Abstract
dc:description.abstractMultiple sclerosis (MS) is a common, debilitating autoimmune disorder of the central nervous system (CNS). The most visible element of MS pathology is white matter (WM) lesions. However, extra-lesional abnormalities are recognised and appear most marked at the outer (subpial) brain surfaces at post-mortem. Magnetisation transfer ratio (MTR) is a non-conventional MRI sequence that correlates with myelin density and axonal count, and has recently uncovered reductions in the innermost (periventricular) layers and outermost (cortical) layers of patients with longstanding MS. These abnormalities are termed “outside-in” changes. The cause, extent, evolution and treatment-responsiveness of these outside-in gradients is unknown. Most patients present with relapsing-remitting (RR) MS for which numerous immunomodulatory disease-modifying therapies (DMTs) are licensed. However, after approximately 20 years most convert to secondary progressive (SP) MS where immunomodulatory therapies have little if any effect. Whether DMTs delay or prevent this transition remains unclear. During this PhD I examined whether outside-in MTR gradients occur in different disease stages, their clinical associations and predictive capabilities, and (for periventricular gradients) their response to a potent immunomodulatory DMT. In a separate project, I used real-world data to explore whether DMT use is associated with a lower risk of conversion to SPMS. Outside-in MTR gradients of tissue damage were seen in periventricular and cortical regions at all stages of relapse-onset MS and primary-progressive MS. The periventricular MTR gradient was reversed by peripheral immunomodulation and independently predicted subsequent relapse activity on and off DMTs. The underlying process(es) remain unknown but appear at least partially distinct from those underlying lesion formation; a CSF-mediated process – secondary to meningeal inflammation or primarily degenerative – might explain both periventricular and cortical gradients. Among patients with RRMS, initial treatment with fingolimod, natalizumab or alemtuzumab was associated with a lower risk of conversion to SPMS compared to initial treatment with glatiramer acetate or interferon beta over a median 5.8 years of follow-up. A lower risk of conversion was also associated with early (versus late) commencement of glatiramer acetate or interferon beta; and with early escalation from these therapies to fingolimod, natalizumab or alemtuzumab compared to late escalation. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2020
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Brown, James William Lyle
- Advisors dc:contributor.advisor
-
- Coles, Alasdair
- Tomas, Kalincik
- Declan, Chard
Subjects
dc:subject × 3Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.52109
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/305028