# Transbulbar B-Mode Sonography for Clinical Phenotyping Multiple Sclerosis
## 4 Discussion and Conclusions  
In a comparative, unblinded, cross-sectional study of a relapse-free MS population and matched healthy controls we found broad variation in ONSD, which proved to be significantly smaller in the MS group, at both 3 and 5 mm from the eyeball. Furthermore, ONSD at 5 mm from the eyeball proved to be significantly smaller in the SP group than the RR group. In contrast, the gap between ONSD at 3 mm in the two groups was not statistically significant. This finding was not seen in RR patients with a mean EDSS of 2.0 compared with transitional patients who have a mean EDSS of 3.7. These RR patients with a mean EDSS of 2.0 had a higher mean ONSD3 (0.53 cm) and MI (0.90) than the transitional group (0.48 cm and 0.84), (\(p\) = 0.050 and \(p\) = 0.050 respectively). These data demonstrate that MS phenotypes are characterized by readily detectable degrees of ON atrophy and neuropathy. Therefore, we can state that the major contributors to ON neuropathy are axonal loss and demyelination. These findings are in accordance with the common interpretation of optical coherence tomography (OCT) data, which is that retinal atrophy in multiple sclerosis reflects loss of retinal ganglion cells and their axons [17]. Based on different physical principles, OCT and ONSD are not complementary methods, but reflect structural aspects of separated but highly correlated organs: the retina and the ON. To our knowledge, no published studies have explored the degree of correlation and concordance between the two methods. Further investigations are warranted. Specifically, it should be stressed that in the literature there is no evidence of correlation between age and ONSD, as well as height and body mass index [18]. Thus, despite the significantly greater age of the SPMS patients, the differences in ONSD with respect to the RRMS group are due to disease activity and disease duration. Figure 3: Correlation between MI and ONSD3. Significant correlation between Myelination Index (MI) and optic nerve sheath diameter measured at 3 mm from the eyeball (ONSD3). (\(r\) = 0.499; \(p\) = 0.001). Moreover, we demonstrated a linear correlation between the MI and ONSD3 among the MS population, but not between the MI and ONSD5. This means that neurodegeneration in the ON begins early in RRMS and reaches a plateau during the transitional phase. However, it remains stable and mild throughout the patient's life, even in the SP phase. On the other hand, the inflammatory demyelination process begins during the RR phase and continues over time during the SP phase, where it is preponderant. In addition, as expected, we found lower PGMv and TBv as well as higher T1 LL, T2 LL, EDSS (and its sensitive, pyramidal, cerebellar, brain stem and sphincter sub-scores), age, and DD in the SP group than in the RR group, but the mean MI was not found to be statistically different between the two groups. The latter finding can have only one explanation: subclinical ON demyelination during the natural progression of MS. For this reason, although the absolute size of the ON is lower in MS than in healthy controls, and the ONSD measured at 5 mm from the eyeball is higher in the RR patients than in the SP group, the relative amount of myelin can raise the MI, reducing its statistical significance. In contrast, at 3 mm from the eyeball, the myelin coating is significantly thinner, so the axonal loss or shrinkage already detected in this segment in comparison to the healthy controls is mild and distributed equally between the RR and the SP patients. This explanation is in accordance with previous observations regarding the brain lesion re-myelination process, the effectiveness of which is largely dependent on the subjective characteristics of the MS patient, including genetics, age, and DD [19; 20]. For the same reason, the MI does not correlate with the clinical or neurophysiological variables, nor can it distinguish RR from SP patients, as demonstrated by the ROC analysis.