Systemic infections in Multiple Sclerosis

Abstract

Infections outside the brain can affect the brain. These ‘systemic infections’ are very common and occur much more frequently than infections inside the brain itself. Despite the existence of a blood-brain barrier (BBB), the systemic immune system does communicate with the brain. In people with a neurological disease, such as multiple sclerosis (MS), the effect of systemic infections on the brain can be magnified, and harmful.
In the SIMS study (Systemic Infections in MS), 53 people with progressive MS were followed up for an average of two and a half years. In that time, over half of the group experienced progression in their level of disability. Systemic inflammatory episodes were common, occurring on average more than 3 times per year, most commonly infections. People with a high systemic inflammatory response, measured by urinary neopterin, experienced significantly faster brain atrophy than those people with a low response, and had nearly 10 times the chance of developing significant brain atrophy. This effect was particularly marked in those people with a high level of disability to start with.
People with MS have a leaky BBB. It may be that the BBB is disrupted during an inflammatory episode, and that this leads to disease progression. If this is the mechanism, then repairing or protecting the BBB may be a therapeutic target in MS. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to study the BBB in humans and test this hypothesis. In a series of experiments, a protocol for DCE-MRI was devised, refined, and tested. It was found that the marker of BBB permeability derived from DCE-MRI, Ki, behaves as expected, and that measurement variability could be significantly improved with a series of optimisations.
In the SIBIMS study (Systemic Infections and the BBB in MS), BBB permeability was measured using DCE-MRI in 12 individuals during a urinary tract infection (UTI) and again once fully recovered. There was strong evidence for an effect of UTI on the brain, with significant increases in symptoms. There was also modest evidence for BBB disruption during UTI, with a 53% increase in Ki during infection.
This thesis demonstrates two main points. Firstly, that DCE-MRI can be used to study the human BBB in health and disease. Secondly, that systemic infections can have both short- and long-term effects on the brain. BBB disruption may be one possible mechanism linking systemic events with the brain, and warrants further study.

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Identifiers

ORCID for Aravinthan Varatharaj: orcid.org/0000-0003-1629-5774

ORCID for Ian Galea: orcid.org/0000-0002-1268-5102

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