the STN group (P < . Limousin et al77 evaluated 24 PD patients who received bilateral STN stimulation for 12 months and found that off-medication UPDRS ADLs and motor scores improved 60% (P < . GPi and STN groups demonstrated a similar response when off levodopa.75 It has also been hypothesized that STN projection burst firing in the SNc may lead to excitotoxic damage.001) and dyskinesias improved by 77% (P < . gait score (P < . ballismus. Levodopa-equivalent daily dose was decreased by 65%. and stimulation-induced dyskinesias that resolved with adjustment of stimulation parameters. P < . The severity of off-period dystonia was also reduced by 90% at 6-month follow-up. including chorea. Bilateral STN stimulation also resulted in greater improvement in postural stability. PALLIDAL VERSUS SUBTHALAMIC NUCLEUS STIMULATION Krack et al83 followed 13 advanced PD patients with disease onset prior to age 40 for 6 months.9. with approximately a 40% improvement in UPDRS motor scores at 12 months. randomized.01 for UPDRS motor scores. and dystonia. while levodopa dosage was decreased by 50%. Bilateral STN stimulation improved parkinsonian symptoms by 54%.4. Eight patients received STN stimulation. blinded trials are required. UPDRS motor scores were more improved by GPi stimulation than STN stimulation.001).05). tremor. STN stimulation has been shown to improve symptoms of PD dramatically. Off-medication UPDRS motor scores improved by 41. particularly off-period akinesia and rigidity. and other axial motor features than unilateral stimulation.05). P < . Krack et al81 followed eight advanced PD patients who received STN stimulation and suffered from severe off-period dystonia. neither procedure affected cognitive performance at 3 to 6 month followup.3 0.001).6 months and reported significant improvements in rigidity. and hand-tapping score (P < . mean UPDRS off-levodopa motor score was improved by 27% in the Gpi stimulation group (3 months follow-up) and 41% in the STN (1 to 6 months follow-up). HUMAN FETAL CELL TRANSPLANTATION Transplantation of fetal tissue cells into the nigrostriatal pathway of PD patients is aimed at replacing lost dopaminergic neurons. P < .01) in the STN group. Duration of on-period dyskinesias decreased by 52% (from 2. P = . Although UPDRS motor scores and ADLs were improved by both procedures.76 and therefore strategies that reduce STN overactivity might provide neuroprotection. Transient side effects included postoperative confusion. seizures. Transient side effects related to stimulation were common. No significant adverse events occurred in this cohort. and five received bilateral pallidal stimulation.05).001) in the off state and 55% (11 2 to 5 1. P < . and total “on” dyskinesias (60%) at 3-month follow-up. Kumar et al82 compared the clinical effects of unilateral and bilateral STN stimulation in 10 advanced PD patients and reported that bilateral STN stimulation resulted in a greater reduction of parkin- sonism. Houeto et al79 prospectively followed 23 advanced PD patients who received bilateral STN stimulation for 6 months. gait.3 to 1.86 The number of patients followed in these series is too small to draw any definitive conclusion about the relative merits of the two procedures. although there was greater improvement in akinesia score (P < .8 1. total ADL scores (26%). Hoehn and Yahr motor disability score in the off state decreased by 58% (P <. lower limb thrombophlebitis. and motor fluctuation severity decreased by 78% (P <. Krack et al78 followed 15 PD patients with tremor who received STN stimulation and reported a reduction of 80% in UPDRS tremor score and a 65% reduction in rigidity 1 to 12 months following surgery.1 0. Burchiel et al85 performed a randomized. patient-reported pain in off-periods decreased by 66% (from 3.9% at the last visit (P = .05 for UPDRS ADLs). Larger.96 SEMINARS IN NEUROLOGY/VOLUME 21.3 7. When compared with STN stimulation (five bilateral and one unilateral). NUMBER 1 2001 humans. Six months postoperatively. UPDRS ADLs improved by 66% (30 3 to 10 2.001). Three patients experienced a confusional state after surgery that resolved within 1 day. PD is an attractive choice for . When patients were taking levodopa. blinded comparison of pallidal and STN stimulation in 10 advanced PD patients with follow-up of 12 months after implantation.2% (P = . and improved with refinement of stimulation settings. Kumar et al84 followed eight patients who underwent Gpi DBS (four unilateral and four bilateral) and reported mean improvements in total motor “off ” scores (27%).001). Common side effects included ballistic or choreic movements. Medication requirements were more reduced in the STN group.01) in the on state.0002).

Similarly. Whereas Madrazo et al87 reported a “dramatic” improvement in parkinsonism in two patients who received adrenal transplantation. There were significant improvements in off time and off UPDRS motor scores. However.01). Fahn118 reported the emergence of continuous dyskinesias in some patients years after transplantation even while off medication for prolonged periods. PET demonstrated a 68% increase in fluorodopa uptake in the grafted putamen 8 to 12 months after implantation. At 12 months.NEUROSURGERY FOR PARKINSON’S DISEASE/ZESIEWICZ. Schumacher et al121 studied the safety and efficacy of transplanting embryonic porcine ventral mesencephalic tissue into the striatum of 12 advanced PD patients. Tissue was tested for porcine endogenous retrovirus (PoERV). Fluorodopa PET demonstrated a significant increase in mean putamenal uptake at 6 and 12 months compared with baseline. and total UPDRS scores in the off state at the final visit compared with baseline. Long-term graft survival is possible. Grafts of porcine mesencephalic tissue have been shown to improve parkinsonism in animal models. Experience indicates that transplanted fetal mesencephalic neurons survive.109 and grafts have been found to survive up to 6 years after transplantation. fetal grafts restored dopamine release in a PD patient 10 years after implantation into the right putamen. A randomized. Adrenal cell transplantation provided limited clinical benefit in animal studies.88–92 Autopsy results of several patients indicated that few or none of the adrenal cells survived. However. There was a 32% improvement in mean total UPDRS off score. Older patients failed to demonstrate improvements in motor ability. Both patients experienced modest improvement in motor function during off time.99. using bilateral solid grafts with tissue from three or four donors per side.112 Freeman et al113 performed an open-label study of fetal transplantation in four PD patients.109. PET revealed an increase in dopamine activity in more than 66% of the treated patients 1 year following implantation that correlated with improved motor function. and improve parkinsonism. UPDRS total scores during the off state improved approximately 19% (P = .103–108 depending on the amount of tissue grafted and implantation into the appropriate location. Significant improvements were reported in off UPDRS and disability scores. and mean percentage on time without dyskinesia improved from 22 to 66%. the brain of one patient who died 18 months after surgery of an unrelated cause114 revealed large viable grafts bilaterally that were well integrated into the striatum.97.100. there were modest motor improvements in off UPDRS scores in patients younger than 60 years of age. subsequent studies revealed a modest benefit in off-period function that was essentially lost within 2 years. After 1 year. placebo-controlled trial to study the ef- . there was no appreciable change in UPDRS motor scores and there was no significant change in 18F-labeled levodopa uptake on PET. and roughly 12 million cells were transplanted unilaterally. and contralateral bradykinesia and rigidity. Wenning et al117 followed six PD patients for 10 to 72 months after fetal graft implantation from four to seven donors. PORCINE CELL TRANSPLANTATION Ethical concerns regarding use of human fetal tissue for transplantation and limited availability of donor material119 have led to interest in other sources of dopaminergic cells for transplantation. form synaptic connections.101 Lindvall et al102 later reported results of fetal grafting in two PD patients using a mesencephalic cell suspension from single donors. specifically in rigidity and bradykinesia.110 In one report. At autopsy. motor.115 Hauser et al116 reported results of transplantation in six PD patients (including the four just mentioned) 2 years following bilateral fetal cell transplantation and found significant improvements in ADL.120 In an open-label pilot study. unexpected.98 In the late 1970s.93–97 and the procedure was subsequently abandoned. Early attempts at cell transplantation utilized autologous adrenal medullary cells. This finding has reemphasized the experimental nature of these procedures and indicates that further observation and analysis of patients who have undergone transplantation are warranted. amount of off time. Positron emission tomography (PET) studies have generally demonstrated increased striatal fluorodopa uptake after transplantation. disabling off period dyskinesias emerged in four patients who were not taking medicine. No serious adverse events were noted. The benefit of adrenal transplantation in animals may be explained by trophic or lesion effects. Two additional patients who received grafts from four donors experienced progressive improvements in motor function during off time. HAUSER 97 this procedure because the neuronal degeneration is relatively site and type specific. Forty PD patients were randomly assigned to receive either fetal tissue transplantation or sham surgery. blinded. and off time and on time with dyskinesia were significantly reduced. Bjorklund99 and Perlow100 and their colleagues demonstrated that embryonic dopamine cells transplanted into the denervated striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats decreased drug-induced rotation. Six patients received cyclosporine immunosuppression and six received tissue treated with monoclonal antibody directed against major histocompatibility complex class I. Processes from these grafts were noted to have grown out to reinnervate the striatum.111 Long-term immunosuppression has not been found to be necessary for survival of grafts.

New York: Grune & Stratton. Koller WC.and 6-month follow-up. and provide benefit in some patients. Springfield. Additional cell types are being designed using genetic engineering.6-tetrahydropyridine (MPTP). The surgeries that we use change over time on the basis of new technology. these procedure can provide important benefit for patients with PD. RPE cells secrete dopamine and can be grown in culture to yield a large number of cells.89:865–873 4. Minor K. Torvik A. Lowe R. Riechert T. Irving S. in some patients even while off medication for prolonged periods. increase fluorodopa uptake in the striatum. IL: Charles C Thomas. Arch Neurol Psychiatry 1940. New cell types. Cortical extirpation in the treatment of involuntary movements.” It has been demonstrated that fetal cells survive in the long term following transplantation. this would provide a ready source of cells and avoid the ethical concerns related to human fetal tissue. surgery is reserved for aspects of the disease that are not adequately controlled by medication treatment. and festination by surgery of the basal ganglia. N Engl J Med 1998. Surgical treatment of parkinsonism.35: 717–723 2. Fetal cell transplantation studies to date have provided “proof of concept. Meyers HR. understand its physiologic basis. Chemopallidectomy and chemothalamectomy for parkinsonism. 13:127–144 9. When done correctly. 1961 12. Bravo GJ. If a patient requires bilateral procedures to reduce tremor. REFERENCES 1. Clinical and Physiological Applications. Lozano AM. Both pallidal stimulation and STN stimulation dramatically improve off-period function.339:1130–1143 3. Bilateral thalamotomies are usually avoided. 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