Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease: concept and standards of the EARLYSTIM-study.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for advanced Parkinson's disease (PD) with disabling motor complications. However, stimulation may be beneficial at an earlier stage of PD when motor fluctuations and dyskinesia are only mild and psychosocial competence is still maintained. The EARLYSTIM trial was conducted in patients with recent onset of levodopa-induced motor complications (≤ 3 years) whose social and occupational functioning remained preserved. This is called 'early' here. The study was a randomized, multicenter, bi-national pivotal trial with a 2 year observation period. Quality of life was the main outcome measure, and a video-based motor score was a blinded secondary outcome of the study. Motor, neuropsychological, psychiatric and psychosocial aspects were captured by established scales and questionnaires. The patient group randomized here is the earliest in the disease course and the youngest recruited in controlled DBS trials so far. The methodological innovation for DBS-studies of this study lies in novel procedures developed and used for monitoring best medical treatment, neurosurgical consistency, best management of stimulation programming, blinded video assessment of motor disability, and prevention of suicidal behaviors.

Thalamic stimulation for tremor: can target determination be improved?

High frequency stimulation of the ventral intermedius nucleus (Vim) of the thalamus is successfully used for the treatment of postural tremor. Target coordinates are most commonly calculated using a statistical method. Here, we compare a statistical and an individual targeting method, using an histology-based three-dimensional deformable brain atlas which allows localization of the Vim on individual patient's MR images by adaptation of the atlas onto the patient's brain. Twenty-nine consecutive patients had electrodes implanted in the Vim uni-or bilaterally for severe essential tremor. Thirty-five targets were determined by calculating the statistical target and then using the deformable atlas to compute the individual target. Pythagorean distance between these targets was calculated. Statistical and individual targets were compared by double blind evaluation of perioperative stimulation effects. For most cases (n = 24), the Pythagorean distance was higher than 1.5 mm. In 79% of these cases, the definitive electrode was implanted using the position of the individual target. For the remaining cases (n = 11, distance < 1.5 mm), the definitive electrode was implanted according to the statistical target location in 73% of the cases. As a whole, when individual target was used, it was located at least 2 mm more medial than the statistical one in 86% cases. These results suggest that Vim target determination based on a statistical method might be inaccurate. In particular, laterality might be overestimated, leading to nonoptimal clinical results. In clinical practice, this means that microelectrode exploration during Vim surgery should include at least one trajectory more medial than the statistical target.

Subthalamic nucleus stimulation in severe obsessive-compulsive disorder.

BACKGROUND: Severe, refractory obsessive-compulsive disorder (OCD) is a disabling condition. Stimulation of the subthalamic nucleus, a procedure that is already validated for the treatment of movement disorders, has been proposed as a therapeutic option. METHODS: In this 10-month, crossover, double-blind, multicenter study assessing the efficacy and safety of stimulation of the subthalamic nucleus, we randomly assigned eight patients with highly refractory OCD to undergo active stimulation of the subthalamic nucleus followed by sham stimulation and eight to undergo sham stimulation followed by active stimulation. The primary outcome measure was the severity of OCD, as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), at the end of two 3-month periods. General psychopathologic findings, functioning, and tolerance were assessed with the use of standardized psychiatric scales, the Global Assessment of Functioning (GAF) scale, and neuropsychological tests. RESULTS: After active stimulation of the subthalamic nucleus, the Y-BOCS score (on a scale from 0 to 40, with lower scores indicating less severe symptoms) was significantly lower than the score after sham stimulation (mean [+/-SD], 19+/-8 vs. 28+/-7; P=0.01), and the GAF score (on a scale from 1 to 90, with higher scores indicating higher levels of functioning) was significantly higher (56+/-14 vs. 43+/-8, P=0.005). The ratings of neuropsychological measures, depression, and anxiety were not modified by stimulation. There were 15 serious adverse events overall, including 1 intracerebral hemorrhage and 2 infections; there were also 23 nonserious adverse events. CONCLUSIONS: These preliminary findings suggest that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events. (ClinicalTrials.gov number, NCT00169377.)

Internal pallidal and thalamic stimulation in patients with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) is thought to result from dysfunction of the associative-limbic territories of the basal ganglia, and patients with severe symptoms of TS respond poorly to medication. High-frequency stimulation has recently been applied to patients with TS in open studies using the centromedian-parafascicular complex (CM-Pf) of the thalamus, the internal globus pallidus (GPi), or the anterior limb of the internal capsule as the principal target. OBJECTIVE: To report the effect of high-frequency stimulation of the CM-Pf and/or the GPi, 2 associative-limbic relays of the basal ganglia, in patients with TS. DESIGN: Controlled, double-blind, randomized crossover study. SETTING: Medical research. PATIENTS: Three patients with severe and medically refractory TS. INTERVENTION: Bilateral placement of stimulating electrodes in the CM-Pf (associative-limbic part of the thalamus) and the GPi (ventromedial part). MAIN OUTCOME MEASURES: Effects of thalamic, pallidal, simultaneous thalamic and pallidal, and sham stimulation on neurologic, neuropsychological, and psychiatric symptoms. RESULTS: A dramatic improvement on the Yale Global Tic Severity Scale was obtained with bilateral stimulation of the GPi (reduction in tic severity of 65%, 96%, and 74% in patients 1, 2, and 3, respectively). Bilateral stimulation of the CM-Pf produced a 64%, 30%, and 40% reduction in tic severity, respectively. The association of thalamic and pallidal stimulation showed no further reduction in tic severity (60%, 43%, and 76%), whereas motor symptoms recurred during the sham condition. No neuropsychological, psychiatric, or other long-term adverse effect was observed. CONCLUSIONS: High-frequency stimulation of the associative-limbic relay within the basal ganglia circuitry may be an effective treatment of patients with TS, thus heightening the hypothesis of a dysfunction in these structures in the pathophysiologic mechanism of the disorder.

Subthalamic stimulation in Parkinson disease: with or without anesthesia?

OBJECTIVE: To study the effects of general anesthesia on the postoperative outcome of patients with Parkinson disease (PD) who underwent surgery using bilateral placement of stimulating electrodes within the subthalamic nucleus (STN). DESIGN: Retrospective analysis. SETTING: Hôpital de la Salpêtrière, Paris, France. PATIENTS: Fifteen PD patients who underwent bilateral implantation of electrodes within the STN received general anesthesia because of severe anxiety, poorly tolerated off-period dystonia, or respiratory difficulties. These patients were compared with 15 patients matched for age, disease duration, and parkinsonian motor disability who underwent the same neurosurgical procedure under local anesthesia. MAIN OUTCOME MEASURE: Motor disability scores. RESULTS: After surgery, the severity of parkinsonian motor disability was markedly improved in both groups of patients. Compared with patients who were under local anesthesia during the operation, the residual parkinsonian motor score under stimulation (with ["on"] or without ["off"] levodopa) and the intensity of stimulation were higher in patients who were under general anesthesia during the operation. CONCLUSIONS: Although the improvement of parkinsonian motor disability is greater in PD patients who receive local anesthesia during surgery, general anesthesia can be performed in patients unable to tolerate prolonged states without levodopa.

Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus (STN) is a neurosurgical alternative to medical treatment in levodopa-responsive forms of Parkinson disease. The mechanism of action of STN stimulation remains controversial, although an inhibition of overactive STN neurons has been postulated. OBJECTIVE: To determine the effects of high-frequency STN stimulation on the neuronal activity of STN neurons in Parkinson disease patients. PATIENTS: Single-unit recordings of the neuronal activity of the STN were obtained before, during, and after the application of intra-STN electrical stimulation in 15 Parkinson disease patients. Changes in firing frequency and pattern were analyzed using various combinations of stimulus frequency (range, 14-140 Hz). RESULTS: Stimulation at a frequency greater than 40 Hz applied within the STN significantly decreased the firing frequency and increased the burst-like activity in the firing pattern of STN neurons. An aftereffect was observed in cells that had been totally inhibited during high-frequency stimulation. CONCLUSION: The beneficial effects of high-frequency stimulation result from a change in the firing pattern of cellular discharge and a blockade of the spontaneous overactivity of STN neurons.

Parkinson's disease, subthalamic stimulation, and selection of candidates: a pathological study.

We report on a patient with Parkinson's disease (PD) who was moderately improved by stimulation of the subthalamic nucleus (STN) and died 2 years after electrode implantation. After neurosurgery, symptoms that had responded to levodopa treatment preoperatively continued to improve. Postural instability, dysarthria, and cognitive impairment continued to worsen, despite STN stimulation and levodopa treatment. Postmortem examination of the brain confirmed the diagnosis of PD and showed that the electrodes had been correctly positioned within the STN. The failure of STN stimulation in this patient confirms the importance of screening and excluding patients from surgery with evolving parkinsonian axial symptoms or cognitive impairment.

Localization of stimulating electrodes in patients with Parkinson disease by using a three-dimensional atlas-magnetic resonance imaging coregistration method.

OBJECT: The aim of this study was to correlate the clinical improvement in patients with Parkinson disease (PD) treated using deep brain stimulation (DBS) of the subthalamic nucleus (STN) with the precise anatomical localization of stimulating electrodes. METHODS: Localization was determined by superimposing figures from an anatomical atlas with postoperative magnetic resonance (MR) images obtained in each patient. This approach was validated by an analysis of experimental and clinical MR images of the electrode, and the development of a three-dimensional (3D) atlas-MR imaging coregistration method. The PD motor score was assessed through two contacts for each of two electrodes implanted in 10 patients: the "therapeutic contact" and the "distant contact" (that is, the next but one to the therapeutic contact). Seventeen therapeutic contacts were located within or on the border of the STN, most of which were associated with significant improvement of the four PD symptoms tested. Therapeutic contacts located in other structures (zona incerta, lenticular fasciculus, or midbrain reticular formation) were also linked to a significant positive effect. Stimulation applied through distant contacts located in the STN improved symptoms of PD, whereas that delivered through distant contacts in the remaining structures had variable effects ranging from worsening of symptoms to their improvement. CONCLUSIONS: The authors have demonstrated that 3D atlas-MR imaging coregistration is a reliable method for the precise localization of DBS electrodes on postoperative MR images. In addition, they have confirmed that although the STN is the main target during DBS treatment for PD, stimulation of surrounding regions, particularly the zona incerta or the lenticular fasciculus, can also improve symptoms of PD.

Subthalamic stimulation in Parkinson disease: intraoperative predictive factors.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus (STN) is an effective treatment for advanced forms of Parkinson disease. Postoperative improvement of motor parkinsonian disability is known to depend on patient selection and surgical targeting. OBJECTIVE: To determine which clinical and electrophysiological variables evaluated during the operation predict the postoperative clinical outcome of patients with Parkinson disease treated by bilateral high-frequency stimulation of the STN. METHODS: Intraoperative clinical and electrophysiological data obtained in 41 patients with Parkinson disease who underwent bilateral implantation of electrodes for STN stimulation were correlated with the improvement in parkinsonian disability assessed 6 months after the operation. RESULTS: The extent of STN neuronal activity recorded along the trajectory of the therapeutic electrode had no effect on the postoperative clinical outcome. The intraoperative improvement in segmental akinesia, but not rigidity, was predictive of the postoperative improvement in parkinsonian motor disability and reduction in daily levodopa-equivalent dosage. Parkinsonian motor disability scores assessed after surgery were lower in patients with intraoperative stimulation-induced dyskinesias than in those without stimulation-induced dyskinesias. CONCLUSION: The improvement of segmental akinesia and the observation of dyskinesias provoked by stimulation during the operation predict the best postoperative effects of bilateral STN stimulation on parkinsonian motor disability.

Compulsions, Parkinson's disease, and stimulation.

Pathophysiological models suggest that obsessive compulsive disorder (OCD) might be associated with dysfunctions in cortico-striato-pallido-thalamo-cortical neuronal circuits. We implanted subthalamic electrodes to alleviate parkinsonian symptoms in two patients who had Parkinson's disease and a history of severe OCD. Parkinsonian disability improved postoperatively in both patients, and 2 weeks after the procedure, their compulsions had disappeared and obsessive symptoms improved (58% improvement for patient 1 on the Yale-Brown obsessive compulsive scale, 64% for patient 2). The improvements in these two patients suggest that high-frequency stimulation could improve function in the subcortical-limbic circuitry in patients with severe OCD.