Sex-specific optic nerve changes in multiple sclerosis and transorbital sonography. The PROMISING study

Introduction: The multiparametric study of the optic nerve in multiple sclerosis (MS) embodies a potential window to the central nervous system (CNS), and particularly in relation to the ongoing revision of MS diagnostic criteria. Sex-specific optic nerve related biomarkers may be informative as to MS prognosis. Objectives/Aims: We aimed to explore optic nerve morphology with respect to past inflammation and detect sex-specific changes with transorbital sonography (TOS). Methods: 122 MS patients (70.5% women) were enrolled, of whom 68 had history of optic neuritis. To avoid in-between dependence, ONs population was randomized into three samples: with no (NI-ON, N=54) and with (I-ON, 72) history of inflammation, and unaffected companions of I-ON (C-ON, 52). TOS was used to detect optic nerve diameter at 3 mm (OND3) from the optic disc and optic nerve sheath diameter at 3-(ONSD3) and 5- (ONSD5) mm. Sex-specific TOS parameters were compared by ON status and after adjusting for age at study time and body mass index (BMI) as potential confounders (ANCOVA). Results: With ANCOVA, ONs were significantly larger in men than women in all three groups. Among NI-ON ONSD3 was 4.941 mm (95%CI: 4.677, 5.206) in men and 4.733 mm (95%CI: 4.536, 4.930) in women (p=0.028), while ONSD5 was 5.353 mm (95%CI: 5.009, 5.697) and 5.029 mm (95%CI: 4.773, 5.285) (p=0.003). Although I-ONs were smaller than NI-ONs, a significant difference between men and women was also observed: 4.958 mm (95%CI: 4.660, 5.257) in men and 4.618 mm (95%CI: 4.456, 4.779) in women, respectively (p=0.003) for ONSD3, and 5.306 mm (95%CI: 4.940, 5.673) and 4.879 mm (95%CI: 4.681, 5.078), respectively (p=0.001) for ONSD5. Similar evidence was found when comparing ONSD3 and ONSD5 by sex in C-ON (p=0.004 and p=0.005, respectively). When comparisons were made between the different ON status but separately in men and women, as expected ONSD3 was smaller in I-ON vs. NI-ON in women (p=0.003), while surprisingly ONSD5 was significantly larger in I-ON than NI-ON and only in women (p=0.0001). Both ONSD3 and ONSD5 were larger in C-ON vs. NI-ON (p=0.001 and p=0.00002) and also vs. I-ON (p=0.0002 for both diameters). No significant differences were detected in measurements in males. Conclusion: TOS provides reliable information in retrobulbar optic nerve evaluation. I-ON are smaller than NI-ON and C-ON are larger than I-ON and NI-ON, likely reflecting nerve atrophy and neuronal plasticity, respectively. Here, we showed that women contribute to such differences more significantly than men. Sex-specific biological changes in the most retrobulbar region of optic nerve are hypothesized.