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

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.

Inclusion Criteria:

- Diagnosis of MS of any course and duration

- Evidence of mild to moderate internuclear ophthalmoparesis (INO), that is slowing of
the adducting eye on physical examination of saccadic speed, whether INO is unilateral
or bilateral, symmetrical or asymmetrical

- Medically stable conditions, ability to give informed consent and understand and
cooperate with the testing

- Dalfampridine-naive as well as history of taking dalfampridine in the past, whether
there was benefit in gait impairment or not, after a washout period of at least 2
weeks

Exclusion Criteria:

- Lack of evidence of INO (slowing of the adducting eye) on physical examination of
saccadic speed

- Severe INO (i.e., exotropia in primary gaze) on physical examination

- Medically unstable conditions, inability to give informed consent and understand and
cooperate with the testing

- History of side effects from dalfampridine

- History of seizures

- Moderate or severe renal failure, assessed by clearance of creatinine