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. 2020 Feb 24;16(3):171–182. doi: 10.1038/s41582-020-0314-x

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a | Transverse T2-weighted fluid attenuation inversion recovery images from a patient with highly active relapsing–remitting multiple sclerosis (MS) who started a disease-modifying therapy at baseline. The T2 lesion load (T2LL) is stable during the first 3 years of treatment while the patient remained clinically stable (no relapses and no disability worsening), but markedly increases at the fourth year after treatment discontinuation associated with clinical activity (the rebound effect). b | Contrast-enhanced T1-weighted images from the same patient showing the change in brain parenchymal fraction (BPF) over time. The decrease in global brain volume in the first 3 years is mild (annualized percentage of brain volume change (aPBVC) −0.089%), but the volume loss at the fourth year is severe (aPBVC −3.8%), matching the change in T2LL and clinical evolution. The severe loss observed in year 4 is well beyond the −0.4% suggested as a pathological cut-off for brain volume loss in MS²⁴. c | Graphical representation of the changes in BPF over time, emphasizing the dramatic loss of volume in year 4.