Abstract Background Among young people, multiple sclerosis (MS) accounts for the majority of non-traumatic neurological impairments. Almost all MS patients develop optic neuritis as the illness progresses. In MS, the optic nerve (ON) is vulnerable to demyelinating injury and is considered “eloquent” in comparison with the brain. Thus, it serves as a clinical model for MS. Since the eye is a suitable target for ultrasonography due to its high-water content, non-invasive trans-orbital sonography (TOS) can determine the optic nerve sheath diameter (ONSD). This research aimed to determine the effectiveness of ON ultrasonography as a simple, low-cost method for diagnosing and following up MS patients, facilitating their treatment plan. It correlates the findings of ONSD using TOS and visual-evoked potential (VEP), the number of magnetic resonance imaging (MRI) black holes, and other clinically significant parameters in 30 relapsing–remitting MS (RRMS) patients versus 30 controls. Results We examined a total of 120 eyes. The ONSD values at 3 mm, 5 mm, and myelination index were significantly lower in the patients (4.7 ± 0.3, 5.5 ± 0.3, and 0.86 ± 0.03, respectively) versus the controls (5.6 ± 0.3, 6.2 ± 0.4, and 0.90 ± 0.03, respectively) (p < 0.001 in each). The mean P 100 latency was significantly delayed in the patients (125.5 ± 6.1 ms) than the controls (100.2 ± 3.3 ms), (p < 0.001). The mean VEP amplitude was significantly lower in the patients (4.9 ± 0.7 μV) than the controls (6.8 ± 0.8 μV) (p < 0.001). There was a highly significant positive correlation between the ONSD and P 100 amplitude, and highly significant negative correlations between the ONSD and disease duration, number of optic neuritis attacks, EDSS, MRI black holes number, and P 100 latency. Conclusions Trans-orbital sonography is a practical and easily accessible approach for assessing ON atrophy in MS. It can measure axonal loss and brain atrophy indirectly and is a reliable paraclinical diagnostic tool, suggesting that ONSD could be a biomarker of disease activity.
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