Development and Interrelation of Whole-Brain Atrophy and Lesion Volume in Patients with a First Clinical Demyelinating Event in the REFLEX/ION Study

Background: White matter (WM) lesions and atrophy are present early in the disease course of multiple sclerosis (MS). However, the temporal relation between whole-brain atrophy and lesion processes remains unclear.

Objectives: Study temporal development of whole-brain atrophy and WM lesions in patients (pts) with a first clinical demyelinating event (FCDE), how these processes are related, and how this relates to treatment and conversion to clinically definite MS (CDMS).

Methods: Yearly whole-brain images during 5 years were analyzed in 392 pts presenting with FCDE from the REFLEX/ION study. Pts received early (from baseline; N=262; ET) or delayed (from Month-24; N=130; DT) treatment with subcutaneous interferon beta-1a; 162 pts converted to CDMS and 230 did not. Global and central atrophy were assessed using FSL-SIENA to provide yearly % volume change of brain (PBVC) and ventricles (PVVC), respectively. Yearly total lesion volume change (TLVC) was determined by an automated method based on subtraction imaging. Linear mixed models correcting for age and sex were used for statistical analysis; p<0.05 was considered significant.

Results: PBVC, PVVC, and TLVC increased significantly faster in pts with CDMS compared to those without (all p<0.01), and there were no significant differences between treatment groups. In Year 1, ET pts showed more brain volume loss (corresponding to pseudo-atrophy) and lesion volume loss (corresponding to resolving edema) versus DT pts. In Year 2, atrophy was slower in ET (mean %/year ±SD: PBVC, -0.35±0.60; PVVC, 2.37±4.58) versus DT pts (PBVC, -0.54±0.75; PVVC, 4.02±5.97). In Year 4, PBVC %/year was -0.31±0.58 in ET and ‑0.51±0.53 in DT pts. Incorporating a time-lag in the linear mixed model showed that higher TLVC was related to significantly greater atrophy in the following year (PBVC: B=-0.04, SE=0.01; PVVC: B=0.52, SE=0.10 [both p≤0.001]). After removing the first year of treatment to prevent confounding by pseudo-atrophy and resolving edema, the strength of the relationship increased (PBVC: B=-0.11, SE=0.02; PVVC: B=1.16, SE=0.16 [both p<0.001]). For PVVC, during this stable treatment phase, the significant relationship was only present in ET pts (B=1.35, SE=0.18; p<0.001).

Conclusions: WM lesions and whole-brain atrophy progressed faster in pts with CDMS during the study. The rate of whole-brain atrophy is predicted by previous lesion volume change.