25 PwMS underwent at the 2-3^rd week (intermediate visit) and at the 6-7^th week (end-of-dose visit) after Natalizumab infusion an assessment of: [1] processing speed - PASAT, SDMT, [2] self-reported fatigue - Fatigue Severity Scale, [3] cortical GABAergic and glutamatergic activity using transcranial magnetic stimulation techniques, [4] relative abundance of the main T-lymphocytes subsets using flowcytometry, [5] plasma neurofilaments. For the latter, 25 SID controls were enrolled.

All EID subjects but one reported end-of-dose symptoms, but no change in processing speed or self-reported fatigue was detected. We observed a substantial drop in the proportion of IFN??-producing lymphocytes (CD4+: -57.7%, p=0.01; CD8+: -41.45%, p=0.014; NK: -54.23%, p=0.033) and other pro-inflammatory subsets at the end-of-dose. A concomitant increase in the GABA-A dependent inhibition of the primary motor cortex was observed (0.49, CI95% 0.36–0.61 vs 0.72, CI95% 0.52–0.92; F_(1,20) 5.76; p=0.026). Plasma neurofilaments were higher in EID compared with SID (12.08 pg/mL, CI95% 10.41–13.76 vs 9.38, CI95% 7.71–11.05; F_(1,48) 5.28; p=0.026).

It is possible to hypothesize that at the end-of-dose pro-inflammatory lymphocytes pass towards the CNS, thus dropping in the periphery, and cause the observed changes in cortical excitability, axonal damage and conceivably vague end-of-dose symptoms.