Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder restricted to central nervous system (CNS) white matter, our contemporary view has evolved to encompass a broader understanding of the variable mechanisms that contribute to tissue injury, in a disorder now recognized to affect white and grey matter compartments.

A constellation of inflammation, ion channel derangements, bioenergetic supply: demand mismatches within the intra-axonal compartment, and alterations in the dynamics and oximetry of blood flow in CNS tissue compartments are observed in MS. These findings have raised questions regarding how histopathologic heterogeneity may influence the diverse clinical spectrum of MS; and, accordingly, how individual treatment needs vary from 1 patient to the next.

We are now on new scaffolding in MS; one that promises to translate key clinical and laboratory observations to the application of emerging patient-centered therapies.

This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients.