Examining multiple sclerosis through the eyes of a child.

Retinal ganglion cells (RGCs) receive input from photoreceptive cells, have unmyelinated axons that constitute the retinal nerve fiber layer (RNFL), and gain myelin as they pass through the lamina cribrosa to form the optic nerve. RGC axons project to several structures within the CNS, including the lateral geniculate nucleus of the thalamus. The ganglion cell layer (GCL) constitutes a readily quantifiable layer of neuronal cell bodies. Whereas research methods of cortical neuronal quantification in multiple sclerosis (MS) continue to evolve, the advent of high-resolution optical coherence tomography (OCT) images, derived from software that segments discrete retinal layers, has enabled quantification of retinal neuronal loss by assessing the GCL/inner plexiform layers. Recent studies in adult MS have shown that GCL thickness correlates with visual outcomes and is reduced in eyes with or without history of optic neuritis (ON). Thinning of GCL appears accelerated in MS, associated with the presence of inflammatory disease activity, such as relapses, new brain MRI lesions, and sustained worsening of disability. In acute ON, the RNFL becomes swollen and precludes obtaining an accurate baseline measure. However, GCL thickness appears resistant to edema, and may be a good measure to quantify and track neurodegenerative changes for MS clinical trials. The literature on optical coherence tomography (OCT) in the pediatric MS population is limited and mostly focused on earlier time-domain OCT technology. In the current issue of Neurology®, Yeh et al. studied 74 eyes from 37 children, ages 8–18 years, using high-resolution spectral-domain (SD)–OCT and visual function measures. Diagnoses included 43% with MS, 52% with demyelination not otherwise specified, and 5% with acute disseminated encephalomyelitis. Optic nerve was involved in 76% of eyes. Inclusion of high-resolution SD-OCT allows segmenting individual retinal layers around the macula, making this among the first published studies to analyze GCL thickness in children with demyelinating disorders. Similar to adults, the risk of clinical vision involvement increases dramatically below a certain thickness. For children with mean RNFL ,87 mm (a 15% reduction), 100% had abnormal scores on the highly sensitive low-contrast visual acuity chart. For children with a mean GCL,76 mm (a 10% reduction), 100% had abnormal low contrast score. However, Yeh et al. also found something that was different from what has been seen in adults: a disconnect between the presence or number of ON episodes and the thickness of the GCL. The mean RNFL for the overall group was 26% lower compared to controls, and declined by 9 mm per ON episode. In contrast, GCL did not decline with ON episodes, despite mean GCL being 20% reduced for the group compared to controls. Why does the GCL not decline proportionate to the presence or number of ON episodes? Are these cells primarily affected in pediatric demyelination, as part of the overall disease process? Or, as the authors suggest, could a single ON episode lead to substantial neuronal loss, thereby sparing very little for subsequent episodes to detect a change? Another location for neuronal cells includes the thalamus, and some investigators have found thalamic gray matter loss by MRI in pediatric MS, supporting the latter hypothesis. For the present study, such results need to be interpreted with caution, given the cross-sectional nature of the study and a relatively small sample of non-ON eyes. While this study cannot differentiate the etiology, involvement of neuronal cell bodies as a substrate for disability is critical in elucidating the pathophysiology of MS. The present study is an important start, but more definitive data will require larger studies, longitudinal follow-up, and inclusion of brainMRIs. OCT is highly reproducible, quick to perform, and offers an objective measure of neuronal damage. This could be critical in the pediatric population, where subjective assessment of visual status could sometimes be unreliable. We need to better understand how the retina in children with MS reacts to disease and treatment. Studying pediatric MS has advantages for understanding the cause of MS from its earliest stages. The retina presents an opportunity to learn further how inflammation and degeneration are intertwined.