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.).

Startle stimuli exert opposite effects on human cortical and spinal motor system excitability in leg muscles.

Increased excitability of the spinal motor system has been observed after loud and unexpected acoustic stimuli (AS) preceding H-reflexes. The paradigm has been proposed as an electrophysiological marker of reticulospinal tract activity in humans. The brainstem reticular formation also maintains dense anatomical interconnections with the cortical motor system. When a startling AS is delivered, prior to transcranial magnetic stimulation (TMS), the AS produces a suppression of motor evoked potential (MEP) amplitude in hand and arm muscles of healthy subjects. Here we analyzed the conditioning effect of a startling AS on MEP amplitude evoked by TMS to the primary motor leg area. Ten healthy volunteers participated in two experiments that used a conditioning-test paradigm. In the first experiment, a startling AS preceded a suprathreshold transcranial test stimulus. The interstimulus interval (ISI) varied between 20 to 160 ms. When given alone, the test stimulus evoked a MEP amplitude of approximately 0.5 mV in the slightly preinervated soleus muscle (SOL). In the second experiment, the startling AS was used to condition the size of the H-reflex in SOL muscle. Mean MEP amplitude was calculated for each ISI. The conditioning AS suppressed MEP amplitude at ISIs of 30-80 ms. By contrast, H-reflex amplitude was augmented at ISIs of 100-200 ms. In conclusions, acoustic stimulation exerts opposite and ISI-specific effects on the amplitude of MEPs and H-reflex in the SOL muscle, indicating different mechanism of auditory-to-motor interactions at cortical and spinal level of motor system.

Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism.

OBJECTIVES: To study the frequency of different gene mutations in patients with early-onset parkinsonism and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and the short- and long-term surgical outcome in mutation-positive (MUT+) and -negative (MUT-) patients. METHODS: Eighty patients with disease onset at age

Subthalamic nucleus stimulation modulates audiospinal reactions in Parkinson disease.

BACKGROUND: Axial symptoms of Parkinson disease (PD) may result from dysfunctional basal ganglia-brainstem connections. In this study, we assessed whether modulation of basal ganglia activity by high-frequency stimulation of the subthalamic nucleus (STN-HFS) in PD had an impact on the brainstem-controlled startle system. METHODS: We assessed auditory startle responses (recorded from right orbicularis oculi, masseter, sternocleidomastoid, biceps brachii, and soleus muscle) and audiospinal facilitation (startle conditioned soleus H-reflexes at interstimulus intervals of 0-250 msec) in 24 patients with PD with chronically implanted, bilateral STN electrodes in the stimulation on (STIM ON) and off condition (STIM OFF) and 20 healthy controls. RESULTS: The mixed linear analysis of variance model revealed a significant effect for the startle onset latency in the orbicularis oculi muscle for the factors GROUP (patients with PD vs controls; p < 0.0001, F = 44.66) and STIM (nested within GROUP) (p = 0.0034, F = 8.79). Audiospinal facilitation was modulated by STN-HFS as shown by highly significant effects for STIM [GROUP] (p < 0.0001, F = 15.9), ISI [GROUP] (p < 0.0001, F = 3.5), and the interaction of ISI x STIM [GROUP] (p = 0.0085, F = 2.65) in the mixed linear model. CONCLUSION: High-frequency stimulation of the subthalamic nucleus alters the excitability of the brainstem startle system in Parkinson disease, most likely by releasing the reticular motor system from abnormal descending input of the basal ganglia via pallidotegmental pathways.

The effect of subthalamic nucleus stimulation on autogenic inhibition in Parkinson disease.

BACKGROUND: Recent animal experiments suggest an important role of descending input from basal ganglia to brainstem and via the reticulospinal tract (RST) to spinal cord in the genesis of motor symptoms in Parkinson disease (PD). In humans, a marker for RST activity is Ib mediated autogenic inhibition, which is reduced in PD patients. The authors investigated the effect of high frequency stimulation of the subthalamic nucleus (STN-HFS) on autogenic inhibition in PD. METHODS: In 10 controls and 10 PD patients with chronically implanted STN electrodes, the soleus H-reflex conditioned by gastrocnemius nerve stimulation (interstimulus interval 2 to 10 msec) was used to examine the effect of STN-HFS on the activity of Ib spinal interneurons. RESULTS: STN-HFS was able to restore the abnormally reduced autogenic inhibition. The H-reflex changes during STN-HFS significantly correlated with the clinical improvement of gait and posture. CONCLUSIONS: Observed changes in spinal autogenic inhibition may allow measurement of the contribution of subcortical routes to the STN-HFS induced motor benefit in PD.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: evaluation of active electrode contacts.

BACKGROUND: The subthalamic nucleus is the preferred target for deep brain stimulation in patients with advanced Parkinson's disease. The site of permanent stimulation is the subject of ongoing debate, as stimulation both within and adjacent to the subthalamic nucleus may be effective. OBJECTIVE: To assess the position of active electrode contacts in relation to the dorsal margin of the subthalamic nucleus as determined by intraoperative microrecordings and magnetic resonance imaging (MRI). METHODS: In 25 patients suffering from severe levodopa sensitive parkinsonism, deep brain stimulating electrodes (n = 49) were implanted following mapping of the subthalamic nucleus by microrecording and microstimulation along five parallel tracks. Postoperative stereotactic radiography and fusion of pre- and postoperative MRI studies were used to determine the stereotactic position relative to the midcommissural point of the most effective electrode contacts selected for permanent stimulation (n = 49). Intraoperative microrecordings were analysed retrospectively to define the dorsal margin of the subthalamic nucleus. In cases where the dorsal margin could be defined in at least three microrecording tracks (n = 37) it was correlated with the position of the active contact using an algorithm developed for direct three dimensional comparisons. RESULTS: Stimulation of the subthalamic nucleus resulted in marked improvement in levodopa sensitive parkinsonian symptoms and levodopa induced dyskinesias, with significant improvement in UPDRS III scores. In several instances, projection of the electrode artefacts onto the T2 weighted MRI visualised subthalamic nucleus of individual patients suggested that the electrodes had passed through the subthalamic nucleus. When the actual position of active electrode contacts (n = 35) was correlated with the dorsal margin of the subthalamic nucleus as defined neurophysiologically, most contacts were located either in proximity (+/- 1.0 mm) to the dorsal border of the subthalamic nucleus (32.4%) or further dorsal within the subthalamic region (37.8%). The other active contacts (29.7%) were detected within the dorsal (sensorimotor) subthalamic nucleus. The average position of all active contacts (n = 49) was 12.8 mm (+/- 1.0) lateral, 1.9 mm (+/- 1.4) posterior, and 1.6 mm (+/- 2.1) ventral to the midcommissural point. CONCLUSIONS: Subthalamic nucleus stimulation appears to be most effective in the border area between the upper subthalamic nucleus (sensorimotor part) and the subthalamic area containing the zona incerta, fields of Forel, and subthalamic nucleus projections.

Deep brain stimulation of the subthalamic nucleus for Parkinson's disease: a therapy approaching evidence-based standards.

DBS of the STN is one of the most promising new therapies for the treatment of PD. However - like many other therapies for PD - the present stage of the scientific assessment does not yet suffice the rigid criteria of evidence-based medicine. Further studies should specifically address the questions of efficacy and side effects as well as the impact on quality of life.

Technical complication in deep brain stimulation.

With a growing number of patients treated with deep brain stimulation (DBS) operations for both hardware-related complications and routine replacements of impulse generators will be performed more frequently. Failure of DBS systems have to be analyzed thoroughly as this thwarts the enormous efforts required for proper electrode implantation and operative revisions increase the morbidity associated with DBS. A female patient implanted with DBS electrodes for advanced Parkinson's disease presented with straining of the right extension lead and deteriorating gait because of electrode migration. This was due to a malpositioned set screw connector adapting the electrode lead to the extension wire which had been placed below the mastoid process. Following surgical revision with implantation of a new electrode into the STN, electrode dislocation recurred requiring another surgical revision. This was due to renewed connector migration from its parietal position into the cervical region. Straining of extension leads should be recognized as a warning sign for (imminent) electrode dislocation or lead fracture. This may just be the case with connectors located below the mastoid process or in the cervical region, a risk which appears to be increased further with reduced-length extensions. Renewed dislocation of revised extensions may be prevented by securing the position of the connector (e.g. with manipulates).

Magnetic resonance imaging-based morphometry and landmark correlation of basal ganglia nuclei.

The two principle targets for deep brain stimulation or lesioning in patients with Parkinson's disease, the subthalamic nucleus (STN) and the globus pallidus internus (GPi), reveal a high degree of individual variability which is relevant to the planning of stereotactic operations. Both nuclei can clearly be delineated in T2WI spin echo MRI which was acquired under stereotactic conditions in general anesthesia before surgery. Such images of 35 patients served for retrospective morphometric analysis of different basal ganglia nuclei (STN, GP, red nucleus, and substantia nigra) and several anatomical landmarks (anterior and posterior commissure, maximum width of third ventricle, brain length and width). The average AC-PC distance was 25.74 mm (range 21 to 29 mm) and is in agreement with previous studies. On average, the center of the STN was located 12.65 mm (+/-1.3) lateral from the midline as determined 3 mm ventral to the intercommissural plane. The average width of the third ventricle was 7.05 mm (+/-2.41). The width of the third ventricle correlated with the laterality of the STN (r(right)=.78; r(left)=.83) and GP (r(right)=.76; r(left)=.68). Although to a lesser extent, significant correlations were also observed between the laterality of the STN and brain width, improving prediction of STN laterality by multiple linear regression analysis (r(right)=.82; r(left)=.87). Similarly, the laterality of GP correlated with brain width. In addition, gender-specific differences were detected. The STN and GP was located farther lateral in males which may be due to overall brain anatomy as gender-specific differences were also observed for brain width and length and AC-PC distance. MRI-based in vivo-localization of different basal ganglia nuclei extend statistical information from common histological brain atlases which are based on a limited number of brains. The correlations observed between different basal ganglia nuclei, i.e. the STN and GPi, and anatomical landmarks may be useful for surgical planning.

MRI- and skull x-ray-based approaches to evaluate the position of deep brain stimulation electrode contacts--a technical note.

Deep brain stimulation (DBS) has developed into an established therapy for the treatment of movement disorders, most commonly Parkinson's disease and tremor of different etiology. The subthalamic nucleus (STN) has evolved as the preferred target for DBS in patients with idiopathic Parkinson's disease. The principal target for DBS in tremor patients is the ventrolateral thalamus which has been explored for ablative procedures (thalamotomy) for some decades. Detailed information about the exact site of chronic stimulation, i.e. the location of the active electrode contacts, are important to map the actual subcortical structures modulating the therapeutic effects of DBS. We compared two different methods not requiring intra-operative teleradiography to determine the stereotactic coordinates of single electrode contacts, (i) correlation of pre- and post-operative MRI, and (ii) post-operative stereotactic skull x-ray. For seven patients implanted bilateral with quadripolar DBS electrodes the coordinates for each contact were determined by both approaches. This revealed for a total of 56 electrode contacts a median euclidean 3D-difference between both methods of 1.18 mm (range 0.42 to 1.93 mm). These data suggest that both approaches may be used to determine the position of single electrode contacts.

Evaluation of healthcare utilization and health status of patients with Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus.

OBJECTIVE: To assess the effects on motor functioning, health status and direct medical costs of high-frequency stimulation of the subthalamic nucleus (DBS-STN) in patients with idiopathic Parkinson's disease (PD). In addition, the cost-effectiveness of DBS-STN vs. drug treatment was investigated. METHODS: 16 consecutive patients with PD from two centers (Düsseldorf/Cologne; Kiel) treated by DBS-STN were prospectively evaluated. Clinical evaluations were done at baseline and 1, 3, 6, 12 months following surgery by means of the Unified Parkinson's disease Rating Scale (UPDRS). Health status of PD patients was assessed using the Sickness Impact Profile (SIP) at baseline and 6 months following surgery. Relevant economic data were taken from the medical records and costs (1999) were derived from different German medical economic resources. Costs were determined from the perspective of the health care provider. RESULTS: Following DBS-STN UPDRS scores (subscores and sum score) as well as health status improved considerably in PD patients. The overall SIP score and the physical dimension score (p < 0.009) were significantly different (p < 0.01) six month after surgery compared with baseline values. Mean costs of DM 40,020 (US dollars 20,810, EURO 20,410, GB pounds 12,810) per patient were spent during the 12 month observation period for in-patient and out-patient care. These expenses included already the costs for the electronic device for bilateral stimulation. Following DBS-STN medication was considerably reduced. Mean daily drug costs at baseline were DM 46.7+/-21.8 (US dollars 24, EURO 24, GB pounds 15) and DM 18.3+/-17.7 (US dollars 10, EURO 9, GB pounds 6) at 12 months following DBS-STN. Accounting for the decreased drug consumption, total annual costs amounted to DM 31,400 (US dollars 16,330, EURO 16,010, GB pounds 10,050). Further, we estimated the incremental cost effectiveness as DBS-STN had higher costs but was more effective than baseline treatment. The incremental total cost-effectiveness ratio for DBS-STN was DM 1.800 (US dollars 940, EURO 920, GB pounds 580) for one point decrease of the UPDRS. CONCLUSION: DBS-STN is an effective treatment that considerably alleviates the severity of signs and symptoms and improves the health status of patients with PD. Compared with drug treatment, however, the expenditures associated with DBS-STN are increased when only direct medical costs are considered in a one year horizon. However, on a long-term basis costs will decrease considerably because of the reduction of the drug expenditure and improved functioning in all activities of daily living. To adequately evaluate the cost-effectiveness of DBS-STN compared with standard drug regimen for PD it is necessary to include direct, indirect and intangible costs on a long-term basis and under standardized circumstances.

Effects of pallidal deep brain stimulation and levodopa treatment on reaction-time performance in Parkinson's disease.

Basal ganglia-thalamocortical circuits play an important role in movement preparation and execution. Tracer, single-cell, and lesion studies in monkeys suggest the existence of topologically segregated motor and nonmotor basal ganglia cortical circuits. In this study we used deep brain stimulation (DBS) of the posteroventrolateral globus pallidus internus (GPi) in patients with Parkinson's disease to elucidate the function of the GPi in human sensorimotor behavior. This question was investigated by comparing the influence of DBS on patients' performance in various reaction-time tasks that differed with respect to cognitive but not motor requirements. As a main result, DBS improved performance on the different tasks independently of the complexity of the involved cognitive processing functions. Furthermore, the observed effects did not depend on the modality of the processed information. These results suggest that the functional state of the posteroventrolateral GPi selectively affects the motor stage in simple sensorimotor acts, because this stage was the only stage involved in all investigated tasks. In addition to DBS, we manipulated the levodopa medication state of the PD patients. In contrast to DBS, levodopa effects on reaction times were less consistent. Levodopa improved reaction times in choice reaction tasks significantly, while affecting reaction times in a simple reaction task to a lesser extent. Error analysis revealed that the medication-dependent reaction-time improvement in the choice reaction tasks was accompanied by an increase in errors, suggesting a shift of the speed-accuracy criteria of the patients. A similar pattern of results was not observed for the DBS effects. Taken together, our data are in agreement with recent findings in monkeys that indicate a topological organization of the GPi in which motor functions are localized in posterolateral regions apart from cognitive regions. Furthermore, our data show a way to uncover the subcortical-cortical circuitry serving human sensorimotor behavior.

Deep-brain stimulation for Parkinson's disease.

Deep brain simulation (DBS) is a powerful new therapeutic approach for patients with Parkinson's disease. However, patient selection is critical for a valuable therapeutic result. Dopa sensitivity of the target symptoms, severe disability and low neurosurgical risks are among the major criteria for this indication. Other criteria like age or cognition must still be addressed in future prospective studies. The preferred target for DBS in PD is the subthalamic nucleus for various good reasons. However, prospective studies for this procedure are lacking and some clinical problems may be more easily solved with targeting the internal pallidum or the thalamus. Despite major progress in this field, much work remains to be done.

Effects of bilateral pallidal or subthalamic stimulation on gait in advanced Parkinson's disease.

Bilateral high-frequency stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) both alleviate akinesia, rigidity, and tremor in idiopathic Parkinson's disease. To test the specific effect of these procedures on gait, we used quantitative gait analysis in addition to relevant subscores of the Unified Parkinson's Disease Rating Scale in a group of 10 patients with advanced Parkinson's disease treated by GPi stimulation and eight patients treated by STN stimulation. Patients were assessed before and 3 months after surgery. Thirty age-matched healthy subjects served as controls. The non-random selection allowed a descriptive but no direct statistical comparison of the respective procedure. Gait analysis showed significant stimulation-induced improvements of spatiotemporal gait and step parameters in both patient groups. Moreover, the effects on step length and cadence suggested a differential effect of both basal ganglia targets. Hence, the increase in gait velocity in the STN group was almost exclusively due to a significant increase in step length, while in the GPi group statistically non-significant increases in both step length and cadence contributed.

Deep brain stimulation of the internal pallidum did not improve chorea in a patient with neuro-acanthocytosis.

We report the failure of bilateral globus pallidus internus deep brain stimulation to improve chorea in a patient with chorea-acanthocytosis. Prior to this surgery the patient had experienced a striking but short lived amelioration of symptoms with clozapine therapy.

Bilateral high-frequency stimulation of the internal globus pallidus in advanced Parkinson's disease.

We report here the results of an open prospective study in 9 patients suffering from severe Parkinson's disease with on/off fluctuations and restricted off-period mobility, who underwent bilateral implantation of stimulating electrodes in the internal pallidum. At 3-month follow-up, the total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the medication-off state was reduced from 54.1+/-14.8 to 23.9+/-11.7 (44.2%) when stimulation was turned on. Comparison of UPDRS subscores revealed significant improvements for tremor, rigidity, bradykinesia, gait and posture, and dyskinesias. The results of the clinical scoring could be confirmed by significant changes in the quantitative assessment of hand function and walking. Bilateral pallidal stimulation reduced the amount and severity of on/off fluctuations. Additional follow-up at 6 months (n=6), 9 months (n=6), and 12 months (n=4) did not show a decline in effectiveness of stimulation. There was no permanent morbidity associated with the procedure. A subtle reduction of verbal fluency, which was not evident to the patients, was the only cognitive side effect of the procedure in neuropsychological testing. Chronic bilateral high-frequency stimulation of the internal pallidum seems to be a neurologically safe and highly effective treatment for "off" symptoms, dyskinesias, and motor fluctuations in advanced stages of Parkinson's disease.