Abstract
Background and Objectives Microglia, the resident immune cell of the brain and retina, is widespread activated in the white and gray matter (GM) in multiple sclerosis (MS). The objective of this study is to evaluate the presence and number of hyperreflecting foci (HRF), considered clusters of activated and proliferating retinal microglia, and their association with clinical and radiologic disease parameters in relapsing-remitting MS (RRMS).
Methods At baseline, 80 patients with RRMS underwent optical coherence tomography (OCT) and 3T-MRI (including 3-dimensional T1, fluid-attenuated inversion recovery, and double inversion recovery sequences), closed to their disease onset (6.3 ± 5.1 months). These patients were then clinically and radiologically followed up for a mean of 43 months, evaluating the no evidence of disease activity (NEDA) condition, further divided into clinical (cNEDA) and radiologic (rNEDA). Patients with a clinical history or MRI/OCT findings suggestive of optic neuritis (ON) were excluded from the study.
Results Compared with healthy controls, the HRF number was significantly higher in the inner nuclear layer (INL) of patients with RRMS (19.55 ± 5.65 vs 13.84 ± 2.57, p < 0.001) and associated with INL volume (β: 1.21, p < 0.001). GM lesion volume significantly correlated with the INL HRF count (p = 0.008). Survival analysis revealed a significant association between INL HRF and both cNEDA (p = 0.017) and rNEDA (p = 0.002).
Discussion We found a strong association between retinal microglial proliferation and cortical pathology in RRMS, a finding suggesting a possible underlying common immunopathologic mechanism. Furthermore, microglial activation at baseline was observed to predict subsequent inflammatory events, indicating that HRF might be a candidate prognostic biomarker worthy of further investigation.
Classification of Evidence This study provides Class II evidence that in patients with early RRMS but without ON, the number of HRF on OCT of the retinal inner nuclear layer is associated with cNEDA and rNEDA.
Glossary
- 3D=
- 3 dimensional;
- ANT=
- advanced normalization tool;
- BRB=
- blood-retina barrier;
- cNEDA=
- clinical NEDA;
- DMT=
- disease-modifying therapy;
- EDSS=
- Expanded Disability Status Scale;
- ET=
- echo time;
- FLAIR=
- fluid-attenuated inversion recovery;
- FOV=
- field of view;
- GEE=
- generalized estimating equation;
- GCL=
- ganglion cell layer;
- GM=
- gray matter;
- GMLV=
- GM lesion volume;
- HC=
- healthy control;
- HRF=
- hyperreflecting foci;
- IL=
- interleukin;
- INL=
- inner nuclear layer;
- IPL=
- inner plexiform layer;
- IRL=
- inner retinal layer;
- IT=
- inversion time;
- LGN=
- lateral geniculate nucleus;
- MHC=
- major histocompatibility complex;
- MS=
- multiple sclerosis;
- NEDA=
- no evidence of disease activity;
- OCT=
- optical coherence tomography;
- ON=
- optic neuritis;
- OR=
- optic radiation;
- PMB=
- papillomacular bundle;
- rNEDA=
- radiologic NEDA;
- RNFL=
- retinal nerve fiber layer;
- ROC=
- receiver operating characteristic;
- RRMS=
- relapsing-remitting MS;
- RT=
- repetition time;
- WM=
- white matter;
- WMLV=
- WM lesion volume
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally to this work.
The Article Processing Charge was funded by “Progetto di Eccellenza 2020,” Department of Neuroscience, Università degli Studi di Padova, and “Roche per la Ricerca 2016.”
- Received August 17, 2021.
- Accepted in final form March 8, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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