Central Vein Sign in Multiple Sclerosis Extension Study

Multiple sclerosis (MS) is a common disease of the central nervous system that affects almost 1 million people in the United States. However, diagnosing MS can be difficult and often leads to misdiagnosis. More sensitive and specific biomarkers are needed to help with the diagnosis, prognosis, and evaluation of treatment response for MS. The central vein sign (CVS) and the paramagnetic rim lesion (PRL) are two biomarkers that have shown promise in improving diagnostic accuracy for MS. The goal of this study is to provide pilot information on the long-term performance of the CVS and PRL to help diagnose and follow people with MS. The study will follow 40 participants over 48 months to determine if the CVS and PRL help make a diagnosis of MS and how they can be used to follow people with MS. The study will also examine how PRL and CVS change over 48 months. The results of this pilot study will inform the development of a grant application to extend 5-year follow-up for all 420 participants of the CAVS-MS study. The study will use high-resolution T2\*-weighted MRI to detect the CVS and PRLs. An MRI of the brain with contrast will be used to examine CVS, PRL and longitudinal analysis of lesions that slowly grow over time (slowly expanding lesions \[SELs\]). The results of this study have the potential to improve the accuracy of diagnosing and treating MS.

The goal of this study is to provide pilot information on the long-term diagnostic and prognostic performance of the CVS and PRL. This study will be leveraged on the Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" (IRB 20-063) which is an NIH-supported (1U01NS116776-01), 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as an MRI-based diagnostic biomarker for immediate translation into clinical care. This study will extend follow-up in a pilot study of 3 sites to confirm the diagnostic performance of the CVS and PLR at 4-year follow-up and explore the prognostic value of PRLs in those with MS at 4 years. The CVS is proposed as a diagnostic biomarker with improved sensitivity for a diagnosis of MS, while retaining diagnostic specificity - all in an-easy-to use diagnostic test that can be applied in patients with both typical and atypical disease presentation. There is extensive research demonstrating the ability of the CVS criteria to discriminate MS lesions from common mimickers, such as vascular disease and migraine. However, the CVS has mainly been applied in cross-sectional studies. In addition, the majority of these studies have focused analysis primarily on patients presenting with typical clinical events of demyelination (i.e. a classic CIS). This study will evaluate CVS criteria prospectively in individuals with typical and atypical MS presentations. In Aim 1, we will examine sensitivity and specificity of CVS criteria in conjunction with, and in comparison to, the McDonald Criteria. In Aim 2, we will examine CVS in a population where McDonald criteria explicitly cannot be applied. Because the likelihood of MS is lower in this group, we will focus on specificity, which is where the unmet need exists. Although current MS diagnostic criteria are sensitive in most typical cases, the use of the CVS may hasten diagnosis in patients with low lesion numbers and those without dissemination in time. In the past, studies that informed revision of the diagnostic criteria used "clinically definite MS" (defined as two separate clinical events) as the definitive determination of a diagnosis. In the current treatment era, however, clinically definite MS is less relevant, since most patients will be diagnosed after a first clinical event (relapse) and will go on to start treatment prior to even having a second relapse. For this reason, we will use the 2017 McDonald Criteria as the "gold standard" for our proposed study. Importantly, in the current study the CVS will be applied in a population where the McDonald Criteria are not applicable (atypical presentations) and where currently a significant unmet clinical need exists. Because the studies that informed the diagnostic criteria did not include patients presenting with atypical syndromes, such patients are not covered in the McDonald Criteria path, but are frequently given a diagnosis of MS on the basis of MRI findings. To address this limitation, we will examine the presence of CVS as a predictor of development of future clinical events, within a 24-month period, that would satisfy the 2017 McDonald Criteria. Thus, the results of this study will have a significant impact on both improving sensitivity in those presenting with typical presentations and providing a specific test for MS in those with atypical presentations, thereby avoiding unnecessary costs associated with misdiagnosis. We will leverage the NAIMS Cooperative to conduct a multicenter study, based on an initial cross-sectional pilot study using the CVS criteria as a diagnostic biomarker for MS. The CVS and PRL have emerged as specific and sensitive biomarkers for MS with pathologic specificity and are posed to improve diagnostic accuracy in MS. The CVS is a radiological sign that demonstrates perivenular demyelination that is specific for MS.39 PRL are a diagnostic biomarker of chronic active lesions, characterized by a core of demyelinated tissue surrounded by activated microglia with iron accumulation, making them visible on high-resolution T2\*-weighted imaging.40 The definitions of both CVS and PRL have already been defined and operationalized as published by the North American Imaging in MS Cooperative (NAIMS) in two separate publications38,41 and will be incorporated into the next diagnostic criteria for MS.42 Analysis of the CAVS Pilot Study (funded by the Race to Erase MS foundation) showed that selecting up to 6 CVS+ lesions had a specificity of 98% for a diagnosis of MS,43 and definitive diagnostic performance of both the CVS and PRL is currently under way in the prospective CAVS-MS study to examine the diagnostic performance of the CVS in 420 participants who presented to 11 NAIMS sites for a diagnostic evaluation of MS with both typical and atypical presentations. This study is following patients who presented to MS Centers for a diagnostic evaluation of MS over the course of 24 months. CAVS-MS is also leveraging acquisition of the T2\*-weighted segmented echo-planar imaging to extract phase images and test the diagnostic performance of PRLs. In addition to the use of T2\*-weighted images to improve the diagnosis of MS, the identification of PRL lesions in patients with MS may also serve as a prognostic marker of the disease. Studies have found that PRL are radiological biomarkers of chronic active lesions, occur despite the use of disease modifying treatment, and are associated with greater accumulation of disability.44 The slowly expanding lesion (SEL) is another proposed biomarker of chronic active lesion that employs a Jacobian determinant to identify lesions with concentric and constant growth over serial images.45 Current studies demonstrate an imperfect overlap between PRL and SEL,46 and comparative studies of these markers early in the disease are needed.47 The CAVS-MS study, therefore, is an ideal dataset on which to test both the diagnostic and prognostic properties of CVS and PRLS. However, 24-month follow-up may be insufficient time to detect new demyelinating events, especially in individuals with atypical presentations including radiologically isolated syndrome (RIS). 24 months may also be too short to detect worsening disability in those diagnosed with MS.