The North American Imaging in Multiple Sclerosis (NAIMS) cooperative has issued a consensus statement on chronic active lesions (CAL) in MS and how biomarkers may be employed to evaluate them (Bagnato et al. Brain 2024; epublished January 16, 2024).

CAL (also referred to as mixed active/inactive lesions) evolve from gadolinium-enhancing white-matter lesions and indicate chronic compartmentalized inflammation within the CNS (Prineas et al. Ann Neurol 2001;50:646-657). They have a hypocellular core with few macrophages/microglia present. CALs may show ongoing demyelination (smouldering lesions) or volume change over time (slowly expanding lesions, SEL), although it should be noted that not all SEL are CAL.

CALs are associated with a number of reactive glial cell types. The subtype featuring a rim of activated microglia with iron deposition (paramagnetic rim lesions, PRL) corresponds histopathologically with CAL. However, a subset of CAL lack an iron rim that cannot be detected with susceptibility-sensitive MRI but may be identified with 18-kDa translocator protein (TSPO)-PET imaging, which detects activated myeloid cells.

According to the NAIM consensus, useful CAL biomarkers include PRL using susceptibility-sensitive MRI; SEL using T1- and T2-weighted sequences; and TSPO-positive lesions on PET imaging. These enable some measure of quantification of CAL in white matter and to a lesser degree in cortical grey matter, but at present they cannot detect CAL in the spinal cord.

PRLs are considered the most robust biomarker of histopathological changes seen with CAL. PRLs occur in all MS phenotypes and are generally prognostic of a more severe clinical course. An estimated 50% of Gd+ lesions are rim+ at the time of lesion formation (Zhang et al. AJNR 2019;40:987-993). Over the next few years, PRLs may slowly enlarge, or the rim may resolve. The presence of an iron rim is an indicator of greater tissue injury in the lesion and to the surrounding tissues. PRLs are associated with lower whole-brain and grey-matter volume, cortical lesions and spinal cord atrophy.

PRLs have a high specificity for MS (>90%) that may be useful in distinguishing MS from its mimics. The International Advisory Committee on Clinical Trials in MS is currently considering whether to include PRLs in its diagnostic criteria (see McDonald criteria 2024: what changes can we expect?, NeuroSens, January 30, 2024).

The NAIMS group stated that additional studies are needed to determine the impact of disease-modifying therapies on PRLs and whether the prevention/resolution of PRLs will improve outcomes. At present, only a few studies have incorporated these imaging biomarkers as an endpoint. A phase II trial of tolebrutinib evaluated PRL as an exploratory endpoint but results were inconclusive due to the short duration of the trial (Reich et al. Lancet Neurol 2021;20:729-738); results remained inconclusive at 96 weeks (Reich et al. AAN 2023;3-012). A post-hoc analysis of the evobrutinib phase II trial reported improvement in SEL volume (Arnold et al. Neurology 2024;102:e208058). An ongoing phase IV study of ocrelizumab (NCT04230174) and the CLADPET study of cladribine (NCT04239820) are using PET imaging to evaluate the effect of treatment on microglial activation.