Study and Treatment of Visual Dysfunction and Motor Fatigue in Multiple Sclerosis
Condition: Multiple Sclerosis; Internuclear Ophthalmoplegia; Fatigue
MeSH terms: Multiple Sclerosis; Ophthalmoplegia; Vision Disorders; Ocular Motility Disorders; Sclerosis; Fatigue
Study type: Interventional
Phase: Phase 2

Summary: 
      Primary fatigue represents a major cause of disability in patients with multiple sclerosis
      (MS), being reported in about 90% of cases. Fatigue interferes with everyday functioning but,
      unfortunately, little is known about its mechanisms. The investigators propose a
      characteristic eye movement abnormality (internuclear ophthalmoparesis, INO), commonly
      encountered in MS, as a simple model for primary motor fatigue. The investigators described
      worsening of ocular performance in MS patients with INO following visual tasks (ocular motor
      fatigue), which is likely due to decreased neural conduction along brain pathways injured by
      MS. This mechanism could represent a major component of MS-related primary motor fatigue.
      Relevant to Veterans' care, INO is a significant cause of visual disability, especially when
      complicated by ocular fatigue, and limits daily activities such as reading and driving. The
      investigators propose a medical treatment to improve ocular performance/fatigue in INO, which
      can reduce visual disability and improve quality of life in Veterans with MS.
    

Detailed description: 
      This project focuses on fatigue, an extremely common yet poorly understood complaint in
      patients affected by multiple sclerosis (MS). Primary fatigue, that 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. As fatigue limits everyday
      activities and interferes 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, the investigators 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. The
      investigators 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. The investigators 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. The investigators will determine whether ocular motor fatigue is associated
      with symptomatic subjective fatigue as assessed with standard fatigue questionnaires. Second,
      The investigators 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. Preliminary
      results document improved binocular conjugacy in three MS patients taking dalfampridine for
      gait impairment (the FDA-approved indication for this medication). These data also showed
      improvement of ocular motor fatigue after dalfampridine in one patient. The investigators
      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, the investigators will conduct a randomized, placebo-controlled,
      double-blind, crossover trial of dalfampridine (10mg twice a day) of 10 weeks duration.
      Before and after treatment, the investigators 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. the investigators will determine whether improvement of
      visual performance has positive effects on overall disability and quality of life of MS
      patients with INO. The investigators will also determine whether there is an association
      between response of eye movement and gait performances to dalfampridine.
    

Intervention name(s): Dalfampridine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 10-week randomized, placebo controlled, double-blind, crossover trial, which includes a period of wash out of two weeks between treatment with dalfampridine and placebo.; 10-week randomized, placebo controlled, double-blind, crossover trial, which includes a period of wash out of two weeks between treatment with dalfampridine and placebo.
Intervention MeSH terms: 4-Aminopyridine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science