Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal

OBJECT: Glial cell line-derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months has been previously shown to improve significantly motor functions and quality of life measures in 10 patients with Parkinson disease (PD) in a Phase I trial. In the present study the authors report the safety and efficacy of continuous treatment for a minimum of 1 year. After the trial was halted by the drug sponsor, the patients were monitored for an additional 1 year during which the effects of drug withdrawal were evaluated. METHODS: During the extended study period, patients received a 30-microg/day unilateral intraputamenal infusion of GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 microl/hour. The Unified Parkinson's Disease Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38% in the off- and on-medication states; the motor UPDRS scores were also improved 45 and 39%, respectively. Benefits from treatment were lost by 9 to 12 months after the cessation of GDNF infusion. The UPDRS scores returned to their baseline and the patients required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of risk of infection. Seven patients developed antibodies to GDNF but without evident clinical sequelae. There was no evidence for GDNF-induced cerebellar toxicity, as evaluated by magnetic resonance imaging and clinical testing. CONCLUSIONS: The unilateral administration of GDNF results in significant, sustained bilateral benefits in patients with PD. These improvements are lost within 9 months of drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.     

Histological effects of intraputaminal infusion of glial cell line-derived neurotrophic factor in Parkinson disease model macaque monkeys

Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotection and regeneration molecule for dopamine neurons in the substantia nigra. A recent clinical study showed that intraputaminal infusions of GDNF restored the striatal dopaminergic function, resulting in improvement in patients with Parkinson disease. To investigate the efficacy and the safety of this treatment, the histological changes associated with intraputaminal GDNF infusions were investigated in non-human primate models of Parkinson disease. Two types of Parkinson disease model were constructed: unilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) into the internal carotid artery to induce hemiparkinsonism and intermittent systemic injection to induce Parkinson disease. GDNF (50 microg) was infused into the putamen on the day of the first MPTP treatment and 4 weeks later. The monkey brains were examined by immunohistochemistry 2-4 weeks after the second GDNF infusion. Losses of the nigral dopamine neurons were mild (30-50% loss) on the side of GDNF infusion, and moderate (approximately 70% loss) on the side of vehicle infusion in the Parkinson disease model. The dopamine fibers were thick and dense in the striatum around the GDNF infusion sites. Both GDNF- and vehicle-treated monkeys of the hemiparkinsonian model showed severe decrease of dopamine neurons to 10% of the intact side. Although reactive astrocytes proliferated around the GDNF infusion sites, the densities of striatal neurons involving GABAergic and cholinergic neurons were not affected. Intraputaminal infusions of GDNF have beneficial effects in parkinsonian monkeys, but dose control is required according to the severity of the disease. The specificity for dopamine neurons is quite high and there are no serious histological changes.     

Subthalamotomy for advanced Parkinson disease

OBJECT: The aim of this study was to determine if subthalamotomy is effective in treating advanced Parkinson disease (PD). METHODS: The authors performed microelectrode mapping-guided stereotactic surgery on the subthalamic nucleus in eight patients with PD. Lesioning was performed using radiofrequency heat coagulation and confirmed with magnetic resonance imaging. Three patients who underwent unilateral and four with bilateral subthalamotomy were evaluated for up to 18 months according to the Unified PD Rating Scale (UPDRS). One patient who underwent unilateral subthalamotomy died 6 months postsurgery. At 3 months into the "off" period after surgery, there were significant improvements in contralateral bradykinesia (p < 0.0002), rigidity (p < 0.0001), tremor (p < 0.01), axial motor features (p < 0.02), gait (p < 0.03), postural stability (p < 0.03), total UPDRS scores (p < 0.03), and Schwab and England scores (p < 0.04). The benefits were sustained at 6, 12, and 18 months, except for the improvement in tremor. At 12 months into the "on" period, significant benefits were present for motor fluctuation (p < 0.04), on dyskinesia (p < 0.006), off duration (p < 0.05), total UPDRS score (p < 0.02), and contralateral tremor (p < 0.05). Benefits for motor fluctuation, off duration, and off-period tremor were lost after the 18-month follow-up period. The levodopa requirement was reduced by 66% for the unilateral and 38% for the bilaterally treated group. Bilateral subthalamotomy offered more benefits than did unilateral surgery for various parkinsonian features in both the on and off periods. Three patients suffered hemiballismus, two recovered spontaneously, and one died of aspiration pneumonia after discontinuation of levodopa. CONCLUSIONS: These findings indicate that subthalamotomy can ameliorate the cardinal symptoms of PD, reduce the dosage of levodopa, diminish complications of the drug therapy, and improve the quality of life.     

Long-term efficacy of globus pallidus stimulation for the treatment of Parkinson's disease

OBJECTIVE: To determine the long-term efficacy and safety of globus pallidus internus (GPi) stimulation for Parkinson's disease (PD). BACKGROUND: We previously reported 3-month data for 5 patients who underwent GPi stimulation for PD. We now report long-term data on these 5 patients and 4 additional patients. METHODS: Nine PD patients, 5 men and 4 women, with an average age of 49 years and disease duration of 10 years, underwent GPi stimulation. Six patients had staged bilateral implants and 3 patients had unilateral implants. The mean follow-up was 48.5 months. All patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) and completed 2-day diaries before and after surgery. RESULTS: There was a 21% improvement in UPDRS Part II (activities of daily living; ADL) scores and a 37% improvement in UPDRS Part III (motor) scores when the longest follow-up in the 'stimulation-on/medication-off' state was compared to the 'medication-off' state at baseline. The UPDRS Part II (ADL) scores improved by 30% and the UPDRS Part III (motor) scores improved by 39% when the longest follow-up in the 'stimulation-on/mediation-on' state was compared to the 'medication-on' state at baseline. As measured by patient diaries, 'on' time increased from 25 to 59% and 'on with dyskinesia' decreased from 42 to 15%. Surgical- and device-related complications included transient hemiparesis in the operating room, postoperative seizures, and implantable pulse generator and lead problems. There were seven device-related events requiring additional surgical procedures. CONCLUSIONS: GPi stimulation continues to be effective for the long-term treatment of the disabling symptoms of PD; however, the physician and patient should be aware that device-related problems are not uncommon and additional surgery may be necessary.     

Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease

OBJECT: The use of deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been associated with a marked initial improvement in individuals with advanced Parkinson disease (PD). Few data are available on the long-term outcomes of this procedure, however, or whether the initial benefits are sustained over time. The authors present the long-term results of a cohort of 25 individuals who underwent bilateral DBS of the STN between 1996 and 2001 and were followed up for 1 year or longer after implantation of the stimulator. METHODS: Patients were evaluated at baseline and repeatedly after surgery by using the Unified Parkinson's Disease Rating Scale (UPDRS); the scale was applied to patients during periods in which antiparkinsonian medications were effective and periods when their effects had worn off. Postoperative UPDRS total scores and subscores, dyskinesia scores, and drug dosages were compared with baseline values, and changes in the patients' postoperative scores were evaluated to assess the possibility that the effect of DBS diminished over time. In this cohort the median duration of follow-up review was 24 months (range 12-52 months). The combined (ADL and motor) total UPDRS score during the medication-off period improved after 1 year, decreasing by 42% relative to baseline (95% confidence interval [CI 35-50%], p < 0.001) and the motor score decreased by 48% (95% CI 42-55%, p < 0.001). These gains did diminish over time, although a sustained clinical benefit remained at the time of the last evaluation (41% improvement over baseline, 95% CI 31-50%; p < 0.001). Axial subscores at the time of the last evaluation showed only a trend toward improvement (p = 0.08), in contrast to scores for total tremor (p < 0.001), rigidity (p < 0.001), and bradykinesia (p = 0.003), for which highly significant differences from baseline were still present at the time of the last evaluation. Medication requirements diminished substantially, with total medication doses reduced by 38% (95% CI 27-48%, p < 0.001) at 1 year and 36% (95% CI 25-48%, p < 0.001) at the time of the last evaluation; this decrease may have accounted, at least in part, for the significant decrease of 46.4% (95% CI 20.2-72.5%, p = 0.007) in dyskinesia scores obtained by patients during the medication-on period. No preoperative demographic variable, such as the patient's age at the time of disease onset, age at surgery, sex, duration of disease before surgery, preoperative drug dosage, or preoperative severity of dyskinesia, was predictive of long-term outcome. The only predictor of a better outcome was the patient's preoperative response to levodopa. CONCLUSIONS: In this group of patients with advanced PD who underwent bilateral DBS of the STN, sustained improvement in motor function was present a mean of 2 years after the procedure, and sustained reductions in drug requirements were also achieved. Improvements in tremor, rigidity, and bradykinesia were more marked and better sustained over time than improvements in axial symptoms. A good preoperative response to levodopa predicted a good response to surgery.     

Long-term motor effect of unilateral pallidal stimulation in 26 patients with advanced Parkinson disease

OBJECT: The aim of this study was to evaluate the long-term effects of unilateral pallidal stimulation on motor function in selected patients with advanced Parkinson disease (PD). METHODS: The authors enrolled 26 patients with idiopathic PD in whom there was an asymmetric distribution of symptoms and, despite optimal pharmocological treatment, severe response fluctuations and/or dyskinesias. After the patient had received a local anesthetic agent, a quadripolar electrode (Medtronic model 3387) was implanted at the side opposite the side affected or, if both sides were affected, the side contralateral to the more affected side. No serious complications occurred. After 3 months, the total Unified PD Rating Scale (UPDRS) Part III score decreased by 50.7% while patients were in the off-medication state (from 26.5 +/- 9.2 to 13.1 +/- 6.1) and by 55.4% while they were in the on-medication state (from 10.6 +/- 6.3 to 4.7 +/- 4.4). Only during the on state was the contralateral effect clearly more pronounced. The UPDRS Part IVa score decreased by 75% (from 3.7 +/- 2.5 to 0.9 +/- 1.1) and the UPDRS Part IVb score by 54.7% (from 3.3 +/- 1.3 to 1.5 +/- 1.3). At long-term follow-up review (32.7 +/- 10.7 months), there was an 8.3% increase in the UPDRS Part III score while patients were in the off state (from 26.5 +/- 9.2 to 28.7 +/- 7.6) and a 40.2% increase in this score while patients were in the on state (from 10.6 +/- 6.3 to 14.9 +/- 5.1). The UPDRS Part IVa score decreased by 28.1% (from 3.7 +/- 2.5 to 2.7 +/- 2.3) and the UPDRS Part IVb score increased by 3.5% (from 3.3 +/- 1.3 to 3.4 +/- 1.6). CONCLUSIONS: Based on these unsatisfactory results at long-term review, the authors conclude that unilateral pallidal stimulation is not an effective treatment option for patients with advanced PD.     

Unilateral stimulation of the subthalamic nucleus in Parkinson disease: a double-blind 12-month evaluation study

OBJECT: Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been established as an effective treatment for Parkinson disease (PD). Nevertheless, bilateral surgical procedures can be associated with frequent and severe complications. The aim in the present study was to assess the safety and efficacy of unilateral STN stimulation, and the need for a second procedure. METHODS: Twelve patients with PD underwent unilateral DBS of the STN and were followed up for 12 months. Patients were assessed at baseline and at each visit in a double-blind fashion by analyzing the Unified PD Rating Scale (UPDRS), ambulation speed, and home diaries. Levodopa-off/stimulation-on UPDRS motor scores were improved by 26 +/- 8% (p < 0.05, mean +/- standard deviation [SD]) compared with the baseline levodopa-off score; there was a 50% improvement in contralateral features, a 17% improvement ipsilaterally, and a 36% improvement in axial features. The mean ambulation speed increased by 83 +/- 44% (p < 0.01, mean +/- SD). The medication-on time with dyskinesias was significantly reduced (p < 0.01) and the daily levodopa dose was reduced by 19 +/- 6% (p < 0.05, mean +/- SD). There were no clinically significant side effects. CONCLUSIONS: Unilateral DBS of the STN is safe and well tolerated, and may provide sufficient benefit so that additional surgery is not required.     

Staged bilateral deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease

Background  Several investigators have described the efficacy and safety of unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of Parkinson’s disease (PD). Some patients who underwent unilateral STN DBS required additional surgery on the contralateral side because the unilateral treatment was insufficient. The goal of this study was to assess the efficacy and safety of staged bilateral STN DBS compared to the simultaneous bilateral procedure. Methods  Ten patients with medically intractable PD underwent staged bilateral STN DBS, and 12 patients underwent a simultaneous bilateral procedure. Clinical assessments were performed preoperatively and 6 months after the last surgery using the Unified Parkinson’s Disease Rating Scale (UPDRS), motor and activity of daily living (ADL) subscores, and Hoehn and Yahr stages. Findings  Both the staged and simultaneous groups experienced significant improvement in the UPDRS motor and ADL scores, and the Hoehn and Yahr stages. There were no statistical differences between the two groups in the percent improvement in UPDRS scores. The rate of adverse events in the staged group (20%) was less than that of the simultaneous group (42%), although the difference was not statistically significant. Conclusions  Both the staged bilateral STN DBS and the simultaneous bilateral procedure are effective and safe treatment options, but the staged bilateral procedure may be regarded as the preferred choice for the treatment of some patients. No financial support was received for this research. The findings presented herein have not been previously published.     

Preoperative clinical predictors of response to bilateral subthalamic stimulation in patients with Parkinson's disease

BACKGROUND: Younger age and a response to a supra-threshold levodopa challenge have been reported to predict a favorable response to bilateral subthalamic nucleus (STN) stimulation. OBJECTIVE: To identify and evaluate clinical factors which predict a positive outcome after bilateral STN stimulation in patients with Parkinson's disease, using each patient's typical doses of antiparkinsonian medication rather than a supra-threshold levodopa challenge. METHODS: Forty-five Parkinson's disease patients who underwent bilateral STN implantation were included in the study. There were 33 men and 12 women. Mean age and disease duration were 59.4 and 12.7 years, respectively. All patients underwent Unified Parkinson Disease Rating Scale (UPDRS) evaluations in the medication off and on states at baseline and postsurgically with stimulation on at 3, 6 and 12 months. The percentage improvement in UPDRS motor scores at baseline (medication off vs. on) was compared with the percentage improvement after stimulation optimization (baseline medication off vs. follow-up medication off/stimulation on). RESULTS: The preoperative percentage improvement in UPDRS motor scores with antiparkinsonian medications was predictive of the postoperative percentage improvement in the UPDRS motor scores in the medication off/stimulation on state (r = 0.53, p < 0.001). However, preoperative UPDRS motor scores in the medication on state were more strongly correlated with the postsurgical effect of stimulation (r = 0.64, p < 0.001). The postoperative improvement in UPDRS motor scores with stimulation did not correlate with age, disease duration or time to programming optimization. CONCLUSIONS: The preoperative percentage improvement in UPDRS motor scores with antiparkinsonian medications and UPDRS motor score in the medication on state at baseline are the strongest clinical predictors of responsiveness to bilateral STN stimulation.     

Staged bilateral pallidotomy for treatment of Parkinson disease

OBJECT: Several investigators have described the motor benefits derived from performing unilateral stereotactic pallidotomy for the treatment of Parkinson disease (PD), but little is known about the efficacy and complication rates of bilateral procedures. The goal of this study was to assess both these factors in 12 patients. METHODS: Eleven patients with medically intractable PD underwent staged bilateral pallidotomy and one patient underwent a simultaneous bilateral procedure. Unilateral pallidotomy resulted in an improvement in the patients' Unified Parkinson Disease Rating Scale (UPDRS) total scores and motor subscores, Hoehn and Yahr stages, and Schwab and England Activities of Daily Living scores. There were no complications. The second procedures were performed 5 to 25 months after the first, and nearly complete 3-month follow-up data are available for eight of these patients. Staged bilateral pallidotomy did result in further improvements in some symptoms, but the patients proved to be less responsive to levodopa. In contrast to outcomes of the initial unilateral pallidotomy, there were significant complications. One patient suffered an acute stroke, two patients suffered delayed infarctions of the internal capsule, four patients had mild-to-moderate worsening of speech and increased drooling, and one patient complained of worsening memory. CONCLUSIONS: Bilateral pallidotomy results in modest benefits but is associated with an increased risk of complications.     

Unilateral deep brain stimulation of the subthalamic nucleus for Parkinson disease

OBJECT: The object of this study was to assess the results of unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for management of advanced Parkinson disease (PD). METHODS: A clinical series of 24 patients (mean age 71 years, range 56-80 years) with medically intractable PD, who were undergoing unilateral magnetic resonance imaging-targeted, electrophysiologically guided STN DBS, completed a battery of qualitative and quantitative outcome measures preoperatively (baseline) and postoperatively, using a modified Core Assessment Program for Intracerebral Transplantations protocol. The mean follow-up period was 9 months. Statistically significant improvement was observed in the Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (18%), the total UPDRS PART III score (31%), the contralateral UPDRS Part III score (63%), and scores for axial motor features (19%), contralateral tremor (88%), rigidity (60%), bradykinesia (54%), and dyskinesia (69%), as well as the Parkinson's Disease Quality of Life questionnaire score (15%) in the on-stimulation state compared with baseline. Ipsilateral symptoms improved by approximately 15% or less. Performance on the Purdue pegboard test improved in the contralateral hand in the on-stimulation state compared with the off-stimulation state (38%, p < 0.05). The daily levodopa-equivalent dose was reduced by 21% (p = 0.018). Neuropsychological tests revealed an improvement in mental flexibility and a trend toward reduced letter fluency. There were no permanent surgical complications. Of the 16 participants with symmetrical disease, five required implantation of the DBS unit on the second side. CONCLUSIONS: Unilateral STN DBS is an effective and safe treatment for selected patients with advanced PD. Unilateral STN DBS provides improvement of contralateral motor symptoms of PD as well as quality of life, reduces requirements for medication, and possibly enhances mental flexibility. This method of surgical treatment may be associated with a reduced risk and may provide an alternative to bilateral STN DBS for PD, especially in older patients or patients with asymmetry of parkinsonism.     

Long-term benefits in quality of life provided by bilateral subthalamic stimulation in patients with Parkinson disease

OBJECT: The goals of this study were to evaluate long-term benefits in quality of life in patients with Parkinson disease (PD) after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and to evaluate the relationship between improvements in motor function and quality of life. METHODS: Seventy-one patients who received bilateral STN stimulation implants and participated in follow-up review for at least 12 months were included in the study. Fifty-nine patients participated in a 12-month follow-up review and 43 patients in a follow-up review lasting at least 24 months. Patients' symptoms were assessed preoperatively by using the Unified PD Rating Scale (UPDRS) in the "medication-on" and "medication-off' conditions and quality of life was examined using the 39-item PD Questionnaire (PDQ-39). Patient evaluations were repeated postoperatively during periods of stimulation. The UPDRS activities of daily living (ADL) and motor scores as well as the PDQ-39 total, mobility, ADL, emotional well-being, stigma, and bodily discomfort scores were significantly improved at 12 months compared with baseline scores; the UPDRS ADL and motor scores as well as the PDQ-39 total, mobility, ADL, stigma, and bodily discomfort scores were significantly improved at the longest follow-up examination compared with baseline scores. There was a strong correlation between UPDRS motor and ADL scores and the PDQ-39 total, mobility, and ADL scores. Further analyses indicated that improvements in tremor were only correlated with PDQ-39 ADL subscale scores and rigidity was not correlated with any aspect of quality of life. Nevertheless, bradykinesia was strongly correlated with improvements in the PDQ-39 total, mobility, and ADL scores. CONCLUSIONS: Improvements in quality of life following bilateral DBS of the STN are maintained in the long term. These improvements are strongly correlated with improvements in motor function, primarily with regard to bradykinesia.     

Long-term outcomes of bilateral subthalamic nucleus stimulation in patients with advanced Parkinson's disease

BACKGROUND: In patients with advanced Parkinson's disease (PD), deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to improve motor function and decrease medication requirements in the short term. However, the long-term benefits of DBS are not yet established. OBJECTIVE: It was the aim of this study to evaluate long-term outcomes of patients with PD treated with bilateral DBS of the STN. DESIGN AND METHODS: Thirty-three subjects who had bilateral STN DBS were followed prospectively after surgery. We evaluated subjects, using the Unified Parkinson's Disease Rating Scale (UPDRS), preoperatively, 12 months after surgery and at a long-term follow-up visit. Ratings were performed on and off dopaminergic medications. We compared postoperative UPDRS scores, dyskinesia ratings and medication dosages with preoperative values. RESULTS: Twenty-seven subjects had evaluations beyond 18 months (median 33.7 months). Total UPDRS scores in the 'medication-off' state were improved by 37% (p < 0.001) at 12 months and 17.7% (p = 0.0051) at the long-term evaluation. Medication-off state UPDRS part III scores were significantly improved at both 1 year and at the last evaluation (37.6 and 29.3%; p < 0.001). Dopaminergic medication requirements were decreased by 35.3% (p < 0.001) during the first postoperative year and remained below preoperative levels at the long-term evaluation. Average duration of 'off' time remained decreased by about 40% at both 1 year and at the time of last evaluation. Subjects had a sustained reduction in dyskinesia severity (88.6% at 1 year and 68.8% at last evaluation). CONCLUSIONS: In this cohort of subjects with advanced PD, bilateral STN stimulation improved 'off' medication motor function, reduced time spent in the medication-off state and reduced medication requirements for up to 4 years after surgery. We conclude that STN DBS is an effective long-term therapy for selected patients with advanced PD.     

Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in Parkinson's disease: one year follow-up of a randomised observer-blind multi centre trial

BACKGROUND: To investigate whether STN stimulation is more efficacious than unilateral pallidotomy in advanced Parkinson's disease (PD) one year after surgery. METHOD: Thirty-four patients with advanced PD were randomly assigned to unilateral pallidotomy or bilateral STN stimulation. Outcome measures were parkinsonian symptoms in off and on phases (UPDRS 3), dyskinesias, functional status, Parkinson's disease quality of life questionnaire, the effects on separate symptoms, timed tests, patient diaries, dopaminergic drugs changes, adverse effects, and global outcome scale. Patients were assessed before surgery, six months and one year after surgery. The primary outcome measure was the off phase UPDRS 3 at six months follow-up. FINDINGS: The off phase UPDRS 3 score improved from 46.5 to 32 points in the pallidotomy patients and from 51.5 to 24 in the STN stimulation patients (p = 0.002). On phase UPDRS 3 and off phase Schwab and England functional scale improved significantly in favour of the STN stimulation patients. Dopaminergic drugs reduction was larger in the STN group although the difference between the treatment groups was not significant. One patient in each group had a major adverse effect. CONCLUSIONS: Bilateral STN stimulation is more efficacious than unilateral pallidotomy in advanced PD up to one year after surgery.     

Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up

OBJECT: Bilateral subthalamic nucleus (STN) stimulation is increasingly used in patients with advanced Parkinson disease (PD). This study was performed to evaluate the long-term efficacy and safety of bilateral STN stimulation in cases of PD. METHODS: The authors performed a prospective, open-label study in patients with PD who underwent bilateral STN stimulation. The authors compared motor scores and activities of daily living (ADL) scores based on the Unified PD Rating Scale (UPDRS) obtained before surgery while patients were in the medication-off state with scores obtained at follow-up evaluations of these patients while in the medication-off/stimulator-on state. Data contained in patient diaries were also compared. Thirty-three patients with PD were evaluated 12 months postoperatively and 19 were evaluated at a mean follow-up time of 28 months. A comparison between UPDRS scores obtained in patients in the medication-off/stimulator-on state and those obtained when patients were in the baseline medication-off state showed a 27% improvement in ADL scores and a 28% improvement in motor scores after surgery. There was a 57% reduction in the use of levodopa-equivalent medication doses. The percentage of the waking day that patients were in the medication-on state increased from 38 to 72%. Surgical complications included seizures (three patients), confusion (five patients), hemiballismus (one patient), and visual disturbance (one patient). Stimulation-related adverse effects were mild. Device-related events included nine lead replacements, seven lead revisions, six extension replacements, and 12 implantable pulse generator (IPG) replacements; one IPG was cleaned and one IPG was placed in a pocket because of the presence of a shunt. CONCLUSIONS: Bilateral STN simulation is associated with a significant improvement in the motor features of PD. Device-related events were common in the first 20 patients who underwent surgery, often requiring repeated surgeries.     

Bilateral contemporaneous posteroventral pallidotomy for the treatment of Parkinson's disease: neuropsychological and neurological side effects. Report of four cases and review of the literature.

The authors report the underestimated cognitive, mood, and behavioral complications in patients who have undergone bilateral contemporaneous pallidotomy, as seen in their early experience with functional neurosurgery for Parkinson's disease (PD) that is accompanied by severe motor fluctuations before pallidal stimulation. Four patients, not suffering from dementia, with advanced (Hoehn and Yahr Stages III-IV), medically untreatable PD featuring severe "on-off" fluctuations underwent bilateral contemporaneous posteroventral pallidotomy (PVP). All patients were evaluated according to the Core Assessment Program for Intracerebral Transplantations (CAPIT) protocol without positron emission tomography scans but with additional neuropsychological cognitive, mood, and behavior testing. For the first 3 to 6 months postoperatively, all patients showed a mean improvement of motor scores on the Unified Parkinson's Disease Rating Scale (UPDRS), in the best "on" (21%) and worst "off" (40%) UPDRS III motor subscale, a mean 30% improvement in the UPDRS II activities of daily living (ADL) subscore, and 60% on the UPDRS IV complications of treatment subscale. Dyskinesia disappeared almost completely, and the mean daily duration of the off time was reduced by an average of 60%. Despite these good results in the CAPIT scores, one patient experienced a partially regressive corticobulbar syndrome with dysphagia, dysarthria, and increased drooling. No emotional lability was found in this patient, but he did demonstrate severe bilateral postoperative pretarsal blepharospasm (apraxia of eyelid opening), which interfered with walking and which required treatment with high-dose subcutaneous injections of botulinum toxin. No patient showed visual field defects or hemiparesis, but postoperative depression, changes in personality, behavior, and executive functions were seen in two individuals. Postoperative abulia was reported by the family of one patient, who lost his preoperative aggressiveness and drive in terms of ADL, speech, business, family life, and hobbies, and became more sleepy and fatigued. One patient reported postoperative mental automatisms, such as compulsive mental counting, and circular thoughts and reasoning during off phases; postoperative depression was found in two patients. However, none of the patients demonstrated these symptoms during intraoperative microelectrode stimulation. These findings are compatible with previous reports on bilateral pallidal lesions. A progressive lowering of UPDRS subscores was seen after 12 months, consistent with the progression of the disease. Bilateral simultaneous pallidotomy may be followed by emotional, behavioral, and cognitive deficits such as depression, obsessive-compulsive disorders, and loss of psychic autoactivation-abulia, as well as disabling corticobulbar dysfunction and apraxia of eyelid opening, in addition to previously described motor and visual field deficits, which make this surgery undesirable even though significant improvement in motor deficits can be achieved.     

Progression of Parkinson's disease following thalamic deep brain stimulation for tremor

We assessed the long-term effect of thalamic deep brain stimulation (DBS) on motor symptoms and progression of Parkinson's disease (PD) in PD patients treated for resting and postural/action tremor. Thalamic DBS was performed in 17 patients with treatment-resistant resting and postural/action tremor. Nine patients were available for follow-up examination a mean of 5.5 years after surgery. Three had tremor-dominant PD. DBS produced marked improvement in resting and postural/action tremor in target upper extremity in all 9 patients, which persisted unchanged at the time of the last follow-up visit 5.5 years after surgery. PD severity with DBS 'on' and 'off' 1 year after surgery was compared to PD severity at the last follow-up visit using UPDRS (Unified Parkinson's Disease Rating Scale) III motor scores and individual motor item subscores. Patients were tested while on medication. There was no significant worsening of tremor, rigidity, speech, postural stability, gait, or axial bradykinesia with DBS either on or off at the last follow-up visit compared to the 12-month visit. UPDRS III motor scores were unchanged. However, global assessment of PD progression and increased mean L-dopa dose and L-dopa equivalent daily dose at the time of last follow-up visit indicated that a progression of PD had occurred.     

微电极引导苍白球腹后核毁损术治疗帕金森病

目的：评估微电极引导苍白球腹后核毁损术治疗帕金森病的效果。方法：应用微电极导向苍白球腹后核毁损术治疗帕金森病48例（单侧毁损47例,双侧1例）。术前及术后每间隔6个月采用统一帕金森病等级量表（unified Parkinson′s disease rating scale,UPDRS）进行1次疗效评估。结果：术后对患者随访6-34个月,平均24个月。经靶点毁损患者手术对侧肢体症状明显改善,“开“或“关“状态均有改进。UPDRS积分显示“开“状态平均改善率为28.7％,“关“状态改善率为47.6％。本组4例患者（占8.3％）术后遗留对侧肢体肌张力下降,无手术死亡和视野缺损发生。结论：微电极技术可行内囊和视束通道的定位,结合射频电极刺激更有利于上述结构的鉴别和苍白球腹后核的靶点定位。     

Results of chronic subthalamic nucleus stimulation for Parkinson's disease: a 1-year follow-up study

BACKGROUND: Deep brain stimulation (DBS) has been established as an alternative approach for the treatment of advanced Parkinson's disease (PD). Recently, the subthalamic nucleus (STN) has been identified as the optimal target for DBS. METHODS: Thirty-eight patients have undergone surgery for advanced PD since 1996. They include 12 females and 26 males with a mean age of 55.6 years. The mean stage on the Hoehn and Yahr Scale was 3.5 (off condition). Electrodes (Medtronic DBS 31389) were stereotactically implanted into the STN bilaterally. Targeting was performed using computerized tomography (CT) scans and ventriculography (VG). After 4 days of external stimulation, permanent neurostimulators were implanted. Patients were evaluated preoperatively and 1, 6, and 12 months postoperatively. Evaluations were performed in defined on and off states using the Unified Parkinson's Disease Rating Scale (UPDRS) as well as the Hoehn and Yahr Scale, the dyskinesia scale, and the Activities of Daily Living (ADL) Scale. RESULTS: Significant improvement of all motor symptoms was found in all patients (UPDRS motor score 32/48 preoperatively versus 15/30 at 12-month follow-up, p < 0.001). Daily off-times were reduced by 35%. Dyskinesias also improved markedly (UPDRS IV: 3.2/3.1 [on/off] vs. 0.9/1.3 at 12 months follow-up). Postoperative L-dopa medication was adjusted (mean reduction: 53%). Complications occurred in two patients (5%) who developed infections, leading to system removal. Systems were replaced after 6 months. Two patients (5%) had a permanent worsening of a previously known depressive state and developed progressive dementia. CONCLUSIONS: TN stimulation is a relatively safe procedure for treating advanced PD. The possibility of readjusting the stimulation parameters postoperatively improves the therapeutic outcome and reduces side effects in comparison to ablative methods.