A model-based study of internuclear ophthalmoparesis and ocular-motor fatigue in multiple sclerosis

Internuclear ophthalmoparesis (INO) in multiple sclerosis (MS) is due to demyelination of the medial longitudinal fasciculus (MLF). INO is typically modeled as an increased peak-velocity and peak-acceleration ratio of abducting to adducting eye (pulse-size ratio, PSR). PSR can be affected by fatigue during prolonged ocular-motor tasks (ocular-motor fatigue). We propose that an important component of horizontal disconjugacy in INO is due to a delayed delivery of the saccadic pulse to the adducting eye (pulse-time delay, PTD). We expanded a control-system model to account for both abnormal PSR and PTD reflecting faulty axonal transmission in INO and to provide a better understanding of possible changes induced by fatigue. Saccades were measured in 19 MS patients with INO and 10 controls, using a 10-min saccadic "fatigue test" consisting of repetitive back-to-back 20 degrees saccades. In the horizontal saccades model the unitary MLF connection was partitioned into parallel sub-tracts representing progressive degrees of disease effect. INO patients showed baseline abnormal PSR and PTD with some changes during the fatigue test. Manipulations of gain and transmission delay in the model provided simulated saccades that closely resembled those of INO. Ocular-motor fatigue may be a heterogeneous phenomenon that involves inter-saccadic fluctuation of PSR and PTD and adaptation during demanding ocular-motor tasks. INO as a model of abnormal axonal conduction has a potential role in assessing efficacy of reparative therapies in MS.