Endoscopic Characteristics of Dysphagia in Multiple System Atrophy Compared to Parkinson's Disease.

BACKGROUND: Dysphagia is a major clinical concern in multiple system atrophy (MSA). A detailed evaluation of its major endoscopic features compared with Parkinson's disease (PD) is lacking. OBJECTIVE: This study systematically assessed dysphagia in MSA compared with PD and correlated subjective dysphagia to objective endoscopic findings. METHODS: Fifty-seven patients with MSA (median, 64 [interquartile range (IQR): 59-71] years; 35 women) underwent flexible endoscopic evaluation of swallowing using a specific MSA-flexible endoscopic evaluation of swallowing task protocol. Findings were compared with an age-matched cohort of 57 patients with PD (median, 67 [interquartile range: 60-73] years; 28 women). In a subcohort, subjective dysphagia was assessed using the Swallowing Disturbance Questionnaire and correlated to endoscopy findings. RESULTS: Patients with MSA predominantly showed symptoms suggestive of oral-phase disturbance (premature spillage, 75.4%, piecemeal deglutition, 75.4%). Pharyngeal-phase symptoms occurred less often (pharyngeal residues, 50.9%; penetration/aspiration, 28.1%). In contrast, pharyngeal symptoms were the most common finding in PD (pharyngeal residues, 47.4%). Oral symptoms occurred less frequently in PD (premature spillage, 15.8%, P < 0.001; piecemeal deglutition, 1.8%, P < 0.01). Patients with MSA had a greater risk for oral-phase disturbances with increased disease severity (P < 0.05; odds ratio, 3.15). Patients with MSA showed a significantly higher intraindividual interswallow variability compared with PD. When correlating Swallowing Disturbance Questionnaire scores with endoscopy results, its cutoff, validated for PD, was not sensitive enough to identify patients with MSA with dysphagia. We developed a subscore for identifying dysphagia in MSA and calculated a new cutoff (sensitivity 85%, specificity 100%). CONCLUSIONS: In contrast with patients with PD, patients with dysphagic MSA more frequently present with oral-phase symptoms and a significantly higher intraindividual interswallow variability. A novel Swallowing Disturbance Questionnaire MSA subscore may be a valuable tool to identify patients with MSA with early oropharyngeal dysphagia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deviation of the orientation angle of directional deep brain stimulation leads quantified by intraoperative stereotactic X-ray imaging.

Directional deep brain stimulation (dDBS) provides multiple programming options. Knowledge of the spatial lead orientation is useful for time-efficient programming. Recent studies demonstrated deviations of up to 90° from the intended orientation angle. We examined the deviation of dDBS-lead orientation for leads from two different manufacturers using intraoperative stereotactic (STX) X-ray images. Intraoperative 2D-X-ray images were acquired after implantation of the first lead (TP1) and the second lead (TP2) enabling the estimation of the spatial position of the first lead at TP1 and TP2 and of changes of the orientation for a defined time period. Two investigators retrospectively estimated the orientation of the directional marker for 64 patients. The mean deviation from intended spatial orientation was 40.8° ± 46.1° for all examined leads. The spatial orientation of the first lead did not significantly change within a period of approximately 1 h. The degree of deviation did not differ significantly between two lead manufacturers but depended on the lead fixation technique. Our results showed deviations from the intended orientation angle immediately after the insertion of dDBS leads. The initial spatial orientation remained stable for approximately 1 h and was not caused by technical properties of the implanted lead. Hence, it was most probably the result of unintended mechanical torsion during insertion and/or fixation. Because precise determination of the lead orientation is mandatory for target-oriented dDBS programming, the use of additional imaging suitable for precise 3D visualization of lead contacts and/or the positioning marker is recommended.

Long-term effects of pallidal and thalamic deep brain stimulation in myoclonus dystonia.

OBJECTIVE: Observational study to evaluate long-term effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the ventral intermediate thalamic nucleus (VIM) on patients with medically refractory myoclonus dystonia (MD). BACKGROUND: More recently, pallidal as well as thalamic DBS have been applied successfully in MD but long-term data are sparse. METHODS: We retrospectively analyzed a cohort of seven MD patients with either separate (n = 1, VIM) or combined GPi- DBS and VIM-DBS (n = 6). Myoclonus, dystonia and disability were rated at baseline (BL), short-term (ST-FU) and long-term follow-up (LT-FU) using the United Myoclonus Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Tsui rating scale, respectively. Quality of life (QoL) and mood were evaluated using the SF-36 and Beck Depression Inventory questionnaires, respectively. RESULTS: Patients reached a significant reduction of myoclonus at ST-FU (62% ± 7.3%; mean ± SE) and LT-FU (68% ± 3.4%). While overall motor BFMDRS changes were not significant at LT-FU, patients with GPi-DBS alone responded better and predominant cervical dystonia ameliorated significantly up to 54% ± 9.7% at long-term. Mean disability scores significantly improved by 44% ± 11.4% at ST-FU and 58% ± 14.8% at LT-FU. Mood and QoL remained unchanged between 5 and up to 20 years postoperatively. No serious long-lasting stimulation-related adverse events were observed. CONCLUSIONS: We present a cohort of MD patients with very long follow-up of pallidal and/or thalamic DBS that supports the GPi as the favourable stimulation target in MD with safe and sustaining effects on motor symptoms (myoclonus>dystonia) and disability.

Laryngeal Movement Disorders in Multiple System Atrophy: A Diagnostic Biomarker?

BACKGROUND: Multiple system atrophy (MSA) is a rare neurodegenerative disorder, and its parkinsonian variant can be difficult to delineate from Parkinson's disease (PD). Despite laryngeal dysfunction being associated with decreased life expectancy and quality of life, systematic assessments of laryngeal dysfunction in large cohorts are missing. OBJECTIVES: The objective of this study was to systematically assess laryngeal dysfunction in MSA and PD and identify laryngeal symptoms that allow for differentiating MSA from PD. METHODS: Patients with probable or possible MSA underwent flexible endoscopic evaluation of swallowing performing a systematic task protocol. Findings were compared with an age-matched PD cohort. RESULTS: A total of 57 patients with MSA (64 [59-71] years; 35 women) were included, and task assessments during endoscopic examination compared with 57 patients with PD (67 [60-73]; 28 women). Patients with MSA had a shorter disease duration (4 [3-5] years vs 7 [5-10]; P < 0.0001) and higher disease severity (Hoehn & Yahr stage 4 [3-4] vs 3 [2-4]; P < 0.0001). Of the patients with MSA, 43.9% showed clinically overt laryngeal dysfunction with inspiratory stridor. During endoscopic task assessment, however, 93% of patients with MSA demonstrated laryngeal dysfunction in contrast with only 1.8% of patients with PD (P < 0.0001). Irregular arytenoid cartilages movements were present in 91.2% of patients with MSA, but in no patients with PD (P < 0.0001). Further findings included vocal fold motion impairment (75.4%), paradoxical vocal fold motion (33.3%), and vocal fold fixation (19.3%). One patient with PD showed vocal fold motion impairment. CONCLUSION: Laryngeal movement disorders are highly prevalent in patients with MSA when assessed by a specific task protocol despite the lack of overt clinical symptoms. Our data suggest that irregular arytenoid cartilage movements could be used as a clinical marker to delineate MSA from PD with a specificity of 1.0 and sensitivity 0.9. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longterm outcome of cognition, affective state, and quality of life following subthalamic deep brain stimulation in Parkinson's disease.

Normal cognition is an established selection criteria for subthalamic (STN) deep brain stimulation (DBS) in Parkinson's disease (PD), while concern has been raised as to aggravated cognitive decline in PD patients following STN-DBS. The present longterm study investigates cognitive status in all patients (n = 104) suffering from PD, who were treated via continuous bilateral STN-DBS between 1997 and 2006 in a single institution. Preoperative neuropsychological results were available in 79/104 of the patients. Thirty-seven of these patients were additionally assessed after 6.3 ± 2.2 years (range 3.6-10.5 years) postsurgery via neuropsychological and motor test batteries, classifying cognitive conditions according to established criteria. At DBS-surgery patients, available for longterm follow-up (n = 37; mean age 67.6 ± 6.9 years, mean disease duration 11.3 ± 4.1 years), showed no (24.3%; 9/37) or mild preoperative cognitive impairment (MCI, 75.7%; 28/37). Postoperatively (mean disease duration: 17.1 ± 5.1 years), 19% of the patients (7/37) had no cognitive impairment, while 41% of the patients presented with either MCI or dementia (15/37, respectively). Preoperative MCI correlated with conversion to dementia by trend. Overall, STN-DBS-treated patients deteriorated by 1.6/140 points/year in the Mattis dementia rating scale. Disease duration, but not age, at DBS-surgery negatively correlated with postoperative cognitive decline and positively correlated with conversion to dementia. This observational, "real-life" study provides longterm results of cognitive decline in STN-DBS-treated patients with presurgical MCI possibly predicting the conversion to dementia. Although, the present data is lacking a control group of medically treated PD patients, comparison with other studies on cognition and PD do not support a disease-modifying effect of STN-DBS on cognitive domains.

Disease-specific longevity of impulse generators in deep brain stimulation and review of the literature.

Deep brain stimulation (DBS) represents an established and internationally approved therapy for movement disorders. In the present retrospective analysis, we evaluated disease-specific longevity of dual channel impulse generators (IPG) used in different movement disorders. We correlated the battery lifetime with electrical stimulation settings, "total electrical energy delivered" (TEED), stimulation modi (monopolar, double monopolar and bipolar) and targets. Specifically, we reviewed the longevity and stimulation settings of 464 IPGs implanted between 1996 until 2011 in a single university center. Disease entities comprised Parkinson's disease (PD, n = 257), dystonia (n = 130) and essential tremor (ET, n = 50). Further subanalyses aimed at assessing differential longevity in different subtypes of PD and dystonia. The main finding relates to longer IPG longevity in ET (thalamic DBS) and PD (subthalamic DBS) vs. dystonia (pallidal DBS; 71.9 ± 6.7 vs. 51.5 ± 2.3 vs. 37 ± 2 months). In PD the tremor-dominant type was associated with a significant shorter battery survival than in the akinetic-rigid type without tremor or the "balanced" type with tremor, bradykinesia and rigidity (38.8 ± 3.9 vs. 53.6 ± 3.4 vs. 58.8 ± 4.1 months), while there were no significant differences in longevity between the subtypes of dystonia. Frequency, amplitude, pulse widths and TEED correlated inversely with battery lifetime. Pallidal DBS in dystonia is associated with a shorter lifetime of IPGs than subthalamic or thalamic DBS for PD or ET. The present results may contribute to the rapidly evolving refinement of DBS devices. Future studies that assess energy consumption both in patients with and without IPG replacement could help to avoid potential underestimation of longevity of IPGs.

Postoperative MRI localisation of electrodes and clinical efficacy of pallidal deep brain stimulation in cervical dystonia.

INTRODUCTION: Pallidal deep brain stimulation (DBS) has been shown to be effective in cervical dystonia (CD) with an improvement of about 50-60% in the Toronto Western Spasmodic Torticollis Rating (TWSTR) Scale. However, predictive factors for the efficacy of DBS in CD are missing with the anatomical location of the electrodes being one of the most important potential predictive factors. METHODS: In the present blinded observational study we correlated the anatomical localisation of DBS contacts with the relative clinical improvement (CI %) in the TWSTR as achieved by DBS at different pallidal contacts in 20 patients with CD. Localisations of DBS contacts were derived from postoperative MRI-data following anatomical normalisation into the standard Montreal Neurological Institute stereotactic space. The CIs following 76 bilateral test stimulations of 24 h were mapped to stereotactic coordinates of the corresponding bilateral 152 active contacts and were allocated to low CI (<30%; n=74), intermediate CI (≥30%; <60%; n=52) or high CI (≥60%; n=26). RESULTS: Euclidean distances between contacts and the centroid differed between the three clusters (p<0.001) indicating different anatomical variances between clusters. The Euclidean distances between contacts and the centroid of the cluster with high CIs correlated with the individual level of CIs (r=-0.61; p<0.0001). This relationship was best fitted with an exponential regression curve (r(2)=0.41). DISCUSSION: Our data show that the clinical effect of pallidal DBS on CD displays an exponential decay over anatomical distance from an optimised target localisation within a subregion of the internal pallidum. The results will allow a comparison of future DBS studies with postoperative MRI by verifying optimised (for instance pallidal) targeting in DBS-treated patients.

Levodopa inhibits habit-learning in Parkinson's disease.

Mixed dopaminergic medication, comprising dopamine agonists and levodopa, may affect habit-learning in patients with Parkinson's disease (PD). However, the specific impact of levodopa on this effect is unknown. We assessed habit-learning in 20 non-demented PD-patients both with and without levodopa. We observed intact habit-learning in PD-patients OFF-medication. In contrast, the administration of 200 mg of levodopa impaired habit-learning. We conclude that potential deficits in habit-learning in PD may be attributed to the intake of levodopa.

The comorbidity and co-medication profile of patients with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. OBJECTIVES: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. METHODS: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik®. RESULTS: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions. CONCLUSIONS: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients.

The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis.

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management. OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Sexual Dysfunctions in Parkinson's Disease and Their Influence on Partnership-Data of the PRISM Study.

BACKGROUND: Sexual dysfunctions (SD) are common but underreported in Parkinson's disease (PD) and have negative impacts on the quality of life (QoL) and partnership. METHODS: We analyzed the data set from the PRISM study for demographics of SD and their influence on quality of life and partnership. RESULTS: 449/861 (52.1%) PD patients reported SD, with male patients being affected more often and having a longer course of disease. The most common SD in men was erectile dysfunction (ED) (n = 152), while women's most frequent complaints were orgasm dysfunction (n = 84) and reduced libido (n = 81). Hypersexual SDs were reported significantly more often by men. Spousal caregivers of patients reporting inability to relax and enjoy sex and reduced libido indicated a negative influence on the relationship in general. Negative effects on the sexual relationship were reported significantly more often for patients with ED, difficulties with sexual arousal, inability to relax and enjoy sex, and reduced libido. Hypersexual dysfunctions showed no effect on the relationship. CONCLUSION: SD is a common but underreported problem in the treatment of patients with PD. Due to the negative influence on the relationship and QoL of patients and caregivers, SD should be assessed routinely.

Long-term effects of pallidal deep brain stimulation in tardive dystonia: a follow-up of 5-14 years.

INTRODUCTION: Pallidal DBS is an established treatment for severe isolated dystonia. However, its use in disabling and treatment-refractory tardive syndromes (TS) including tardive dyskinesia and tardive dystonia (TD) is less well investigated and long-term data remain sparse. This observational study evaluates long-term effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with medically refractory TS. METHODS: We retrospectively analyzed a cohort of seven TD patients with bilateral GPi-DBS. Involuntary movements, dystonia and disability were rated at long-term follow-up (LT-FU) after a mean of 122 ± 33.2 SD months (range 63-171 months) and compared to baseline (BL), short-term (ST-FU; mean 6 ± 2.0 SD months) and 4-year follow-up (4y-FU; mean 45 ± 12.3 SD months) using the Abnormal Involuntary Movement Scale (AIMS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), respectively. Quality of life and mood were evaluated using the SF36 and Beck Depression Index (BDI) questionnaires, respectively. RESULTS: At LT-FU patients had improved by 73% ± 14.2 SD in involuntary movements and 90% ± 1.0 SD in dystonia. Mood had improved significantly whereas quality of life remained unchanged compared to baseline. No serious long-lasting stimulation-related adverse events (AEs) were observed. Three patients of this cohort presented without active stimulation and ongoing symptom relief at long-term follow-up after 3-10 years of continuous DBS. CONCLUSION: Pallidal DBS is a safe and effective long-term TD treatment. Even more interesting, three of our patients could stop stimulation after several years of DBS without serious relapse. Larger studies need to explore the phenomenon of ongoing symptom relief after DBS cessation.

Overnight unilateral withdrawal of thalamic deep brain stimulation to identify reversibility of gait disturbances.

BACKGROUND: Gait disturbances are frequent side effects related to chronic thalamic deep brain stimulation (DBS) that may persist beyond cessation of stimulation. OBJECTIVE: We investigate the temporal dynamics and clinical effects of an overnight unilateral withdrawal of DBS on gait disturbances. METHODS: 10 essential tremor (ET) patients with gait disturbances following thalamic DBS underwent clinical and kinematic gait assessment ON DBS, after instant and after an overnight unilateral withdrawal of DBS of the hemisphere corresponding to the non-dominant hand. The effect of stimulation withdrawal on gait performance was quantitatively assessed using clinical rating and inertial sensors and compared to gait kinematics from 10 additional patients with ET but without subjective gait impairment. DBS leads were reconstructed and active contacts were visualized in relation to surrounding axonal pathways and nuclei. RESULTS: Patients with gait deterioration following DBS exhibited greater excursion of sagittal trunk movements and greater variability of stride length and shank range of motion compared to ET patients without DBS and without subjective gait impairment. Overnight but not instant unilateral withdrawal of DBS resulted in significant reduction of SARA axial subscore and stride length variability, while tremor control of the dominant hand was preserved. Cerebellothalamic, striatopallidofugal and corticospinal fibers were in direct vicinity of transiently deactivated contacts. CONCLUSION: Non-dominant unilateral cessation of VIM DBS may serve as a therapeutic option as well as a diagnostic intervention to identify stimulation-induced gait disturbances that is applicable in ambulatory settings due to preserved functionality of the dominant hand.

Long-term clinical outcome in meige syndrome treated with internal pallidum deep brain stimulation.

Deep brain stimulation of the globus pallidus internus (GPi DBS) is effective in the treatment of primary segmental and generalized dystonia. Although limb, neck, or truncal dystonia are markedly improved, orofacial dystonia is ameliorated to a lesser extent. Nevertheless, several case reports and small cohort studies have described favorable short-term results of GPi DBS in patients with severe Meige syndrome. Here, we extend this preliminary experience by reporting long-term outcome in a multicenter case series, following 12 patients (6 women, 6 men) with Meige syndrome for up to 78 months after bilateral GPi DBS. We retrospectively assessed dystonia severity based on preoperative and postoperative video documentation. Mean age of patients at surgery was 64.5 ± 4.4 years, and mean disease duration 8.3 ± 4.4 years. Dystonia severity as assessed by the Burke-Fahn-Marsden Dystonia Rating Scale showed a mean improvement of 45% at short-term follow-up (4.4 ± 1.5 months; P < 0.001) and of 53% at long-term follow-up (38.8 ± 21.7 months; P < 0.001). Subscores for eyes were improved by 38% (P = 0.004) and 47% (P < 0.001), for mouth by 50% (P < 0.001) and 56% (P < 0.001), and for speech/swallowing by 44% (P = 0.058) and 64% (P = 0.004). Mean improvements were 25% (P = 0.006) and 38% (P < 0.001) on the Blepharospasm Movement Scale and 44% (P < 0.001) and 49% (P < 0.001) on the Abnormal Involuntary Movement Scale. This series, which is the first to demonstrate a long-term follow-up in a large number of patients, shows that GPi DBS is a safe and highly effective therapy for Meige syndrome. The benefit is preserved for up to 6 years.

Determining an efficient deep brain stimulation target in essential tremor - Cohort study and review of the literature.

INTRODUCTION: Deep brain stimulation (DBS) is a highly efficacious treatment for essential tremor (ET). Still, the optimal anatomical target in the (sub)thalamic area is a matter of debate. The aim of this study was to determine the optimal target of DBS for ET regarding beneficial clinical outcome and impact on activities of daily living as well as stimulation-induced side effects and compare it with previously published coordinates. METHODS: In 30 ET patients undergoing bilateral DBS, severity of tremor was assessed by blinded video ratings before and at 1-year follow-up with DBS ON and OFF. Tremor scores and reported side effects and volumes of tissue activated were used to create a probabilistic map of DBS efficiency and side effects. RESULTS: DBS was effective both in tremor suppression as well as in improving patient reported outcomes, which were positively correlated. The "sweet spot" for tremor suppression was located inferior of the VIM in the subthalamic area, close to the superior margin of the zona incerta. The Euclidean distance of active contacts to this spot as well as to 10 of 13 spots from the literature review was predictive of individual outcome. A cluster associated with the occurrence of ataxia was located in direct vicinity of the "sweet spot". CONCLUSION: Our findings suggest the highest clinical efficacy of DBS in the posterior subthalamic area, lining up with previously published targets likely representing the dentato-rubro-thalamic tract. Side effects may not necessarily indicate lead misplacement, but should encourage clinicians to employ novel DBS programing options.

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort.

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data. Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity Clinical Trial Registration:ClinicalTrials.gov, NCT04214509.

Pallidal and thalamic deep brain stimulation in myoclonus-dystonia.

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (VIM) are established treatment options in primary dystonia and tremor syndromes and have been reported anecdotally to be efficacious in myoclonus-dystonia (MD). We investigated short- and long-term effects on motor function, cognition, affective state, and quality of life (QoL) of GPi- and VIM-DBS in MD. Ten MD-patients (nine epsilon-sarcoglycan-mutation-positive) were evaluated pre- and post-surgically following continuous bilateral GPi- and VIM-DBS at four time points: presurgical, 6, 12, and as a last follow-up at a mean of 62.3 months postsurgically, and in OFF-, GPi-, VIM-, and GPi-VIM-DBS conditions by validated motor [unified myoclonus rating scale (UMRS), TSUI Score, Burke-Fahn-Marsden dystonia rating scale (BFMDRS)], cognitive, affective, and QoL-scores. MD-symptoms significantly improved at 6 months post-surgery (UMRS: 61.5%, TSUI Score: 36.5%, BFMDRS: 47.3%). Beneficial effects were sustained at long-term evaluation post-surgery (UMRS: 65.5%, TSUI Score: 35.1%, BFMDRS: 48.2%). QoL was significantly ameliorated; affective status and cognition remained unchanged postsurgically irrespective of the stimulation conditions. No serious long-lasting stimulation-related adverse events (AEs) were observed. Both GPi- and VIM-DBS offer equally effective and safe treatment options for MD. With respect to fewer adverse, stimulation-induced events of GPi-DBS in comparison with VIM-DBS, GPi-DBS seems to be preferable. Combined GPi-VIM-DBS can be useful in cases of incapaciting myoclonus, refractory to GPi-DBS alone.