The need for improved diagnostic methods in Multiple Sclerosis (MS) is widely recognized. Although Magnetic Resonance Imaging (MRI) is a longstanding tool for detecting MS lesions, diagnostic inaccuracies persist. Up to 20% of people diagnosed with MS (1 in 5) are later found not to have the disease. This is highly consequential, as more than two-thirds of misdiagnosed patients are unnecessarily exposed to risks from disease-modifying therapies, which in rare cases can be life-threatening.

Moreover, the current standard in MS diagnosis - the McDonald criteria, which combine clinical symptoms and MRI findings - were developed from studies in people with typical clinical presentations of MS. This reduces the specificity of these criteria, rendering them uninformative for the nearly half of MS patients who present to neurologists with atypical or nonclassical symptoms.

Timeliness of MS diagnosis is also key, as diagnostic delay is common in cases of relapsing-remitting MS and can carry severe and lifelong consequences.

The CentrAl Vein Sign in MS (CAVS-MS) study has been designed to assess whether Central Vein Sign (CVS) criteria can help address some of these unmet diagnostic needs. It will specifically explore the role of presentation type by enrolling a mixed population of patients with typical clinical presentations (n = 200) and those with atypical presentations, including suggestive MRI findings in the absence of neurologic symptoms (n = 200) across North America.

The CentrAl Vein Sign in MS (CAVS-MS) study seeks to answer whether the central vein sign (CVS) can be used as a sensitive and specific diagnostic marker for a diagnosis of MS. The study will investigate the CVS in a mixed population of participants with typical and atypical clinical presentations including radiological presentations without neurological symptoms.

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 Clinically Isolated Syndrome (CIS)). This study will evaluate CVS criteria prospectively in individuals with typical and atypical MS presentations. Aim 1 will examine sensitivity and specificity of CVS criteria in conjunction with, and separate from, the McDonald Criteria. Aim 2 will examine CVS in a population where McDonald criteria explicitly cannot be applied. Because the likelihood of MS is lower in this group, the focus will be 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, the 2017 McDonald Criteria is being used as the "gold standard" for the 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, the presence of CVS as a predictor of development of future clinical events will be examined, 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. The investigators will leverage the North American Imaging in Multiple Sclerosis Cooperative (NAIMS) to conduct a multicenter study, based on an initial cross-sectional pilot study using the CVS criteria as a diagnostic biomarker for MS.

Patients will be enrolled when presenting to an MS center for diagnostic referral, and they will undergo follow-up at prespecified intervals for 24 months. Brain MRI will be performed at baseline and 24 months, with scans scored on the basis of CVS criteria. T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging will be combined with T2*-weighted segmented echo-planar imaging to enable simultaneous identification of white matter lesions and venous structures.

The primary objective is to determine whether use of CVS criteria allows for an earlier accurate diagnosis of MS in patients who do not meet the McDonald criteria at baseline. The aim is to show that the CVS is a simple and reliable diagnostic biomarker that will show an increase in sensitivity while preserving specificity.

Secondary objectives include the following:

• Determining concordance of CVS criteria and the McDonald criteria among patients meeting McDonald criteria at baseline.
• Determining whether use of CVS criteria improves diagnostic specificity for MS in people presenting with atypical symptoms.
• Determining whether the CVS predicts development of clinical MS in individuals with suggestive radiologic findings but no symptoms.

The researchers will also begin exploratory studies of optimal methods for integrating CVS findings into MS diagnostic criteria, along with any resulting healthcare-related cost savings. These initial exploratory analyses will be important to how readily positive findings about the utility of CVS criteria can impact clinical practice. The ultimate goal is to have the CVS incorporated into the MS diagnostic criteria.

Inclusion Criteria:

Inclusion criteria for participants with typical presentations will include:

1. Age 18 to 65 inclusive
2. Referral to a study academic site for a clinical suspicion of MS
3. Onset with typical symptom onset including: acute unilateral optic neuritis, double vision due to an internuclear ophthalmoplegia or sixth nerve palsy, facial sensory loss or trigeminal neuralgia in a young adult (<40 years of age), cerebellar ataxia and nystagmus, partial myelopathy, sensory symptoms in a CNS pattern, Lhermitte's symptom, asymmetric limb weakness, urge incontinence or erectile dysfunction, or other neurological presentation considered to be typical by the site investigator.
4. Able to provide written informed consent to participate in the study
5. For participants referred for clinical suspicion of multiple sclerosis who had workup prior to referral or who are taking disease-modifying therapies for MS, digital availability of diagnostic cranial MRI with gadolinium within 3 months of initial symptoms
6. Onset of typical neurological symptoms within 10 years of screening.

Inclusion criteria for participants with atypical presentations will include:

1. Age 18 to 65 inclusive
2. Referral to a study academic site for a suspicion of MS
3. Onset with atypical onset including: bilateral optic neuritis or unilateral optic neuritis with a poor visual recovery, complete gaze palsy or fluctuating ophthalmoparesis, intractable nausea, vomiting, or hiccups, complete transverse myelopathy with bilateral motor and sensory involvement, encephalopathy, subacute cognitive decline, headache or meningismus, isolated fatigue or asthenia, constitutional symptoms, other clinical presentations considered atypical by the site investigator (examples include: vague or patchy sensory symptoms, pain, short lasting bilateral blurred vision, etc.), or absence of clinical symptoms with MRI features suggestive of MS
4. Able to provide written informed consent to participate in the study
5. For participants referred for clinical suspicion of multiple sclerosis who had workup prior to referral or who are taking disease-modifying therapies for MS, digital availability of diagnostic cranial MRI with gadolinium within 3 months of initial symptoms
6. Onset of atypical neurological symptoms within 10 years of screening.

Exclusion Criteria:

Exclusion criteria for both typical and atypical populations will include:

1. Contraindication to MRI studies; metal or metal implants incompatible with MRI
2. Inability to tolerate MRI due to claustrophobia or known excessive movement (e.g. tremor)
3. Contraindication to use of gadolinium containing contrast agents (allergy or renal failure)
4. Treatment with systemic corticosteroids in the 4 weeks preceding enrollment.

The study will recruit a total 400 participants. The study will include 200 patients presenting with typical first syndromes and will enroll an additional 200 patients with atypical presentations and radiological suspicion of the disease. Participants will be recruited from the patient populations followed at eleven different sites including: Cleveland Clinic, Johns Hopkins University, University of California San Francisco, University of Texas Austin, University of Colorado Denver, University of Toronto (St. Michael's Hospital), University of Vermont, University of Pennsylvania, Cedars Sinai Medical Center, University of Southern California, and Yale University. Study investigators will confirm eligibility criteria, and participants will then be enrolled into the study.