Managing the complexity of multiple sclerosis

Abstract

The application of imaging biomarkers has provided new insights into the mechanisms of damage in multiple sclerosis (MS) and the risk of MS development and progression. The goal of eliminating all disease activity requires a timely escalation of treatment. This increasing complexity is compounded by the need to treat comorbidities.Multiple sclerosis (MS) is an increasingly complex disease in terms of its pathogenesis, comorbidities, prognosis and treatment, and successful patient management requires knowledge of this complexity. In 2015, there have been advances in our understanding of the mechanisms of the disease, ways in which to formulate patient prognoses, how best to escalate treatment escalation, and the role of comorbidities. All of these aspects need to be incorporated into an effective management plan (Fig. 1).The mechanisms that underlie the pathogenesis of MS are yet to be fully elucidated, but they are known to include a cascade of events that induce physical and cognitive deficits. A reduction in neuronal integrity and function that affects the grey matter compartment is thought to be the key pathological process that leads to cognitive impairment in MS. However, findings of a study published by Freeman et al. 1 in 2015 suggest that synaptic and/or dendritic damage occurs prior to quantifiable grey matter volume loss, and might reflect neuronal and axonal loss that contributes to clinical deficits.In this study, Freeman et al. 1 used [ 11 C]flumazenil ([ 11 C]FMZ) PET, which quantifies GABAA receptor density in vivo, to identify grey matter damage beyond cortical lesions 2 . FMZ is an antagonist of the central benzodiazepine receptor, a component of the GABAA receptor complex that is present on axosomatic and axodendritic synapses throughout the cortical and subcortical grey matter. The number of [ 11 C]FMZ binding sites per grey matter region was lower in several cortical areas (the parietal, cingulate, and insular cortices and the left frontal cortex) and subcortical regions (the thalamus, hippocampus and amygdala) in patients with MS than in healthy controls. Greater amounts of neuronal damage were seen in patients with secondary-progressive MS than in patients with relapsing-remitting MS (RRMS), but the most striking result was that [ 11 C]FMZ binding was lower in patients with RRMS than in healthy controls, even in the absence of significant grey matter atrophy. A significant relationship was found between the level of cortical [ 11 C]FMZ binding and performance on several cognitive tests. A goal of future research is to provide neuroprotective and reparative therapies that could be applied at such early stages of MS to stop or at least slow down neurodegeneration and reduce cognitive impairment in progressive MS 3 .Clinically isolated syndromes (CIS) represent a patient's first neurological episode that is suggestive of MS. Most patients with CIS develop RRMS within 5 years of onset, and most patients with MS develop progressive MS 10-15 years after onset of MS. Although challenging, formulat...

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