Vitamins and Infusion of Levodopa-Carbidopa Intestinal Gel.

Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.

Levodopa Versus Dopamine Agonist after Subthalamic Stimulation in Parkinson's Disease.

BACKGROUND: No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD). OBJECTIVE: Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD. METHODS: Thirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population. RESULTS: Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders. CONCLUSIONS: This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Non-Motor Fluctuations in Parkinson's Disease: Validation of the Non-Motor Fluctuation Assessment Questionnaire.

BACKGROUND: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms. OBJECTIVES: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA). METHODS: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire. RESULTS: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy. CONCLUSIONS: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.

Programming Directional Deep Brain Stimulation in Parkinson's Disease: A Randomized Prospective Trial Comparing Early versus Delayed Stimulation Steering.

INTRODUCTION: Programming directional leads poses new challenges as the optimal strategy is yet to be established. We designed a randomized control study to establish an evidence-based programming algorithm for patients with Parkinson's disease undergoing subthalamic nucleus deep brain stimulation with directional leads. METHODS: Fourteen consecutive patients were randomized to programming with either early or delayed (i.e., starting with a "ring mode") steered stimulation. Motor scores, number of programming visits, calls to the clinic, battery consumption, and stimulation adjustments required were recorded and compared between groups, using the Wilcoxon signed-ranks test, after 3 months of open-label programming. RESULTS: Thirteen patients (25 electrodes) were included, of which 23 were steerable. Nine out of 14 electrodes allocated to delayed steered stimulation were changed to steered mode due to side effects during the course of the study. No patients (11 electrodes) initially allocated to early steered stimulation were converted to ring mode. The 2 study arms did not differ in any of the considered measures at 3 months. CONCLUSION: Programming with early or delayed steered stimulation is equally effective in the short term. However, delayed steering is less time consuming and is not always needed.

Establishing a Standard of Care for Deep Brain Stimulation Centers in Canada.

During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to share their knowledge regarding deep brain stimulation (DBS) management of movement disorders in three domains: (1) the programming algorithms, (2) the necessary team to run a neurosurgery program, and (3) the appropriate scales to better define in a more comprehensive fashion the effect of the brain surgery. Each presentation was followed by an open discussion, and this article reports on the conclusions of this meeting on these three questions. Concerning programming, the role of the pulse width and the switching off of the stimulation at night for thalamic stimulation for the control of tremor have been discussed. The algorithms proposed in the literature for programming in Parkinson's disease (PD) need validation. In dystonia, the use of monopolar vs bipolar parameters, the use of low vs high frequencies and the use of smaller versus larger pulse widths all need to be examined properly. Concerning the necessary team to run a neurosurgical program, recommendations will follow the suggestions for standardized outcome measures. Regarding the outcome measures for DBS in PD, investigations need to focus on the non-motor aspects of PD. Identifying which nonmotor symptoms respond to DBS would allow a better screening before and satisfaction postoperatively. There is an important need for more data to determine the optimal programming protocol and the standard measures that should be performed routinely by all centers.

Long-term double-blinded unilateral pedunculopontine area stimulation in Parkinson's disease.

BACKGROUND: Gait-related symptoms are often refractory to current available treatment options with a significant reduction in quality of life in Parkinson's disease. OBJECTIVES: The objective of this study was to determine the long-term efficacy and safety of unilateral pedunculopontine area stimulation for refractory gait and balance impairment in Parkinson's disease. METHODS: This study used periodic randomized double-blinded assessments until 4 years postoperatively. The primary outcomes were gait-related items of the UPDRS part II and the MDS-UPDRS part III. RESULTS: At baseline, the median age and disease duration was 63 years (interquartile range: 62, 65) and 15 years (interquartile range: 11, 20). At 2 years, patient-reported freezing (UPDRS part II, off-time) was significantly better when compared with baseline (P =.028), with 62.5% of responders. At 4 years, there was no significant change in the used outcomes, but 66.7 % (n = 4 of 6) were responders for off-time patient-reported freezing and falling. CONCLUSIONS: Pedunculopontine area stimulation has an initial but not sustained benefit for gait-related symptoms. © 2016 International Parkinson and Movement Disorder Society.

Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years.

The local injection of botulinum toxin is accepted as the first-line treatment of primary cervical dystonia. This approach provides adequate symptomatic relief for most patients, but up to one-third will have an unsatisfactory response. Deep brain stimulation of the globus pallidus internus has been increasingly used in dystonic syndromes that are refractory to best pharmacological approaches. Although cervical dystonia is the most common idiopathic focal dystonia, evidence for long-term responsiveness to pallidal stimulation is limited. The primary objective of this study was to prospectively collect outcome data from baseline to last clinical follow-up on patients with idiopathic cervical dystonia treated with bilateral pallidal stimulation. Blinded video assessment of examinations performed preoperatively and at last video assessment were performed. Ten patients had complete prospective clinical follow-up. Baseline total Toronto Western Spasmodic Torticollis Rating Scale score (±standard deviation) was 54.5 ± 12.4 (range, 35.0-70.3). Comparison of the blinded severity sub-score on baseline video and at last video assessment at a mean of 7.7 years postoperatively demonstrated a mean improvement of 47.6% (P = 0.002) and strong inter-observer correlation between blinded raters (Spearman r = 0.78, 95% confidence interval 0.49-0.92, P = 0.0001). All 10 patients had 5 years of open prospective follow-up, documenting a 47.4 ± 26.4% (P < 0.01) mean improvement with respect to baseline. This was maintained at a mean of 7.8 years at last follow-up after surgery (range, 4.9-10.7 years) with a 54.4 ± 27.4% mean improvement (P < 0.01). Deep brain stimulation of the globus pallidus is an effective and long-lasting second-line treatment of cervical dystonia, with benefit in some of our patients extending to >10 years. More data are needed to explain variations in individual responses and to guide individual programming parameters.

Predictive factors of outcome in primary cervical dystonia following pallidal deep brain stimulation.

BACKGROUND: Improvement after bilateral globus pallidus internus deep brain stimulation (DBS) in primary generalized dystonia has been negatively associated with disease duration and age, but no predictive factors have been identified in primary cervical dystonia (CD). METHODS: Patients treated with bilateral globus pallidus internus DBS for primary CD from 2 DBS centers with preoperative and postoperative Toronto Western Spasmodic Torticollis Rating Scales (TWSTRS) were studied retrospectively to explore possible predictors of response. RESULTS: Patients showed significantly improved TWSTRS total and severity scores (n = 28, mean 55.6% and 50.8%, respectively, both P < .001). Patients with lateral shift at baseline had less improvement in TWSTRS severity subscores (P = .02). No correlations between outcomes and disease duration, age at dystonia onset or surgery, baseline scores, or other included variables were found. CONCLUSIONS: Although this is the largest study supporting efficacy of bilateral pallidal DBS in primary CD, no major clinical predictive outcomes of surgical benefit were identified.

Clinicopathological study in progressive supranuclear palsy with pedunculopontine stimulation.

BACKGROUND: Pedunculopontine nucleus (PPN) DBS has emerged as a potential intervention for patients with gait and balance disorders. However, targeting this nucleus can be challenging. We report on the first neuropathological analyses after PPN-DBS surgery in advanced progressive supranuclear palsy (PSP). METHODS: Two patients with PSP underwent unilateral PPN-DBS surgery and were clinically followed to autopsy. Both patients underwent postmortem neuropathological analysis, including choline acetyltransferase immunohistochemistry, to ascertain PPN boundaries and electrode location. RESULTS: Both patients experienced partial improvement in some motor and nonmotor domains postintervention, but died shortly of other complications. Postmortem neuropathological analysis of each patient confirmed the electrode in a region of cholinergic neuronal loss corresponding to the PPN. CONCLUSIONS: We provide histopathological evidence for the validity of our stereotactic approach to target the PPN and correlate electrode location with clinical outcomes.

Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson's disease.

Epidural motor cortex stimulation has been reported to be effective in treating some movement disorders. Nevertheless, clinical results have been variable and no double-blinded evaluations have been reported. The aim of this study was to investigate efficacy and safety of unilateral subdural motor cortex stimulation in patients with essential tremor and Parkinson's disease. Six patients with essential tremor and five parkinsonian patients were selected. Craniotomy was performed under local anaesthesia with conscious sedation. A four contact electrode (Resume II model 3587, Medtronic, Inc) was positioned on the motor cortex, after identification of the area with direct monopolar cortical stimulation. Soon after surgery, a variety of different settings of stimulation were assessed using standard rating scales to select the optimal stimulation parameters. The effects of chronic stimulation were evaluated in both groups of patients after 3 months (double-blinded fashion) and 1 year (open fashion). In essential tremor, contralateral hand tremor scores significantly improved (P = 0.04) with stimulation during the double-blinded study, whereas in Parkinson's disease, there were no changes in the OFF medication/on stimulation motor scores compared with off stimulation. At 1 year, tremor was improved by stimulation in two out of three patients with essential tremor available at follow-up, whereas no improvement was observed in the five parkinsonian patients. One parkinsonian patient had a cortical venous infarct. Three other patients had self-limiting seizures with aggressive trials of stimulation in the period of dosage selection. These findings suggest that unilateral subdural motor cortex stimulation may be useful for contralateral hand tremor in selected patients with essential tremor but was not effective in improving parkinsonian signs in our series.

Axial Impairment Following Deep Brain Stimulation in Parkinson's Disease: A Surgicogenomic Approach.

BACKGROUND: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed "surgicogenomics". OBJECTIVE: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson's disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. METHODS: Retrospective clinical data was extracted from 150 patient's charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. RESULTS: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2. CONCLUSION: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.

The dominant-STN phenomenon in bilateral STN DBS for Parkinson's disease.

In some patients with Parkinson's disease (PD) and bilateral STN-DBS the motor benefit from one STN alone appears similar to the improvement obtained with bilateral STN-DBS. Thus, we hypothesized that some patients have a "dominant-STN," whose stimulation achieves similar results than bilateral stimulation. Twenty-two consecutive PD patients with bilateral STN-DBS were assessed in 4 randomized conditions: bilateral off-stimulation, bilateral on-stimulation, unilateral right- and unilateral left-stimulation. A hierarchical agglomerative cluster analysis of the motor UPDRS scores in these 4 conditions showed that 11 patients (50%) presented with a "dominant-STN." Interestingly, in 3 of these patients the dominant-STN was ipsilateral to the most affected side of the body. Our results support the presence of different phenotypes of response to bilateral STN stimulation. In our sample 50% of the patients presented with a dominant-STN, suggesting that a non-negligible part of PD patients might not need bilateral STN-DBS surgery.

Unilateral pedunculopontine stimulation improves falls in Parkinson's disease.

Postural instability and falls are a major source of disability in patients with advanced Parkinson's disease. These problems are currently not well addressed by either pharmacotherapy nor by subthalamic nucleus deep-brain stimulation surgery. The neuroanatomical substrates of posture and gait are poorly understood but a number of important observations suggest a major role for the pedunculopontine nucleus and adjacent areas in the brainstem. We conducted a double-blinded evaluation of unilateral pedunculopontine nucleus deep-brain stimulation in a pilot study in six advanced Parkinson's disease patients with significant gait and postural abnormalities. There was no significant difference in the double-blinded on versus off stimulation Unified Parkinson's Disease Rating Scale motor scores after 3 or 12 months of continuous stimulation and no improvements in the Unified Parkinson's Disease Rating Scale part III scores compared to baseline. In contrast, patients reported a significant reduction in falls in the on and off medication states both at 3 and 12 months after pedunculopontine nucleus deep-brain stimulation as captured in the Unified Parkinson's Disease Rating Scale part II scores. Our results suggest that pedunculopontine nucleus deep-brain stimulation may be effective in preventing falls in patients with advanced Parkinson's disease but that further evaluation of this procedure is required.

Advanced Therapies for the Management of Dopamine Dysregulation Syndrome in Parkinson's Disease.

BACKGROUND: Dopamine Dysregulation Syndrome (DDS) is an adverse non-motor complication of dopamine replacement therapy in Parkinson's disease. The current literature on this syndrome is limited, and it remains underdiagnosed and challenging to manage. OBJECTIVE: To assess the role of advanced therapies in the management of DDS. METHODS: We performed a retrospective chart review and identified patients who fit the inclusion criteria for DDS. They were classified according to risk factors that have been identified in the literature, motor and complication scores, intervention (medical or surgical) and outcome. Multivariate analyses were performed to analyze these characteristics. RESULTS: Twenty-seven patients were identified (23 males, mean age of onset: 49 ± 8.8 years). Average levodopa equivalent daily dose was 1916.7 ± 804 mg and a history of impulse control disorders, psychiatric illness, and substance abuse was present in 89%, 70% and 3.7% of the patients, respectively. Overall 81.5% of patients had symptom resolution at follow up, on average 4.8 ± 3.5 years after management, with medication only (7/9), levodopa-carbidopa intestinal gel (1/3), deep brain stimulation of subthalamic nucleus (10/13), or globus pallidus pars interna (2/2). Reduction of medications occurred with deep brain stimulation of subthalamic nucleus (P = 0.01) but was associated with a relapse in two patients. CONCLUSION: Although the small sample size of some subgroups limits our ability to draw meaningful conclusions, our results did not suggest superiority of a single treatment option. Advanced therapies including deep brain stimulation can be considered in patients with DDS refractory to conservative measures, but outcome is variable and relapse is possible.

Stimulation of the subthalamic nucleus and impulsivity: release your horses.

OBJECTIVE: In Parkinson disease (PD) patients, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may contribute to certain impulsive behavior during high-conflict decisions. A neurocomputational model of the basal ganglia has recently been proposed that suggests this behavioral aspect may be related to the role played by the STN in relaying a "hold your horses" signal intended to allow more time to settle on the best option. The aim of the present study was 2-fold: 1) to extend these observations by providing evidence that the STN may influence and prevent the execution of any response even during low-conflict decisions; and 2) to identify the neural correlates of this effect. METHODS: We measured regional cerebral blood flow during a Go/NoGo and a control (Go) task to study the motor improvement and response inhibition deficits associated with STN-DBS in patients with PD. RESULTS: Although it improved Unified Parkinson Disease Rating Scale motor ratings and induced a global decrease in reaction time during task performance, STN-DBS impaired response inhibition, as revealed by an increase in commission errors in NoGo trials. These behavioral effects were accompanied by changes in synaptic activity consisting of a reduced activation in the cortical networks responsible for reactive and proactive response inhibition. INTERPRETATION: The present results suggest that although it improves motor functions in PD patients, modulation of STN hyperactivity with DBS may tend at the same time to favor the appearance of impulsive behavior by acting on the gating mechanism involved in response initiation.