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

描述 这个项目的重点是疲劳，这是多发性硬化症(MS)患者中一种非常常见但知之甚少的主诉。原发性疲劳不是其他MS相关症状(如睡眠障碍或抑郁)的继发性症状，是一种独特的临床实体，在大多数患者中是严重残疾的原因。S疲劳限制了日常活动，并干扰了以运动为基础的康复，了解其机制对于改善退伍军人的功能和生活质量至关重要。初级疲劳分为两大类，精神(认知)疲劳和身体(运动)疲劳，后者是本提案的重点。有证据表明，初级运动疲劳起源于中枢神经系统(CNS)，但尽管已有多种因素被引用(如脱髓鞘、轴突丢失、炎症)，但仍缺乏一个神经生理学模型来解释其潜在机制。首先，在这个项目中，我们提出了一种特征性的眼球运动异常，核间眼球麻痹(INO)，作为一种简单易行的初级运动疲劳模型。INO是一种双眼协调(共轭)障碍，在水平凝视转移中，由于特定中枢神经系统通路(内侧纵束，MLF)的脱髓鞘，内收眼(即眼睛向鼻子移动)的快速眼球运动(眼跳)缓慢。在一小部分MS患者中的初步结果显示，在10分钟的扫视疲劳测试中，INO患者的眼睛共轭能力(即眼睛运动疲劳)发生了变化，但正常受试者没有。我们推测，眼运动疲劳是多发性硬化症患者初级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。我们的目的是通过测量双眼共轭在眼球运动记录上的变化来显示更多患有INO的MS人群中发生眼运动疲劳的情况：1)眼跳峰值速度的外展/内收眼比率(脉冲大小比)；2)在10分钟的疲劳测试中，内收眼和外展眼出现峰值加速度的时间差(脉冲时延)。我们将用标准的疲劳问卷评估眼球运动疲劳是否与症状性主观疲劳有关。其次，我们打算测试达法普利定的疗效，达法普林是一种钾通道阻滞剂，可以增强沿脱髓鞘轴突的神经传导，对伴有或不伴有眼球运动疲劳的多发性硬化症患者的疗效。患有INO的MS患者的视觉功能障碍是导致残疾的主要原因，因为他们在日常活动(如驾驶)中受到严重限制，当在持续的视觉任务(如阅读)中出现眼运动疲劳时，可能会进一步残疾。然而，目前还没有针对INO/眼运动疲劳的药物治疗。我们的初步结果证明，服用达法普利定治疗步态障碍(FDA批准的这种药物的适应症)的三名MS患者的双眼共轭能力得到了改善。我们的数据还显示，在一名患者服用达法普定后，眼球运动疲劳有所改善。我们推测，达法普定可改善患有INO的MS患者的视觉表现，并抵消眼运动疲劳，进而减少视力障碍，提高生活质量。因此，我们将进行一项随机、安慰剂对照、双盲、交叉试验，达法普定(每天两次，每次10毫克)，为期9周。在治疗前后，我们将通过上述眼球运动测量来评估双眼共轭的变化，以及临床测量的变化，如阅读敏锐度和速度、眼跳表现、步态表现、症状性疲劳、视力残疾和生活质量。我们将确定视觉能力的改善是否对患有INO的MS患者的总体残疾和生活质量有积极影响。我们还将确定眼球运动的反应和达法普林的步态表现之间是否存在关联。

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.