Fig. 1.

The association of ChP volume with MS cumulative disease burden and treatment responses. The vast majority of patients who are diagnosed with MS have a relapsing remitting disease course. These patients experience clinical relapses and accumulate new lesions on brain MRI, two events that are often termed “disease activity” and, for the purpose of this illustration, “cumulative disease burden.” All currently approved DMT for MS reduce this cumulative disease burden. In the study by Fleischer et al. (8) there was a positive correlation between ChP volume and cumulative disease burden. Furthermore, the authors show that, despite a positive correlation between disease duration and ChP volume in treatment-naïve patients, treatment with DMF was not a predictor for ChP volume attenuation in follow-up assessments, whereas treatment with natalizumab was. Natalizumab is a humanized mAb that prevents the interaction of α4-integrin on leukocytes with its ligands on the BBB and within the extracellular matrix, reducing the adhesion and diapedesis into the brain. In contrast, DMF has no known direct effect of leukocyte migration across the BBB. This observation supports the assumption that ChP volume may be an imaging correlate of immune cell trafficking into the CNS rather than a mere readout of clinical improvement or treatment responses. Eventually, many MS patients no longer have clinical relapses, and they transition to a disease phenotype called SPMS. In patients with SPMS, currently approved DMT are no longer effective, including natalizumab. This suggest that 1) leukocyte traffic into the CNS no longer occurs through the ChP in patients with SPMS, 2) the composition of leukocytes changes at that disease stage, or 3) adhesion molecules other than α4-integrin are utilized for adhesion and diapedesis by those leukocytes in SPMS. This may further suggest that ChP volumetrics would no longer be a good imaging marker in SPMS. Perhaps most importantly, changes in ChP volume dynamics may serve as a marker of transition from RRMS to SPMS, a meaningful biological event for which there is currently no biomarker.