Amyotrophic lateral sclerosis, a neurodegenerative motor neuron disease with retinal involvement
Authors: Lozano María Pilar Rojas 
Published: December 2022

Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurological disease that predominantly affects the brain, the brainstem and the spinal cord; therefore, the neurological involvement is far from the visual pathway. Moreover, ophthalmological symptoms are scarce or absent. Consequently, there are few studies that analyse visual changes in these patients, and they sometimes produce contradictory results.

Since the retina is considered a window to the rest of the central nervous system, it could serve as a biomarker of neuronal damage that would help diagnose and monitor each patient's progression, and it also assesses the effectiveness of different treatments.

All neurodegenerative diseases have common pathophysiological mechanisms although some of them may predominate over others. In addition to environmental and genetic factors, in ALS glial activation and the accumulation of protein aggregates mechanisms stand out. Furthermore, asymmetric central nervous system involvement has been described in ALS.

This SIS course analyses whether changes occur in the anterior visual pathway in ALS patients at both functional and anatomical levels. Furthermore, it examines the evolution of these changes as the pathology progresses in order to determine whether there is a detectable progression of the disease in the anterior visual pathway. In addition, it is also analyses whether these retinal changes have a histological correlation using animal's models.

The retina is sensitive enough to detect changes in neuromuscular diseases with a spinal onset, as in the case of ALS. On one hand, in ALS patients, optic coherence tomography (OCT) is the best ophthalmological exploratory method that has shown first significant changes in the anterior visual system, showing a thickening in OCT parameters in early stages, with subsequent thinning, allowing the assessment of disease progression. These retinal changes correlate with neurological disability, duration of the disease and pulmonary function tests. In addition, there is an asymmetric involvement in the retina, as in the central nervous system, by visual evoked potentials and OCT.

On the other hand, histopathologically, there is an accumulation of protein aggregates with characteristic ubiquitin‐reactive inclusions, which are positive for P62 and negative for TDP‐43, both in one patient and in animal models. | Moreover, in 120‐day‐old TG(SOD1G93A) ALS mice retinas, there are signs of microglial activation (neuroinflammation) and a decrease in the number of retinal ganglion cells (neurodegeneration) in the late stages of the disease. Microglial cells are in an M1 or pro‐inflammatory activation phenotype, which is neurotoxic to retinal ganglion cells and could help cause this neuronal loss. These microglial changes have also been described in the spinal cord of TG(SOD1G93A) ALS mice. Microglial activation, an accumulation of protein aggregates and decreases in retinal ganglion cells could explain the thickness changes found by OCT in ALS patients at the macular and papillary level.