Leo Verhagen Metman

Deep brain stimulation for Parkinson's disease: Prevalence of adverse events and need for standardized reporting

Deep brain stimulation (DBS) has assumed a prominent role in the treatment of Parkinsons disease (PD). In this manuscript, we attempt to estimate the prevalence and categorize adverse events (AEs) of DBS in PD, based on efficacy studies published over the last decade. We conclude that reliable categorization and quantification of AEs based on available data poses many challenges and argue that a standardized scheme for reporting AEs should be created. This would provide a foundation for a meaningful risk/benefit analysis, for comparison of results between centers and, ultimately, for a well informed decision by physicians and patients as to whether surgery should be pursued.

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 Parkinsons disease. The development of motor complications in Parkinsons 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 individuals 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease therapy will limit the development of motor complications.

Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease.

The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinsons disease.

Factors involved in long-term efficacy of deep brain stimulation of the thalamus for essential tremor

OBJECT Although nucleus ventralis intermedius stimulation has been shown to be safe and efficacious in the treatment of essential tremor, there is a subset of patients who eventually lose benefit from their stimulation. Proposed causes for this phenomenon include tolerance, disease progression, and suboptimal location. The goal of this study was to assess the factors that may lead to both stimulation failure, defined as loss of meaningful tremor relief, and less satisfactory outcomes, defined as leads requiring voltages>3.6 V for effective tremor control. METHODS The authors present their clinical outcomes from 31 leads in 27 patients who had effective tremor control for >1 year following nucleus ventralis intermedius stimulation. All patients postoperatively had a mean decrease in both the writing and drawing subscales of the Fahn-Tolosa-Marin Tremor Rating Scale (p<0.001). RESULTS After a mean follow-up of 40 months, 22 patients continued to have tremor control with stimulation. Four patients eventually lost efficacy of their stimulation at a mean of 39 months. There was no difference in age, duration of disease, or disease severity between the groups. Examination of perioperative factors revealed that suboptimal anteroposterior positioning as evidenced on intraoperative fluoroscopy occurred significantly more frequently in patients with stimulation failure (p=0.018). In patients with less satisfactory outcomes, no difference was seen between group demographics. Fluoroscopy again revealed suboptimal positioning more frequently in these patients (p=0.005). CONCLUSIONS This study provides further evidence that suboptimal lead position in combination with disease progression or tolerance may result in less satisfactory long-term outcomes.

Effects of STN DBS on Rigidity in Parkinson's Disease

We quantified the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and medication on Parkinsonian rigidity using an objective measure of work about the elbow joint during a complete cycle of imposed 1-Hz sinusoidal oscillations. Resting and activated rigidity were analyzed in four experimental conditions: 1) off treatment; 2) on DBS; 3) on medication; and 4) on DBS plus medication. Rigidity at the elbow joint was also assessed using the unified Parkinsons disease rating scale (UPDRS). We tested ten patients who received STN DBS and ten age-matched neurologically healthy control subjects. The activated rigidity condition increased work in both Parkinsons disease (PD) patients and control subjects. In PD patients, STN DBS reduced both resting and activated rigidity as indicated by work and the UPDRS rigidity score. This is the first demonstration that STN stimulation reduces rigidity using an objective measure such as work. In contrast, the presurgery dose of antiParkinsonian medication did not significantly improve the UPDRS rigidity score and reduced work only in the activated rigidity condition. Our results suggest that STN DBS may be more effective in alleviating rigidity in the upper limb of PD patients than medications administered at presurgery dosage level.

Transdermal dopaminergic D2 receptor agonist therapy in Parkinson's disease with N-0923 TDS: A double-blind, placebo-controlled study

N‐0923 is a non‐ergot, dopaminergic D2 agonist designed to be transdermally available. It has anti‐parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N‐0923 transdermally (N‐0923 TDS).

The effect of unilateral electrostimulation of the subthalamic nucleus on respiratory/ phonatory subsystems of speech production in Parkinson's disease: a preliminary report

This paper reports findings on the respiratory/phonatory subsystems from an on‐going study investigating the effect of unilateral electrostimulation of the subthalamic nucleus (STN) on different speech subsystems in people with Parkinsons disease (PD). Speech recordings were made in the medication‐off state at baseline, three months post surgery with stimulation‐on, and with stimulation‐off, in six right‐handed PD patients. Subjects completed several speech tasks. Acoustic analyses of the maximally sustained vowel phonation were reported. The results were compared to the scores of the motor section of the Unified Parkinsons Disease Rating Scale (UPDRS‐III) obtained under the same conditions. Results showed that stimulation‐on improved UPDRS‐III scores in all six subjects. While mild improvement was observed for all subjects in the Stimulation‐on condition, three subjects received left‐STN stimulation showed a significant decline in vocal intensity and vowel duration from their baseline indicating the speech function was very susceptible to micro lesions due to the surgical procedure itself when the surgical site was in the dominant hemisphere.

Stimulation-induced parkinsonism after posteroventral deep brain stimulation of the globus pallidus internus for craniocervical dystonia

The authors report on a patient with craniocervical dystonia who was treated with bilateral GPi stimulation, with excellent improvement in dystonia but at the cost of stimulation-induced, reversible parkinsonism. Stimulation through ventral contacts resulted in maximal relief of craniocervical dystonia but induced considerable hypophonia, bradykinesia, rigidity, freezing, and impaired postural reflexes. Stimulation through dorsal contacts alleviated parkinsonism, but resulted in the return of dystonia. No stimulation parameters could alleviate the dystonia without inducing parkinsonism over the course of his 4-year follow-up.

Pathological tremor prediction using surface electromyogram and acceleration: potential use in 'ON-OFF' demand driven deep brain stimulator design.

OBJECTIVE We present a proof of concept for a novel method of predicting the onset of pathological tremor using non-invasively measured surface electromyogram (sEMG) and acceleration from tremor-affected extremities of patients with Parkinsons disease (PD) and essential tremor (ET). APPROACH The tremor prediction algorithm uses a set of spectral (Fourier and wavelet) and nonlinear time series (entropy and recurrence rate) parameters extracted from the non-invasively recorded sEMG and acceleration signals. MAIN RESULTS The resulting algorithm is shown to successfully predict tremor onset for all 91 trials recorded in 4 PD patients and for all 91 trials recorded in 4 ET patients. The predictor achieves a 100% sensitivity for all trials considered, along with an overall accuracy of 85.7% for all ET trials and 80.2% for all PD trials. By using a Pearsons chi-square test, the prediction results are shown to significantly differ from a random prediction outcome. SIGNIFICANCE The tremor prediction algorithm can be potentially used for designing the next generation of non-invasive closed-loop predictive ON-OFF controllers for deep brain stimulation (DBS), used for suppressing pathological tremor in such patients. Such a system is based on alternating ON and OFF DBS periods, an incoming tremor being predicted during the time intervals when DBS is OFF, so as to turn DBS back ON. The prediction should be a few seconds before tremor re-appears so that the patient is tremor-free for the entire DBS ON-OFF cycle and the tremor-free DBS OFF interval should be maximized in order to minimize the current injected in the brain and battery usage.

Test–retest reliability of UPDRS-III, dyskinesia scales, and timed motor tests in patients with advanced Parkinson's disease: An argument against multiple baseline assessments

The primary objective of this study was to assess the intra‐rater reliability of the motor section of the Unified Parkinsons Disease Rating Scale (UPDRS‐III) in patients with advanced Parkinsons disease (PD). The secondary objective was to assess the intra‐rater reliability of standard timed motor tests and dyskinesia scales to determine the necessity of multiple baseline core evaluations before surgery for PD. We carried out two standardized preoperative core evaluations of patients with advanced PD scheduled to undergo deep brain stimulation. Patients were examined in the defined off and on conditions by the same rater. UPDRS‐III, timed tests, and dyskinesia scores from the two evaluations were compared using Wilcoxon Signed Ranks tests and intraclass correlation coefficients (ICC). Differences in UPDRS‐III scores for the two visits were clinically and statistically nonsignificant, and the ICC was 0.9. Similarly, there were no significant differences in timed motor tests or dyskinesia scores, with a median ICC of 0.8. The results indicate that previous findings of high test–retest reliability of UPDRS‐III in early untreated PD patients can now be extended to those with advanced disease complicated by motor fluctuations. In addition, test–retest reliability of dyskinesia scales and timed motor tests was high. Taken together, these findings challenge the need for multiple baseline assessments as currently stipulated in core assessment protocols for surgical intervention in PD.