The rationale for continuous dopaminergic stimulation in advanced Parkinson's disease

Control of movement depends on the continuous release of dopamine by neurons in the basal ganglia of the brain. The degeneration of these neurons in Parkinson's disease (PD) interferes with the flow of dopamine, leading to classic motor symptoms. In early PD, enough dopaminergic neurons remain to store dopamine provided by periodic dosing with oral levodopa and relatively normal, tonic levels of dopamine release are maintained. PD progression leads to degeneration of remaining dopaminergic terminals and loss of buffering capacity for exogenous levodopa. As a result, there are supraphysiological levels of dopamine after dosing and troughs when the available dopamine has been depleted. These divergent levels are associated with dyskinesia and ‘off’ states, respectively. Treatment strategies that provide a continuous flow of dopamine and can thus mimic normal physiological dopamine stimulation have potential to improve motor control for patients with advanced PD.     

Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications.     

Deep brain stimulation for Parkinson's disease

Dopaminergic replacement therapy with levodopa/carbidopa is still the cornerstone for the treatment of Parkinson's disease (PD). However, the medical management of PD is complicated by the appearance of disabling motor response fluctuations, levodopa-induced dyskinesias and psychosis. Since the early 1990s, surgical therapies have made a rapid reentry into the therapeutic armamentarium for PD and deep brain stimulation (DBS) of the globus pallidus interna or subthalamic nuclei is currently the most promising of such interventions. Recognition of the physiological changes in basal ganglia circuits in animal models of PD has provided the much-needed theoretic basis for targeting these areas. DBS of these areas has proven to be a safe procedure and effective against all the major motor symptoms of PD. Though not curative it can substantially reduce motor response fluctuations, levodopa-induced dyskinesias, and improve the quality of life of these patients. DBS is an expensive treatment and hardware-related complications are not rare. The results of the procedure are dependent on careful patient selection and the experience of the performing team. An update on the principles, methods and results of such procedures is essential to raise the awareness of this new therapeutic modality and to provide guidelines to the referring physicians.     

Deep brain stimulation for Parkinson's disease

Chronic high-frequency stimulation of the subthalamic nucleus has evolved into a routine treatment for motor fluctuations, dyskinesia and medically refractory tremor in Parkinson's disease. The most important predictors for surgical benefit include excellent responsiveness of akinetic-rigid and axial motor symptoms to levodopa, a normal cognitive status and younger age. Current evidence suggests that for patients fulfilling these selection criteria deep brain stimulation of the subthalamic nucleus is superior to standard oral drug therapy in maintaining a good level of health-related quality of life.     

Deep brain stimulation for Parkinson's disease

Deep brain stimulation (DBS) is making a major impact in patients with advanced Parkinson's disease who continue to be disabled despite the best available medical therapy. Stimulation of the internal segment of the globus pallidus (GPi) or the subthalamic nucleus (STN) can improve tremor, rigidity, bradykinesia and gait disturbances in Parkinson's disease and improve the day-to-day activities of patients with these disabling symptoms. While the mechanism of action of DBS remains poorly understood, the success of technique in the treatment of movement disorders is bringing into question traditional concepts of the organization and of the basal ganglia and spearheading a re-examination of the nature and function of brain areas involved in the control of movement. Future developments in this rapidly advancing area will include the elucidation of the mechanism of action of DBS and technical advances in surgical techniques, in electrode design and in choosing better stimulation parameters. These advances will improve the scope and effectiveness of DBS and expand its clinical indications.     

Deep brain stimulation in the management of Parkinson's disease

Deep brain stimulation (DBS) is a neurosurgical treatment of Parkinson's disease and other movement disorders. This surgical technique is applied to three brain targets: the ventral intermediate nucleus of the thalamus (Vim), the globus pallidus internus (Gpi) and the subthalamic nucleus (STN). Vim DBS improves contralateral parkinsonian tremor. STN and GPi DBS improve contralateral bradykinesia, rigidity, parkinsonian tremor and also levodopa-induced dyskinesia. There is little comparative data between bilateral STN and bilateral GPi procedures but the improvement with bilateral STN DBS seems more pronounced than with bilateral GPi DBS. Moreover, only STN BDS allows a significant decrease of antiparkinsonian medication. The other advantage of STN over GPi DBS is the lower consumption of current. The DBS procedure contrary to ablative surgery has the unique advantage of reversibility and adjustability over time. Patients with no behavioral, mood and cognitive impairments benefit the most from bilateral STN DBS. The stimulation-induced adverse effects related to DBS are reversible and adjustable. More specific adverse effects related do hardware are: disconnection, lead breaking, erosion or infection. The disadvantage of DBS is a relatively high cost. The setting of stimulation parameters to achieve the best clinical result may be very time-consuming. Most authors agree that DBS is a safer and more favorable procedure than ablative surgery.     

Deep brain stimulation of subthalamic nucleous in Parkinson's disease

We present the preliminary results in patients well selected to be implanted by deep brain stimulation (DBS) for Parkinsons's disease (PD). METHODS: 8 PD patients with disabled tremor, akinetic/bradikinetic and rigidity, in spite of best therapeutic assay with poor response were referred to surgery. It was implanted DBS Itrell 2. Theses patients were evaluated by the following scales: UPDRS, Schwab and England. RESULTS: The preliminary results in 6 months showed significant improvement of motor performance and it is shown by the scores. There were no complications so far with these procedures. CONCLUSION: The preliminary results indicate that DBS is highly effective, with benefit to those patients and it is according to literature.     

Deep brain stimulation for the treatment of Parkinson's disease

Approximately 30,000 patients have been treated throughout the world with deep brain stimulation for Parkinson's disease and other conditions. With accumulating experience, there has been an appreciation of the important benefits of this procedure, including the alleviation of disability and improvement in the quality of life. We have also become aware of some limitations of DBS surgery. Among the important issues that remain to be resolved are the timing of surgery, whether early or late in the course of the disease, and the best target for the individual patient, including a reassessment of the relative merits of globus pallidus versus subthalamic nucleus surgery. A better understanding of the symptoms that are resistant to both levodopa therapy and DBS surgery is also required.     

Deep brain stimulation effects on gait variability in Parkinson's disease

The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on fall risk in patients with Parkinson's disease (PD) currently remain unclear. Although several gait parameters, such as gait speed, have shown improvement with DBS, some studies have reported an increased fall risk following DBS. The purpose of this study was to examine the effect of bilateral DBS on gait variability, a marker of fall risk. The gait of 13 patients with idiopathic PD was analyzed to determine the influence of DBS, levodopa and both therapies together. Following treatment with both levodopa and STN DBS, subjects displayed improved gait speed, reduced gait variability (enhanced stability), and lower Unified Parkinson's Disease Rating Scale (UPDRS) scores. Although UPDRS scores improved with STN DBS alone, parallel improvements were not seen for gait variability. These findings suggest that different mechanisms may contribute to performance on UPDRS motor testing and gait stability in response to DBS. © 2009 Movement Disorder Society     

Deep brain stimulation in Parkinson's disease following fetal nigral transplantation

OFF‐period dyskinesias have been reported as a consequence of fetal nigral transplantation for Parkinson's disease. This type of dyskinesias may appear in patients even in the prolonged absence of antiparkinson medication and be aggravated by levodopa. Therefore, pharmacological therapeutic approaches in these patients are limited. Here we report two patients with bilateral fetal nigral grafts in the caudate and putamen subjected to deep brain stimulation (DBS) of the globus pallidus internus (GPi) or subthalamic nucleus (STN). Clinical assessment was performed according to UPDRS and the clinical dyskinesia rating scale. In both patients, we found significant improvement in OFF‐period symptoms as well as levodopa‐induced dyskinesias. However, only GPi‐DBS led to a significant reduction of OFF‐period dyskinesias whereas STN‐DBS did not influence dyskinesias unrelated to external dopaminergic application. These findings, based on two case reports, highlight the pivotal role of the GPi in mediating dyskinesia‐related neural activity within the basal ganglia loop. © 2008 Movement Disorder Society     

Deep brain stimulation in Parkinson's disease patients: biochemical evidence

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.     

Deep brain stimulation and its effect on sleep in Parkinson's disease

Deep Brain Stimulation (DBS) is an effective treatment for patients with advanced Parkinson's disease (PD) and motor complications whose condition can no longer be improved by adjustment of medical therapy. PD patients often report increased daily somnolence and night sleep abnormalities partially related to dopaminergic treatment. In a survey of 386 consecutive non-demented non-depressed PD patients seen in our clinic over a period of 3 months we found increased daily somnolence to be relatively uncommon in non-demented PD patients, although it may be associated with stable treatment with high dose dopamine agonists. Disease related factors seemed responsible for night sleep abnormalities. Because DBS of the subthalamic nucleus (STN) reduces motor disability, as well as total medication intake, one would expect a similar benefit on sleep abnormalities. Indeed, recent evidence suggests that chronic STN-DBS may improve sleep quality through increased nocturnal mobility and reduction of sleep fragmentation.     

Unilateral subthalamic deep brain stimulation in advanced Parkinson's disease.

Eight patients with advanced PD received a unilateral STN DBS. The UPDRS III off drug-on DBS was improved by a mean 44%. Dyskinesias were ameliorated. Levodopa daily dose was reduced. Three patients required the implantation of the second electrode. Unilateral DBS may be efficacious in some patients with advanced PD.