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Central Vein in the Clinic Next Steps

This study aims to evaluate the use of the central vein sign (CVS) as a diagnostic tool for multiple sclerosis (MS) in order to reduce misdiagnosis, facilitate early diagnosis, and simplify clinical decision-making. The study will assess the feasibility, reproducibility, and diagnostic accuracy of the CVS across 10 different sites using 3T FLAIR* imaging.

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Central Vein in the Clinic Next Steps

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  1. Central Vein in the ClinicNext Steps Daniel Ontaneda MD MSc Cleveland Clinic Mellen Center for Multiple Sclerosis

  2. Disclosures • Grant Support: NIH, Race to Erase, Patient Centered Outcome Research Institute, National Multiple Sclerosis Society, Genentech, Genzyme, Novartis. Consulting Biogen Idec, Genentech, Novartis. • Work presented was supported by Race to Erase MS Foundation

  3. Challenges in diagnosis and misdiagnosis • Costs associated with MS total over $48.4 billion annually, and 40% of direct care expense is related to disease modifying therapy (DMT) cost.1 • Up to 20% of individuals referred for a diagnosis of MS are incorrectly diagnosed with MS.2 • >2/3 of misdiagnosed patients are exposed to unnecessary and sometimes life-threatening risks associated with DMTs2 • Gooch CL. The burden of neurological disease in the United States: A summary report and call to action. Ann Neurol 2017; 81: 479–84. • Solomon AJ, The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study . Neurology 2016; 87: 1393–9.

  4. MS DMT in misdiagnosis • Kaisey. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. MSARD, 2018; 30: 51-56

  5. MRI as a diagnostic biomarker • MRI is a sensitive tool for diagnosis of MS and is an integral component of the diagnostic criteria for multiple sclerosis.1 Thompson AJ. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The LancetNeurology 2018; 17: 162–73.

  6. Problems with MRI implementation • Approximately half of individuals referred to an MS clinic, present with atypical syndromes (not typical clinically isolated syndrome). 1 • Increasing diagnostic sensitivity may have come at the price of decreased specificity.2 • MRI criteria have specificity of 32% for dissemination in space (DIS) and 42% for dissemination in time (DIT).3 Kelly SB. Using atypical symptoms and red flags to identify non-demyelinating disease. J NeurolNeurosurg Psychiatry 2012; 83: 44–8 RommerPS. Applying the 2017 McDonald diagnostic criteria for multiple sclerosis. Lancet Neurol 2018; 17: 497–8. Filippi M, Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol 2018; 17: 133–42.

  7. MRI/Central Vein • Misdiagnosis appears to be mainly due to over interpretation of abnormal MRI findings • CVS may differentiate: • 85% of white matter lesions in MS12 • 8% small vessel ischemic disease13 • 34 % Migraine 14 • 14% Other inflammatory or autoimmune diseases12 Sati, Nature Reviews Neurology 2016 Maggi P. Central vein sign differentiates Multiple Sclerosis from central nervous system inflammatory vasculopathies. Ann Neurol 2018; 83: 283–94. Mistry N. Imaging central veins in brain lesions with 3-T T2*-weighted magnetic resonance imaging differentiates multiple sclerosis from microangiopathic brain lesions. MultScler 2016; 22: 1289–96. Solomon AJ. ‘Central vessel sign’ on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine . Ann ClinTranslNeurol 2015; 3: 82–7.

  8. Central Vein: Next Steps • There is a significant unmet need for more specific and accurate diagnostic tests to facilitate early confirmation of a diagnosis of MS. • We propose a prospective evaluation of the central vein sign (CVS) — which we hypothesize will reduce misdiagnosis, hasten early diagnosis, and simplify clinical decision-making.

  9. CentrAl Vein Sign in MS (CAVS-MS) • Multi-center prospective observational study • Cross-sectional initial pilot study across 10 sites • Establish feasibility of CVS implementation in a multi-site study

  10. Aims Primary Objective: • Establish the CNR of lesion-to-NAWM and central vein-to-lesion across the 10 different sites using 3T FLAIR* imaging in subjects with a clinical or radiological suspicion of MS. Secondary Objectives: • Investigate the difference in CNR identified in the primary objective between pre-contrast FLAIR* imaging and post contrast FLAIR* imaging to identify whether gadolinium injection is required for central vein detection. • Determine the reproducibility of different methods for detection of positive CVS across sites. • Determine the sensitivity and specificity of the different methods for the diagnosis of MS compared to the McDonald 2010 MS criteria.

  11. Study Population • Individuals referred to an MS center based on a clinical or radiological suspicion of MS • Broad inclusion criteria, total sample size 30 • Sites • Cleveland Clinic • Johns Hopkins University • University of California San Francisco • University of Texas Houston • University of Toronto (St. Michael’s Hospital) • University of Vermont • University of Southern California • Cedars Sinai • Yale University • University of Pennsylvania

  12. Progress • Study funded by Race to Erase MS Foundation • 30 subjects enrolled across the different sites • Development of software platform for rating of central veins through imaging software partner: QMENTA • Study coordination Cleveland Clinic • Central image analysis at NIH (Reich/Sati) • Statistical analysis University of Pennsylvania (Shinohara)

  13. Creation of FLAIR *

  14. Lesion Segmentation

  15. CVS rating

  16. Prospective Study AIMS • Aim 1: To determine if incorporation of CVS for the diagnosis of MS improves diagnostic accuracy and hastens diagnosis in individuals presenting with typical first clinical events. • Aim 2: To determine if incorporation of CVS for the diagnosis of MS improves specificity among individuals presenting with atypical syndromes. • Aim 3: Central vein as a predictor of clinical/MRI disease activity associated with disability in MS.

  17. Conclusions • Low specificity and misuse of diagnostic criteria may expose mis diagnosed patients to risk and increase health care costs • Central vein sign is a tool that offers promise both for increasing specificity, and perhaps enabling earlier diagnosis of MS. • Studies will determine if central vein sign can be incorporated into the diagnostic criteria • NIH is working with MRI manufacturers to make sequences available for disseminated clinical use

  18. Acknowledgements • NAIMS • NIH • Pascal Sati, Danny Reich • University of Pennsylvania • Taki Shinohara • University of Vermont • Andy Solomon • Cedars Sinai • Nancy Sicotte

  19. QUESTIONS

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