A 5 year prospective follow-up clinical and imaging investigation of demyelinating clinically isolated syndrome (CIS)

Multiple sclerosis (MS) is caused by damage to the myelin, which is a fatty white substance that surrounds the nerves; myelin is necessary for the normal function of the nerve, and if damaged, the function of the nerve becomes impaired and the person presents with acute neurological symptoms. If the damage occurs in the optic nerve there will be visual symptoms, if the damage is simultaneous in different locations, there will be multiple symptoms, such as pins and needles, incoordination and bladder symptoms. The term CIS (clinically isolated syndrome) refers to the first neurological episode of potential MS. Some people with CIS may never experience further neurological problems again. The occurrence of a second clinical episode (or relapse), however, marks the conversion to clinically definite MS. According to the past studies, the proportion of people with CIS converting to MS, in the subsequent years, varies up to 80%.

Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the brain and the abnormalities caused by the disease. MRI scanners use strong magnetic fields, radio waves, and field gradients to generate images of the inside of the brain. In MS, Brain MRI shows the regions where the damage to the brain tissue (including myelin) has occurred, which are called inflammatory lesions. If the MRI scan shows brain lesions at the onset of CIS, then the chances of having further relapses are high (60-80%) over the next few decades.

Nevertheless, conventional MRI only gives an indication of whether the risk of developing MS is high or low, but does not tell us whether MS will happen to a particular person with CIS and the timing of it. It also unknown, if a person with CIS develops MS, then how severe or mild it will be and how likely is it to progress? Therefore, clinicians are still faced with many questions. What is the likelihood that this person will develop MS? If MS does develop, is it possible to establish the likelihood of future disability? What should we tell patients who want to know about their future? We are committed to finding answers to these questions.

Therefore, we have decided to use novel types of MRI to identify the changes occurring in the brain at a microscopic level, which is usually studied with brain biopsy. The novel way we will use MRI will help us understand the causes that make someone to develop MS sooner or later and help us to work out how severe the MS will potentially be. Once we obtain this information, we can also think of how to target these causes with medications and will know when these medications should be initiated. In addition, this will help to tell people with CIS what will happen to them in their future, so that support and treatments are appropriately planned.

We wish to study at five years a cohort of 50 people, who originally presented and were studied at baseline with CIS. This longitudinal assessment will allow us to ascertain the imaging correlates of risk of conversion to MS, disease activity and progression.

Participants will attend UCL Institute of Neurology and undergo 1) Magnetic Resonance Imaging (MRI), 2) Optical Coherence Tomography (OCT), 3) Clinical assessment.

1) 3T MRI
Conventional and advanced MRI acquisitions will be employed:
a) T1/T2-weighted images brain and spine - for white matter lesions, and T1 parcellation volumes
b) Phase Sensitive Inversion Recovery (PSIR) brain - for grey matter lesions
c) Diffusion weighted imaging brain - for (i) Tractography and diffusion connectivity metrics, (ii) Metrics of neurite dispersion and orientation and neuronal density
d) Sodium MRI (NaMRI) - for sodium metric
e) Resting-state fMRI brain - for functional connectivity

2) OCT Acquisition
A Heidelberg Spectralis high resolution OCT system will acquire:
a) Optic nerve scans (peripapillary) - for peripapillary RNFL (pRNFL)
b) Macular volume - for Macular RFNL (mRNFL) and Macular ganglion cell layer (mGCL)

3) Clinical assessment
a) History
b) Physical disability recorded with EDSS, MSFCS, MRC power/sensory.
c) Cognitive assessment with MACFIMS
d) Visual assessment - high and low contrast acuity charts, colour vision
e) Lifestyle questionnaires

Statistical models will be constructed using mainly mixed (mulit-level) regression models to address (i) longitudinal changes over time in imaging measures of OCT and MRI, (ii) imaging and OCT predictors of five year clinical outcomes e.g. conversion to MS, disease activity, disability, (iii) associations between imaging and clinical metrics at five years.

The results will inform our understanding of neurobiological processes responsible for disease activity and progression in early MS.

ACADEMIC IMPACT
We will implement the following actions to maximize the academic impact of the findings from this grant.

1) National and international conferences
We shall disseminate key and novel results from the grant as they become available at national and international conferences. This will provide exposure to the wider academic community and an opportunity to discuss the implications of our findings directly with academic peers internationally.

2) Journal publications
Interim and key results shall be submitted for publication in appropriate scientific journals. As this project aims to advance this field, we will aim for similar journals to publish important findings of clinical impact. Technical achievements discovered during the grant will be submitted to high impact neuroimaging journals. This will enhance and broaden the overall academic impact of our project.

3) Internet dissemination
Several pathways will be utilized regularly to disseminate the academic results of our grant in order to maximise impact. We will update our departmental and UCL News website to provide information to the lay and scientific community. We shall employ other social media channels such as twitter to increase visibility of our results.

4) PPI event
We plan to organize a PPI event at the conclusion of the project for the MS participants and their carers during which the main findings will be presented and discussed. The event will be catered and travel expenses offered. The audience will be informed about how our findings have moved the field forward and their feedback will be discussed in an interactive forum to promote healthy discussion and inform future research directions.

5) Further research studies
The academic impact and feedback from this project will help to promote applications that aim to follow up this cohort in the future. This will provide even greater insights into the objectives of this proposal and deliver further valuable prognostic information. It will also be used to inform multicentre studies (via MAGNIMS - an established European collaborative network in MS) that are able to recruit large numbers of participants to address specific issues arising from the findings of this project.

6) Translatability to other neurological conditions
The techniques performed in this study could be adapted to the investigations of other neurological conditions, for example, those characterized by CNS neurodegeneration. We shall disseminate our findings to other neurological sub-specialties to foment collaborative studies that can contribute to the CNS neurobiological understanding other degenerative conditions.

ECONOMIC AND SOCIETAL IMPACT

1) Health sector benefits
We aim to improve our understanding of the progression at the early stage of MS, including the factors that are associated with a more or less rapid disease course. In the short to medium term, this knowledge can help to inform disease modifying treatment algorithms formulated by health policy committees. In the medium term, the results can be used choose relevant imaging biomarkers that can monitor novel therapies in phase II clinical studies. In the long term, a contribution to our understanding of MS neurobiology will help the development of future therapies. All these factors will benefit the affected patients.

2) Economic benefits
The potential economic benefits of beneficially altering the disease course are significant. Patients benefiting from appropriate disease modifying treatments will experience better clinical outcomes with relevant treatment risk of side effects, and be more likely to financially contribute to society through employment. Likewise, if our results allow the accelerated development of future therapies, the long term effects will be to improve patient quality of life and improve their chances of providing greater economic productivity for longer periods of time.