Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.
Background Microcystic macular edema (MME) of the retinal inner nuclear layer (INL) has recently been identified in multiple sclerosis (MS) patients with optical coherence tomography (OCT). We aimed to determine if MME of the INL, and/or higher thickness of the INL, are associated with disease activity, or disability progression. Methods This retrospective study was performed at Johns Hopkins Hospital (between 09/2008 and 03/2012). 164 MS patients and 60 healthy-controls underwent serial OCT scans and clinical evaluation (including visual function). OCT scanning, including automated intra-retinal layer segmentation, yielded thicknesses of the retinal nerve fiber layer, ganglion cell layer (plus inner plexiform layer), INL (plus outer plexiform layer), and outer nuclear layer. MS patients also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relationships of baseline OCT thicknesses with clinico-radiological parameters. Findings Mean follow-up (standard deviation) for MS patients and healthy-controls was 25·8-months (9·1-months) and 22·4-months (11·4-months) respectively. 10 MS patients (6·1% of the cohort) demonstrated MME during at least one study visit, but MME was not visible at baseline in 6 of these patients. MS patients with vs. without MME (151 MS patients) at any time during the study had higher baseline multiple sclerosis severity scores (p=0·032), although expanded disability status scale (EDSS) scores were not significantly different (p=0·097). MS eyes with MME (12 eyes) vs. without MME (302 eyes) had lower letter-acuity scores (100%-contrast: p=0·017; 2·5%-contrast: p=0·031; 1·25%-contrast: p=0·014), and higher INL thicknesses (p=0·003) at baseline. Higher baseline INL thickness in MS predicted the development of contrast-enhancing lesions (p=0·007), new T2 lesions (p=0·015), EDSS progression (p=0·034), and relapses (in relapsing-remitting MS; p=0·008) during the study. MME was not associated with disease activity during follow-up. Healthy-controls did not demonstrate MME. Interpretation Increased INL thickness on OCT, potentially representing inflammation of the unmyelinated retina, is associated with disease activity in MS. If this finding is confirmed, INL thickness may be a useful predictor of disease progression in MS. Funding National Multiple Sclerosis Society (TR3760-A-3, RG4212-A-4), National Eye Institute (R01-EY014993, R01-EY019473), Braxton Debbie Angela Dillon and Skip Donor Fund.
We have identified a pattern of retinal morphologic abnormalities in NMO that is associated with severe retinal axonal and neuronal loss and corresponding visual disability. MME may contribute to poor visual outcomes following NMO-associated ON or alternatively represent a marker of ON severity. Additionally, our results support that subclinical involvement of the anterior visual pathway may occur in NMO spectrum disorders.
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