The earliest stages of MS: understanding susceptibility and the MS prodrome
Multiple sclerosis (MS) has been subject to intensive investigation, with data indicating that autoimmune inflammation and progressive degeneration both influence the pathophysiology – yet the fundamental cause remains an enigma. With there being variety in MS, why do some individuals adopt a relapsing-remitting pattern when others assume a progressive course further down the line?
Data has appeared to support the notion that all types of MS could be variants of an underlying pathophysiological premise – inferring that neurodegeneration and concomitant inflammation begin much earlier than anticipated. This is believed to proceed in an inexorable manner, irrespective of relapse-remitting characteristics being a prominent feature in MS pathophysiology.1 It is likely that genetic determinants and environmental risk factors play a crucial role in which clinical phenotypes of MS are expressed – emphasizing the importance for building an understanding of MS susceptibility.
At ACTRIMS 2022, Adil Harroud, MD, University of California, San Francisco, San Francisco, CA, discussed the importance of understanding MS susceptibility through genetics and the environment – stating that this would “allow us to identify populations that are of greater risk of MS than the general population – and be able to follow them and study them before they develop the disease.” Dr Harroud continued to talk about a session at ACTRIMS 2022 where Dr De Jager presented the Genes and Environment in MS (GEMS) project. This project is an example of a prospective study investigating high-risk individuals who are first degree relatives of patients with a diagnosis of MS. Dr Harroud states that “evidence from the study indicates that signs of neurological involvement may be present in healthy individuals identified as high-risk” – inferring the possibility of an increased risk of developing MS. This bold study is anticipated to span at least 20 years – recruiting many more participants since the study was first published in 2015.
Dr Harroud further discussed how the GEMS project divides the participants regarding their risk of MS based on both genetics and environmental factors. This demonstrated signs of neurological involvement in individuals who would otherwise be considered healthy but are at greater risk of developing MS. Thus, with the growing attention in this field of study, this presents an array of interesting questions regarding the prodrome of MS. There are many ways to discuss the prodromal phase of MS – however, radiologically isolated syndrome (RIS) is of foremost importance to the disease prior to clinical onset. Yet, it is believed that disease progression has already been initiated by this point. Hence, highlighting the importance of understanding MS processes prior to clinical onset.
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Radiologically isolated syndrome (RIS) refers to a case whereby brain or spinal magnetic resonance imaging (MRI) scans exhibit incidental white matter lesions, which fulfill the revised 2017 McDonald Criteria2 – being characteristic of the morphology and region of a demyelinating disease, without a clinical history of demyelination or neurodegenerative disorders. It is argued that RIS is not a true clinical diagnosis, yet a transition to a state of disease that is currently not distinguishable from imaging alone. Reports of T2 lesions and FLAIR pulse sequences observed on MRI appear almost identical to those seen in multiple sclerosis (MS)3 – yet these individuals do not have any current or prior symptoms typical of MS. Most cases of RIS are predominantly found in patients who are in evaluation through MRI for symptoms not typically characterized by MS: headaches, head trauma, dizziness, etc. Therefore, the prevalence of RIS is largely unknown.
Due to the unknown prevalence and asymptomatic nature of RIS, it is challenging to manage individuals clinically; there is not yet a clear evidence-based guideline on how to approach it. Scrupulous neurological examinations and a thorough clinical history are necessary to dismiss any evidence of MS prior to classifying an individual with RIS. Only with the presence of relapsing-remitting or the progressive onset of MS may an individual meet the criteria for MS diagnosis.4 However, in the RIS population, it is known that a substantial proportion of these individuals are at risk of ultimately developing MS.
At ACTRIMS 2022, Jiwon Oh, MD, PhD, St. Michael’s Hospital, University of Toronto, Toronto, Canada, discussed the management of RIS – highlighting the challenges presented by its classification and, thus, the approach taken in a clinical environment. Dr Oh commented on the prevalence of MS post RIS – stating that “at 10 years, the risk is cited to be a little over 50%”. The question then lies in how clinicians face this new information; Dr Oh further states that “most people follow these patients annually with a clinical exam and MRI. And, obviously, if they develop symptoms of MS, then you treat them as MS, but it gets challenging sometimes because some people will develop new lesions every year”. This can portray a challenge as clinicians cannot diagnose an individual with MS unless clinical symptoms are exhibited.
In a study conducted by Dr Oh et al., it was mentioned that cognitive impairment is a common occurrence in RIS – found to be in association with biomarkers of perivenular demyelination and chronic inflammation in white matter lesions like central vein signs and paramagnetic rim lesions.5 Additionally, Bisulca et al., mention that cerebrospinal fluid (CSF) biomarkers have been investigated in patients with RIS; oligoclonal bands are thought to be one of the most significant CSF biomarkers for predictive clinical progression to MS. Therefore, spinal cord lesions and oligoclonal bands in the CSF are vital for predicting RIS conversion to MS. However, new research has come to fruit regarding the central vein sign (CVS) and paramagnetic rim lesions (PRLs), which if validated, would both prove extremely useful as predictive tools for MS.
The central vein sign in multiple sclerosis
Being an extremely sensitive tool in detecting white matter lesions, magnetic resonance imaging (MRI) has become paramount in the diagnosis of multiple sclerosis (MS). However, with the frequent ambiguity of clinical cases, the diagnostic specificity of MRI for MS is currently inadequate – resulting in potential misdiagnosis. The central vein sign (CVS) is a novel MRI biomarker intended to ameliorate the speed and accuracy of diagnosis in MS. Having been studied by several different research groups across a variety of different neurological conditions – the CVS has demonstrated much potential in both screening MS and differentiating MS from mimicry conditions.6
Misdiagnosis can be detrimental towards health when treating any disorder – therefore, being able to differentiate MS from other conditions is of utmost importance. The CVS has demonstrated enormous potential in the differentiation of MS from microangiopathic brain lesions; conventional MRI has not always been able to do so. In a study of 40 patients, 3-T T2*-weighted MRI scans were evaluated to see if they could distinguish MS from microangiopathic brain lesions. Within the test cohort, all the patients with MS had CVS in >45% of lesions, whereas the remainder had CVS in <45% of lesions.7 This led to the conclusion that 3-T T2*-weighted brain MRI scans can distinguish MS lesions from microangiopathic lesions through identification of CVS.
Another example described in the literature is the MS-mimicry of autoimmune diseases akin to central nervous system (CNS) inflammatory vasculopathies. In a study of 31 patients with CNS inflammatory vasculopathies and 52 patients with relapse-remitting MS, 3D T2*-weighted and T2-fluid-attenuated inversion recovery images were acquired through MRI. The CVS was evaluated for each lesion – with the MS population demonstrating CVS with a median frequency of 88%, and the CNS inflammatory vasculopathies population demonstrating CVS with a frequency of 14%.8 These results suggest that the CVS can differentiate MS from CNS inflammatory vasculopathies in a clinical environment. Even with the ability of the CVS to act as a biomarker for MS, there are still unknowns regarding the CVS in new or developing MS lesions.
Pascal Sati, PhD, Cedars-Sinai Medical Center, Los Angeles, CA, discusses a study exploring the CVS as an imaging biomarker of MS pathophysiology. There was already an understanding of the baseline proportion of CVS+ lesions in a patient’s brain – classifying them as MS or not. However, the CVS had not yet been meticulously investigated in newly developing MS lesions. Through a retrospective, longitudinal cohort study over a median duration of three years, participants with new T2 or enhancing lesions were identified. The cohort consisted of 153 adults (95 relapsing-remitting MS, 27 secondary progressive MS, 16 primary progressive MS, 5 clinically isolated syndrome, and 10 healthy; 67% female) – whereby most newly developing T2 or enhancing lesions were CVS+ (68%), and near half (48%) developed new CVS+ lesions alone.9 Patients who formed a greater number of new CVS+ lesions tended to be younger and have a higher rate of CVS+ lesions at baseline. Furthermore, the data indicates that patients tend to longitudinally develop lesions, matching their overall baseline CVS proportion. The results emphasize the need for future studies which investigate the effect of disease-modifying therapies (DMTs) on the likelihood of developing new lesions stratified by CVS characteristics.
Research and development
Hear from expert colleagues discussing novel treatment strategies & sharing the latest data from the clinical trials presented at ACTRIMS 2022!
Assessing the peripheral immune compartment of patients with RIS
The central nervous system (CNS) is regarded as an immunoprivileged site, inferring the parameters of the CNS are protected from autoimmune responses.10 However, animal model studies in multiple sclerosis (MS) have suggested that maleficent immune cells pass through the blood-brain-barrier (BBB) and into the CNS11 – where they are able to initiate or contribute towards the formation of MS lesions. RIS exhibits similar lesions to that in MS, yet patients do not possess symptoms typically associated with MS.12 Furthermore, it is not fully understood how RIS converts to MS – thus, making it vital to understand the peripheral immune compartment of patients with radiologically isolated syndrome (RIS) in the context of MS.
A key avenue of study would be to determine if the immune cells or profiles of individuals with RIS demonstrate a potential risk of developing MS in the near future. At a poster session at ACTRIMS 2022, Raphael Schneider, MD, PhD, FRCPC, CIP, St. Michael’s Hospital, Toronto, Canada, discussed comparisons made in the peripheral immune compartments of patients with RIS and MS. It was hypothesized that studying the immune mechanisms underlying RIS will provide a better understanding of the disease processes leading up to MS and help identify novel prognostic biomarkers for individuals with RIS. By using high-parametric single-cell analysis combined with automated computational tools – they captured the peripheral immune compartment of individuals with RIS, MS, and healthy controls. Dr Schneider stated that by combining the images of MRI and data from the peripheral blood samples, “we will be one step closer to making a diagnosis – at least for those that do have an immune profile that is similar to individuals with MS”.
At ACTRIMS 2022, Dr Schneider explained how they measured the immune cell activation profiles of patients with RIS and MS, and healthy controls using cytometry by time of flight (CyTOF) – allowing for the study of many immune cell markers on individual cells. The main focus was on T-cells and B-cells, but data was also acquired on smaller cell populations.
The results demonstrate that in the cohort of 11 healthy controls, 12 RIS patients, and 8 MS patients – there was a significantly higher number of CXCR4-positive CD4 and CD8 T-cells in the blood of RIS patients compared to the healthy controls.13 This infers that CXCR4-expression on T-cells could help identify those RIS patients who show evidence of immune cell activation. These individuals may benefit from DMTs prior to the onset of MS symptoms.
Dr Schneider stated that at this current point in time, they have cross-sectional data – effectively being able to compare individuals with RIS, MS, and healthy controls at a given point in time. This study has acted as a preliminary phase for future studies – allowing for the prospect of being able to follow individuals over time, seeing who will develop clinical symptoms of MS from the RIS group. A longitudinal follow-up study will be able to find if any of the present biomarkers will have a prognostic value.