The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study.

Background: White matter (WM) lesions and brain atrophy are present early in multiple sclerosis (MS). However, their spatio-temporal relationship remains unclear.
Methods: Yearly magnetic resonance images were analysed in 387 patients with a first clinical demyelinating event (FCDE) from the 5-year REFLEXION study. Patients received early (from baseline; N = 258; ET) or delayed treatment (from month-24; N = 129; DT) with subcutaneous interferon beta-1a. FSL-SIENA/VIENA were used to provide yearly percentage volume change of brain (PBVC) and ventricles (PVVC). Yearly total lesion volume change (TLVC) was determined by a semi-automated method. Using linear mixed models and voxel-wise analyses, we firstly investigated the overall relationship between TLVC and PBVC and between TLVC and PVVC in the same follow-up period. Analyses were then separately performed for: the untreated period of DT patients (first two years), the first year of treatment (year 1 for ET and year 3 for DT), and a period where patients had received at least 1 year of treatment (stable treatment; ET: years 2, 3, 4, and 5; DT: years 4 and 5).
Results: Whole brain: across the whole study period, lower TLVC was related to faster atrophy (PBVC: B = 0.046, SE = 0.013, p < 0.001; PVVC: B = -0.466, SE = 0.118, p < 0.001). Within the untreated period of DT patients, lower TLVC was related to faster atrophy (PBVC: B = 0.072, SE = 0.029, p = 0.013; PVVC: B = -0.917, SE = 0.306, p = 0.003). A similar relationship was found within the first year of treatment of ET patients (PBVC: B = 0.081, SE = 0.027, p = 0.003; PVVC: B = -1.08, SE = 0.284, p < 0.001), consistent with resolving oedema and pseudo-atrophy. Voxel-wise: overall, higher TLVC was related to faster ventricular enlargement. Lower TLVC was related to faster widespread atrophy in year 1 in both ET (first year of treatment) and DT (untreated) patients. In the second untreated year of DT patients and within the stable treatment period of ET patients (year 4), faster periventricular and occipital lobe atrophy was associated with higher TLVC.
Conclusions: WM lesion changes and atrophy occurred simultaneously in early MS. Spatio-temporal correspondence of these two processes involved mostly the periventricular area. Within the first year of the study, in both treatment groups, faster atrophy was linked to lower lesion volume changes, consistent with higher shrinking and disappearing lesion activity. This might reflect the pseudo-atrophy phenomenon that is probably related to the therapy driven (only in ET patients, as they received treatment from baseline) and "natural" (both ET and DT patients entered the study after a FCDE) resolution of oedema. In an untreated period and later on during stable treatment, (real) atrophy was related to higher lesion volume changes, consistent with increased new and enlarging lesion activity.
Competing Interests: Declaration of Competing Interest RMM has received research support from Merck. IB has received research support from Merck, Novartis, Teva, and the Dutch MS Research Foundation. BMJU reports research support and/or consultancy fees from Biogen, Merck, Novartis, Roche, Sanofi, Teva, and Immunic Therapeutics. LK's institution (University Hospital Basel) has received the following exclusively for research support: Steering committee, advisory board, and consultancy fees from Actelion (Janssen/J&J), Bayer, Biogen, BMS, Janssen (J&J), Merck, Novartis, Roche, Sanofi, Santhera, and TG Therapeutics; speaker fees from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi; support of educational activities from Allergan, Bayer, Biogen, CSL Behring, Desitin, Merck, Novartis, Roche, Pfizer, Sanofi, Shire, and Teva; license fees for Neurostatus products; and grants from Bayer, Biogen, European Union, InnoSwiss, Merck, Novartis, Roche, Swiss MS Society, and Swiss National Research Foundation. MSF has received honoraria or consultation fees from Alexion, Atara Biotherapeutics, Bayer, BeiGene, BMS (Celgene), EMD Serono, Janssen (J&J), Merck, Novartis, PendoPharm, Roche, and Sanofi; has been a member of a company advisory board, board of directors, or other similar group for Alexion, Atara Biotherapeutics, Bayer, BeiGene, BMS (Celgene), Clene Nanomedicine, Janssen (J&J), McKesson, Merck, Novartis, Roche, and Sanofi; has participated in a company sponsored speaker’s bureau for EMD Serono and Sanofi; and has been in receipt of research or educational grants from Sanofi. GC has received consulting fees from Bayer, Biogen, Merck, Novartis, Receptos, Roche, Sanofi, and Teva; lecture fees from Bayer, Biogen, Merck, Novartis, Sanofi, Serono Symposia International Foundation, and Teva; and trial grant support from Bayer, Biogen, Merck, Novartis, Receptos, Roche, Sanofi, and Teva. DJ is an employee of Merck Serono Ltd, Feltham, UK (an affiliate of Merck KGaA, Darmstadt, Germany). FB is supported by the NIHR Biomedical Research Centre at UCLH and is a consultant to Biogen, Combinostics, IXICO, Merck, and Roche. NDeS is a consultant for Biogen, Merck, Novartis, Sanofi, Roche, and Teva; has grants or grants pending from FISM and Novartis, is on the speakers’ bureaus of Biogen, Merck, Novartis, Roche, Sanofi, and Teva; and has received travel funds from Merck, Novartis, Roche, Sanofi, and Teva. HV has received research support from Merck, Novartis, Pfizer, and Teva; consulting fees from Merck; and speaker honoraria from Novartis. All funds were paid to his institution. GG, RAvS, JWRT, and MB report no disclosures.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)