Background Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. Methods In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. Findings Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference −20·10 μm, 95% CI −22·76 to −17·44; p<0·0001) and in MSNON eyes (–7·41 μm, −8·98 to −5·83; p<0·0001). The macula showed RNFL thinning of −6·18 μm (–8·07 to −4·28; p<0·0001) in MSON eyes and −2·15 μm (–3·15 to −1·15; p<0·0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was −16·42 μm (–19·23 to −13·60; p<0·0001) for MSON eyes and −6·31 μm (–7·75 to −4·87; p<0·0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0·77 μm, 0·25 to 1·28; p=0·003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1·21 μm, 0·24 to 2·19; p=0·01). Interpretation The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. Funding None.
Bibliographical noteFunding Information:
AJG reports grants and other support from Inception Biosciences; grants from the National Multiple Sclerosis Society and from the US National Institutes of Health; other support from MedImmune, Mylan, Sandoz, Dr Reddy, Amneal, Momenta, Synthon, and JAMA Neurology, outside the submitted work; and that the Multiple Sclerosis Center, Department of Neurology, University of California San Francisco has received grant support from Novartis for participating in the OCTIMS study. AP reports that the VUmc Multiple Sclerosis Center Amsterdam participated in the OCTIMS study and the PASSOS study, which were sponsored by Novartis, and the centre has received research support for OCT projects from the Dutch Multiple Sclerosis Society. The research of AP was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and University College London Institute of Ophthalmology. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. PVi has received an honorarium from Heidelberg Engineering in 2014, has received unrestricted research grants from Novartis (including for the OCTIMS study), Biogen, Genzyme, and Roche, and has participated in advisory boards for Novartis, Roche, Genzyme, and Biogen. PVi holds stocks in the following spin-off companies: Bionure Inc, Spire Bioventures, Mintlabs, and Health Engineering. TCF reports personal fees from Acorda, Novartis, and Genzyme. EMF has received speaker fees from Novartis, Acorda, Genzyme, and TEVA. SS reports grants from the University of Zurich, Clinical Research Priority Program, and Swiss Multiple Sclerosis Society, during the conduct of the study; personal fees from Bayer Healthcare, Biogen, Merck, TEVA, and Roche; and grants and personal fees from Novartis and Sanofi-Genzyme, outside the submitted work. The University Hospital of Zurich participated in the OCTIMS study, which was sponsored by Novartis. PVe received honoraria and consulting fees from Biogen, Sanofi Genzyme, Bayer, Novartis, TEVA, Merck Serono, Roche, and Almirall, and research support from Biogen, Bayer, Novartis, Sanofi Genzyme, Celegene, Sevier, and Merck Serono. EHM-L receives funding from the Instituto de Salud Carlos III, Spain, and Fondo Europeo de Desarrollo Regional (JR16/00006), Grant for Multiple Sclerosis Innovation, and Marató TV3 Charitable Foundation. EHM-L is a researcher in the OCTIMS study sponsored by Novartis; has received speaking honoraria from Biogen and Genzyme and travel reimbursement from Genzyme and Roche for international and national meetings over the past 3 years; has participated in a scientific board from Genzyme; and is a member of the working committee of International Multiple Sclerosis Visual System (IMSVISUAL) Consortium and has received non-financial support for this activity and from the Consortium. OO has received grants and personal fees from Biogen, Sanofi Genzyme, Merck Serono, Novartis, and Teva Pharmaceuticals Industries. RK reports receipt of grants from the US Department of Defense (DOD) and Veterans Affairs Office of Research and Development (VA-ORD), and the Chronic Effects of Neurotrauma Consortium: Center for the Prevention and Treatment of Visual Loss, C9251-C, Veterans Administration Rehabilitation Research Development (RRD), VA-ORD; I01 RX000889-01A1 Veterans Administration RRD, VA-ORD; 1IO1 RX002101 Veterans Administration RRD, VA-ORD; 1R01EY023279-01, National Eye Institute W81XWH-16-1-0071 DOD, CDMRP USAMRAA; and W81XWH-16-1-0211 DOD, CDMRP USAMRAA. RK reports that the University of Iowa Neuro-ophthalmology Division also participated in the Novartis-sponsored OCTIMS Study as one of the research sites and RK served on the OCTIMS Steering Committee and receives honoraria from Novartis for this activity. RK reports other support from MedFace LLC and FaceX LLC, has a patent application for assessing facial features in ophthalmological and neurological disorders pending, and has a patent application to use pupil and eye movement recordings to diagnose eye and CNS disorders, such as traumatic brain injury. PAC has received grants from Biogen-IDEC, Teva, Novartis, Annexon, and MedImmune. He has received consulting fees from Biogen-IDEC and Vertex. FP has received research support and personal compensation for activities with Alexion, Chugai, Biogen, Bayer, Merck Serono, Teva, Genzyme, Novartis, and MedImmune, is sitting on the steering committee of the MedImmune N-Momentum study and receives honoraria. FP receives funding from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, and Guthy Jackson Charitable Foundation. FC has received consulting fees from Clene, EMD Serono, and PRIME, and is participating as a site investigator in the Novartis-funded OCTIMS study. LJBalc reports personal fees from Biogen. LJBalk reports grants from TEVA and that the VUmc MS Center Amsterdam received financial research support for OCT projects from TEVA and participated in the OCTIMS trial, which was sponsored by Novartis.
© 2017 Elsevier Ltd