Brownlee, Wallace J; (2017) Understanding long-term disability in multiple sclerosis: A clinical, MRI and genetic study in patients with clinically isolated syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis concerns a 15 year follow-up study of a cohort of people with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS). I investigate (1) how MRI can be used to improve the diagnosis of MS around the time of CIS; (2) early MRI predictors of long-term disease course in people with CIS; and (3) mechanisms responsible for long-term disability and disease progression in relapse-onset MS. There has been significant evolution of the diagnostic criteria for MS in recent years. I examined the influence of changing diagnostic criteria for MS by retrospectively applying the McDonald criteria in the CIS cohort. I found that MS can be diagnosed significantly earlier in CIS patients using the McDonald criteria. I investigated two possible modifications to dissemination in space (DIS) criteria: firstly whether lesions in the symptomatic region should be included in DIS; and secondly whether the number of periventricular lesions in DIS criteria should be increased from 1 to 3. Including lesions in the symptomatic region improved the performance of MRI criteria but increasing the number of periventricular lesions in DIS did not improve diagnostic accuracy or specificity. These findings will inform future revisions to the diagnostic criteria for MS. MS-related disability is frequently referable to the spinal cord. I investigated early brain and spinal cord MRI abnormalities in the CIS cohort and found that spinal cord measures explained more of the disability after 5 years than brain MRI measures. Asymptomatic spinal cord lesions at the time of presentation in patients with a non-spinal CIS were the strongest early MRI predictor of disability after 5 years. These findings were then confirmed with long-term follow-up: spinal cord lesions at the time of presentation with CIS and new spinal cord lesions after 1 year and 3 years were associated with both physical disability and secondary progressive disease course after 15 years. These findings suggest that spinal cord MRI may provide important prognostic information in people with CIS and early MS. Early spinal cord damage may be an important mechanism contributing to long-term disability and disease progression in relapse-onset MS. Disease course heterogeneity in MS remains poorly explained. I investigated the influence of HLA-DRB1*15:01 on disease course and MRI measures of inflammation and neurodegeneration in the CIS cohort. Carriage of the HLA-DRB1*15:01 allele was associated with a faster accrual of disability, greater inflammatory disease burden and a faster rate of brain atrophy over the 15 year follow-up period. The HLA-DRB1*15:01 allele may not only influence the susceptibility to MS but also the disease phenotype and long-term clinical course. Neuroaxonal energy failure is thought to be central to disease progression in MS. I applied the novel metabolic imaging method sodium (23Na) MRI in patients followed up after 15 years to investigate the relationship of brain sodium accumulation in vivo with long-term disease course and disability. I found evidence of sodium accumulation in grey matter, in normal-appearing white matter and in lesions in people who developed MS. Cortical grey matter sodium concentration was associated with physical disability and cognitive performance at 15 years, even after adjusting for brain atrophy. 23Na-MRI should be investigated further as a possible outcome measure in future neuroprotection trials.

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