Multiple sclerosis progression: time for a new mechanism-driven framework

Abstract

Traditionally, multiple sclerosis has been categorised by distinct clinical descriptors-relapsing-remitting, secondary progressive, and primary progressive-for patient care, research, and regulatory approval of medications. Accumulating evidence suggests that the clinical course of multiple sclerosis is better considered as a continuum, with contributions from concurrent pathophysiological processes that vary across individuals and over time. The apparent evolution to a progressive course reflects a partial shift from predominantly localised acute injury to widespread inflammation and neurodegeneration, coupled with failure of compensatory mechanisms, such as neuroplasticity and remyelination. Ageing increases neural susceptibility to injury and decreases resilience. These observations encourage a new consideration of the course of multiple sclerosis as a spectrum defined by the relative contributions of overlapping pathological and reparative or compensatory processes. New understanding of key mechanisms underlying progression and measures to quantify progressive pathology will potentially have important and beneficial implications for clinical care, treatment targets, and regulatory decision-making.

Figure 1.. Mechanisms of injury and compensation and associated measures in MS.

Early in the disease (left half of the figure), injury caused by focal lesions and associated axon damage can be compensated by mechanisms such as remyelination. Over time, lesions in grey and white matter, as well as axon damage, accumulate, and meningeal inflammation, diffuse microglial activation in the extralesional white matter, and slow expansion of existing lesions become more prominent (right side). Progression is further driven by decreased remyelination capacity and damage to neuronal networks mediated by loss of neurons and synapses. Ongoing low-level inflammation and loss of compensatory mechanisms result in segmental and global atrophy. In the figure, headings explain the content of each panel. The histological panel depicting the optic nerve shows axon neurofilaments, whereas the inset shows CD68-positive myeloid cells. The VEP trace depicts delayed latency, indicating slow conduction related to demyelination. Neuronal and synaptic pathology can be detected by NeuN, a marker for neurons (panel), and synaptophysin, a marker for synapses (insert); the blue lines in the radiological correlate symbolize neuronal connectivity. White arrows indicate radiological correlates of histopathological findings. Abbreviations: Gd, gadolinium; NfL, neurofilament light chain; CSF, cerebrospinal fluid; fMRI, functional magnetic resonance imaging; PET, positron emission tomography; TSPO, translocator protein 18 kilodaltons; OCT, optical coherence tomography; VEP, visual evoked potentials.

Figure 2.. Assessments relevant to a mechanism-driven framework for MS progression.

MS progression reflects a combination of mechanisms of injury and compensation (red box) that exist contemporaneously and contribute to clinical expression. The activation of these mechanisms marks the biological onset of the disease and initiate the prodromal period. The balance of such mechanisms, together with tissue repair, jointly determine clinical expression during the whole disease course. The age-associated decrease in reserve and repair capacity also influences clinical progression. Development of clinical and biological measures with high sensitivity and specificity is required to continuously monitor the clinical presentation of the disease and identify relevant injury and compensatory mechanisms in individuals. Potential mediators (light blue box on the left) exert positive and negative influences on injury and compensatory mechanisms and thus impact clinical expression over the whole disease course. The list of mediators is illustrative rather than comprehensive. Abbreviations: CSF, cerebrospinal fluid; MRI, magnetic resonance imaging, fMRI, functional MRI; MRS, magnetic resonance spectroscopy; PET, positron emission tomography; OCT, optical coherence tomography; VEP, visual evoked potentials.