Multiple 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.Grand Charity of the Freemason