Ophthalmic Manifestations of Amyotrophic Lateral Sclerosis (An American Ophthalmological Society Thesis)

Abstract

Purpose: To determine if clinical and histopathologic findings were present in the eyes of patients with amyotrophic lateral sclerosis (ALS) and explore correlations to an animal model of ALS.

Methods: Two patients with ALS were studied histopathologically as well as the retinas of ALS/dementia transgenic mice with dysfunctional ubiquilin2, UBQLN2(P497H). Clinical study 1, an observational, cross-sectional study, was performed using optical coherence tomography (OCT) to obtain and compare mean total macular thickness and average and quadrant specific peripapillary retinal nerve fiber layer (pRNFL) scans from 16 patients with ALS to controls. Correlation analysis was performed to evaluate the association with disease duration. Clinical study 2 consisted of measuring visual acuity, color vision, contrast sensitivity, and quality of life in 12 patients.

Results: Histopathologic studies demonstrated intraretinal inclusions in one patient and loss of ganglion cell axons in another. Mouse eyes had intraretinal inclusions in the inner plexiform layers. Total macular volume was thinner in patients compared to controls (P<.05), and 37.5% of patients with ALS had an average pRNFL below the 1st percentile. Total macular and pRNFL thickness correlated inversely with disease duration.

Conclusions: Histopathologic analysis of ALS eyes and mice with the UBQLN2(P497H) mutation, as well as OCT measurements, supports involvement of the anterior visual pathway. We identified pathologies, including intraretinal deposits and axonal loss. pRNFL and total macular thinning found on OCT correlated with disease duration. A pattern of vision loss specific for ALS was not identified. This study confirms ocular involvement in patients and transgenic animals with ALS/dementia.

Figures

FIGURE 1

Transgenic mouse model and human drusen in age-related macular degeneration retina containing ubiquilin2 immunoreactive deposits. Top left, Eye of normal control mouse shows no evidence of immunoreactive ubiquilin (hematoxylin nuclear stain). Top right, Transgenic mouse retina (UBQLN2P497H) shows numerous ubiquilin2 immunoreactive deposits. A few deposits are intracellular (ganglion cell layer [GCL], white arrowhead), whereas the majority are located in the inner plexiform layer (IPL) and outer plexiform layers (OPL) (white arrows) (hematoxylin nuclear stain). Bottom left, Confocal microscopy image of human donor eye shows drusen and basal laminar deposits with positive ubiquilin2 immunoreactivity (green fluorescence). Bottom right, Cross-section of transgenic mouse showing ubiquilin2 immunoreactive deposits suggestive of drusenoid deposits located underneath the retinal pigment epithelium (RPE). INL, inner nuclear layer. ONL, outer nuclear layer; PR, photoreceptor.

FIGURE 2

p62+ perinuclear inclusions found in the inner nuclear layer (INL) and some recoverin+ bipolar cells in a human C9orf72 retina. Left, p62+ immunofluorescence in C9orf72 retina. Abundant p62+ (green) perinuclear inclusions are seen in the INL of the C9orf72 macula, and rare p62+ inclusions are seen in the ganglion cell layer (GCL). Right, Colocalization of p62 and recoverin (red) in the INL of theC9orf72 macula. Scale bar = 100 µm. ONL, outer nuclear layer.

FIGURE 3

Temporal atrophy of the optic nerve in a patient with amyotrophic lateral sclerosis/frontotemporal dementia. Left, nonsymmetric atrophy of the optic nerve (hematoxylin and eosin). More severe nuclear loss is seen on the temporal (t) side of the optic nerve (center) than on the nasal (n) side (right). Scale bar = 100 µm.

FIGURE 4

Abnormal pupils in patient with familial amyotrophic lateral sclerosis (FALS). Pupillary examination of one of the siblings with FALS associated with autonomic dysfunction demonstrated large pupils that were not reactive to light and near and constricted with full-strength (not dilute) pilocarpine.

FIGURE 5

Temporal retinal nerve fiber atrophy and a drusenoid deposit in sibling pair with juvenile recessive familial amyotrophic lateral sclerosis (FALS) on optical coherence tomography (OCT). Top row, Fundus photos (left and center) of 20-year-old sister (OD on left and OS in center) and peripapillary retinal nerve fiber layer OCT measurements (right). Middle row, Fundus photos (left and center) of 26-year-old brother (OD on left, OS in center) and OCT measurements (right). Fundus photos demonstrate temporal pallor of the optic nerve and reduced thickness of the papillomacular bundle. Bottom row, Fundus autofluorescence (left) shows focal area with increased autofluorescence in the nasal macula (arrow). Corresponding OCT scan (right) shows sub-RPE drusenoid elevation corresponding to the abnormal autofluorescence (arrow).

FIGURE 6

Optical coherence tomography of the peripapillary retinal nerve fiber layer measurements in amyotrophic lateral sclerosis patients compared to normative database. Number of quadrant peripapillary retinal nerve fiber layer measurements of 16 ALS patients determined to be normal (green, above 5th percentile), borderline (yellow, between 1st and 5th percentile), or below normal limits (red, below 1st percentile) compared to a normative database.