“We were treating MS patients with nothing until 1995”. At the Plenary II Session at MSMilan2023, former ECTRIMS President Professor Xavier Montalban delivered the Charcot Lecture, a bi-annual speech reserved for the recipient of the MS Charcot Award. This prestigious award is organised by the MS International Federation in recognition of a lifetime of achievements in groundbreaking MS research.
During his lecture, Montalban recalled his 30-year journey into MS research and clinical care. But he also took care to emphasise the collective efforts that led to what he called a “team award” – ie those who collaborated with him in shaping innovation and working “toward a future where the burden of multiple sclerosis is alleviated”.
A “Team” Award
The team story starts at the Multiple Sclerosis Center of Catalonia (Cemcat) in Barcelona, Spain – a world-class, multidisciplinary center, entirely dedicated to multiple sclerosis, of which Montalban is director. About 100 professionals work there. Since 1994, they have visited more than 9,000 patients. Currently, 4,223 of these patients are participating in one of more research study protocols. The trove and variety of collected data are impressive, including MRI images, fluid biomarkers, and visual pathway metrics. Most importantly, the databases capture the full history of the disease.
In 1995, Montalban’s team at Cemcat was a pioneer in collecting data from the earliest stages of MS with prospective cohorts, that have completely revolutionised our knowledge of MS and approaches to diagnosis and treatment.
Several prognostic factors have been identified thanks to the “Deeply phenotyped Barcelona CIS/early” cohort. This is one of the most well-characterised single-center prospective cohort of more than 1,000 patients, who are assessed within the first three months after the first symptom of a clinically isolated syndrome (CIS). The CIS prospective cohort is run by Professor Mar Tintoré, current president of ECTRIMS, Dr. Alex Rovira, and Dr. Manuel Cornabella.
Another widely recognised prospective cohort, the “Treated MS patients”, aims at evaluating the treatment response in more than 2,000 patients. This information is collected since the first patients with MS started the treatment at Cemcat in 1995. Dr Jordi Rìo is responsible of this cohort together with Dr Rovira and Dr Cornabella.
Changing the Course of MS: Defining the Diagnosis
Research at Cemcat has been instrumental in defining MS diagnosis. The group contributed to different revisions of the McDonald guidelines, in 2001, 2010 and 2017. Montalban’s role in these revisions – including the development of the MRI criteria while serving as an active member of the MAGNIMS group – was pivotal.
When making MS diagnosis, stringent criteria for lesions in the brain detected by MRI should be followed. The first paper published at Cemcat [1] modified one of the original 4 MRI criteria for the diagnosis of MS lesions developed by Prof. Frederik Barkhof and coauthors [2]. In 2001, the criteria derived from these two studies (Barkhof and colleagues and Tintoré and colleagues) were integrated in the McDonald guidelines for the MS diagnosis.
Several years later, the efforts of Cemcat group focused on making earlier diagnoses of multiple sclerosis. First, the researchers observed that very early MRI scans, performed within one month of symptom onset, already showed dissemination in time in MS [3]. And finally, in 2009, a key study [4] demonstrated that a single brain MRI performed 24 hours after the first symptom of CIS, and identifying both gadolinium enhancing and non-enhancing lesions, was sufficient to make a MS diagnosis. This study was incorporated in the McDonald Criteria revised in 2010.
The criteria derived from two studies conducted at the Cemcat were also inserted in the McDonald guidelines for MS diagnosis in 2017. In one study, Tintoré and coauthors [5] observed that symptomatic lesions could be included in the MRI determination of dissemination in space and in time to increase the diagnostic sensitivity. And in another study, Dr. Georgina Arrambide and colleagues [6] showed the value of oligoclonal bands in MS diagnosis.
Diagnosis of MS: An Evolving Issue
Accurate diagnostic criteria are essential to minimise the time between the first MS symptom and the treatment. Therefore, it is fundamental to understand how the diagnostic criteria of MS can evolve.
One question to explore is whether the optical nerve can be included as the fifth typical topography for the demonstration of distribution in space. “One third of patients with CIS has optic neuritis. Over time, the optic nerve is affected in almost 100% of patients. Therefore, it seems very logical to include the optic nerve into the typical topography”, Montalban said. Dr. Angela Vidal-Jordana and co-authors [7] showed that the addition of the optic nerve, assessed by visual evoked potentials, as a fifth region in the distribution in space (DIS) criteria in patients presenting a CIS slightly improves the diagnostic performance, by increasing the sensitivity of the diagnosis, without losing specificity.
Another topic to address is the potential role of diagnostic biomarkers, such as kappa free light chains (KFLC). “Besides oligloclonal bands (OB), there is an excess of KFLC in the cerebrospinal fluid of people with MS”, Montalban highlighted. “The measurement of kappa free light chains is particularly interesting, because it is a rapid, quantitative tool, and easier to measure than OB”, he added.
Moreover, it would be important to understand whether dissemination in space in patients with symptoms (typical or not so typical) is enough to diagnose MS. A study based on the CIS cohort proposes that in patients with CIS, radiological dissemination in space at any time combined with positive OB can represent an additional criterion for MS diagnosis [6]. However, Montalban, who directed the study, said the risk of developing MS is also very high for patients with DIS and negative oligoclonal band, and for patients who have an abnormal MRI, who have no dissemination in space and time, and positive OB. “Perhaps there is some room for improvement here. I believe that when making a MS diagnosis it is very important to find the typical MRI lesions”, he concluded.
These and many other inquires will be addressed in the forthcoming meeting in Barcelona this year, at the end of November. The International Advisory Committee on Clinical Trials in MS, a global body sponsored by ECTRIMS and the US National MS Society (NMSS), will meet at Cemcat to review the available evidence concerning MS diagnosis and to evaluate whether new elements can be included in the diagnostic classification.
References
[1] Tintoré M et al. AJNR Am. J. Neuroradiol. (2000); 21.4: 702-706.
[2] Barkhof F al. Brain (1997); 120: 2059–2069.
[3] Tur C et al. Mult. Scler. (2008); 14: 631-635.
[4] Rovira A et al. Arch. Neurol. (2009); 66.5: 587-592.
[5] Tintoré M et al. Neurol. (2016); 87: 1368–74.
[6] Arrambide G et al. Brain (2018); 141: 1075-1084.
[7] Vidal-Jordana A et al. Neurol. (2021); 96: e482-e490.