Aim of this study was to investigate the reliability and validity of 2D linear measures of ventricular enlargement as indirect markers of brain atrophy and possible predictors of clinical disability.

In this retrospective longitudinal analysis of relapsing-remitting MS patients, brain volumes were computed at baseline and after 2 years. Frontal horn width (FHW), intercaudate distance (ICD), third ventricle width (TVW), and 4th ventricle width were obtained. Two-dimensional measures associated with brain volume at correlation analyses were entered in linear and logistic regression models testing the relationship with baseline clinical disability and 10-year confirmed disability progression (CDP), respectively. Possible cutoff values for clinically relevant atrophy were estimated via receiver operating characteristic (ROC) analyses and probed as 10-year CDP predictors using hierarchical logistic regression.

Eighty-seven patients were available (61/26 = F/M; 34.1 ± 8.5 years). Moderate negative correlations emerged between ICD and TVW and normalized brain volume (NBV; p < 0.001) and percentage brain volume change per year (PBVC/y) and FHW, ICD, and TVW annual changes (p ≤ 0.005). Baseline disability was moderately associated with NBV, ICD, and TVW (p < 0.001), while PBVC/y predicted 10-year CDP (p = 0.01). A cutoff percentage ICD change per year (PICDC/y) value of 4.38%, corresponding to − 0.91% PBVC/y, correlated with 10-year CDP (p = 0.04). These estimated cutoff values provided extra value for predicting 10-year CDP (PBVC/y: p = 0.001; PICDC/y: p = 0.03).

Two-dimensional measures of ventricular enlargement are reproducible and clinically relevant markers of brain atrophy, with ICD and its increase over time showing the best association with clinical disability. Specifically, a cutoff PICDC/y value of 4.38% could serve as a potential surrogate marker of long-term disability progression.

• Assessment of ventricular enlargement as a rapidly accessible indirect marker of brain atrophy may prove useful in cases in which brain volume quantification is not practicable.

• Two-dimensional linear measures of ventricular enlargement represent reliable, valid, and clinically relevant markers of brain atrophy.

• A cutoff annualized percentage brain volume change of − 0.91% and the corresponding annualized percentage increase of 4.38% for intercaudate distance are able to discriminate patients who will develop long-term disability progression.