Optic Nerve Lesion Volume, White Matter Hyperintensities, and Brain Volumetrics in Multiple Sclerosis: A Multi-Sequence MRI-Based Analysis

Objectives To investigate the relationship between optic nerve lesion volume (ONLV), measured on double inversion recovery (DIR) MRI, and other radiological biomarkers of disease burden in multiple sclerosis (MS), including white matter hyperintensities (WMHs), T1-weighted hypointensities ("black holes"), and brain volumetrics. This study aims to determine whether ONLV correlates with a more severe neurodegenerative profile and could serve as a potential biomarker for disease severity. Materials and Methods In this cross-sectional study, 212 MS patients underwent 3T MRI including 3D T1W, FLAIR, and DIR sequences. Optic nerve lesions were manually segmented on DIR images and quantified volumetrically. Patients were grouped by optic nerve involvement: none (n = 59), unilateral (n = 60), or bilateral (n = 93). WMHs were segmented and anatomically categorized using an AI-based tool. T1W hypointensities were extracted via FreeSurfer, and brain volumetrics were assessed using a machine learning-based segmentation algorithm on both 3D T1W and FLAIR images. Statistical comparisons and correlation analyses were performed using multivariate models adjusted for total intracranial volume. Results ONLV was positively correlated with periventricular (r = 0.365, p < 0.001), deep white matter (r = 0.165, p = 0.005), and juxtacortical (r = 0.163, p = 0.007) WMHs. Patients with bilateral optic nerve involvement exhibited significantly higher WMH burden, greater T1W hypointensities (β = 10.91, p < 0.001), and more pronounced cerebral white matter atrophy (β = -107.02, p = 0.016). Regional brain atrophy was most evident in structures along the visual pathway (e.g., cuneus, fusiform gyrus, pericalcarine cortex, and thalamus). Additionally, periventricular WMH volume was significantly associated with global brain atrophy, including cortical and subcortical gray matter loss. Conclusions This study demonstrates that ONLV, as quantified on DIR MRI, is associated with increased lesion burden, irreversible white matter damage, and widespread brain atrophy in MS. These findings suggest that ONLV may serve as a potential imaging biomarker of disease severity and could be integrated into standard MRI protocols for MS assessment. Future longitudinal studies are warranted to validate ONLV as a marker of disease progression and treatment response.