# Transbulbar B-Mode Sonography for Clinical Phenotyping Multiple Sclerosis
## 1 Introduction  
Transbulbar B-mode sonography (TBS) has recently been standardized with reference to magnetic resonance imaging (MRI) for the reproducible and accurate study of the optic nerve (ON) in healthy controls and diseased subjects [1; 2]. Since then, ultrasound imaging studies have identified a number of new pathological elements regarding other cranial nerves and peripheral trunks in many diseases, from optic neuritis and idiopathic intracranial hypertension (IIH) [3; 4] to chronic idiopathic demyelinating polyneuropathy (CIDP) [5]. As regards multiple sclerosis (MS), the initialfindings showed that TBS was suitable for the study of the ON and its chronic and subclinical involvement in disease in form of ON atrophy, regardless of the degree of acute retrobulbar optic neuritis (ARON), which it also described [6; 7]. Specifically, chronic ON atrophy has been demonstrated in unselected MS patients and optic nerve sheath diameter (ONSD) has also been correlated with neurological impairment detected by the expanded disability status scale (EDSS) [8]. However, the ON has never been studied selectively in the relapsing remitting (RR) and secondary progressive (SP) phenotypes of the disease and neither has ONSD in terms of the clinical or paraclinical variables of diseased subjects. Accordingly, we have not considered patients that experienced ARON in the past, for excluding the effect of acute inflammatory demyelination onto development of chronic ON atrophy, whose assessment is the main target of the present study.  
The importance of studying the ON in MS lies in the certainty of its features that make it a good clinical model of the disease. First, the convergence of the ganglion cell output fibres in the ON makes it a clinically and instrumentally eloquent structure for all lesions [9]. Second, ON fibres are only unmyelinated in the lamina cribrosa, starting from the last 3 mm before their entry into the eyeball [10]. Therefore, we can study the thickness of the myelinated and unmyelinated parts of the ON (at 5 mm and 3 mm from the eyeball, respectively) under a range of experimental conditions. Third, its derivation from the diencephalon makes the ON sensitive to abiotrophic phenomena in distant structures of hemispheric white matter and the cortex [11; 12]. Finally, we know the nature of subclinical histological processes leading to the end-stage atrophy of the ON in the large number of patients affected by MS. Specifically, common neuroinflammatory-dependent aspects involving the optic nerves and cerebral hemispheres include perivular infiltrative T cells with axonal loss and reactive gliosis [13].  
Based on this premise, the primary aim of this study is to assess putative differences in ONSD between RR and SP MS patients. A secondary aim is to evaluate which demographic, instrumental or clinical variables are associated with these differences among the MS study population. These data have a descriptive value since they constitute a novel application of the sonographic technique. However, they can also characterize sub-clinical disease progression in clinical practice.