Will CSF biomarkers guide future therapeutic decisions in multiple sclerosis?

Contrast-enhancing lesions (CELs) on MRI of the brain and spinal cord revolutionized care of patients with relapsing-remitting multiple sclerosis (RRMS) by facilitating screening of new therapeutics in economical, but still well-powered, phase II trials, and by providing an assessment of efficacy of approved agents in individual patients. However, CELs capture only a specific aspect of multiple sclerosis (MS) pathology: opening of the blood–brain barrier, which is associated with perivascular inflammation, acute demyelination, and axonal loss in RRMS. As disease progresses, CELs and relapses become less common, and pathology studies indicate that immune cell infiltration shifts from predominantly perivascular locations to diffuse permeation of CNS parenchyma and to consolidation in meninges. Whenever disease-modifying treatments (DMTs) were tested in different stages of the MS disease process (i.e., clinically isolated syndrome, RRMS, and progressive MS), their efficacy decreased with disease duration, suggesting that either this more diffuse inflammation is inaccessible to current DMTs, or that other neurodegenerative mechanisms drive progression of disability. Consequently, even those drugs that exert a dramatic inhibitory effect on CELs do not completely abrogate all signs of MS disease activity: a large proportion of patients in 2-year clinical trials either still form new lesions or progress on disability or brain atrophy measures.1 Because axonal loss is considered the most definite substrate of sustained disability in MS, reliable biomarkers of axonal damage are needed to replace CELs as a measurable target of therapeutic development for this residual disease activity, especially in progressive MS.