The International Advisory Committee on Clinical Trials in MS convened in Barcelona on November 29 to discuss the latest round of revisions to the McDonald diagnostic criteria. The criteria were last revised in 2017 (Thompson et al. Lancet Neurol 2018;17:162-173). The in-person meeting followed a series of virtual meetings of the group in 2022 to discuss some of the issues not addressed in the 2017 criteria, such as the role of the visual system in diagnosis, the use of high-field MRI and which biomarkers can be used to support an MS diagnosis.

The following is a summary of some of the topics being discussed:

• Is dissemination in time (DIT) needed for diagnosis? This would be a continuation of the process begun in the 2017 criteria, which permitted oligoclonal bands (OCB) to substitute for DIT. In CIS, the presence of Gd-enhancing and non-enhancing lesions in the same scan, which implies different time points, also meets DIT criteria.
• Optic nerve involvement for dissemination in space (DIS) criteria. In 2016, the MAGNIMS group suggested that the optic nerve be included as a fifth topography to meet DIS criteria (Filippi et al. Lancet Neurol 2016;15: 292-303). Optical coherence tomography (OCT) data were lacking, and this revision was not incorporated at that time. MAGNIMS has now updated its recommendation based on more robust data from optic nerve-MRI, OCT and visual evoked potentials (VEP) (Vidal-Jordana et al. Neurology 2024;102:e200805).
• Addition of central vein sign (CVS) and paramagnetic rim lesions (PRL) for diagnosis. Several groups have proposed CVS as a biomarker to differentiate MS from MS mimics in cases of diagnostic uncertainty (Clarke et al. Mult Scler 2020;26:433-441). The North American Imaging in MS (NAIMS) Cooperative’s CAVS-MS study was launched to examine the utility of CVS in diagnosis (Ontaneda et al. Neuroimage Clin 2021:32:102834). One issue that will need to be addressed is the optimal cut-off value (the 40% rule, the 50% rule, the 3- or 6-lesion criteria). As for PRLs, the MAGNIMS group reported that the presence of >1 PRL was highly specific (99.7%) for differentiating CIS/MS from MS mimics or healthy controls (Meaton et al. Mult Scler 2022;28:2212-2220). Specificity was improved (100%) when CVS was present in a PRL.
• Radiologically isolated syndrome (RIS) is MS in some situations. The RISConsortium recently reported that CVS lesions were as useful in differentiating RIS from non-MS as they were for distinguishing MS from non-MS (Landes-Chateau et al. Ann Clin Transl Neurol 2024; epublished January 8, 2024). The proportion of CVS+ white-matter lesions was 66.4% for RIS, 70.4% for MS and 12.9% in non-MS. Diagnostic accuracy was 87% when a 6-CVS+ lesion cut-off was used (sensitivity 95%, specificity 83%). The specificity was 100% when fluid biomarkers (OCBs, kappa index) were added.
• Use of neurofilament-light chain (NfL) as a diagnostic biomarker. CSF and serum levels of NfL, a biomarker of axonal damage, may be a useful aid in diagnosis. A recent meta-analysis found that NfL levels were significantly higher in CIS/MS patients compared to age-matched controls and could be useful in differentiating RMS from PMS (Ning et al. PLoS One 2022;17:e0274565).
• Use of kappa free light chain (kFLC) as a diagnostic biomarker. Like OCBs, kFLC is a biomarker of intrathecal IgG synthesis. A meta-analysis reported that the kFLC index had a high sensitivity and specificity (weighted average 88% and 89%) in identifying CIS/MS; diagnostic accuracy was similar to that of OCBs (Hegen et al. Mult Scler 2023;29:169-181). kFLC detection is simple, cost-effective and reliable, which has led some groups to recommend inclusion in McDonald 2024 (Hegen et al. Mult Scler 2023;29:182-195). One group has proposed kFLC analysis as the initial screening. An MS diagnosis could be made if the kFLC index >1; if <6.1, OCB testing would only then be performed (Monreal et al. Front Immunol 2023;14:1288169).

The International Advisory Committee’s recommendations have not yet been made public so it is not known how the group will address these topics. Some details may be made available at the upcoming ACTRIMS Forum meeting, to be held February 29-March 2 in West Palm Beach, Florida. The full recommendations are expected to be revealed later this year at ECTRIMS 2024.