Retinal asymmetry in multiple sclerosis
Authors: Petzold Axel , Chua Sharon Y L , Khawaja Anthony P , Keane Pearse A , Khaw Peng T , Reisman Charles , Dhillon Baljean , Strouthidis Nicholas G , Foster Paul J , Patel Praveen J ,   UK Biobank Eye and Vision Consortium, Atan Denize , Aslam Tariq , Barman Sarah A , Barrett Jenny H , Bishop Paul , Bunce Catey , Carare Roxana O , Chakravarthy Usha , Chan Michelle , Chua Sharon Y L , Crabb David P , Day Alexander , Desai Parul , Dhillon Bal , Dick Andrew D , Egan Cathy , Ennis Sarah , Ennis Sarah , Foster Paul J , Fruttiger Marcus , Gallacher John E J , Garway-Heath David F , Gibson Jane , Gore Dan , Guggenheim Jeremy A , Hammond Chris J , Hardcastle Alison , Harding Simon P , Hogg Ruth E , Hysi Pirro , Keane Pearse A , Khaw Sir Peng T , Khawaja Anthony P , Lascaratos Gerassimos , Lotery Andrew J , Macgillivray Tom , Mackie Sarah , McGaughey Michelle , McGuinness Bernadette , McKay Gareth J , McKibbin Martin , Moore Tony , Morgan James E , Muthy Zaynah A , O’Sullivan Eoin , Owen Chris G , Patel Praveen , Paterson Euan , Peto Tunde , Petzold Axel , Rahi Jugnoo S , Rudnikca Alicja R , Self Jay , Sivaprasad Sobha , Steel David , Stratton Irene , Strouthidis Nicholas , Sudlow Cathie , Thomas Dhanes , Trucco Emanuele , Tufail Adnan , Vitart Veronique , Vernon Stephen A , Viswanathan Ananth C , Williams Cathy , Williams Katie , Woodside Jayne V , Yates Max M , Zheng Yalin 
Published: October 2020

Abstract
The diagnosis of multiple sclerosis is based on a combination of clinical and paraclinical tests. The potential contribution of retinal optical coherence tomography (OCT) has been recognized. We tested the feasibility of OCT measures of retinal asymmetry as a diagnostic test for multiple sclerosis at the community level. In this community-based study of 72 120 subjects, we examined the diagnostic potential of the inter-eye difference of inner retinal OCT data for multiple sclerosis using the UK Biobank data collected at 22 sites between 2007 and 2010. OCT reporting and quality control guidelines were followed. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (RNFL), ganglion cell inner plexiform layer (GCIPL) complex and ganglion cell complex. Area under the receiver operating characteristic curve (AUROC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and co-morbidities. Cut-off levels were optimized by ROC and the Youden index. The prevalence of multiple sclerosis was 0.0023 [95% confidence interval (CI) 0.00229–0.00231]. Overall the discriminatory power of diagnosing multiple sclerosis with the IEPD AUROC curve (0.71, 95% CI 0.67–0.76) and IEAD (0.71, 95% CI 0.67–0.75) for the macular GCIPL complex were significantly higher if compared to the macular ganglion cell complex IEPD AUROC curve (0.64, 95% CI 0.59–0.69, P = 0.0017); IEAD AUROC curve (0.63, 95% CI 0.58–0.68, P &lt; 0.0001) and macular RNFL IEPD AUROC curve (0.59, 95% CI 0.54–0.63, P &lt; 0.0001); IEAD AUROC curve (0.55, 95% CI 0.50–0.59, P &lt; 0.0001). Screening sensitivity levels for the macular GCIPL complex IEPD (4% cut-off) were 51.7% and for the IEAD (4 μm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%, respectively. The number of co-morbidities was important. There was a stepwise decrease of the AUROC curve from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus, other eye disease and a non-white ethnic background were relevant confounders. For most interactions, the effect sizes were large (partial ω2 &gt; 0.14) with narrow confidence intervals. In conclusion, the OCT macular GCIPL complex IEPD and IEAD may be considered as supportive measurements for multiple sclerosis diagnostic criteria in a young patient without relevant co-morbidity. The metric does not allow separation of multiple sclerosis from neuromyelitis optica. Retinal OCT imaging is accurate, rapid, non-invasive, widely available and may therefore help to reduce need for invasive and more costly procedures. To be viable, higher sensitivity and specificity levels are needed.