Investigate reliability and validity of linear measures of ventricular enlargement as indirect markers of brain atrophy and explore their relationship with clinical disability.

In this retrospective longitudinal analysis of relapsing-remitting MS patients evaluated from January 2006 to December 2009, brain volumes were computed at baseline and after 2-years. Frontal Horn Width (FHW), Intercaudate Distance (ICD), Third Ventricle Width (TVW) and 4^th Ventricle Width (4VW) were obtained. Linear measures correlating with brain volume were entered in regression models testing the relationship between MR metrics and clinical disability. Possible cut-offs for clinically relevant brain atrophy were estimated and tested as 10-years disability progression predictors.

Eighty-seven patients were available (61/26=F/M; 34.14±8.50 years). Both ICD and TVW correlated with normalized brain volume (NBV; p<0.001). Annual percentage brain volume (PBVC/y) was related to annual percentage change in FHW, ICD and TVW (p≤0.005). Baseline clinical disability was associated with NBV, ICD and TVW (p<0.001), while confirmed disability progression (CDP) at 10-years was predicted by PBVC/y (p=0.013). A cut-off value of 4.38% for annual percent ICD change (PICDC/y), corresponding to a threshold PBVC/y rate of -0.91%, correlated with 10-years CDP (p=0.037). These estimated cut-off values in addition to the conventional clinical and MRI markers of disease activity provided extra value for the prediction of long-term CDP, both for PBVC/y (p<0.0001) and PICDC/y (p=0.002).

Linear measures of ventricular enlargement are reproducible and clinically relevant markers of brain atrophy. In particular, ICD and its increase over time show the best association with clinical disability, with a cut-off PICDC/y value of 4.38% as a potential surrogate marker of long-term disability progression.