Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

[Behavioral disorders in Parkinson's disease: from pathophysiology to the mastery of dopaminergic treatment]. / Maladie de Parkinson: de la physiopathologie des troubles psychiques à la maîtrise du traitement dopaminergique.

INTRODUCTION: Behavioral changes in Parkinson's disease are complex and their pathophysiology is not yet fully understood. The dopaminergic system seems to play a major role and most of the behavioral disorders in Parkinson's disease can be classified into either hypodopaminergic if related to the disease itself or hyperdopaminergic if related to dopaminergic treatment. STATE OF THE ART: Subthalamic stimulation, which enables withdrawal of dopaminergic medication at an advanced stage in the disease, provides a model for the study of certain nonmotor, dopamine-sensitive symptoms. Such a study has shown that apathy, which is the most frequent behavioral problem in Parkinson's disease, is part of a much broader hypodopaminergic behavioral syndrome which also includes anxiety and depression. Nonmotor fluctuations--essential fluctuations in the patient's psychological state--are an expression of mesolimbic denervation, as shown in positron emission tomography. Drug-induced sensitization of the denervated mesolimbic system accounts for hyperdopaminergic behavioral problems that encompass impulse control disorders that can be alternatively classified as behavioral addictions. The association of impulse control disorders and addiction to the dopaminergic medication has been called dopamine dysregulation syndrome. While L-dopa is the most effective treatment for motor symptoms, dopamine agonists are more effective in improving the nonmotor levodopa-sensitive symptoms. On the other hand, L-dopa induces more motor complications and dopamine agonist more behavioral side effects. There is increasing data and awareness that patients' quality of life appears to be dictated by hypo- and hyperdopaminergic psychological symptoms stemming from mesolimbic denervation and dopaminergic treatment rather than by motor symptoms and motor complications related to nigrostriatal denervation and dopaminergic treatment. PERSPECTIVES: Better management requires knowledge of the clinical syndromes of hyper- and hypodopaminergic behaviors and nonmotor fluctuations, a better understanding of their underlying mechanisms and the development of new evaluation tools for these nonmotor symptoms. CONCLUSIONS: The neurologist who strives to gain mastery of dopaminergic treatment needs to fine tune the dosage of levodopa and dopamine agonists on an individual basis, depending on the presence of motor and nonmotor signs respectively.

Subthalamic nucleus stimulation in Parkinson's disease : anatomical and electrophysiological localization of active contacts.

OBJECTIVES: 1 - To assess the anatomical localization of the active contacts of deep brain stimulation targeted to the subthalamic nucleus (STN) in Parkinson's disease patients. 2 - To analyze the stereotactic spatial distribution of the active contacts in relation to the dorsal and the ventral electrophysiologically-defined borders of the STN and the stereotactic theoretical target. METHODS: Twenty-eight patients underwent bilateral high-frequency stimulation of the STN (HFS-STN). An indirect anatomical method based on ventriculography coupled to electrophysiological techniques were used to localize the STN. Clinical improvement was evaluated by Unified Parkinson's Disease Rating Scale motor score (UPDRS III). The normalized stereotactic coordinates of the active contact centres, dorsal and ventral electrophysiologically-defined borders of the STN were obtained from intraoperative X-rays images. These coordinates were represented in a three-dimensional stereotactic space and in the digitalized atlas of the human basal ganglia. RESULTS: HFS-STN resulted in significant improvement of motor function (62.8%) in off-medication state and levodopa-equivalent dose reduction of 68.7% (p < 0.05). Most of the active contacts (78.6%) were situated close to (+/- 1.6 mm) the dorsal border of the STN (STN-DB), while 16% were dorsal and 5.4% were ventral to it. Similar distribution was observed in the atlas. The euclidean distance between the STN-DB distribution center and the active contacts distribution center was 0.31 mm, while the distance between the active contacts distribution center and the stereotactic theoretical target was 2.15 mm. Most of the space defined by the active contacts distribution (53%) was inside that defined by the STN-DB distribution. CONCLUSION: In our series, most of the active electrodes were situated near the STN-DB. This suggests that HFS-STN could influence not only STN but also the dorsal adjacent structures (zona incerta and/or Fields of Forel).

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson's disease--A [(11)C]-raclopride PET study.

CONTEXT: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. OBJECTIVE: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [11C]-Raclopride, whether STN stimulation induces a striatal DA release. METHODS: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [11C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [11C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. RESULTS: For PD patients, the mean [(11C]-Raclopride BP (+/- SD) were, in Off stimulation condition: 1.7 +/- 0.3 for the right caudate nucleus, 1.8 +/- 0.4 for the left caudate nucleus, 2.6 +/- 0.5 for the right putamenand 2.6 +/- 0.5 for the left putamen. In On stimulation condition: 1.7 +/- 0.4 for the right caudate nucleus, 1.9 +/- 0.5 for the left caudate nucleus, 2.8 +/- 0.7 for the right putamen and 2.7 +/- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. CONCLUSION: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [11C]-Raclopride.

Multicentre European study of thalamic stimulation in essential tremor: a six year follow up.

BACKGROUND: Thalamic stimulation is an efficient treatment for disabling essential tremor, as previously shown, but follow up has mostly been short term. OBJECTIVES: To see whether good results can be maintained in the longer term. METHODS: 37 patients with essential tremor had implantation of a thalamic stimulator, either unilaterally or bilaterally. The results at one year have been reported earlier. After six years, 19 patients were available for follow up. The main instrument for evaluation was the essential tremor rating scale. The patients were examined with pulse generators turned on and off. RESULTS: In the majority of patients, the very good results with stimulation seen at one year were maintained after a mean of 6.5 years. The reduction in tremor scores and improvement in activities of daily living were highly significant compared with baseline and with the stimulation turned off. There were few serious adverse events. Minor side effects related to stimulation were common. Few device related complications were observed and most could be resolved. CONCLUSIONS: Good reduction in tremor can be maintained for more than six years in the majority of these severely disabled patients. Thalamic stimulation can be recommended in essential tremor where there is insufficient response to drug treatment. Surgical procedures and follow up should be concentrated in relatively few centres, which will thereby acquire a high degree of expertise.

The timing of antiparkinsonian treatment reduction after subthalamic nucleus stimulation.

The objective of this work was to precisely analyse the reduction of the antiparkinsonian treatment in 18 consecutive patients with Parkinson's disease (PD) operated on for bilateral subthalamic nucleus (STN) stimulation, first after 1 month of follow-up, then at 1 year postoperatively. Trihexyphenidyle, selegiline, entacapone, apomorphine and lisuride could be withdrawn shortly after starting STN electrical stimulation. The levodopa mean daily dose was reduced by 57% at 1 month after surgery and remained stable at 1 year. The mean ropinirole and bromocriptine daily dose decrements after surgery corresponded to 54 and 63%, respectively, at 1 month and to 77 and 40% at 1 year. At 12 months postoperatively, one third of the patients no longer received any antiparkinsonian drugs and the others were on monotherapy of either levodopa or dopamine agonists or received a combined treatment of a dopaminergic agonist and levodopa. In conclusion, STN stimulation allows a major reduction and simplification of antiparkinsonian treatment which can usually be achieved during the early postoperative period.

Subthalamic nucleus stimulation in Parkinson's disease: clinical evaluation of 18 patients.

The aim of the present study was to assess the efficacy and safety of chronic subthalamic nucleus deep-brain stimulation (STN-DBS) in patients with Parkinson's disease (PD). 18 consecutive severely affected PD patients were included (mean age, SD: 56.9+/-6 years; mean disease duration: 13.5+/-4.4 years). All the patients were evaluated clinically before and 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS). Additionally, a 12 months follow-up was available in 14 patients. The target coordinates were determined by ventriculography under stereotactic conditions, followed by electrophysiology and intraoperative stimulation. After surgery, continuous monopolar stimulation was applied bilaterally in 17 patients at 2.9+/-0.4 V through 1 (n = 31) or 2 contacts (n = 3). One patient had bilateral bipolar stimulation. The mean frequency of stimulation was 140+/-16 Hz and pulse width 68+/-13 micros. Off medication, the UPDRS part III score (max = 108) was reduced by 55 % during on stimulation (score before surgery: 44.9+/-13.4 vs at 6 months: 20.2+/-10; p < 0.001). In the on medication state, no difference was noted between the preoperative and the postoperative off stimulation conditions (scores were respectively: 17.9+/-9.2 and 23+/-12.6). The severity of motor fluctuations and dyskinesias assessed by UPDRS IV was reduced by 76 % at 6 months (scores were respectively: 10.3+/-3 and 2.5+/-3; p < 0.001). Off medication, the UPDRS II or ADL score was reduced by 52.8 % during on stimulation (26.9+/-6.5 preop versus 12.7+/-7 at 6 months). The daily dose of antiparkinsonian treatment was diminished by 65.5 % (levodopa equivalent dose -- mg/D -- was 1045 +/- 435 before surgery and 360 +/- 377 at 6 months; p < 0.01). These results remained stable at 12 months for the 14 patients studied. Side effects comprised lower limb phlebitis (n = 2), pulmonary embolism (n = 1), depression (n = 6), dysarthria and freezing (n = 1), sialorrhea and drooling (n = 1), postural imbalance (n = 1), transient paresthesias and dyskinesias. This study confirms the great value of subthalamic nucleus stimulation in the treatment of intractable PD. Some adverse events such as depression may be taken into account in the inclusion criteria and also in the post-operative outcome.

Contributions of PET and SPECT to the understanding of the pathophysiology of Parkinson's disease.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) provide the means to studying in vivo the neurochemical, hemodynamic or metabolic consequences of the degeneration of the nigrostriatal dopaminergic system in Parkinson's disease (PD). The extent of striatal dopaminergic denervation can be quantified with radiotracers as [18F]FDopa for PET and [123I]tropanes for SPECT. There are other radiotracers such as [11C]Dopa and meta-tyrosines as well as PET tracers for uptake sites. Striatal uptake of [18F]FDopa and [123I]tropanes is markedly decreased in PD, more in the putamen than in the caudate nucleus, and inversely correlates with the severity of motor signs and with duration of disease. PET and SPECT make possible the assessment by noninvasive means of the changes in dopamine receptor density, the effect of neuronal transplants or neuroprotective treatments in PD patients, or the nigrostriatal dopaminergic function in at-risk subjects. Activation studies using cerebral blood flow and metabolism measurements during a motor task reveal an impaired ability to activate the supplementary motor area and dorsolateral prefrontal cortex in PD. This functional disability is reversed by the use of dopaminergic medication or by surgical treatment by pallidotomy or deep brain stimulation. The differential diagnosis between PD and multiple system atrophy, progressive supranuclear palsy or corticobasal degeneration is not yet clearly established by PET and SPECT, even though these syndromes have some particular neurochemical and metabolic profiles. On the other hand, PET and SPECT are useful for distinguishing PD from Dopa-responsive dystonia, or for assessing the integrity of the nigrostriatal dopaminergic pathway in atypical cases of postural tremor or iatrogenic parkinsonian syndromes.