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.

[Deep brain stimulation]. / La stimulation cérébrale profonde dans la maladie de Parkinson.

The present renewal of the surgical treatment of Parkinson's disease, almost abandoned for twenty Years, arises from two main reasons. The first is the better understanding of the functional organization of the basal ganglia. It was demonstrated in animal models of Parkinson's disease that the loss of dopaminergic neurons within the substantia nigra, at the origin of the striatal dopaminergic defect, induces an overactivity of the excitatory glutamatergic subthalamo-internal pallidum pathway. The decrease in this hyperactivity might lead to an improvement in the pakinsonian symptoms. The second reason is the improvement in stereotactic neurosurgery in relation with the progress in neuroimaging techniques and with intraoperative electrophysiological microrecordings and stimulations, which help determine the location of the deep brain targets. In the 1970s chronic deep brain stimulation in humans was applied to the sensory nucleus of the thalamus for the treatment of intractable pain. In 1987, Benabid and colleagues suggested high frequency stimulation of the ventral intermediate nucleus of the thalamus in order to treat drug-resistant tremors and to avoid the adverse effects of thalamotomies. How deep brain stimulation works is not well known but it has been hypothetized that it could change the neuronal activities and thus avoid disease-related abnormal neuronal discharges. Potential candidates for deep brain stimulation are selected according to exclusion and inclusion criteria. Surgery can be applied to patients in good general and mental health, neither depressive nor demented and who are severely disabled despite all available drug therapies but still responsive to levodopa. The first session of surgery consists in the location of the target by ventriculography and/or brain MRI. The electrodes are implanted during the second session. The last session consists in the implantation of the neurostimulator. The ventral intermediate nucleus of the thalamus was the first target in which chronic deep brain stimulation electrodes were implanted in order to alleviate tremor. This technique can be applied bilaterally without the adverse effects of bilateral thalamotomies. Like pallidotomy, internal globus pallidum stimulation has a dramatic beneficial effect on levodopa-induced dyskinesia but its effects on the parkinsonian triad are less constant and opposite motor effects are sometimes observed in relation with the stimulated contact. The inconstant results, perhaps related to the complexity of the structure led to the development of subthalamic nucleus stimulation. The alleviation of motor fluctuations and the improvement in all motor symptoms allows a significant decrease in levodopa daily dose and in levodopa-induced dyskinesia. Presently, deep brain stimulation is a fashionable neurosurgical technique to treat Parkinson's disease. Subthalamic nucleus stimulation seems to be the most suitable target to control the parkinsonian triad and the motor fluctuations. Because of the possible adverse effects it must be reserved for disabled parkinsonian patients. No large randomized study comparing different targets and different neurosurgical techniques has been performed yet. Such studies, including cost benefit studies would be useful to assess the respective value of these different techniques.

Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson's disease.

BACKGROUND: Long term effects of subthalamic nucleus (STN) stimulation on cognition, mood, and behaviour are unknown. OBJECTIVE: This study evaluated the cognitive, mood, and behavioural effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) followed up for three years. METHODS: A consecutive series of 77 PD patients was assessed before, one, and three years after surgery. Mean (SD) age at surgery was 55 (8). Seven patients died or were lost for follow up. Neuropsychological assessment included a global cognitive scale, memory, and frontal tests. Depression was evaluated using the Beck depression inventory. Assessment of thought disorders and apathy was based on the unified Parkinson's disease rating scale. Reports of the behavioural changes are mainly based on interviews done by the same neuropsychologist at each follow up. RESULTS: Only two cognitive variables worsened (category fluency, total score of fluency). Age was a predictor of decline in executive functions. Depression improved whereas apathy and thought disorders worsened. Major behavioural changes were two transient aggressive impulsive episodes, one suicide, four suicide attempts, one permanent apathy, one transient severe depression, four psychoses (one permanent), and five hypomania (one permanent). CONCLUSIONS: Comparing baseline, one year, and three year postoperative assessments, STN stimulation did not lead to global cognitive deterioration. Apathy scores mildly increased. Depression scores mildly improved. Behavioural changes were comparatively rare and mostly transient. Single case reports show the major synergistic effects of both medication and stimulation on mood and behaviour, illustrating the importance of a correct postoperative management.

Bilateral subthalamic nucleus stimulation improves health-related quality of life in PD.

In order to assess the impact of bilateral subthalamic nucleus (STN) stimulation in PD on quality of life, the PD Quality of Life questionnaire was assessed in 60 consecutive patients with PD before surgery and 12 months after surgery. All aspects of quality of life, including motor (+48%), systemic (+34%), emotional (+29%), and social (+63%) dimensions, significantly improved with long-term STN stimulation.

Predictors of effective bilateral subthalamic nucleus stimulation for PD.

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.

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.

Mirthful laughter induced by subthalamic nucleus stimulation.

High-frequency stimulation of the subthalamic nucleus (STN) improves the motor signs of Parkinson's disease (PD). The three main components (motor, associative, and limbic) of the cortical-basal ganglia-cortical circuits pass through the STN. It is not known whether STN stimulation can influence the limbic loop. We present two PD patients in whom acute stimulation of an electrode located in the STN using high stimulation parameters (50% higher than therapeutic) induced funny associations, leading to infectious laughter and hilarity, whereas the therapeutic parameters induced a hypomanic behavior and marked improvement of akinesia. Our report suggests that the STN, with its sensorimotor, cognitive, and limbic parts is not only involved in motor, but also in psychomotor regulation.

Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease.

BACKGROUND: Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson's disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson's disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. METHODS: We performed a prospective, double-blind, crossover study in patients with advanced Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson's Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. RESULTS: Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson's disease whose condition cannot be further improved with medical therapy.

Review of the functional surgical treatment of dystonia.

A review of functional surgery for dystonia is presented. Recently renewed interest in stereotaxy for dystonia has followed the resurgence of pallidotomy and the introduction of deep brain stimulation (DBS) in Parkinson's disease (PD) in the early 1990s. However, even since the 1950s, small series of patients treated with ablative surgery have been carefully studied, providing useful information, notably regarding the tolerability of surgery. In the setting of dystonia, thalamotomy was first performed with substantial benefits, but some authors outlined the great variability in outcome, and the high incidence of operative side-effects. In the 'modern' era of functional surgery for movement disorders, the globus pallidus internus (GPi) has emerged to be currently the best target for dystonia, based on small series of patients published in the last few years. Both bilateral posteroventral pallidotomy (PVP) and bilateral pallidal stimulation, performed by several teams, have benefited a variety of patients with severe dystonia, the most dramatic improvements being seen in primary dystonia with a mutation in the DYT1 gene. Whereas patients with secondary dystonia have often shown a lesser degree of improvement, some publications have nevertheless reported major benefit. There is today a strong need for carefully controlled studies comparing secondary and primary dystonia, DYT1 and non-DYT1 dystonia, ablative surgery and DBS, with additional assessment of neuropsychological changes, especially in children treated with bilateral pallidal procedures.

Effects of bilateral subthalamic nucleus stimulation on parkinsonian gait.

Gait analysis was carried out to assess the effects of L-dopa and bilateral subthalamic nucleus stimulation on gait velocity, cadence, stride length, and gait kinematics in nine patients with PD. Substantial effects of bilateral subthalamic nucleus stimulation on gait, with an increase in gait velocity and stride length comparable to that of a suprathreshold L-dopa dose, were found. Interestingly, stride length was more improved by L-dopa and cadence more by subthalamic nucleus stimulation. In two patients with freezing during the "on" period, subthalamic nucleus stimulation failed to reduce this symptom effectively.

Effect of bilateral subthalamic nucleus stimulation on parkinsonian gait.

Clinical reports show that bilateral subthalamic nucleus (STN) stimulation is effective in improving parkinsonian gait. Quantitative analysis of the efficacy of STN stimulation on gait is of interest and can be carried out using a commercially available stride analyser. Ten parkinsonian patients (5 men, 5 women) with a mean age of 55.8, SD 9.6 years were included in our study. They had a mean duration of Parkinson's disease (PD) of 13.3, SD 4.5 years and a motor examination score (part III of the Unified Parkinson's Disease Rating Scale) (UPDRS) of 43, SD 13 in off-stimulation off-drug condition. All the patients had bilateral chronic STN stimulation which had started from 3 to 36 months before the study. Patients were evaluated in off-drug and on-drug conditions both with and without stimulation. We analysed the principal gait measures: velocity, cadence, stride length, gait cycle, duration of single and double limb support. The clinical parkinsonian signs were evaluated with the part III of the UPDRS. In the off-drug condition, STN stimulation significantly (p < 0.05) improved velocity and stride length. The effect was similar to that of levodopa. When STN stimulation was switched on at the best of the levodopa induced effect, no further improvement was observed. The UPDRS motor score was significantly (p < 0.001) decreased after both stimulation and levodopa. In conclusion, STN stimulation is effective on parkinsonian gait.

The pathophysiology of parkinsonian tremor: a review.

Parkinsonian tremor is most likely due to oscillating neuronal activity within the CNS. Summarizing all the available evidence, peripheral factors only play a minor role in the generation, maintenance and modulation of PD tremor. Recent studies have shown that not a single but multiple oscillators are responsible. The most likely candidate producing these oscillations is the basal ganglia loop and its topographic organization might be responsible for the separation into different oscillators which, nevertheless, usually produce the same frequency. The neuronal mechanisms underlying these oscillations are not yet clear, but three hypotheses would be compatible with the presently available data from animal models and data recorded in patients. The first is a cortico-subthalamo-pallido-thalamic loop, the second is a pacemaker consisting of the external pallidum and the subthalamic nucleus, and the third is abnormal synchronization due to unknown mechanisms within the whole striato-pallido-thalamic pathway leading to a loss of segregation. Assuming the oscillator within the basal ganglia pathway, the mechanism of stereotactic surgery might be a desynchronization of the activity of the basal ganglia-thalamo-cortical or the cerebello-thalamo-cortical pathway.

Thalamic, pallidal, or subthalamic surgery for Parkinson's disease?

Levodopa is a highly effective treatment of all motor symptoms of Parkinson's disease. However, long-term treatment with levodopa can lead to motor fluctuations and levodopa-induced dyskinesias. Motor side effects can become so disabling as to warrant surgical treatment. Both ablative surgery and deep brain stimulation (DBS) for Parkinson's disease (PD) can be performed in different target areas. Thalamic surgery mainly improves tremor, and to a lesser extent also rigidity and dyskinesias, whereas pallidal and subthalamic nucleus surgery improves all motor symptoms and levodopa-induced dyskinesias. The efficacy and safety of unilateral pallidotomy is well established. DBS has a lower morbidity and is safe enough to be performed bilaterally. The subthalamic nucleus (STN) presently seems to be the most promising target for DBS in advanced stage PD.

Neuropsychological changes between "off" and "on" STN or GPi stimulation in Parkinson's disease.

BACKGROUND: In a previous study on a consecutive series of 62 patients with PD, the authors showed that bilateral subthalamic or pallidal continuous high-frequency deep brain stimulation (DBS) affects neither memory nor executive functions 3 to 6 months after surgery. OBJECTIVE: To investigate the specific effects of DBS by comparing the performance of patients with the stimulator turned "on" and "off." METHODS: The performance of 56 patients on clinical tests of executive function was compared after 3 and 12 months of DBS of the subthalamic nucleus (STN; n = 48) or the internal globus pallidus (GPi; n = 8) with the stimulator "on" or "off." Global intellectual efficiency, verbal learning, and mood were also evaluated with the stimulator "on." The performance of another group of 20 patients was compared after 6 months of DBS of the STN (n = 15) or the GPi (n = 5) with the stimulator "on" or "off" on more experimental tests recently shown to be more sensitive to l-dopa therapy. RESULTS: When the stimulator was "on," STN patients showed a mild but significant improvement in psychomotor speed and working memory. In comparison with the presurgical state, STN patients had no cognitive deficit at 12 months, except for lexical fluency. There was no differential effect of STN or GPi stimulation. CONCLUSIONS: 1) The specific effect of DBS seems to mimic the action of l-dopa treatment in the cognitive as in the motor domain; 2) the surgery associated with DBS does not appear to affect the cognitive performance of patients with PD 12 months later, except for a mild deficit in lexical fluency.

Deep brain stimulation of the subthalamic nucleus for Parkinson's disease: methodologic aspects and clinical criteria.

The technique of deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD) is evolving very rapidly. The subthalamic nucleus (STN) has become the preferred target in the past few years since our group demonstrated that high-frequency stimulation in this nucleus improves all cardinal features of PD, including resting tremor. This benefit in the parkinsonian symptoms allows a drastic reduction in daily levodopa requirements. Dyskinesias become drastically attenuated, possibly as a consequence of reduced dopaminergic medication but also because STN DBS may stabilize basal ganglia output activity, thus avoiding the problems associated with standard levodopa replacement therapy. DBS of the STN is associated with a marked improvement of motor function even in patients with advanced PD. Such a large degree of benefit in parkinsonian features relies on two crucial points that must be taken into consideration for achieving the best possible results with this technique: proper selection of patients and accuracy in targeting the STN. From a neurosurgical point of view, we believe that the most precise localization of the STN is obtained by using ventriculography to determine the stereotactic coordinates of the STN. This is complemented with intraoperative neuronal microrecording to define physiologically the sensorimotor region of the nucleus. Future advances in neuroimaging techniques may well lead to modifications of our current methodology.

Relicts of dancing mania: the dancing procession of Echternach.

In the small town of Echternach in Luxembourg, remnants of chorea St. Vitii can be found every year when pilgrims gather at the grave of St. Willibrord (658-739) to take part in the so-called Dancing Procession on Whit Tuesday. Miracles and healings are reported to have taken place in front of Willibrord's sarcophagus in the late eighth century. News of the miraculous healings inspired the celebratory folkdances in Echternach. Willibrord became the patron saint of patients with movement disorders. Important annual pilgrimages to the grave of Saint Willibrord, with pilgrims from Gallic and Teutonic provinces, were reported around 1100. The Dancing Procession is first mentioned in the Echternach city archives in 1497. In 1900, Henri Meige, a neurologist with a special interest in movement disorders, visited Echternach to observe the annual Dancing Procession. Although Meige was disappointed with the lack of hysteria, he concluded that the Dancing Procession of Echternach was not without grandeur. Outbreaks of mass hysteria with a background of religious fervor, pagan traditions, or superstition are the most likely explanation for the medieval dancing mania. This view is supported by the religious motivation behind the present-day Dancing Procession in Echternach, a ritual with mixed pagan-Christian origins related to Saint Vitus' dance.