# Transbulbar B-Mode Sonography for Clinical Phenotyping Multiple Sclerosis
## 4 Discussion and Conclusions
However, the similarity statistics blindly identified two groups, one with MI\({}^{\rm H}\) and another with MI\({}^{\rm L}\). In the MI\({}^{\rm H}\) group, patients with a mean EDSS of 2.0 and DD \(\leq\) 38.29 y form a cluster corresponding to the RR phenotype, whereas in the MI\({}^{\rm L}\) group, patients with a mean EDSS of 3.7 and DD \(\geq\) 45.47 y form a cluster corresponding to the transitional phenotype. In all these cases we found the distances between the centres of each variable, including the MI, to be statistically significant. This means that the MI is statistically associated with a qualitative state variable, not with a continuous quantitative variable expressible as a number, for example the T1 LL, DD, etc. In physiopathological terms, in the transitional phase of MS, demyelination is not yet advanced enough to modify the MI. In contrast, in clinical terms, we can state that the MI is associated with either an RR or a transitional clinical phenotype, depending on whether it exceeds the cut-off of 0.84. However, this association becomes stringent only if the MI is supported by at least one of the following: DD, age, T1 LL, T2 LL, P100A, P100L. This means that subclinical axonal loss, as well as de/re-myelination, can vary subjectively. However, when considered together with another patient-specific neurophysiological parameter, it contributes to establishing the clinical phenotype. Specifically, a patient with an MI of 0.90 with ONSD3 \(\geq\) 0.53 or ONSD5 \(\geq\) 0.59 will belong to the RR group, while an MI of 0.84 with an ONSD3 ranging from 0.46 to 0.48 indicates the transitional group. Finally, an MI of \(<\) 0.83 with ONSD5 \(\leq\) 0.55 or ONSD3 \(\leq\) 0.46 indicates the SP group (Figure 4). In our study population, these conditions correctly clustered the subgroups with \(\approx\)90% accuracy. Considering these physiopathological elements as a whole, we found significant similarities between the ON and the brain: early subclinical involvement; co-existing inflammatory demyelination with possible exacerbation phases and chronic axonal loss, leading to progressive nerve atrophy; and correlations between ONSD and clinical/paraclinical impairment. Coherently, TBS-detected ONSD reflects the demyelination induced by inflammation, but not the inflammation itself that is underlying pathological process. These elements, numerous and consistent with each other, are supported by statistics and therefore, in our view, are not mere coincidence. These non-casual similarities make the ON a \"long brain\" and a useful clinical model of disease. The limitation of the study is that the sonographer was unblinded concerning the clinical conditions. This bias was in part offset by calculating the COV, which confirmed the reliability of the measurements. Another issue is that the measurements are very small in size, although we should consider the wider context of the study. Specifically, the high sensitivity of the B-mode system, accurate to a tenth of a millimetre with a very low standard deviation of measurements, ensures the statistical significance of even apparently small differences between compared means. The same consideration applies to normative data, according to which an ONSD of 5.4 \(\pm\) 0.6 mm is considered normal, while \(\geq\)6.3 \(\pm\) 0.6 mm is considered predictive of elevated intracranial pressure [21]. As for the papilla, a disc elevation of 1.2 \(\pm\) 0.3 mm is considered strongly indicative of papilloedema [1]. Moreover, based on sub-millimetric measurement, the high-resolution B-mode system also provides an appropriate evaluation of the intima-media thickness as a marker of atherosclerosis [22]. Finally, in this paper we have not considered primary progressive MS (PPMS) and neuromylitis optica (NMO) as comparison groups with respect to our MS study population. These interesting evaluations are missing in both cases, but we must consider that these are nosografically isolated pathologies not evolving from other demyelinating subtypes and requiring specific diagnostic guidelines.