Clinical trial NCT04024969: DiagnosE Using the Central veIn SIgn
Official title: DECISIve - DiagnosE Using the Central veIn SIgn. A Prospective Diagnostic Superiority Study Comparing T2* MRI and Lumbar Puncture in Patients Presenting With Possible Multiple Sclerosis
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Multiple Sclerosis
Keywords: Central Vein Sign
Translational Neuroimaging
Multiple Sclerosis
Lead sponsor: Nottingham University Hospitals NHS Trust
Sponsor class: OTHER
First posted: 2019-07-18
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Most participants are expected to have been evaluated by a hospital doctor (usually neurologist or ophthalmologist) at the local site and referred for diagnostic testing to the local MS team.

Brief summary: There is currently no agreement on the best way to diagnose Multiple Sclerosis (MS). Frequently, people suspected of having MS have a standard MRI scan and undergo a 'lumbar puncture' (a thin needle is inserted between the bones in the lower spine). Patients often report they find it painful and it can cause unintended complications requiring hospitalisations or time off work to recover.

Although the fluid taken during a lumbar puncture can show evidence of disease, this is not always the case. Doctors do not find abnormalities in everyone who has MS but some people with conditions that can mimic MS, but need very different treatment, have similar lumbar puncture abnormalities. Both of these problems can lead to misdiagnosis.

A new MRI scan allows doctors to see small veins that run through damaged areas of the brain in people with MS. It has been shown that this is a specific finding to MS, seldom seen in other conditions. It is not painful and carries few or no risks.

This research aims to change the way people are diagnosed with MS and reduce the number of lumbar punctures used. The investigators will recruit a large number of people from different hospitals whose doctors suspect they may have MS. They will be invited to have the new eight-minute MRI scan. After 18 months, the investigators will find out what diagnosis is eventually reached and compare this to the finding of the new scan. The investigators will then compare the accuracy, speed, costs and acceptability of the different tests needed to make a diagnosis of MS and establish if most lumbar punctures can be replaced by a slightly longer MRI scan. This research could provide the National Health Service with a scientific approach to diagnose MS which is safer, more cost effective and importantly, more acceptable to patients.

Detailed description: The North American Imaging in MS Cooperative has reviewed the utility of the central vein sign (CVS) in the diagnosis of MS in 2015. They concluded that "To formally establish the clinical value of the CVS for the differential diagnosis at disease onset, a large, prospective, multicentre study including patients at first presentation of possible MS is necessary". The paper outlining the 2017 McDonald diagnostic criteria for MS specifically mentions the promise of the CVS but suggests that it "requires detailed investigation to determine whether it is useful and practical". The rationale of this study is to provide an overwhelming case for a straightforward and rapid clinical adoption of our MRI test, which will change our ability to confirm or refute the diagnosis of MS.

Radiologists and neurologists can also readily interpret our proposed CVS using a simple 'rule of six' that was described in a previous study. This involves the detection of any six lesions with a central vein present. This rule has the potential to be easily implemented in clinical practice if it has superior diagnostic sensitivity, when compared to lumbar puncture results.

If the CVS can be shown to have superior diagnostic sensitivity at first presentation of MS, when compared to performing a lumbar puncture, then lumbar punctures can be avoided in many patients. These patients will benefit in several ways. The patients will avoid a procedure that is often painful or unpleasant. Those who currently refuse to have lumbar puncture will benefit from expedited diagnosis, limiting their anxiety and uncertainty. A secure diagnosis could lead to more rapid treatment decisions and a better long-term prognosis. In addition, fewer workdays will be lost attending hospital for investigation. From the NHS' perspective, it would avoid day case hospital admissions for lumbar punctures and readmissions to treat the common complication of post lumbar puncture headaches. This would create significant cost savings, when considering the significant number of patients undergoing this diagnostic process.

Eligibility criteria: Inclusion Criteria:

1. Aged 18 to 65 years.
2. Presentation with a typical clinically isolated syndrome (Thompson et al. 2017) for diagnostic evaluation of MS.

Exclusion Criteria:

1. Fulfils the diagnosis of MS, as defined by the 2017 revision of McDonald diagnostic criteria (Thompson et al. 2017).
2. Unwilling or unable to comply with the requirements of this protocol including the presence of any condition (physical, mental, or social) that, in the opinion of the PI, is likely to affect the participant's ability to comply with the study protocol.
3. Unable to provide informed consent.
4. Contraindication or inability to undergo MRI due to metal or metal implants, pregnancy, claustrophobia, pain, spasticity, or excessive movement related to tremor.

Primary outcomes:
measure: The sensitivity of the central vein sign (CVS) on T2* MRI scan and lumbar puncture with oligoclonal band testing at diagnosing MS at the time of the patients' first presentation.
timeFrame: 18 months
Secondary outcomes:
measure: The specificity of the central vein sign (CVS) on T2* MRI scan and lumbar puncture with oligoclonal band testing at diagnosing MS at the time of the patients' first presentation.
timeFrame: 18 months
measure: The sensitivity and specificity of the 'rule of six' proposed in Mistry et al. 2016.
timeFrame: 18 months
Other outcomes:
measure: The percentage agreement between blinded raters of the CVS amongst different observers.
timeFrame: 18 months
measure: The sensitivity and specificity of combing the CVS with the results of the lumbar puncture.
timeFrame: 18 months
measure: A sensitivity analysis, allowing for variation in test performance between sites, using a mixed effects logistic regression model.
timeFrame: 18 months
measure: The sensitivity and specificity of the 3D FLAIR* (a research imaging technique)
timeFrame: 18 months
Locations:
city: Cardiff
country: United Kingdom
facility: Cardiff & Vale University Lhb
city: London
country: United Kingdom
facility: Barts Health Nhs Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals Nhs Foundation Trust
Study officials:
affiliation: Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham
name: Nikos Evangelou, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintore M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2. Epub 2017 Dec 21.
citation: Mistry N, Abdel-Fahim R, Samaraweera A, Mougin O, Tallantyre E, Tench C, Jaspan T, Morris P, Morgan PS, Evangelou N. Imaging central veins in brain lesions with 3-T T2*-weighted magnetic resonance imaging differentiates multiple sclerosis from microangiopathic brain lesions. Mult Scler. 2016 Sep;22(10):1289-96. doi: 10.1177/1352458515616700. Epub 2015 Dec 10.