Preventing Neurodegeneration in Multiple Sclerosis Is Required From the Earliest Stages of the Disease

The traditional clinical understanding of multiple sclerosis (MS) is that the early phase is dominated by acute inflammation leading to clinical relapses or new lesions visible on brain MRI (relapsing MS [RMS]). By contrast, the later stage is dominated by chronic compartmentalized inflammation and neurodegeneration (progressive MS [PMS]). Such a model has important therapeutic implications because it implies that relapse prevention is the main goal during the RMS phase. By contrast, the PMS stage will require new therapies targeting trapped inflammation, neuroprotection, or regeneration. However, this model has been challenged by the realization that MS is progressive from the onset in most cases, as revealed in patients with RMS showing progression independent of relapses (PIRAs).^1-3 In addition, recent studies have shown that most brain and retinal atrophy happen in the first years of the disease, during the RMS phase.^4,5 Thus, brain volume loss seems to follow a nonlinear trajectory, and certain areas, particularly in the deep gray matter and cortical areas, have a larger vulnerability to earlier volume loss. On-going inflammatory activity has been linked to accelerated concomitant atrophy rates in several clinical trials. Patients with radiologic activity or relapses have larger volume loss than stable patients, equivalent to those with PIRA.⁶ Indeed, the relationship between inflammatory activity and changes in the brain and retinal volume is stronger early in the disease but seems similar in active and stable patients later on.⁵ Still, neurodegeneration in the later stage (PMS) is smaller in magnitude although more visible clinically,^5,7,8 when compensation mechanisms become exhausted. These new insights about the evolution of MS have significant implications for defining the best therapeutic strategy for people with MS.