Brain volume increase after discontinuing natalizumab therapy: Evidence for reversible pseudoatrophy

Background: The phenomenon of pseudoatropy after initiation of anti-inflammatory therapy is believed to be reversible, but a rebound in brain volume following cessation of highly-effective therapy has not been reported. Objectives: To evaluate brain volume change in a treatment interruption study (RESTORE) in which relapsing-remitting multiple sclerosis (RRMS) patients were randomized to switch from natalizumab to placebo, from natalizumab to once-monthly intravenous methylprednisolone (IVMP), or to remain on natalizumab. Methods: T2 lesion volume (T2LV), baseline normalized brain volumes, and follow-up percent brain volume changes (PBVC) were calculated. Approximate T2 relaxation-time (pT2) was calculated within the brain mask and the T2 lesions to estimate changes in water content. Linear mixed effects models were used to detect differences in T2LV, pT2 in whole brain, pT2 in T2-weighted lesions, and PBVC among the placebo, natalizumab, and IVMP groups. We also estimated contributions of T2LV and pT2 (in whole brain and T2 lesions) to PBVC. Results: T2LV increased in the placebo group (by 0.66 ml/year, p<0.0001) and IVMP (+1.98 ml/year, p = 0.05) groups relative to the natalizumab group. The rates of PBVC were significantly different: -0.239%/year with continued natalizumab and +0.126 %/year after switch to placebo (p = 0.03), while the IVMP group showed brain volume loss (-0.74 %/ year, p = 0.08). pT2 was not statistically different between the groups (p >= 0.29) and did not have significant effects on PBVC (p >= 0.25). Conclusion: The increase in the brain volume in patients witching from natalizumab to placebo is consistent with reversal of so-called pseudoatrophy after starting natalizumab.