With the growing body of scientific evidence over the past eight years, it was time to refine the 2017 McDonald criteria. While the 2017 update offered valuable recommendations and clarifications to reduce the risk of misdiagnosis, that risk persisted if the criteria were not applied with care [1]. The 2024 revisions introduce new elements designed to support clinicians in making early diagnoses and to improve the ability to distinguish multiple sclerosis (MS) from other conditions that mimic its presentation.
Originally developed in 2001, the McDonald criteria for diagnosing MS have evolved in step with scientific progress. “The impact of the diagnostic criteria was colossal, allowing for an earlier and more precise diagnosis of MS”, Professor Xavier Montalban, Chair of the International Advisory Committee on Clinical Trials in MS, said during our podcast. An international panel of leading experts has updated the criteria four times: in 2005, 2010, 2017, and most recently in 2024.
The McDonald criteria have significantly contributed to reduce the time from clinically isolated syndrome (CIS) to MS diagnosis by 77% and the time needed to start treatment by 82%, compared to the Poser criteria [2]. Furthermore, individuals diagnosed with more recent updates of the criteria have a lower risk of developing disability [2].
Professor Jiwon Oh, medical director of the Barlo MS Program at St. Michael’s Hospital, University of Toronto, tells us, “I believe that the 2017 McDonald diagnostic criteria have been beneficial to the field by simplifying the previous criteria. However, we must acknowledge that misdiagnosis is not uncommon in the field of MS. Emerging technologies can help address some of the current issues. Our goal is to diagnose MS as early as possible while avoiding misdiagnosis. The reason we want to diagnose earlier and earlier is that there is so much evidence showing how important is to treat early, rapidly, and with agents of appropriate efficacy.”
Behind the Scenes: A Global Effort
Professor Montalban stressed during our recent webinar that paraclinical tests – particularly brain and spinal cord MRI – remain essential for accurate diagnosis, as these represent the most informative tools available. At the same time, Prof Montalban emphasized that MS occurs without major differences throughout different geographic regions and ethnic groups. This means that the criteria can, in principle, be applied universally.
Building on this global perspective, Dr Tim Coetzee, Chief Executive at the National MS Society, explains, “We aimed to offer guidance for clinical practice worldwide. Therefore, we discussed how to apply the diagnostic criteria in those regions of the world where specialised imaging centers may be limited.”
Professor Oh outlines the global collaboration behind the latest revisions, “During our meeting in Barcelona, 56 international experts – including 23 women – with diverse expertise, representing 16 countries across all continents, followed a formal consensus methodology to reach agreement. Patient representatives were also present. It was the first time we integrated this approach into the criteria meetings. Many new members contributed for the first time to the revisions: 36 out of 56. In a roundtable discussion, everyone could express their ideas. Each attendee was given a unique voting code. For a statement to be approved, at least 90% of the people in the room had to vote on the statement, and over 80% of respondents were required to agree or strongly agree with it. Everyone was strongly encouraged to vote whenever they felt comfortable doing so. A few statements were in the grey zone, between 70% and 80% approval. These statements were re-discussed and the committee re-voted, and if the statements met the 80% approval criterion, they were then accepted. The process was highly rigorous, with clear rules established from the beginning, ensuring that everyone had a voice. This represented a significant departure from previous versions. It was a very intense few days, given the amount of data presented – the proposed revisions with the supporting evidence and specific recommendations – and it all boiled down to numerous statements. The key objective was to improve the sensitivity of the criteria, to make a correct MS diagnosis without delay, without compromising on specificity, to avoid misdiagnoses.”
Optic Nerve: The Fifth Topographical Area
The classical concepts of dissemination in time (DIT) and dissemination in space (DIS) have been updated in the 2024 revisions. Prof Oh outlines the key changes. As in previous versions, DIS is still defined by the involvement of two distinct regions. However, the total number of recognised typical topographical areas has increased – from 4 to 5. The optic nerve is now the fifth area of the central nervous system (CNS) to demonstrate DIS [3].
Dr Coetzee tells us, “In recent years, there have been substantial advancements in MS research, motivating us to consider revising the previous criteria. One of the fundamental proposed improvements is the inclusion of the optic nerve as an area for determining whether a person has MS. In 2017, we did not have enough evidence to include the optic nerve, but now we do.”
Individuals with CIS, particularly those presenting with optic neuritis, often have optic nerve lesions. These lesions can be detected with magnetic resonance imaging (MRI), optical coherence tomography (OCT) and visual evoked potentials (VEP) [3].
Another important update in the 2024 revisions is the inclusion of kappa free light chain (KFLC) as an alternative to oligoclonal bands (OCBs) for demonstrating DIT, provided there is already evidence supporting the diagnosis of MS. Professor Oh notes that when an individual presents with a typical clinical syndrome and has lesions in four or five of the recognised typical topographies, it is no longer necessary to demonstrate DIT separately – the extent of spatial involvement alone may suffice to establish a diagnosis. However, for cases in which one typical topographical area is involved, the revised criteria introduce a diagnostic pathway that can still support a diagnosis of MS, if certain additional requirements are fulfilled.
MRI Biomarkers in Support of Diagnostic Decision-Making
In 1862, MS plaques were first described as forming around blood vessel during autopsy examinations [4, 5]. Since then, advancements in technology have allowed visualisation of central veins inside the MS plaques in vivo [6].
The central vein sign (CVS) reflects perivenous inflammatory demyelination – typical of MS lesions – and has now been incorporated in the diagnostic criteria in some specific situations [7]. The aim is to facilitate diagnoses and avoid misdiagnosis. CVS stands out as an appealing MRI biomarker and can be acquired on susceptibility-based imaging. It does not demand complicated processing after the acquisition with the MRI or intricate interpretations. It is straightforward – either present or absent [7].
“With MRI sequences that are sensitive to iron, radiologists can easily see when a white matter lesion in the brain has a central vein inside. This is interesting because the pathological hallmark of MS white matter lesions is that they form around a central vein. There are many reasons why people can have white matter lesions, but if a white matter lesion forms around a central vein, the likelihood that it is related to MS is very high. Therefore, in an individual with six lesions with a central vein, the likelihood of a diagnosis of MS is very high. We rely heavily on MRI for our diagnoses. CVS can increase the specificity of an MS diagnosis – the capacity to correctly classify people who do not have MS – and facilitate MS diagnoses in people who clearly have inflammation around veins causing white matter lesions. It is a very practical tool and not complicated. In Toronto we follow over 10,000 patient per year and all our radiologists are excellent clinical neuroradiologists. When they started to use the iron-sensitive sequences required for CVS detection in research studies, they just realised how easy it was. You do not need any fancy post-imaging processing; you can just see the central vein on the clinical scan when the appropriate iron-sensitive sequences are used. So, from a practical standpoint, CVS is very accessible.”
The 2024 criteria include also paramagnetic rim lesions (PRLs) as supportive evidence in specific diagnostic situations. PRLs indicate chronic active inflammation and can be visualised using the same iron-sensitive sequences used for CVS detection [8]. As Prof Daniel Ontaneda said during our webinar, in certain clinical situations, the presence of one or more PRLs on brain MRI may support a diagnosis of MS – for example, in individuals with typical clinical symptoms and lesions confined to a single typical topography, the combination of at least one PRL plus either evidence of DIT or positive cerebrospinal fluid (CSF) findings can be sufficient to establish the diagnosis.
Neither the CVS nor PRLs are mandatory for diagnosis, as the imaging techniques needed to detect them may not be accessible everywhere. However, when available, they can serve as valuable tools to reduce the risk of misdiagnosis and are particularly helpful in challenging cases of differential diagnosis.
***
Written by Stefania de Vito
Special thanks to Professor Jiwon Oh (University of Toronto) and to Dr Tim Coetzee (National MS Society) for their insights.
References
[1] Solomon AJ, Naismith RT, & Cross AH. Neurol. 2019: 92(1), 26-33.
[2] Tintore M et al. Neurol. 2021; 97(17): e1641-e1652.
[3] Vidal-Jordana A et al. Neurol. 2024; 102(1): e200805.
[4] Sati P et al. Nat. Rev. Neurol. 2016; 12(12): 714-722.
[5] Rae-Grant AD et al. Mult. Scler. Relat. Dis. 2014; 3(2): 156-162.
[6] Hammond KE et al. Ann. Neurol. 2008; 64: 707–713.
[7] Oh J & Sati P (2020). Mult. Scler. J. 2020; 26(4): 409-410.
[8] Preziosa P et al. (2025) J. Neurol. 272(2): 145.