Cross-sectional evaluation of clinical neuro-ophthalmic abnormalities in an amyotrophic lateral sclerosis population

Abstract

Objective Ocular motility abnormalities may be a marker of neuro-degeneration beyond motor neurons in amyotrophic lateral sclerosis (ALS). We formally compared clinical neuro-ophthalmic abnormalities in ALS patients and a control population. Methods Patients attending a multidisciplinary ALS clinic (n = 63, age 60.8 +/− 16.4 years) and their caregivers serving as controls (n = 37, ages 55.0 +/− 12.7 years) participated in this cross-sectional study. Visual acuity was assessed. Video recordings of a standardized ocular motility exam including gaze fixation, voluntary saccades, reflex saccades, smooth pursuit, eyelid opening and Bell's phenomenon were rated by two senior neuro-ophthalmologists who were masked to subject group. Results Visual acuity was lower in ALS patients versus control subjects (OR 0.81 (0.71–0.93), p = 0.003, logistic regression). Inter- and intra-rater reliability for ocular motility examination ratings were good (Cohen's Kappa > 0.6). Findings observed only in ALS subjects included gaze impersistence (14%, p = 0.01), moderately or severely restricted voluntary upgaze (13%, p = 0.01), and moderate or severe eyelid opening apraxia (27%, p = 0.0002). Accounting for age, moderately or severely saccadic horizontal smooth pursuits distinguished ALS from control subjects (OR 3.6 (1.2– 10.9), p = 0.02, logistic regression). Conclusions Clinical findings of decreased visual acuity, gaze impersistence, voluntary upgaze restriction, eyelid opening apraxia, and saccadic horizontal smooth pursuits are more frequent in patients with ALS than in similar-aged controls. These findings are potential clinical markers of neurodegeneration beyond upper and lower motor neuron disease in ALS. Further study is warranted regarding their application to disease categorization and outcomes assessment.

Clinicopathologic report of ocular involvement in ALS patients with C9orf72 mutation

“…A recent cross-sectional clinical neuro-ophthalmologic evaluation of ALS patients (sporadic and familial) revealed supranuclear ocular motility findings in this population (15). Reduced high and low contrast acuity was a surprising finding of this study, which was interpreted cautiously given the small difference between patients and controls.…”

“…In patients with advanced disease, clinical and pathologic involvement of oculomotor, abducens and trochlear nuclei has been described (16). Recently, binocular high and low contrast vision deficits were also demonstrated in a representative ALS cohort (15). The pathophysiological basis for these visual deficits has not been elucidated.…”

“…Oculomotor changes that have been described in ALS patients include supranuclear gaze palsy, gaze fixation instability (7), increased saccadic latency (8–11), smooth pursuit impairment (11,12), diminished Bell’s phenomenon (13) and eyelid apraxia (14,15). These abnormalities have been attributed to involvement of supranuclear ocular motor pathways.…”

High and Low Contrast Visual Acuity Are Not Affected in Amyotrophic Lateral Sclerosis

“…[4,5] Altered afferent visual function has also been documented using functional MRI,[6] and high and low contrast visual acuity (VA) measures, though these latter observations have not been confirmed. [7] Structural alterations in the retina may be the basis for these changes. [8–12] Reports of optic nerve involvement are conflicting.…”

Subtle retinal pathology in amyotrophic lateral sclerosis

“…Remarkably, autopsy studies such as recent investigations on phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) distribution have shown alterations beyond the pyramidal tract, including the neo- and allocortex, and the basal ganglia 3. Extra-motor symptoms occur more frequently than previously thought and comprise neuro-ophthalmological abnormalities such as decreased high and low contrast visual acuity 4,5. In line with this evidence, studies on visual evoked potentials6 and voxel-based MRI volumetry of the occipital cortex revealed functional and structural alterations of the visual system in ALS 7…”