Clinical and Paraclinical Biomarkers and the Hitches to Assess Conversion to Secondary Progressive Multiple Sclerosis: A Systematic Review

Conversion to secondary progressive (SP) course is the decisive factor for long-term prognosis in relapsing multiple sclerosis (MS), generally considered the clinical equivalent of progressive MS-associated neuroaxonal degeneration. Evidence is accumulating that both inflammation and neurodegeneration are present along a continuum of pathologic processes in all phases of MS. While inflammation is the prominent feature in early stages, its quality changes and relative importance to disease course decreases while neurodegenerative processes prevail with ongoing disease. Consequently, anti-inflammatory disease-modifying therapies successfully used in relapsing MS are ineffective in SPMS, whereas specific treatment for the latter is increasingly a focus of MS research. Therefore, the prevention, but also the (anticipatory) diagnosis of SPMS, is of crucial importance. The problem is that currently SPMS diagnosis is exclusively based on retrospectively assessing the increase of overt physical disability usually over the past 6-12 months. This inevitably results in a delay of diagnosis of up to 3 years resulting in periods of uncertainty and, thus, making early therapy adaptation to prevent SPMS conversion impossible. Hence, there is an urgent need for reliable and objective biomarkers to prospectively predict and define SPMS conversion. Here, we review current evidence on clinical parameters, magnetic resonance imaging and optical coherence tomography measures, and serum and cerebrospinal fluid biomarkers in the context of MS-associated neurodegeneration and SPMS conversion. Ultimately, we discuss the necessity of multimodal approaches in order to approach objective definition and prediction of conversion to SPMS.