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
Funder: Department of Health and Social Care

Abstract: Can a brain T2* Magnetic Resonance Imaging (MRI) scan replace lumbar puncture in the diagnostic pathway of Multiple Sclerosis (MS)? MS is the commonest cause of progressive neurological disability for young adults in the UK, with roughly 100 people diagnosed each week. Unfortunately, misdiagnosis and diagnostic delays are common; therefore, the aim of this study is to modernize the diagnostic pathway. Brain lesions with a central vein, detected with T2* MRI are thought to be characteristic of MS. Using a single group superiority diagnostic accuracy study, our primary research question is: Is T2* MRI a more sensitive diagnostic test than lumbar puncture with oligoclonal band examination, amongst people at first clinical presentation with possible MS? Secondary questions include which test is more specific, which test patients prefer and what are the costs associated with each diagnostic pathway. In addition, the interrater reproducibility of the T2* MRI will be assessed. A simplified and time efficient interpretation of T2* MRI involving only detecting six MS lesions will be tested to see whether it is sufficiently accurate to use in place of oligoclonal band testing. We will recruit people presenting with a clinically isolated syndrome who require a lumbar puncture to meet 2017 McDonald diagnostic criteria for MS. Trial participants will have a research T2* MRI scan sequence in addition to their lumbar puncture. The diagnostic sensitivity of the T2* MRI scan and the lumbar puncture results will be compared based on the clinical diagnosis reached after 18 months by their treating clinician. (McNemar s paired test) Structured participant and clinician interviews, analysed used framework analysis, will capture the experience of undergoing investigation for MS. This will both guide implementation of the study results and highlight where further patient and clinician support may be required. Healthcare costs will be recorded along with utility status to produce a cost consequence table, and results of this trial will inform future health economic analysis of the MS diagnostic pathway. Recruitment will open across four sites for 12 months. Data analysis, production of materials for publication and result dissemination will be conducted during the last six months of the project. We aim to transform the accuracy and ease of reaching the diagnosis of MS. The team will promote and publicize the results, aiming for national implementation within two years of study completion. It will be of international clinical and academic interest amongst neurologists and radiologists, therefore we expect that the findings will secure publication in a high impact journal. Findings will be presented at international meetings, including the world s largest annual MS meeting run by the European Committee for Treatment and Research in Multiple Sclerosis to maximize the research s impact. In the last two decades, international diagnostic criteria have been revised every 4-7 years to reflect rapid advancements in MRI technology. If the results from this NIHR supported study are positive, we anticipate the T2* MRI scan will replace the role of lumbar puncture in the next iteration of the criteria.

Lay abstract: 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 also cause unintended complications requiring hospitalisations or time off work to recover. Due to new diagnostic criteria, many more people undergo lumbar punctures, resulting in discomfort and additional costs to the NHS. Although the fluid taken during a lumbar puncture can show evidence of disease, this is not always the case. We do not find abnormalities in everyone who has MS; meaning they have to wait for their condition to worsen before treatment is offered. 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 us 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. Our team will recruit a large number of people from different hospitals whose doctors suspect they may have MS. We will invite them to have a new eight minute MRI scan, often at the time of their standard MRI scan. After 18 months we will find out what diagnosis is eventually reached and compare this to the finding of the new scan. We will 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 NHS with a scientific approach to diagnose MS which is safer, more cost effective and importantly, more acceptable to patients. The reason to pursue this research now is that there are powerful new treatments for MS. People with MS will benefit from a more accurate diagnosis and being started on treatment without delay. As with any treatment, there are side effects that we must avoid exposing people misdiagnosed with MS to. MS treatment is also expensive and more accurate prescribing may bring additional cost savings to the NHS. If successful, this research can become standard practice, improving the way doctors reach a diagnosis, clinical care and treatment of people with MS, and equally importantly, the clinical care of patients incorrectly diagnosed with MS.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL