Study and Treatment of Visual Dysfunction and Motor Fatigue in Multiple Sclerosis

多发性硬化症视觉功能障碍和运动疲劳的研究和治疗

• 批准号: 9268457
• 负责人: Alessandro Serra
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268457
• 关键词: Abnormal coordination; Acceleration; Affect; Aftercare; Automobile Driving; Axon; Brain Stem; Caring; Categories; Characteristics; Clinical; Cognitive; Cross-Over Trials; Data; Demyelinations; Deterioration; Disease; Double-Blind Method; Dyskinetic syndrome; Enrollment; Equipment and supply inventories; Exercise; Exhibits; Eye; Eye Movements; FDA approved; Fatigue; Frequencies; Functional disorder; Gait; Generations; Impairment; Inflammation; Limb structure; Measures; Medial; Medical; Mental Depression; Modeling; Motor; Multiple Sclerosis; Muscle Fatigue; Neural Conduction; Neuraxis; Neurons; Nose; Ocular Motility Disorders; Ophthalmopareses; Outcome Measure; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Physiologic pulse; Placebo Control; Play; Population; Potassium Channel Blockers; Psyche structure; Quality of life; Quality-of-Life Assessment; Questionnaires; Randomized; Reading; Rehabilitation therapy; Reporting; Reproducibility; Role; Saccades; Severities; Signal Transduction; Site; Sleep Disorders; Speed; Testing; Time; Veterans; Vision; Visual; Walking; adduct; associated symptom; base; brain pathway; deconditioning; disability; effective therapy; efficacy testing; foot; gaze; horizontal gaze; improved; improved functioning; injured; mathematical model; motor deficit; multiple sclerosis patient; neurophysiology; neurotransmission; oculomotor; public health relevance; response; transmission process; visual performance; Abnormal coordination; Acceleration; Affect; Aftercare; Automobile Driving; Axon; Brain Stem; Caring; Categories; Characteristics; Clinical; Cognitive; Cross-Over Trials; Data; Demyelinations; Deterioration; Disease; Double-Blind Method; Dyskinetic syndrome; Enrollment; Equipment and supply inventories; Exercise; Exhibits; Eye; Eye Movements; FDA approved; Fatigue; Frequencies; Functional disorder; Gait; Generations; Impairment; Inflammation; Limb structure; Measures; Medial; Medical; Mental Depression; Modeling; Motor; Multiple Sclerosis; Muscle Fatigue; Neural Conduction; Neuraxis; Neurons; Nose; Ocular Motility Disorders; Ophthalmopareses; Outcome Measure; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Physiologic pulse; Placebo Control; Play; Population; Potassium Channel Blockers; Psyche structure; Quality of life; Quality-of-Life Assessment; Questionnaires; Randomized; Reading; Rehabilitation therapy; Reporting; Reproducibility; Role; Saccades; Severities; Signal Transduction; Site; Sleep Disorders; Speed; Testing; Time; Veterans; Vision; Visual; Walking; adduct; associated symptom; base; brain pathway; deconditioning; disability; effective therapy; efficacy testing; foot; gaze; horizontal gaze; improved; improved functioning; injured; mathematical model; motor deficit; multiple sclerosis patient; neurophysiology; neurotransmission; oculomotor; public health relevance; response; transmission process; visual performance

DESCRIPTION This project focuses on fatigue, an extremely common yet poorly understood complaint in patients affected by multiple sclerosis (MS). Primary fatigue, is fatigue not secondary to other MS-associated symptoms (e.g., sleep disorder or depression), is a distinct clinical entity and a cause of severe disability in most patients. A s fatigue limits everyday activities and it interfers with exercise-based rehabilitation, understanding its mechanisms is crucial to improving function and quality of life of Veterans with MS. Primary fatigue is divided in two broad categories, mental (cognitive) and physical (motor) fatigue, the latter being the focus of this proposal. Evidence suggests that primary motor fatigue originates within the central nervous system (CNS) but, although several factors have been invoked (e.g., demyelination, axonal loss, inflammation), a neurophysiological model to explain its underlying mechanisms is still lacking. First, with this project, we propose a characteristic eye movement abnormality, internuclear ophthalmoparesis (INO), as a simple and accessible model for primary motor fatigue in MS. INO is a disorder of binocular coordination (conjugacy), in which fast eye movements (saccades) of the adducting eye (i.e., the eye moving towards the nose) are slow during horizontal gaze shifts, due to demyelination of a specific CNS pathway (the medial longitudinal fasciculus, MLF). Preliminary results in a small MS group of patients show that patients with INO exhibit changes in ocular conjugacy (i.e., ocular motor fatigue) during a 10-minute saccadic fatigue test, but normal subjects do not. We hypothesize that ocular motor fatigue is representative of a major component of primary motor fatigue in MS, as it likely reflects deterioration of neural conduction fidelity along the demyelinated MLF axons. We aim at showing that ocular motor fatigue occurs in a larger MS population with INO by measuring changes of binocular conjugacy on eye movement recordings using two main measures: 1) abducting/adducting eye ratio for saccadic peak velocity (pulse size ratio); 2) time difference in occurrence of peak acceleration in the adducting vs. the abducting eye (pulse time delay), during the 10-minute fatigue test. We will determine whether ocular motor fatigue is associated with symptomatic subjective fatigue as assessed with standard fatigue questionnaires. Second, we intend to test efficacy of dalfampridine, a potassium channel blocker that enhances neural conduction along demyelinated axons, in MS patients with INO with or without associated ocular motor fatigue. Visual dysfunction in MS patients with INO is a major cause of disability as they are severely limited in daily activities such as driving and can suffer further disability when developing ocular motor fatigue during a sustained visual task (e.g., reading). However, no medical therapy is available for INO/ocular motor fatigue. Our preliminary results document improved binocular conjugacy in three MS patients taking dalfampridine for gait impairment (the FDA-approved indication for this medication). Our data also showed improvement of ocular motor fatigue after dalfampridine in one patient. We hypothesize that dalfampridine improves visual performance in MS patients with INO and counteracts ocular motor fatigue and, in turn, diminishes visual disability and improves quality of life. Thus, we will conduct a randomized, placebo-controlled, double-blind, crossover trial of dalfampridine (10mg twice a day) of 9 weeks duration. Before and after treatment, we will assess for changes in binocular conjugacy by eye movement measures as above, as well as changes in clinical measures, such as reading acuity and speed, saccades performance, gait performance, symptomatic fatigue, visual disability and quality of life. We will determine whether improvement of visual performance has positive effects on overall disability and quality of life of MS patients with INO. We will also determine whether there is an association between response of eye movement and gait performances to dalfampridine.

描述 该项目侧重于疲劳，这是一个极为普遍但对受多发性硬化症（MS）影响的患者的抱怨。 主要的疲劳是疲劳，而不是其他与其他MS相关症状（例如睡眠障碍或抑郁症）的疲劳，是大多数患者的独特临床实体，是严重残疾的原因。疲劳限制了日常活动，它与基于运动的康复相互交织，了解其机制对于改善MS退伍军人的职能和生活质量至关重要。 主要疲劳分为两个广泛的类别，即心理（认知）和身体（运动）疲劳，后者是该提议的重点。 有证据表明，原发性运动疲劳起源于中枢神经系统（CNS），但尽管已经引用了几个因素（例如，脱髓鞘，轴突丧失，炎症），但仍缺乏解释其潜在机制的神经生理模型。 首先，通过这个项目，我们提出了一个特征性的眼动异常，核次内眼脑（INO），作为MS中原发性运动疲劳的简单且易于访问的模型。 INO是一种双眼配位（结合性）的疾病，其中，由于特定的CNS途径的脱髓鞘（Mential longial longitial fasticinal fasticulus，mlf，MLF），在水平凝视的过程中，加合的眼睛的快速移动（扫视）在水平凝视过程中慢速运动缓慢。 初步结果导致一小部分患者表明，INO患者在10分钟的SACCADIC疲劳测试中表现出眼轭性（即眼运动疲劳）的变化，但正常受试者没有。 我们假设眼运动疲劳代表了MS中原发性运动疲劳的主要组成部分，因为它可能反映了沿脱髓鞘MLF轴突的神经传导保真度的恶化。 我们的目的是表明，通过使用两种主要措施测量双眼偶联性在眼动记录上的双眼连接性的变化，可以表明眼部运动疲劳发生在较大的MS种群中：1）saccadic峰值速度（脉冲尺寸比）绑架/加入眼比。 2）在10分钟的疲劳测试期间，加合力与绑架眼（脉冲时间延迟）中峰值加速度的发生时间差异。 我们将确定眼运动疲劳是否与标准疲劳问卷评估的症状主观疲劳有关。其次，我们打算测试Dalfampridine（一种钾通道阻滞剂）的功效，可增强沿脱髓鞘轴突的神经传导。 INO的MS患者的视觉功能障碍是残疾的主要原因，因为它们在日常活动中受到严重限制，例如在持续的视觉任务（例如阅读）期间患上眼运动疲劳时可能会进一步遭受残疾。 但是，没有用于INO/眼运动疲劳的药物疗法。 我们的初步结果文档改善了三名服用达富氨胺的步态障碍的MS患者的双目结合度（该药物FDA批准的指示）。 我们的数据还表明，一名患者在达富氨酸后眼运动疲劳的改善。我们假设Dalfampridine可以改善INO和抵消眼运动疲劳的MS患者的视觉性能，进而减少视觉障碍并改善生活质量。 因此，我们将进行一项随机的，安慰剂对照，双盲的，跨林胺（每天两次10mg）9周的跨界试验。 治疗前后，我们将评估如上所述的眼动测量方法的变化，以及临床措施的变化，例如阅读敏锐度和速度，囊泡性能，步态性能，有症状性疲劳，视觉障碍和生活质量。 我们将确定视觉性能的改善是否对INO MS患者的整体残疾和生活质量有积极影响。 我们还将确定眼动反应与步态性能对达富卫的反应之间是否存在关联。