Elsevier

The Lancet Neurology

Volume 16, Issue 10, October 2017, Pages 797-812
The Lancet Neurology

Articles
Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis

https://doi.org/10.1016/S1474-4422(17)30278-8Get rights and content

Summary

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.

Introduction

Optical coherence tomography (OCT) is a high-resolution imaging technique suitable for sophisticated postprocessing.1, 2 Since our last meta-analysis,3 use of time domain OCT (TD-OCT) has been overtaken by spectral domain OCT (SD-OCT) in clinical practice.4 The much higher resolution of SD-OCT now permits analysis of individual retinal layer thicknesses.5, 6, 7, 8 This improvement in technique has enabled segmentation of ten additional retinal layers next to the well investigated retinal nerve fibre layer (RNFL).9 Five of these layers have been analysed systematically in patients with multiple sclerosis: ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL). In the present meta-analysis, we aimed to investigate what additional information can be derived by retinal layer segmentation in patients with multiple sclerosis and with optic neuritis associated with multiple sclerosis.

Section snippets

Search strategy and selection criteria

This study was a systematic review and meta-analysis of the thickness of individual retinal layers in multiple sclerosis. AP and LJBalk did the review of the Dutch, English, French, German, Italian, and Spanish literature on all studies (cross-sectional and longitudinal) with OCT in patients with multiple sclerosis published between the first report of the method by Huang and colleagues1 on Nov 22, 1991, and April 19, 2016, including manuscripts published ahead of print. We searched PubMed, Web

Results

Figure 1 summarises the selection process for the 110 articles that reported SD-OCT in multiple sclerosis (the appendix has the full list of references). Of these, 40 articles6, 14, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 presented data suitable (in five cases after contacting the authors for additional information [stated as not estimable when data were not provided]) for

Discussion

In this meta-analysis, the data suggest that multiple sclerosis is associated with atrophy of retinal ganglion cells (GCL and GCIPL) and their axons (peripapillary RNFL and macular RNFL). Importantly, the effect sizes shown for the meta-analysis based on SD-OCT of the peripapillary RNFL almost exactly matched the effect sizes from our meta-analysis3 based on TD-OCT. This outcome emphasises the robustness and accuracy of the peripapillary RNFL as a measure for neurodegeneration in multiple

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