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

Of Mosaicism and Mechanisms:How JAK1 Goes Awry

Personalized medicines require understanding the molecular causes of disease. In this issue of Immunity, Gruber et al. reveal that a gain-of-function JAK1 genetic variant results in a mutant protein with mosaic expression that drives multi-organ immune dysregulation via kinase dependent and independent mechanisms. The work highlights how biochemistry can inform therapies to resolve complex immune disorders.</p

The Shaking Palsy of the Larynx—Potential Biomarker for Multiple System Atrophy: A Pilot Study and Literature Review

In its early stages multiple system atrophy (MSA), a neurodegenerative movement disorder, can be difficult to differentiate from idiopathic Parkinson's disease (PD), and emphasis has been put on identifying premotor symptoms to allow for its early identification. The occurrence of vegetative symptoms in addition to motor impairment, such as orthostatic hypotension and neurogenic bladder dysfunction, enable the clinical diagnosis in the advanced stages of the disease. Usually with further disease progression, laryngeal abnormalities become clinically evident and can manifest in laryngeal stridor due to impaired vocal fold motion, such as vocal fold abduction restriction, mostly referred to as vocal fold paresis, or paradoxical vocal fold adduction during inspiration. While the pathogenesis of laryngeal stridor is discussed controversially, its occurrence is clearly associated with reduced life expectancy. Before the clinical manifestation of laryngeal dysfunction however, abnormal vocal fold motion can already be seen in patients that might not yet fulfill the diagnostic criteria of MSA. In this article we summarize the current literature on pharyngolaryngeal findings in MSA and report preliminary findings from a pilot study investigating eight consecutive MSA patients. Patients showed varying speech abnormalities. Only 2/8 patients exhibited laryngeal stridor. However, during FEES, all patients presented with irregular arytenoid cartilages movements and vocal fold abduction restriction. 3/8 showed vocal fold fixation and 1/8 paradoxical vocal fold motion. All patients presented with oropharyngeal dysphagia, 5/8 with penetration or aspiration events. We suggest that specific abnormal vocal fold motion can help identifying MSA patients and may allow for delimiting this disorder from idiopathic PD. These findings therefore may serve as a novel clinical biomarker for MSA. Based on the available data and our preliminary clinical experience we developed a standardized easy-to-implement task-protocol to be performed during flexible endoscopic evaluation of swallowing (FEES) for detection of MSA-related pharyngolaryngeal movement disorders. Furthermore, we initiated a prospective study to evaluate the diagnostic utility of this protocol

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

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%). Pharyngealphase 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 oralphase 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.Projekt DEAL 202

A Short Progressive Supranuclear Palsy Quality of Life Scale

Objective : The Progressive Supranuclear Palsy quality of life scale (PSP-QoL) has been shown to be a useful tool for capturing health-related quality of life of patients in “everyday life” and in progressive supranuclear palsy (PSP) research. However, at 45 items in length, the questionnaire can take a long time, exhausting PSP patients, in particular if cognitive impaired, which can have a negative impact on the assessment. The aim of this study was to establish a condensed version of the PSP-QoL for research and routine clinical care. Methods : In this retrospective study, data originating from a German cohort of PSP patients was analyzed. Data from 245 PSP patients were included in this study. The short PSP-QoL questionnaire was created using a two-factor solution and item-total and inter-item correlations for mental and physical aspects of daily living of the PSP-QoL followed by confirmatory factor analysis. Results : The final scale included 12 items representing mental (five items) and physical symptoms (seven items). The specified two-factor model displayed an excellent fit in the confirmatory factor analysis. The short Progressive Supranuclear Palsy Quality of Life scale (PSP-ShoQoL) correlated moderately with the PSP Rating Scale (r [243] = 0.514, P < 0.001) and Geriatric depression scale (r [231] = 0.548, P < 0.001). Sensitivity to change confirmed a significant decrease in QoL after 12 months. Discussion : In this study, we created a 12-item PSP-ShoQoL designed to “facilitate” daily clinical work that correlated strongly with the PSP-QoL and was sensitive to change. © 2024 International Parkinson and Movement Disorder Society

A Short Progressive Supranuclear Palsy Quality of Life Scale

Objective: The Progressive Supranuclear Palsy quality of life scale (PSP-QoL) has been shown to be a useful tool for capturing health-related quality of life of patients in “everyday life” and in progressive supranuclear palsy (PSP) research. However, at 45 items in length, the questionnaire can take a long time, exhausting PSP patients, in particular if cognitive impaired, which can have a negative impact on the assessment. The aim of this study was to establish a condensed version of the PSP-QoL for research and routine clinical care. Methods: In this retrospective study, data originating from a German cohort of PSP patients was analyzed. Data from 245 PSP patients were included in this study. The short PSP-QoL questionnaire was created using a two-factor solution and item-total and inter-item correlations for mental and physical aspects of daily living of the PSP-QoL followed by confirmatory factor analysis. Results: The final scale included 12 items representing mental (five items) and physical symptoms (seven items). The specified two-factor model displayed an excellent fit in the confirmatory factor analysis. The short Progressive Supranuclear Palsy Quality of Life scale (PSP-ShoQoL) correlated moderately with the PSP Rating Scale (r [243] = 0.514, P < 0.001) and Geriatric depression scale (r [231] = 0.548, P < 0.001). Sensitivity to change confirmed a significant decrease in QoL after 12 months. Discussion: In this study, we created a 12-item PSP-ShoQoL designed to “facilitate” daily clinical work that correlated strongly with the PSP-QoL and was sensitive to change

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 &amp;Yahr, and Schwab &amp; 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 expressivityClinical Trial Registration:ClinicalTrials.gov, NCT04214509

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.</p