Bilateral subthalamic nucleus deep brain stimulation increases fixational saccades during movement preparation: evidence for impaired preparatory set.

People with Parkinson's disease (PD) exhibit an increase in fixational saccades during the preparatory period prior to target onset in the antisaccade task and this increase is related to an increase in prosaccade errors in the antisaccade task. It was previously shown that bilateral, but not unilateral, subthalamic nucleus deep brain stimulation (STN DBS) in people with PD further increases the prosaccade error rate on the antisaccade task. We investigated whether bilateral STN DBS also increases the number of fixational saccades in the preparatory period of the antisaccade task and if this increase in the number of fixational saccades is related to prosaccade errors. We found that: (1) there were a greater number of fixational saccades during the preparatory period of the antisaccade task during bilateral STN DBS compared to no STN DBS (p < 0.001), unilateral STN DBS (p < 0.001), and healthy controls (p = 0.02), and (2) the increase in the number of fixational saccades increased the probability of a prosaccade error for the antisaccade task during bilateral STN DBS (p = 0.005). This association between number of fixational saccades and probability of a prosaccade error was similar across no STN DBS, unilateral stimulation, and healthy controls. In addition, we found that the proportion of express prosaccade errors and prosaccade error latency were similar across stimulation conditions. We propose that bilateral STN DBS disrupts the integrated activity of cortico-basal ganglia-collicular processes underlying antisaccade preparation and that this disruption manifests as an increase in both fixational saccades and prosaccade error rate.

Current Practices for Outpatient Initiation of Levodopa-Carbidopa Intestinal Gel for Management of Advanced Parkinson's Disease in the United States.

In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson's disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa's site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease "off" time, increase "on" time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors' experiences. FUNDING: AbbVie, Inc. Plain language summary available for this article.

Results from recent studies have shown that continuous infusion of levodopa-carbidopa intestinal gel (LCIG) into the jejunum (a part of the small intestine) effectively manages the motor and nonmotor complications (e.g., tremor, extreme stiffness in arms and legs, difficulty walking, and impaired balance) experienced by patients with advanced Parkinson's disease (PD). LCIG is administered by a portable pump directly into the patient's jejunum by a permanent tube that is inserted surgically. LCIG therapy is beneficial to advanced PD patients over orally administered carbidopa/levodopa for two reasons. First, oral carbidopa/levodopa moves from the stomach to the small intestine where it is intermittently absorbed into the blood stream. LCIG is administered continuously and offers better symptom control for longer. Results from clinical trials and observational studies have shown that LCIG significantly decreases "off" time (poor motor control) and increases "on" time (good motor control) in advanced PD patients without troublesome dyskinesia, which results from the higher doses of oral levodopa required to treat the symptoms. Second, LCIG is absorbed in the jejunum, thereby bypassing the stomach where problems can occur because of inconsistent stomach emptying. In the US, titration of LCIG is performed mostly in an outpatient setting. Some clinicians may view titration of LCIG to be too complex and variable, so they avoid using LCIG therapy for their PD patients. Fortunately, emerging data and clinicians' expanding experience with LCIG have shown that titration can be easily managed in an outpatient setting, allowing for more customized therapeutic regimens for patients.

Patient Knowledge and Attitudes towards Genetic Testing in Parkinson's Disease Subjects with Deep Brain Stimulation.

OBJECTIVES: As genetic testing is becoming more widely commercially available for Parkinson's disease (PD) and may have implications regarding clinical outcomes for deep brain stimulation (DBS) and other therapies, we aimed to determine patient knowledge and attitudes towards genetic testing. METHODS: A sample of 88 PD subjects with bilateral STN-DBS completed a Genetic Attitudes Questionnaire (GAQ). Knowledge and attitudes towards genetic testing were assessed. RESULTS: The mean percent of correct responses regarding genetic testing knowledge was 58.5%. Nearly 90% of subjects were unfamiliar with Genetic Information Nondiscrimination Act (GINA). The most important reasons subjects cited in deciding whether to undergo genetic testing included (1) to be a candidate for clinical trials if positive, (2) to learn that they do not carry a mutation, and (3) because a healthcare provider had recommended it. Individuals who influence decision-making include spouses and children. About 88% of subjects would share results with spouses, children, and siblings. DISCUSSION: These results reveal that there is a major knowledge gap regarding genetic testing in PD and the implications of testing results on treatment, work, insurance, and privacy. Also, subjects would mainly seek genetic testing to participate in clinical trials, with spouses and children being the key stakeholders in decision-making.

Bilateral deep brain stimulation of the subthalamic nucleus increases pointing error during memory-guided sequential reaching.

Deep brain stimulation of the subthalamic nucleus (STN DBS) significantly improves clinical motor symptoms, as well as intensive aspects of movement like velocity and amplitude in patients with Parkinson's disease (PD). However, the effects of bilateral STN DBS on integrative and coordinative aspects of motor control are equivocal. The aim of this study was to investigate the effects of bilateral STN DBS on integrative and coordinative aspects of movement using a memory-guided sequential reaching task. The primary outcomes were eye and finger velocity and end-point error. We expected that bilateral STN DBS would increase reaching velocity. More importantly, we hypothesized that bilateral STN DBS would increase eye and finger end-point error and this would not simply be the result of a speed accuracy trade-off. Ten patients with PD and bilaterally implanted subthalamic stimulators performed a memory-guided sequential reaching task under four stimulator conditions (DBS-OFF, DBS-LEFT, DBS-RIGHT, and DBS-BILATERAL) over 4 days. DBS-BILATERAL significantly increased eye velocity compared to DBS-OFF, DBS-LEFT, and DBS-RIGHT. It also increased finger velocity compared to DBS-OFF and DBS-RIGHT. DBS-BILATERAL did not change eye end-point error. The novel finding was that DBS-BILATERAL increased finger end-point error compared to DBS-OFF, DBS-LEFT, and DBS-RIGHT even after adjusting for differences in velocity. We conclude that bilateral STN DBS may facilitate basal ganglia-cortical networks that underlie intensive aspects of movement like velocity, but it may disrupt selective basal ganglia-cortical networks that underlie certain integrative and coordinative aspects of movement such as spatial accuracy.

Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND: Nondopaminergic pathways represent potential targets to treat levodopa-induced dyskinesia in Parkinson's disease (PD). This pilot-study (NCT01767129) examined the safety/efficacy of the sigma-1 receptor-agonist and glutamatergic/monoaminergic modulator, dextromethorphan plus quinidine (to inhibit rapid dextromethorphan metabolism), for treating levodopa-induced dyskinesia. METHODS: PD patients were randomized to dextromethorphan/quinidine (45 mg/10 mg twice daily)/placebo in two 2-week double-blind, crossover treatment periods, with intervening 2-week washout. After 14 days, a 2-hour intravenous levodopa-infusion was administered. Patient examinations were videotaped before infusion ("off" state) and every 30 minutes during and afterwards until patients returned to "off." The primary endpoint was dyskinesia-severity during infusion measured by Unified Dyskinesia Rating Scale part 3 area-under-curve scores (blinded expert rated). Additional endpoints included other dyskinesia/motor assessments, global measures of clinical-change, and adverse-events. RESULTS: A total of 13 patients were randomized and completed the study (efficacy-evaluable population). Dyskinesia-severity was nonsignificantly lower with dextromethorphan/quinidine than placebo during infusion (area-under-curve 966.5 vs 1048.8; P = .191 [efficacy-evaluable patients]), and significantly lower in a post-hoc sensitivity analysis of the per-protocol-population (efficacy-evaluable patients with ≥ 80% study-drug-compliance, n = 12) when measured from infusion start to 4-hours post-infusion completion (area-under-curve 1585.0 vs 1911.3; P = .024). Mean peak dyskinesia decreased significantly from infusion-start to return to "off" (13.3 vs 14.9; P = .018 [efficacy-evaluable patients]). A total of 9 patients rated dyskinesia "much/very much improved" on dextromethorphan/quinidine versus 1-patient on placebo. Dextromethorphan/quinidine did not worsen PD-motor scores, was generally well tolerated, and was associated with more frequent adverse events. CONCLUSION: This study provides preliminary evidence of clinical benefit with dextromethorphan/quinidine for treating levodopa-induced dyskinesia in PD. Larger studies with a longer treatment duration need to corroborate these early findings. © 2017 International Parkinson and Movement Disorder Society.

Sildenafil in the Treatment of Erectile Dysfunction in Parkinson's Disease.

BACKGROUND: Erectile dysfunction (ED) is a common nonmotor feature in patients with Parkinson's disease (PD). Data regarding the tolerability and efficacy of anti-ED medication in the PD population are limited. The aim of this work was to assess the safety and efficacy of sildenafil in treatment of ED in men with PD. METHODS: This was a double-blind, placebo-controlled, cross-over study consisting of two 4-week arms separated by a 2-week washout period. Treatment sequence (placebo-sildenafil vs. sildenafil-placebo) was randomized. Sildenafil was started at 50 mg and adjusted to 25, 50, or 100 mg after 2 weeks, depending upon side effects. The Erectile Function domain of the International Index of Erectile Function (IIEF-EF; primary outcome measure) and the Parkinson's Disease Quality of Life (secondary outcome measure) were obtained at baseline and end of each treatment period. The UPDRS was obtained at each study visit. The difference between group means was tested for statistical significance using t tests. RESULTS: Twenty men participated and completed both treatment arms of the study. There was one instance of headache as a side effect. There was a significant effect of sildenafil on sexual functioning as measured by the IIEF-EF domain (P < 0.0001; mean for sildenafil = 23.2 ± 7.0; mean for placebo = 12.3 ± 7.5). There were no treatment effects for quality of life (P = 0.3) or PD symptoms (P = 0.86). CONCLUSIONS: Sildenafil was safe and improved ED in this sample of men with PD. Overall, PD symptoms and quality of life were not impacted by use of sildenafil.

The effects of unilateral versus bilateral subthalamic nucleus deep brain stimulation on prosaccades and antisaccades in Parkinson's disease.

Unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson's disease improves skeletomotor function assessed clinically, and bilateral STN DBS improves motor function to a significantly greater extent. It is unknown whether unilateral STN DBS improves oculomotor function and whether bilateral STN DBS improves it to a greater extent. Further, it has also been shown that bilateral, but not unilateral, STN DBS is associated with some impaired cognitive-motor functions. The current study compared the effect of unilateral and bilateral STN DBS on sensorimotor and cognitive aspects of oculomotor control. Patients performed prosaccade and antisaccade tasks during no stimulation, unilateral stimulation, and bilateral stimulation. There were three sets of findings. First, for the prosaccade task, unilateral STN DBS had no effect on prosaccade latency and it reduced prosaccade gain; bilateral STN DBS reduced prosaccade latency and increased prosaccade gain. Second, for the antisaccade task, neither unilateral nor bilateral stimulation had an effect on antisaccade latency, unilateral STN DBS increased antisaccade gain, and bilateral STN DBS increased antisaccade gain to a greater extent. Third, bilateral STN DBS induced an increase in prosaccade errors in the antisaccade task. These findings suggest that while bilateral STN DBS benefits spatiotemporal aspects of oculomotor control, it may not be as beneficial for more complex cognitive aspects of oculomotor control. Our findings are discussed considering the strategic role the STN plays in modulating information in the basal ganglia oculomotor circuit.

Common and unique responses to dopamine agonist therapy and deep brain stimulation in Parkinson's disease: an H(2)(15)O PET study.

BACKGROUND: Dopamine agonist therapy and deep brain stimulation (DBS) of the subthalamic nucleus (STN) are antiparkinsonian treatments that act on a different part of the basal ganglia-thalamocortical motor circuitry, yet produce similar symptomatic improvements. OBJECTIVE/HYPOTHESIS: The purpose of this study was to identify common and unique brain network features of these standard treatments. METHODS: We analyzed images produced by H(2)(15)O positron emission tomography (PET) of patients with Parkinson's disease (PD) at rest. Nine patients were scanned before and after injection of apomorphine, and 11 patients were scanned while bilateral stimulators were off and while they were on. RESULTS: Both treatments produced common deactivations of the neocortical sensorimotor areas, including the supplementary motor area, precentral gyrus, and postcentral gyrus, and in subcortical structures, including the putamen and cerebellum. We observed concomitant activations of the superior parietal lobule and the midbrain in the region of the substantia nigra/STN. We also detected unique, treatment-specific changes with possible motor-related consequences in the basal ganglia, thalamus, neocortical sensorimotor cortex, and posterolateral cerebellum. Unique changes in nonmotor regions may reflect treatment-specific effects on verbal fluency and limbic functions. CONCLUSIONS: Many of the common effects of these treatments are consistent with the standard pathophysiologic model of PD. However, the common effects in the cerebellum are not readily explained by the model. Consistent deactivation of the cerebellum is interesting in light of recent reports of synaptic pathways directly connecting the cerebellum and basal ganglia, and may warrant further consideration for incorporation into the model.

Temporal dynamics of cortical and subcortical responses to apomorphine in Parkinson disease: an H2(15)O PET study.

H2(15)O positron emission tomography (PET) was used to study the temporal course of central nervous system (CNS) responses to apomorphine in patients with idiopathic Parkinson disease (PD). Agonist-induced changes in regional cerebral blood flow (rCBF) were evaluated within corticostriatal-thalamocortical circuits as well as in regions that extend beyond the standard pathophysiological model for PD. Compared with controls, rCBF was increased in PD patients in subcortical regions including the basal ganglia and cerebellum and both increased and decreased in prefrontal, parietal, sensorimotor, and paralimbic cortical areas. Apomorphine reversed many of these effects and had widespread effects throughout the brain. We evaluated the effects of apomorphine as they changed over time, comparing rCBF before the motor response and at later times when the motor response was maximal. Apomorphine's effects on functional connectivity also changed over time; activity in the ventrolateral thalamus was coupled with that in the SMA and cerebellum at the time of maximum motor response, but not at 45 seconds. Apomorphine affected rCBF in regions commonly considered part of the pathophysiological model of PD (eg, basal ganglia, thalamus, SMA), and other effects were seen in regions outside of the model (eg, cerebellum and superior parietal lobule). Results are discussed in light of this model.