The role of σ-receptors in levodopa-induced dyskinesia in patients with advanced Parkinson disease: a positron emission tomography study

2004 ◽  
Vol 100 (4) ◽  
pp. 606-610 ◽  
Author(s):  
Taro Nimura ◽  
Tadashi Ando ◽  
Keiichiro Yamaguchi ◽  
Takeshi Nakajima ◽  
Reizo Shirane ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Severity Score ◽  
Rating Scale ◽  
Binding Potential ◽  
Strong Positive Correlation ◽  
Female Ratio ◽  
Content Type ◽  
Positron Emission ◽  
Before And After ◽  
Fine Print

Object. Levodopa-induced dyskinesia (LID) in patients with Parkinson disease (PD) mimics acute dystonic reactions induced by antipsychotic agents, possibly mediated by σ-receptors; however, there are few reports in which the relationship between σ-receptors and LID in advanced PD is investigated. The binding potential of cerebellar σ-receptors before and after a pallidal surgery for dyskinesia in patients with advanced PD is assessed. Methods. Six patients with advanced PD (male/female ratio 3:3, age 56.7 ± 9.8 years) underwent stereotactic pallidal surgery (two posteroventral pallidotomy procedures and four deep brain stimulation of the globus pallidus internus, including one bilateral case). Clinical features of patients with PD were assessed using Hoehn and Yahr (H & Y) stages, the Unified Parkinson's Disease Rating Scale (UPDRS), and the Schwab and England Activities of Daily Life Scale (S & E). The LID was evaluated by LID severity score. The binding potential of cerebellar σ-receptors was determined before and after the surgery by 11C-nemonapride positron emission tomoraphy, a specific radioligand for σ-receptors in the cerebellum. All clinical scores, especially the LID severity score, were dramatically improved after the surgery (p < 0.05). Preoperatively, contralateral cerebellar binding potential was significantly elevated (p < 0.01), and it was reduced after the surgery, but it was still higher than that of healthy volunteers (p < 0.05). The ipsilateral cerebellar binding potential remained unchanged after the surgery. The level of binding potential did not correlate with H & Y stage, UPDRS, or S & E score, but a strong positive correlation was seen between the binding potential and the preoperative LID severity score when the patients were receiving medication (r = 0.893, p < 0.05). Conclusions. Cerebellar σ-receptors may potentially involve the genesis of LID in advanced PD.

The impact of stereotactic pallidal surgery on the dopamine D2 receptor in Parkinson disease: a positron emission tomography study

2003 ◽  
Vol 98 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Takeshi Nakajima ◽  
Taro Nimura ◽  
Keiichiro Yamaguchi ◽  
Tadashi Ando ◽  
Masatoshi Itoh ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Parkinson Disease ◽  
Receptor Binding ◽  
Emission Tomography ◽  
Binding Potential ◽  
Yahr Stage ◽  
Content Type ◽  
Positron Emission ◽  
The Impact ◽  
Fine Print

Object. The aim of this study was to estimate the impact of stereotactic pallidal surgery on the binding potential of dopamine D2 receptors in patients with advanced Parkinson disease (PD). Methods. Six patients with advanced PD (three men and three women; mean age 56.7 ± 9.8 years, Hoehn and Yahr stage 3.3 ± 1.1/3.9 ± 1.2 [on/off scores], mean ± standard deviation) underwent stereotactic pallidal surgery. One underwent right posteroventral pallidotomy (PVP), one received left PVP, three were treated with deep brain stimulation (DBS) of the left globus pallidus internus (GPi), and one with bilateral DBS of the GPi. The binding potential of the dopamine D2 receptors of these patients was determined before and after surgery by using positron emission tomography scanning with 11C-nemonapride and it was compared with the value in eight healthy volunteers. The authors also examined whether changes in the D2 receptor binding potential were correlated with the clinical outcome. The clinical symptoms, especially those in the off state, were significantly improved after surgery. Preoperatively, the D2 receptor binding potential in the putamen was elevated by 27% (p < 0.01) and that in the thalamus was 29% lower than that in controls (p < 0.01). The D2 receptor binding potential in the putamen and thalamus returned to control levels after surgery. The preoperative level of the D2 receptor binding potential in the anterior cingulate cortex was comparable to that of controls, but it declined significantly after surgery, whereas the D2 receptor binding potential in other regions of both hemispheres showed no significant changes after surgery. Although the D2 receptor binding potential did not correlate with the Hoehn and Yahr stage, the Schwab and England score, or the Unified PD Rating Scale (UPDRS) score, a positive correlation was seen between the percent improvement rate of the total UPDRS score in the off state and the percentage change of the D2 receptor binding potential in the putamen (r = 0.773, p = 0.0417 according to the Pearson linear correlation). Conclusions. The altered dopamine D2 receptor binding potential in the putamen might play a crucial role in clinical improvement after PVP or DBS of the GPi in advanced PD.

Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study

2002 ◽  
Vol 96 (3) ◽  
pp. 589-596 ◽  
Author(s):  
Ivar Mendez ◽  
Alain Dagher ◽  
Murray Hong ◽  
Paula Gaudet ◽  
Swarna Weerasinghe ◽  
...  
Keyword(s):  
Pilot Study ◽  
Parkinson Disease ◽  
Rating Scale ◽  
Perioperative Complications ◽  
Clinical Results ◽  
Neural Transplantation ◽  
Content Type ◽  
Intracerebral Transplantation ◽  
Positron Emission ◽  
Fine Print

✓ The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation. Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson′s Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

The mechanism and effect of chronic electrical stimulation of the globus pallidus for treatment of Parkinson disease

2004 ◽  
Vol 100 (6) ◽  
pp. 997-1001 ◽  
Author(s):  
Mitsuhiro Ogura ◽  
Naoyuki Nakao ◽  
Ekini Nakai ◽  
Yuji Uematsu ◽  
Toru Itakura
Keyword(s):  
Electrical Stimulation ◽  
Parkinson Disease ◽  
Globus Pallidus ◽  
Rating Scale ◽  
Underlying Mechanism ◽  
Clinical Effects ◽  
Content Type ◽  
Chronic Electrical Stimulation ◽  
Fine Print ◽  
Stimulation Of

Object. Although chronic electrical stimulation of the globus pallidus (GP) has been shown to ameliorate motor disabilities in Parkinson disease (PD), the underlying mechanism remains to be clarified. In this study the authors explored the mechanism for the effects of deep brain stimulation of the GP by investigating the changes in neurotransmitter levels in the cerebrospinal fluid (CSF) during the stimulation. Methods. Thirty patients received chronic electrical stimulation of the GP internus (GPi). Clinical effects were assessed using the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr Staging Scale at 1 week before surgery and at 6 and 12 months after surgery. One day after surgery, CSF samples were collected through a ventricular tube before and 1 hour after GPi stimulation. The concentration of neurotransmitters such as γ-aminobutyric acid (GABA), noradrenaline, dopamine, and homovanillic acid (HVA) in the CSF was measured using high-performance liquid chromatography. The treatment was effective for tremors, rigidity, and drug-induced dyskinesia. The concentration of GABA in the CSF increased significantly during stimulation, although there were no significant changes in the level of noradrenaline, dopamine, and HVA. A comparison between an increased rate of GABA concentration and a lower UPDRS score 6 months postimplantation revealed that the increase in the GABA level correlated with the stimulation-induced clinical effects. Conclusions. Stimulation of the GPi substantially benefits patients with PD. The underlying mechanism of the treatment may involve activation of GABAergic afferents in the GP.

Subthalamotomy for advanced Parkinson disease

2002 ◽  
Vol 97 (3) ◽  
pp. 598-606 ◽  
Author(s):  
Philip C. Su ◽  
Ham-Min Tseng ◽  
Hon-Man Liu ◽  
Ruoh-Fang Yen ◽  
Horng-Huei Liou
Keyword(s):  
Parkinson Disease ◽  
Postural Stability ◽  
Rating Scale ◽  
Motor Fluctuation ◽  
Treated Group ◽  
Content Type ◽  
Cardinal Symptoms ◽  
Fine Print

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.

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

2004 ◽  
Vol 101 (1) ◽  
pp. 36-42 ◽  
Author(s):  
Isabelle M. Germano ◽  
Jean-Michel Gracies ◽  
Donald J. Weisz ◽  
Winona Tse ◽  
William C. Koller ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Subthalamic Nucleus ◽  
Rating Scale ◽  
Evaluation Study ◽  
Double Blind ◽  
Levodopa Dose ◽  
Content Type ◽  
Additional Surgery ◽  
Second Procedure ◽  
Fine Print

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.

Pallidotomy for Parkinson disease: a review of contemporary literature

2001 ◽  
Vol 94 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Ahmed Alkhani ◽  
Andres M. Lozano
Keyword(s):  
Parkinson Disease ◽  
Rating Scale ◽  
Visual Field Defects ◽  
Drug Induced ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Content Type ◽  
Pubmed Database ◽  
The Mean ◽  
Fine Print

Object. The authors conducted an evidence-based review of contemporary published articles on pallidotomy to obtain an appraisal of this procedure in the treatment of Parkinson disease (PD). Methods. A search of the Pubmed database performed using the key word “pallidotomy” yielded 263 articles cited between January 1, 1992, and July 1, 1999. Articles that included original, nonduplicated descriptions of patients with PD treated with radiofrequency pallidotomy were selected. In 85 articles identified for critical review, 1959 patients with PD underwent pallidotomies at 40 centers in 12 countries. There were 1735 unilateral (88.6%) and 224 bilateral procedures (11.4%). The mean age of the patients was 61.4 ± 3.6 years and the mean duration of PD symptoms in these patients was 12.3 ± 1.9 years. Microelectrode recordings were used in 46.2% of cases. Outcomes were objectively documented using the Unified Parkinson Disease Rating Scale (UPDRS) in 501 (25.6%) of the cases at 6 months and in 218 (11.1%) of the cases at 1 year. There was a consensus on the benefits of pallidotomy for off period motor function and on period, drug-induced dyskinesias, with variations in the extent of symptomatic benefit across studies. At the 1-year assessment, the mean improvement in the UPDRS motor score during off periods was 45.3% and the mean improvement in contralateral dyskinesias during on periods was 86.4%. The overall mortality rate was 0.4% and the rate of persistent adverse effects was estimated at 14%. Major adverse events, including intracerebral hemorrhages, contralateral weakness, and visual field defects, occurred in 5.3% of patients reported. Conclusions. Unilateral pallidotomy is effective and relatively safe in the treatment of PD; however, limited data are available on the long-term outcome of this procedure.

Attenuation of fluctuating striatal synaptic dopamine levels in patients with Parkinson disease in response to subthalamic nucleus stimulation: a positron emission tomography study

2005 ◽  
Vol 103 (6) ◽  
pp. 968-973 ◽  
Author(s):  
Taro Nimura ◽  
Keiichiro Yamaguchi ◽  
Tadashi Ando ◽  
Satoshi Shibuya ◽  
Takanori Oikawa ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Caudate Nucleus ◽  
Brain Stimulation ◽  
Drug Induced ◽  
Content Type ◽  
Positron Emission ◽  
Before And After ◽  
Wearing Off ◽  
Fine Print ◽  
Deep Brain

Object. The “wearing-off” phenomenon often hampers the treatment of Parkinson disease (PD). Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to ameliorate the wearing-off phenomenon, the mechanism by which it does this remains unclear. As part of an inquiry into the mechanism of STN DBS, the authors measured synaptic dopamine levels in the striatum by performing positron emission tomography (PET) with [11C]raclopride. Methods. Three patients with PD who were experiencing the wearing-off phenomenon underwent PET scanning before and after DBS of the STN. The clinical features in these patients were evaluated by applying the Hoehn and Yahr, United Parkinson's Disease Rating, and Schwab and England Activities of Daily Living Scales. Before and after surgery, PET scans were obtained using [11C]raclopride prior to and 1 hour following an oral administration of levodopa. Regions of interest for the [11C]raclopride binding potential (RacloBP) were set in the bilateral putamen and the caudate nucleus. All clinical scores were dramatically improved postoperatively. Deep brain stimulation of the STN reduced the baseline RacloBP in both the putamen and caudate nucleus, but the differences between the pre- and postoperative levels were insignificant. Before DBS of the STN, the levodopa administration significantly reduced RacloBP in the putamen (p < 0.0001). Postoperatively the drug-induced reduction in RacloBP became statistically insignificant. The drug-induced increase in synaptic dopamine concentrations in the putamen preoperatively was estimated to be approximately four times higher than that after surgery (p < 0.01). The drug-induced RacloBP change in the caudate nucleus was similar to that in the putamen, although the magnitude of the change was lower (p < 0.005). The drug-induced increase in the caudate nucleus was also reduced postoperatively (p < 0.05). Conclusions. Deep brain stimulation of the STN induces the stabilization of synaptic dopamine concentrations in the striatum and may attribute to the alleviation of levodopa-related motor fluctuations.

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

2003 ◽  
Vol 99 (1) ◽  
pp. 71-77 ◽  
Author(s):  
Rajesh Pahwa ◽  
Steven B. Wilkinson ◽  
John Overman ◽  
Kelly E. Lyons
Keyword(s):  
Parkinson Disease ◽  
Rating Scale ◽  
Pulse Generator ◽  
Visual Disturbance ◽  
Open Label ◽  
Content Type ◽  
Long Term Follow Up ◽  
Fine Print

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.

Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease

2004 ◽  
Vol 101 (2) ◽  
pp. 195-200 ◽  
Author(s):  
Antonella Peppe ◽  
Mariangela Pierantozzi ◽  
Andrea Bassi ◽  
Maria Grazia Altibrandi ◽  
Livia Brusa ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Globus Pallidus ◽  
Subthalamic Nucleus ◽  
Rating Scale ◽  
Subcutaneous Administration ◽  
Test Dose ◽  
Globus Pallidus Internus ◽  
Content Type ◽  
Fine Print ◽  
Stimulation Of

Object. The authors compared the effects of deep brain stimulation (DBS) in the globus pallidus internus (GPi) with those in the subthalamic nucleus (STN) in patients with Parkinson disease (PD) in whom electrodes had been bilaterally implanted in both targets. Methods. Eight of 14 patients with advanced PD in whom electrodes had been implanted bilaterally in both the GPi and STN for DBS were selected on the basis of optimal DBS effects and were studied 2 months postsurgery in offand on-stimulus conditions and after at least 1 month of pharmacological withdrawal. Subcutaneous administration of an apomorphine test dose (0.04 mg/kg) was also performed in both conditions. Compared with the off status, the results showed less reduction in the Unified PD Rating Scale Section III scores during DBS in the GPi (43.1%) than during DBS of the STN (54.5%) or DBS of both the STN and GPi (57.1%). The difference between the effects of DBS in the GPi compared with that in the STN or simultaneous DBS was statistically significant (p < 0.01). In contrast, no statistical difference was found between DBS in the STN and simultaneous DBS in the STN and GPi (p < 0.9). The improvement induced by adding apomorphine administration to DBS was similar in all three stimulus modalities. The abnormal involuntary movements (AIMs) induced by apomorphine were almost abolished by DBS of the GPi, but were not affected by stimulation of the STN. The simultaneous stimulation of STN and GPi produced both antiparkinsonian and anti-AIM effects. Conclusions. The improvement of parkinsonian symptoms during stimulation of the GPi, STN, and both nuclei simultaneously may indicate a similar DBS mechanism for both nuclei in inducing antiparkinsonian effects, although STN is more effective. The antidyskinetic effects produced only by DBS of the GPi, with or without STN, may indicate different mechanisms for the antidyskinetic and antiparkinsonian activity related to DBS of the GPi or an additional mechanism in the GPi. These findings indicate that implantation of double electrodes for DBS should not be proposed as a routine procedure, but could be considered as a possible subsequent choice if electrode implantation for DBS of the STN does not control AIMs.

Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line—derived neurotrophic factor

2005 ◽  
Vol 102 (2) ◽  
pp. 216-222 ◽  
Author(s):  
John T. Slevin ◽  
Greg A. Gerhardt ◽  
Charles D. Smith ◽  
Don M. Gash ◽  
Richard Kryscio ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Rating Scale ◽  
Open Label ◽  
Content Type ◽  
Potential Efficacy ◽  
Bilateral Effects ◽  
Fine Print

Object. Glial cell line-derived neurotrophic factor (GDNF) has demonstrated significant antiparkinsonian actions in several animal models and in a recent pilot study in England in which four of five patients received bilateral putaminal delivery. In the present study the authors report on a 6-month unilateral intraputaminal GDNF infusion in 10 patients with advanced Parkinson disease (PD). Methods. Patients with PD in a functionally defined on and off state were evaluated 1 week before and 1 and 4 weeks after intraputaminal catheter implantation in the side contralateral to the most affected side. Each patient was placed on a dose-escalation regimen of GDNF: 3, 10, and 30 µg/day at successive 8-week intervals, followed by a 1-month wash-out period. The Unified Parkinson's Disease Rating Scale (UPDRS) total scores in the on and off states significantly improved 34 and 33%, respectively, at 24 weeks compared with baseline scores (95% confidence interval [CI] 18–47% for off scores and 16–51% for on scores). In addition, UPDRS motor scores in both the on and off states significantly improved by 30% at 24 weeks compared with baseline scores (95% CI 15–48% for off scores and 5–61% for on scores). Improvements occurred bilaterally, as measured by balance and gait and increased speed of hand movements. All significant improvements of motor function continued through the wash-out period. The only observed side effects were transient Lhermitte symptoms in two patients. Conclusions. Analysis of the data in this open-label study demonstrates the safety and potential efficacy of unilateral intraputaminal GDNF infusion. Unilateral administration of the protein resulted in significant, sustained bilateral effects.

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