Selective and Inverse U-Shaped Curve Alteration of the Retinal Nerve in Amyotrophic Lateral Sclerosis: A Potential Mirror of the Disease

Abstract

Introduction: Alterations in the visual pathway involving the retina have been reported in amyotrophic lateral sclerosis (ALS) but they lack consistency and subgroup analysis. We aimed to assess the retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs) alterations in different stages of ALS patients and their association with ALS progression parameters.Methods: The study population consisted of 70 clinically diagnosed ALS patients and 55 age, sex matched controls. All of them underwent ophthalmic assessments and optical coherence tomography imaging. Four quadrants of the peripapillary RNFL and ganglion cell/inner plexiform complex (GCIP) were observed and automatically measured. Early-stage distal motor neuron axon dysfunction in ALS was detected by compound muscle action potential (CMAP) of the distal limbs within 12 months. The ALS disease parameters included the ALSFRS-R score and the disease progression rate (ΔFS).Results: Generally compared with controls, the nasal (p = 0.016) quadrant of the RNFL was thicker in ALS patients. When controlling for age and ΔFS, the RNFL(r = 0.37, p = 0.034) and GCIP(r = 0.40, p = 0.021) were significantly thickened as disease progressed within 12 months, while the RNFL declined with time after one year (r = −0.41, p = 0.037). ALS patients was subclassified into thickened RNFL (T-RNFL, >95th percentile of normal), impaired RNFL (I-RNFL, <5th percentile of normal) and normal RNFL. There were significant differences in the GCIP among the three groups (p < 0.001). In the T-RNFL group (n = 18), the RNFL was negatively correlated with the abductor pollicis brevis-CMAP amplitude within 12 months (r = −0.56, p = 0.01). Patients within 12 months in this group progressed faster than others (p = 0.039). In the normal RNFL group (n = 22), 13 patients were diagnosed beyond 12 months, whose ΔFS was remarkably lower (p = 0.007). In I-RNFL group (n = 30), the early stage patients (<12 months) had significant higher ΔFS (p = 0.006). One patient was with SOD1 pathogenic variant (p.A5V).Conclusion: Alterations of retinal nerve were not consistent in ALS patients with diverse phenotypes and progression rates. Generally speaking, the RNFL thickened during the first year and then gradually declined, which is related to but preceding the thickness change of the RGCs. Patients with a significant RNFL thinning in the early stage may have a faster progression rate. The inverse U-shaped curve transformation might be in accordance with early-stage motor neuron axonopathy.

Retinal Disorders in Humans and Experimental ALS Models

“…Moreover, phenotypic analysis of the microglia showed an M1 phenotype or proinflammatory state of microglia, as the cells were intensely labeled with anti-IFNγ and anti-IL-1β but did not stain with the characteristic M2 markers (anti-arginase 1 and anti-IL-10) [103]. The significant decrease in the total number of Brn3a + RGCs at 120 days of illness would be consistent with the damage observed in the RGCs of the ALS models discussed above [37,101,102], as well as with the thinning of the peripapillary retinal nerve fiber layer (pRNFL), observed by OCT, in ALS patients compared with controls [36][37][38][39][40][41][42][43][44]. Consequently, these data would support that, in ALS, not only are motor neurons affected but also RGC loss occurs, considering this disease as a multisystemic disease [103].…”

“…Even a significant interocular difference of the P100 in ALS patients was demonstrated in a study of visual evoked potentials [33], similar to the existing asymmetry in the CNS of these patients [14]. Some researchers have also analyzed changes in the visual pathway (a nonmotor neuron area) using optical coherence tomography (OCT) in ALS patients [35][36][37][38][39][40][41][42][43][44], finding different changes in the retina and optic nerve, some with contradictory results, stressing the importance of classifying patients by both stage and type of ALS, given the high heterogeneity of the disease.…”

Brain metabolic signatures in patients with genetic and nongenetic amyotrophic lateral sclerosis

“…These studies indicate that pathological changes of visual pathway were solid evidence in neurodegenerative diseases. Recently, reported alteration of the retinal nerve in ALS was reported implied that the ALS visual pathway may be damaged 49 . The effects of genetic factors on pathological changes in the visual pathway in ALS require more investigation.…”

Retinal nerve fiber layer thinning found in amyotrophic lateral sclerosis – Correlation with disease duration and severity

“…Thinning of the RNFL is either due to death of the ganglion cells or Wallerian degeneration secondary to death of the cortical neurons. [ 13 , 18 – 20 ]…”

“…[ 12 ] found some evidence of asymmetric RNFL involvement. Although several studies[ 18 ] have shown asymmetric CNS involvement in ALS, our study is the first in India to assess ALS’s asymmetricity by evaluating the thickness of the RNFL in the right and left eyes. In other words, our study proves that this laterality is not confined to the motor system.…”