Optical Coherence Tomography Reflects Brain Atrophy in Multiple Sclerosis: A Four-Year Study

Multiple sclerosis (MS) is regarded as an immune-mediated demyelinating disorder of the central nervous system. Although magnetic resonance imaging (MRI) is regarded as the gold-standard imaging modality for monitoring MS, the association between MRI parameters of inflammation and disability progression in MS is modest.1 Conversely, MRI estimates of neurodegeneration correlate better with disability progression.2,3 Indeed, it is now widely accepted that axonal and neuronal degeneration represents the principal pathological substrate underlying disability in MS.4–10 Nonconventional MRI techniques, including brain-substructure volumetrics, reveal that gray matter (GM) atrophy is a common, early feature of MS and may be better associated with disability than white matter (WM) atrophy.9–12 Such techniques, however, may lack sensitivity to assess progression at the individual level or in small numbers of patients. The development of novel techniques for objectively quantifying neurodegeneration in MS has therefore been an ongoing goal. Optical coherence tomography (OCT) is an inexpensive, reproducible, well-tolerated, high-resolution imaging technique. Recently developed segmentation algorithms (now transitioning into clinical practice) allow reliable quantification of discrete retinal layers.13–16 Because the retina is unmyelinated, retinal axonal and neuronal measures are not confounded by myelin, making them ideal for assessing neuroaxonal degeneration. The retinal nerve fiber layer (RNFL) is the innermost retinal layer (Fig 1). RNFL axons (derived from ganglion cell neurons) coalesce at the optic discs to form the optic nerves and acquire myelin beyond the lamina cribrosa. Clinical and subclinical optic nerve involvement is common in MS. At postmortem examination, 94% to 99% of MS patients exhibit demyelinating lesions in the optic nerves.17,18 Over time, retrograde degeneration of optic nerve axons (owing to demyelination and transection)19–21 is captured by OCT and reflected by thinning of the peripapillary RNFL (pRNFL) and combined ganglion cell and inner plexiform layers (GCIP).22,23 Though this suggests a utility for OCT to monitor disease progression, a critical, yet unanswered, question is whether atrophy within specific retinal layers concomitantly mirrors global neurodegeneration in MS. Figure 1 This figure illustrates an en face optical coherence tomography (OCT) fundus image (A) and a corresponding high-definition OCT section of the same retina in the area of the interposed line (panel B), acquired from the right eye of a multiple sclerosis ... OCT also reveals abnormalities of the inner nuclear layer (INL) in MS.13,24,25 Although postmortem analyses reveal neuronal loss in the INL of MS eyes,20 OCT data indicate that in vivo a sizeable proportion of MS eyes have thickening of the INL, suggesting that an inflammatory process might precede this neurodegeneration.25 Indeed, increased INL thickness in MS was associated with inflammatory disease activity.25 However, it remains to be determined whether INL thickness changes mirror ongoing global processes such as inflammation over time. Studies assessing OCT-brain substructure relationships in MS to date have been primarily cross-sectional. Whereas pRNFL and GCIP thicknesses correlate with whole-brain volume,26–32 and INL thickness with lesion volume,33 the utility of tracking OCT measures, and the insight gleaned regarding ongoing global neurodegeneration and inflammation over time, requires a longitudinal study. The utility of OCT by MS subtype also remains unclear and in particular whether tracking OCT in progressive MS is more informative than in relapsing-remitting MS (RRMS). Finally, it remains to be determined whether a history of optic neuritis (ON) affects longitudinal retinal-brain relationships.28,32,33 The primary aims of this longitudinal observational study were to determine (1) whether atrophy within specific retinal layers over time is associated with concomitant atrophy of specific brain substructures and accumulation of lesions in MS, (2) how these relationships vary between RRMS and progressive MS, and (3) whether ON history affects these relationships.