A behind the scene look reveals the depth of collaboration and scientific rigor that shaped the proposed updates of the McDonald Diagnostic Criteria. Discussions leading to the revisions were carefully planned and thorough, involving in-depth reviews of fundamental aspects of multiple sclerosis (MS). These are some of the key points that emerged from our recent webinar.
Thought leader experts, members of the International Advisory Committee of Clinical Trials in MS, chaired by Prof Xavier Montalban – from the MS Centre of Catalonia (Cemcat) – discussed the methods and the topics of the workshop and the previous meetings that proposed improvements for the 2024 McDonald Criteria.
The International Advisory Committee of Clinical Trials in MS – sponsored by ECTRIMS and the US National MS Society – provides perspectives and guidance in areas of interest to plan and implement clinical trials for the treatment of MS. It is very well known for its work in developing and systematically revising the McDonald Diagnostic Criteria.
In 2022 and 2023 the Committee had virtual meetings to discuss the revisions of the 2017 McDonald Criteria, in which strengths and limitations were assessed, as Prof Christine Lebrun-Frenay from the University Hospital of Nice remembers. The invited experts had a list of key questions including the role of the visual system and the optic nerve. In 2023, all members met in an International Workshop in Barcelona to consider revisions of the McDonald Criteria.
A transparent and organised process
Prof Jiwon Oh from the University of Toronto tells us about the Consensus Methodology that was applied for the first time during the workshop: the nominal group technique (NGT). Each recommendation was presented by a known expert from the Committee followed by a group discussion. Once all the recommendations were discussed, the experts voted. A few criteria had to be met for these statements and recommendations to be included in the 2024 revisions:
- At least 90% of participants needed to vote. Everyone was encouraged to vote when they felt comfortable doing so.
- For a statement or recommendation to be accepted, it required at least 80% agreement.
- A few statements were in the grey zone, between 70% and 80% approval. These statements were re-discussed and re-voted and if they met the 80% criterion they were then accepted.
Diverse expert group of people
The panel included 56 international panel members, Prof Daniel Ontaneda from the Cleveland Clinic in Ohio points out. The members had expertise in several different areas, including clinical management, radiology, methodology, epidemiology. Patients’ perspective was also taken into account. Many new members contributed for the first time to the revisions of McDonald Criteria: 36 out of 56. This was a global effort. There were representatives of 16 countries from all continents, including areas with lack of resources. Importantly, there was an excellent gender balance with 23 women in the panel.
General concepts of MS
Prof Montalban highlights a number of general concepts of MS outlined during the workshop:
- MS occurs without major differences throughout different regions and races. This means that these criteria in principle can be applied everywhere.
- MS is still a diagnostic of exclusion with no better explanation.
- Practical tests are essential for the diagnosis of MS, with brain and spinal cord MRI being the most useful paraclinical tests.
- Misdiagnosis and under-diagnosis can have harmful consequences for patients. So, neurologists should really be careful.
- MS diagnosis should be reassessed periodically.
Optic nerve: the fifth topographic marker for MS diagnosis
Prof Ontaneda highlights that optic nerve involvement is common in MS. Approximately 1/3 of individuals with clinically isolated syndrome (CIS) present initially with optic neuritis. Prof. Ontaneda discusses the inclusion of optic neuritis as a criterion for dissemination in space in the 2024 revisions, along with the criteria for detecting it using MRI, visual evoked potentials, or optical coherence tomography (OCT).
Dissemination in time and dissemination in space
The classical concepts of dissemination in time (DIT) and dissemination in space (DIS) have also been modified in the 2024 revisions. Prof Oh highlights the major changes. Similar to the prior diagnostic criteria, DIS is fulfilled when two regions are involved. However, the total number of typical topographies has changed – from 4 to 5 – because of the inclusion of the optic nerve. Another important change that has been incorporated is that kappa free light chain (KFLC) can be be used alternatively to oligoclonal bands (OCB) to demonstrate DIT, when there is already evidence of DIT. In addition, Prof Oh thinks that one of the biggest changes is that in certain situations, when an individual has a typical clinical presentation of MS and typical lesions in 4 or 5 typical topographies, one does not need to demonstrate DIT. Demonstrating that so many regions are involved is sufficient to diagnose MS. Moreover, in people who only have a single typical topography involved, there is a part of the diagnostic algorithm that still enables a diagnosis of MS, if certain criteria are met. Finally, in people with a progressive disease, 2 or more spinal cord lesions are enough to demonstrate DIT. As many MS clinicians know, people with progressive MS present a heavy spinal cord lesion burden.
A more biologically based diagnosis
Prof Lebrun-Frenay – expert in radiologically isolated syndrome (RIS) – discusses the shift into diagnosing MS in some of those who do not have typical MS symptoms. In the 2024 revisions, individuals with RIS, who have at least one lesion in two suggestive locations can be considered having MS, with only one additional feature – among demonstration of DIT with the magnetic resonance imaging (MRI) or with either increased cerebrospinal fluid (CSF) OCB or KFLC, or at least 6 central vein signs (CVS).
New tools in the 2024 diagnostic criteria: The “select 6″ criteria
CVS can now be used to make a diagnosis of MS and can increase specificity for an MS diagnosis. Prof Ontaneda talks about this radiological diagnostic biomarker that reflects perivenous inflammatory demyelination – typical of MS lesions. The CVS can be acquired on susceptibility-based imaging. This can be done with a technology that is available worldwide on almost any scan. CVS can be easily identified by neurologists and radiologists. However, CVS is not required for the diagnosis of MS because it may not be available worldwide.
Patients who have typical symptoms and DIS, the presence of “select 6” is used to confirm the diagnosis of MS. “Select 6” refers to the presence of 6 or more CVS on a single MRI study or if the person has fewer than 10 lesions and the majority of these lesions has CVS.
Paramagnetic rim lesions (PRL) – that indicates the presence of chronic active inflammation – can also be visualised on the susceptibility based imaging with phase images and is highly specific for MS. The presence of iron in microphages and microglia appears as a rim around the lesions. These lesions are very specific for MS. Demonstrating one or more PRL lesion on an MRI brain can be used to make a diagnosis of MS in specific situations. Once again, PRL is not required for the diagnosis of MS because it may not be available worldwide.
Specifically, in patients who have typical symptoms and typical lesions in one topography, the presence of one or more PRL plus either DIT or positive CSF is sufficient to diagnose MS.
Kappa free light chain (KFLC) index is an appropriate paraclinical test for the diagnosis of MS. The measurement of KFLC can be done by an automated rapid and low cost test. KFLC index is interchangeable with OCB and consequently can substitute for OCB for diagnosing MS.
Prof Montalban reminds that these tools are not mandatory for the diagnosis of MS but they can be used as additional tools when available. Prof Oh specifies that these tools are really not complicated to get and they are extremely useful.
Prof Oh says:
“One of the great benefits of CVS is that not only is a sensitive tool that facilitates the diagnosis but it really helps prevent misdiagnosis. It is not mandatory but when you have access to it, it can be an incredible useful tool.”
A unified diagnostic algorithm
Prof Oh clarifies that for children the same diagnostic algorithm can apply. However, there are a few differential diagnoses that we need to keep in mind particularly in paediatric-onset patients, because we know that the incidence and prevalence of MS is very different in this population compared to adults. For instance, MOG-antibody testing is strongly recommended, if not mandatory, in children under the age of 12. And this is because it is a very common differential diagnosis in this age. In children above the age of 12, MOG-antibody testing is still strongly recommended if the clinical presentation is atypical for MS. The presence of CVS in more than 50% of white matter lesions in paediatric patients also supports the diagnosis of MS. In typical presentations or even in people without typical presentations, CVS is a very useful tool to facilitate the diagnosis. CVS is a specific measure. When there is uncertainty, CVS is a very useful tool, also in children, older patients or patients with comorbidities.
Increased specificity in specific populations
Misdiagnosis is more likely in people above the age of 50, says Prof Lebrun-Frenay, or in people at any age with comorbidities, such as cardiovascular risk factors, psychiatric disorders, autoimmune diseases associated with increased white matter lesions, or headache disorders. In these cases, additional tools are strongly recommended to confirm the diagnosis of MS.