Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

BACKGROUND AND PURPOSE: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. METHODS: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. RESULTS: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. CONCLUSION: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function.

OBJECTIVE: Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. METHODS: We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates. RESULTS: Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs. CONCLUSIONS: NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Small and Large Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia of Parkinson's Disease Patients.

BACKGROUND: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested. OBJECTIVE: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD. METHODS: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study. RESULTS: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition. CONCLUSIONS: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society.

Brain iron deposition and movement disorders in hereditary haemochromatosis without liver failure: A cross-sectional study.

BACKGROUND AND PURPOSE: Hereditary haemochromatosis (HH) is the most common inherited disorder of systemic iron excess in Northern Europeans. Emerging evidence indicates that brain iron overload occurs in HH. Despite this observation, there is a paucity of literature regarding central neurological manifestations, in particular movement disorders, in HH. The current study documents deep gray matter (DGM) nuclei iron deposition, movement disorders, and clinicoradiological correlations in HH without liver failure. METHODS: This is a cross-sectional study. Consecutive subjects with HFE-haemochromatosis without liver disease were recruited from an outpatient gastroenterology clinic. Age- and sex-matched healthy controls (HCs) were enrolled. Iron content in individual DGM nuclei was measured as mean susceptibility on magnetic resonance imaging using quantitative susceptibility mapping-based regions of interest analysis. Occurrence and phenotype of movement disorders were documented and correlated with patterns of DGM nuclei iron deposition in subjects with HH. RESULTS: Fifty-two subjects with HH and 47 HCs were recruited. High magnetic susceptibility was demonstrated in several DGM nuclei in all HH subjects compared to HCs. Thirty-five subjects with HH had movement disorders. Magnetic susceptibility in specific DGM nuclei correlated with individual movement disorder phenotypes. Serum ferritin, phlebotomy frequency, and duration were poor predictors of brain iron deposition. CONCLUSIONS: Abnormal brain iron deposition can be demonstrated on imaging in all subjects with HH without liver failure. A significant proportion of these subjects manifest movement disorders. Peripheral iron measurements appear not to correlate with brain iron deposition. Therefore, routine neurological examination and quantitative brain iron imaging are recommended in all subjects with HH.

Mercury and Movement Disorders: The Toxic Legacy Continues.

Mercury (Hg) exists in the environment as inorganic (metallic Hg vapor, mercurous and mercuric salts) or organic (bonded to a structure containing carbon atoms) forms. Neurotoxic effect of Hg is known for years. While the organic form (methylmercury (meHg)) led to the Minamata incidence in Japan and "wonder-wheat" disaster in Iraq, the "mad hatters" and "Danbury shakes" were related to the inorganic elemental form (Hg vapor). Human exposure to toxic Hg continues in the modern world to a large extent by artisanal gold mining, biomass combustion, chloralkali production, and indigenous medicine use to name a few. Heavy industrial use of Hg contaminates air and landfills, affecting the aquatic ecosystem and marine food chain. A detailed social and occupational history with a high index of clinical suspicion is required to not miss this toxic etiology for movement disorders like ataxia, tremor, or myoclonus. In this review, we have discussed the past and present global health impact of Hg from a movement disorder perspective. The connection of Hg with neurodegeneration and autoimmunity has been highlighted. We have also discussed the role of chelating agents and the preventive strategies to combat the neurotoxic effects of Hg in the modern world.

How Long Should GPS Recording Lengths Be to Capture the Community Mobility of An Older Clinical Population? A Parkinson's Example.

Wearable global position system (GPS) technology can help those working with older populations and people living with movement disorders monitor and maintain their mobility level. Health research using GPS often employs inconsistent recording lengths due to the lack of a standard minimum GPS recording length for a clinical context. Our work aimed to recommend a GPS recording length for an older clinical population. Over 14 days, 70 older adults with Parkinson's disease wore the wireless inertial motion unit with GPS (WIMU-GPS) during waking hours to capture daily "time outside", "trip count", "hotspots count" and "area size travelled". The longest recording length accounting for weekend and weekdays was ≥7 days of ≥800 daily minutes of data (14 participants with 156, 483.9 min recorded). We compared the error rate generated when using data based on recording lengths shorter than this sample. The smallest percentage errors were observed across all outcomes, except "hotspots count", with daily recordings ≥500 min (8.3 h). Eight recording days will capture mobility variability throughout days of the week. This study adds empirical evidence to the sensor literature on the required minimum duration of GPS recording.

Iron Chelation in Movement Disorders: Logical or Ironical.

Iron is probably as old as the universe itself and is essential for sustaining biological processes. The remarkable property of iron complexes to facilitate electron transfer makes it a significant component of redox reactions that drive the essential steps in nucleic acid biosynthesis and cellular functions. This, however, also generates potentially harmful hydroxyl radicals causing cell damage. In the movement disorder world, iron accumulation is well known to occur in neurodegeneration with brain iron accumulation, while dysfunctional iron homeostasis has been linked with neurodegenerative diseases like Parkinson's disease and Huntington's disease to name a few. Targeting excess iron in these patients with chelation therapy has been attempted over the last few decades, though the results have not been that promising. In this review, we have discussed iron, its metabolism, and proposed mechanisms causing movement disorder abnormalities. We have reviewed the available literature on attempts to treat these movement disorders with chelation therapy. Finally, based on our understanding of the pathogenic role of iron, we have critically analyzed the limitations of chelation therapy in the current scenario and the various unmet needs that should be addressed for selecting the patient population amenable to this therapy.

Expanding the search for genetic biomarkers of Parkinson's disease into the living brain.

Altered gene expression related to Parkinson's Disease (PD) has not been described in the living brain, yet this information may support novel discovery pertinent to disease pathophysiology and treatment. This study compared the transcriptome in brain biopsies obtained from living PD and Control patients. To evaluate the novelty of this data, a comprehensive literature review also compared differentially expressed gene (DEGs) identified in the current study with those reported in PD cadaveric brain and peripheral tissues. RNA was extracted from rapidly cryopreserved frontal lobe specimens collected from PD and Control patients undergoing neurosurgical procedures. RNA sequencing (RNA-Seq) was performed and validated using quantitative polymerase chain reaction. DEG data was assessed using bioinformatics and subsequently included within a comparative analysis of PD RNA-Seq studies. 370 DEGs identified in living brain specimens reflected diverse gene groups and included key members of trophic signaling, apoptosis, inflammation and cell metabolism pathways. The comprehensive literature review yielded 7 RNA-Seq datasets generated from blood, skin and cadaveric brain but none from a living brain source. From the current dataset, 123 DEGs were identified only within the living brain and 267 DEGs were either newly found or had distinct directional change in living brain relative to other tissues. This is the first known study to analyze the transcriptome in brain tissue from living PD and Control patients. The data produced using these methods offer a unique, unexplored resource with potential to advance insight into the genetic associations of PD.

Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities.

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. METHODS: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. RESULTS: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2). CONCLUSION: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society.

Managing autonomic dysfunction in Parkinson's disease: a review of emerging drugs.

Introduction: Autonomic dysfunction is an integral part of Parkinson disease (PD) complex and can be seen both in early and advanced stages. There is a paucity of medicines available to manage autonomic dysfunction in PD and this adds to the considerable morbidity associated with the illness.Areas covered: The pathophysiology and the available therapeutic options of autonomic dysfunction seen in PD are discussed in detail. The potential targets for novel regimens are reviewed and the available literature on the drugs emerging in management of autonomic dysfunction in PD is highlighted.Expert opinion: In the current scenario, there are several drugs that can be tried for constipation viz stool laxatives, prucalopride, prokinetic agents and a high fiber diet. Bladder dysfunction has been treated with ß-agonists and with mirabegron, a selective ß-3 agonist, the anticholinergic side effects are minimized, and the drug has been found to be effective. Orthostatic hypotension is managed with midodrine while droxidopa is a new drug with promising efficacy. Botulinum toxin works best for management of sialorrhea, but repeated injections are needed.

Efficacy and Acceptance of a Lombard-response Device for Hypophonia in Parkinson's Disease.

OBJECTIVE: The purpose of this study was to examine the effectiveness, satisfaction, and acceptance of a low-cost Lombard-response (LR) device in a group of individuals with Parkinson's disease (IWPD) and their communication partners (CPs). METHOD: Sixteen IWPD and hypophonia and their CPs participated in the study. The IWPD wore a LR device that included a small MP3 player (Sony Walkman) and headphones playing a multi-talker noise audio file at 80 dB during lab-based speech tasks and during their daily conversational speech over a 2-week device trial period. Outcome measures included average conversational speech intensity and scores on a questionnaire related to speech impairment, communication effectiveness, and device satisfaction. RESULTS: Conversational speech intensity of the IWPD is increased by 7 to 10 dB with the LR device. Following a 2-week trial period, eight of the IWPD (50%) gave the LR device moderate-to-high satisfaction and effectiveness ratings and decided to purchase the device for long-term daily use. At the 4-month follow-up, none of the IWPDs were still using the LR device. Device rejection was related to discomfort (loudness), headaches, interference with cognition, and difficulty controlling device. CONCLUSION: Short-term acceptance and satisfaction with the LR device was moderate, but long-term acceptance, beyond 4 months, was absent. Future studies are required to determine if other types of low-cost LR devices can be developed that improve long-term efficacy and device acceptance in IWPD and hypophonia.

Neurological Worsening After Implantable Pulse Generator Replacement.

BACKGROUND: Most of the implantable pulse generators (IPGs) in deep brain stimulation (DBS) used to date are non-rechargeable requiring regular replacements. IPG replacement is a minor surgical procedure, but adverse events including neurological worsening have been reported. In this study, we determine the possibility of neurological worsening after IPG replacement in Parkinson's disease (PD) cases on chronic DBS therapy (CDT) and its electrophysiological basis along with the therapeutic interventions used to alleviate them. METHODS: This study is a retrospective chart review of PD cases on CDT followed at London Movement Disorders Centre from January 2010 to December 2016. Included cases were those who underwent one or more IPG replacement. RESULTS: A total of 45 PD cases on CDT underwent 62 IPG replacements involving 121 channels. Neurological worsening was observed in 16 (35.5%) cases following 17 (27.4%) IPG replacements, all following dual-channel IPG replacements. Tremor (41.2%), speech (35.3%), and gait (23.5%) worsened most commonly. Deviation from the pre-replacement parameters including voltage and impedance resulting in change in total electrical energy delivered (TEED) was the most common electrophysiological correlate, observed in 82.4% (14/17) IPGs having neurological worsening. This included switched laterality in a dual-channel IPG. Neurological worsening in the remaining 17.6% cases was hardware-related. CONCLUSION: Neurological worsening followed 27.4% of IPG replacements in PD cases on CDT with approximately 82.4% of these being avoidable by carefully monitoring stimulation parameters to match pre-replacement TEED values.

Évolution défavorable de l'état neurologique de patients après le remplacement de leur générateur d'impulsions implantable. CONTEXTE: La plupart des générateurs d'impulsions implantables (GII) utilisés jusqu'à présent lors de séances de stimulation cérébrale profonde (SCP) ne peuvent être rechargés, ce qui nécessite des remplacements à intervalles réguliers. Même si le remplacement d'un GII demeure une intervention chirurgicale mineure, des manifestations indésirables, notamment la détérioration neurologique de certains patients, ont été signalées. Dans cette étude, nous voulons donc déterminer, après le remplacement d'un GII, les possibilités de détérioration neurologique de patients atteints de la maladie de Parkinson (MP). Rappelons que ces patients ont entrepris, de concert avec d'autres interventions thérapeutiques, des séances de SCP en vue de réduire leurs douleurs chroniques. MÉTHODES: Nous avons donc passé en revue de façon rétrospective les dossiers de patients atteints de MP et bénéficiant de séances de SCP. Ces patients avaient été suivis au London Movement Disorders Centre de janvier 2010 à décembre 2016. Soulignons aussi qu'ils ont subi un ou plusieurs remplacements de leur GII en cours d'étude. RÉSULTATS: Au total, 45 patients atteints de MP bénéficiant de SCP visant à soulager leurs douleurs chroniques ont été visés par 62 remplacements de GII impliquant 121 canaux. Une détérioration neurologique a été observée chez 16 patients (35,5 %) à la suite de 17 (27,4 %) remplacements de GII, lesquels ayant tous été effectués à la suite de remplacements de GII double canal. Parmi les aspects s'étant le plus souvent détériorés, mentionnons des tremblements (41,2 %), la parole (35,3 %) et la démarche (23,5 %). Une déviation par rapport aux paramètres de pré-remplacement, ce qui inclut la tension et l'impédance, tous deux pouvant entraîner des modifications à l'énergie électrique totale produite, est apparue comme le corrélat électro-physiologique le plus fréquent. Ce dernier a en effet été observé dans 82,4 % (14/17) des remplacements de GII ayant entraîné une détérioration neurologique. Cela a inclus notamment une latéralité inversée dans le cas de GII double canal. Quant aux 17,6 % des autres cas, la détérioration neurologique peut s'expliquer par le matériel lui-même. CONCLUSION: Une forme de détérioration neurologique a accompagné 27,4 % des remplacements de GII chez des patients atteints de MP et nécessitant des séances de SCP pour soulager leurs douleurs chroniques. Environ 82,4 % de ces cas seraient évitables en surveillant attentivement les paramètres de stimulation pour qu'ils correspondent ainsi aux niveaux d'énergie électrique totale produits avant remplacement.

Effects of Deep Brain Stimulation of the Subthalamic Nucleus Settings on Voice Quality, Intensity, and Prosody in Parkinson's Disease: Preliminary Evidence for Speech Optimization.

OBJECTIVE: To systematically evaluate how different deep brain stimulation of the subthalamic nucleus (STN-DBS) amplitude, frequency, and pulse-width electrical parameter settings impact speech intensity, voice quality, and prosody of speech in Parkinson's disease (PD). METHODS: Ten individuals with PD receiving bilateral STN-DBS treatments were seen for three baseline and five treatment visits. The five treatment visits involved an examination of the standard clinical settings as well as manipulation of different combinations of frequency (low, mid, and high), pulse width (low, mid, and high), and voltage (low, mid, and high) of stimulation. Measures of speech intensity, jitter, shimmer, harmonics-noise ratio, semitone standard deviation, and listener ratings of voice quality and prosody were obtained for each STN-DBS manipulation. RESULTS: The combinations of lower frequency, lower pulse width, and higher voltage settings were associated with improved speech outcomes compared to the current standard clinical settings. In addition, decreased total electrical energy delivered to the STN appears to be associated with speech improvements. CONCLUSIONS: This study provides preliminary evidence that STN-DBS may be optimized for Parkinson-related problems with voice quality, speech intensity, and prosody of speech.

Long-term Safety and Dosing of OnabotulinumtoxinA: A Prospective, Observational Study.

BACKGROUND: Although therapeutic treatments are intended to help alleviate symptoms associated with disease, safety must be carefully considered and monitored to confirm continued positive benefit/risk balance. The objective of MOBILITY was to study the long-term safety of onabotulinumtoxinA for treatment of various therapeutic indications. METHODS: A prospective, multicenter, observational, Phase IV Canadian study in patients treated with onabotulinumtoxinA for a therapeutic indication. Dosing was determined by the participating physician. Adverse events (AEs) were recorded throughout the study. RESULTS: Patients (n = 1372) with adult focal spasticity, blepharospasm, cerebral palsy, cervical dystonia, hemifacial spasm, hyperhidrosis, or "other" diagnoses were enrolled into the safety cohort. Eighty-three patients (6%) reported 209 AEs; 44 AEs in 24 patients (2%) were considered treatment-related AEs. Seventy-two serious AEs were reported by 38 patients (3%); 10 serious AEs in 5 patients (0.4%) were considered treatment related. Most commonly reported treatment-related AEs were muscular weakness (n = 7/44) and dysphagia (n = 6/44). CONCLUSIONS: In patients with follow-up for up to six treatments with onabotulinumtoxinA, treatment-related AEs were reported in <2% of the safety population over the course of nearly 5 years. Our findings from MOBILITY provide further evidence that onabotulinumtoxinA treatment is safe for long-term use across a variety of therapeutic indications.

Dosage et sécurité à long terme de l'onabotulinumtoxinA : une étude prospective et observationnelle. Contexte : Bien que les traitements thérapeutiques soient destinés à soulager les symptômes associés à une maladie, il importe d'examiner avec grand soin leur sécurité et d'en assurer un suivi afin de maintenir un rapport bénéfice/risque qui soit positif. L'objectif de MOBILITY a donc été d'étudier la sécurité à long terme de l'onabotulinumtoxinA dans le traitement de plusieurs indications thérapeutiques. Méthodes : Nous avons ainsi fait appel à une étude canadienne prospective et observationnelle menée dans plusieurs centres de santé. Dans cette étude de phase IV, des patients ont été traités avec l'onabotulinumtoxinA en vertu d'indications thérapeutiques. Ce sont des médecins participants qui en avaient déterminé le dosage. De plus, tout événement indésirable a été noté en cours d'étude. Résultats : Au total 1372 patients ont été inclus dans cette cohorte (n = 1372). Ces patients étaient atteints des troubles suivants : spasticité focale chez l'adulte, blépharospasme, infirmité motrice cérébrale, dystonie cervicale, spasmes hémifaciaux, hyperhidrose, etc. On a signalé chez 83 patients, soit 6 % d'entre eux, des événements indésirables. On a aussi estimé que 44 événements indésirables ayant affecté 24 patients (2 %) étaient reliés au traitement proprement dit. Ajoutons que 38 patients (3 %) ont signalé avoir été victimes d'événements indésirables et que 10 événements indésirables ont été reliés au traitement chez 5 patients (0,4 %). Enfin, les événements indésirables les plus communément signalés ont été la faiblesse musculaire (n = 7/44) et la dysphagie (n = 6/44). Conclusions : Dans le cas de patients ayant bénéficié de six traitements ou moins avec l'onabotulinumtoxinA, des événements indésirables ont été signalés chez < 2 % d'entre eux au cours des presque cinq prochaines années. Tirés de MOBILITY, nos résultats apportent une preuve additionnelle que les traitements avec l'onabotulinumtoxinA sont à long terme sécuritaires dans le cas de nombreuses indications thérapeutiques.

Spinal Cord Stimulation Therapy for Gait Dysfunction in Advanced Parkinson's Disease Patients.

BACKGROUND: Benefits of dopaminergic therapy and deep brain stimulation are limited and unpredictable for axial symptoms in Parkinson's disease. Dorsal spinal cord stimulation may be a new therapeutic approach. The objective of this study was to investigate the therapeutic effect of spinal cord stimulation on gait including freezing of gait in advanced PD patients. METHODS: Five male PD participants with significant gait disturbances and freezing of gait underwent midthoracic spinal cord stimulation. Spinal cord stimulation combinations (200-500 µs/30-130 Hz) at suprathreshold intensity were tested over a 1- to 4-month period, and the effects of spinal cord stimulation were studied 6 months after spinal cord stimulation surgery. Protokinetics Walkway measured gait parameters. Z scores per gait variable established each participant's best spinal cord stimulation setting. Timed sit-to-stand and automated freezing-of-gait detection using foot pressures were analyzed. Freezing of Gait Questionnaire (FOG-Q), UPDRS motor items, and activities-specific balance confidence scale were completed at each study visit. RESULTS: Spinal cord stimulation setting combinations of 300-400 µs/30-130 Hz provided gait improvements. Although on-medication/on-stimulation at 6 months, mean step length, stride velocity, and sit-to-stand improved by 38.8%, 42.3%, and 50.3%, respectively, mean UPDRS, Freezing of Gait Questionnaire, and activities-specific balance confidence scale scores improved by 33.5%, 26.8%, and 71.4%, respectively. The mean number of freezing-of-gait episodes reduced significantly from 16 presurgery to 0 at 6 months while patients were on levodopa and off stimulation. CONCLUSIONS: By using objective measures to detect dynamic gait characteristics, the therapeutic potential of spinal cord stimulation was optimized to each participant's characteristics. This pilot study demonstrated the safety and significant therapeutic outcome of spinal cord stimulation in advanced PD patients, and thus a larger and longer clinical study will be conducted to replicate these results. © 2018 International Parkinson and Movement Disorder Society.

Botulinum Toxin Type A Injections as Monotherapy for Upper Limb Essential Tremor Using Kinematics.

BACKGROUND: There is a significant need for a targeted therapy for essential tremor (ET), as medications have not been developed specifically for ET, and the ones prescribed are often not well-tolerated, so that many patients remain untreated. Recent work has shown that, unlike previous experience, kinematically guided individualized botulinum toxin type A (BoNT-A) injections provide benefit along with minimal weakness. Ours is the first long-term (96-week) safety and efficacy study of BoNT-A as monotherapy for ET using kinematically driven injection parameters. METHODS: Ten ET patients were administered six serial BoNT-A treatments every 16 weeks and were assessed at 6 weeks following treatment. During each study visit, the Fahn-Tolosa-Marin (FTM) scale, the Unified Parkinson's Disease Rating Scale, and the Quality of Life for Essential Tremor Questionnaire (QUEST) were administered along with kinematic assessment of the treated limb. Participants performed scripted tasks with motion sensors placed over each arm joint. Dosing patterns were determined using the movement disorder neurologist's interpretation of muscles contributing to the kinematically analyzed upper limb tremor biomechanics. RESULTS: There was a 33.8% (p<0.05) functional improvement (FTM part C) and a 39.8% (p<0.0005) improvement in QUEST score at week 96 compared to pretreatment scores at week 0. Although there was a 44.6% (p<0.0005) non-dose-dependent reduction in maximal grip strength, only 2 participants complained of mild weakness. Following the fourth serial treatment, mean action tremor score was reduced by 62.9% (p=0.001) in the treated and by 44.4% (p=0.03) in the untreated arm at week 96 compared to week 48. CONCLUSIONS: Individualized BoNT-A dosing patterns to each individual's tremor biomechanics provided an effective monotherapy for ET as function improved without functionally limiting muscle weakness.