Relevance of optic nerve B-mode sonography in multiple sclerosis diagnosis and follow-up

Axonal degeneration and demyelination of the central nervous system (CNS) are characteristics of multiple sclerosis (MS). Approximately 2.5 million people worldwide suffer from this prevalent neurological disorder. Among young people, MS accounts for the majority of non-traumatic neurological impairments, with over one million individuals suffering from physical disabilities due to MS [1‐4]. Optic neuritis occurs in about 25% of MS patients as their first symptom. As MS progresses, about half of patients experience optic neuritis; post-mortem examinations show that almost all MS patients, regardless of their prior history of the illness, have optic neuritis [5].

Myelinated axon fibers, like those in brain white matter, compose the ON, making it susceptible to inflammatory demyelinating damage in MS. The ON is considered “eloquent” in comparison with the brain because every lesion, no matter how small, causes clinical and/or easily identifiable influential problems. Afferent visual pathway tissue damage in MS patients represents universal CNS consequences [6‐8]. Looking at it in this way, the ON becomes a clinical MS model [9]

Visual-evoked potential (VEP), which allowed for the recording of both symptomatic and asymptomatic lesions, was a standard component of MS diagnosis prior to the development of magnetic resonance imaging (MRI). In addition, VEP assisted in tracking the course and prognosis of MS and give information about the function of the myelin, axons, and synapses in the visual pathway, especially in the pre-chiasmatic region [10, 11].

Ultrasound has now arisen as a potential supplementary evaluation technique for the ON, complementing the more traditional methods of ophthalmoscopy and MRI. The eye is an ideal target for ultrasonography because of the amount of water it contains. Nevertheless, there is a lack of research on its efficacy in detecting MS-related ON alterations [12].

Transorbital sonography (TOS) is a noninvasive technique for assessing ON sheath diameter (ONSD). It is one objective tool for neurologic assessment, and clinicians have recently validated this technique [13].

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 VEP, the number of MRI black holes, and other clinically significant parameters.

This case–control study was conducted in the Suez Canal University Hospital’s Neurology and Diagnostic Radiology departments, Ismailia, Egypt.

Thirty clinically definite RRMS patients attended Neurology Department in Suez Canal University Hospital of both sexes aged 18 years or more were included. The McDonald's criteria 2017 were used for the diagnosis of MS [14].

Patients with MS without a relapse in the preceding 3 months, and taking disease-modifying medication, and did not have a current diagnosis of optic neuritis were included.

Patients with a history of severe head traumas or eye blow, patients with any comorbidities, such as ocular and toxic-deficiency disorders, patients with retrobulbar optic neuritis, patients with any systemic illnesses, such as diabetes mellitus, collagen vascular disease, degenerative disorders, or patients with neurological impairment from a condition other than MS (MS mimics), were excluded.

Thirty age and sex-matched healthy controls who did not have any eye condition in the past (beyond corrected, non-pathologic refractive defect) were involved and after a thorough examination, MS, optic neuritis, and other neurologic disorders were excluded.

Each participant provided written consent after the local ethics commission approved the study.

Each subject underwent a complete laboratory workup to rule out any systemic disorders, as well as a general, ophthalmological, and neurological evaluation. The Expanded Disability Status Scale (EDSS) was employed to determine the patient's disability [15]. A 1.5-T MR unit (Achieva; Philips Medical Systems, The Netherlands) has been utilized for carrying out brain and cervical MRI for all participants, the MRI was done with contrast for patients, and it was reviewed by a Neuro-radiologist in accordance with international guidelines [16]. The MRI protocol included T1WIs in three different planes (sagittal, axial, and coronal) without contrast (TR 400–550 m/s, TE 15 m/s). Axial T2WI (TR 3500–4800 m/s, TE 110 m/s). FLAIR in all three planes (axial, sagittal, and coronal) (TR 9000–9400 m/s, TE 119–150 m/s, TI 2470–2800 m/s). Two to ten minutes after gadolinium delivery, post-contrast axial, coronal, and sagittal T1WI were done. An intravenous dose of 0.2 ml/kg body weight of the contrast agent Omniscan or Magnivist [Gadolinium (Diethelene Triamine Penta acidic acid) or “Gd-DTPA”] was used. A single rater who was not privy to any clinical data conducted all the MRI evaluations for detection of brain T1 black holes.

Using the standard methodology developed by the International Society for Clinical Electrophysiology of VEP, pattern visual-evoked potentials (P-VEPs) were obtained from the occipital scalp [17], Utilizing Neuropack NC/EMG/EP machine (MEB-2300); Nihon-Kohden, Tokyo, Japan. With each vertical division, the gain was fixed at 20 microvolts (μV). The screen time was 300 ms (msec). The low-cut value was 1 Hz while the high-cut value was 100 Hz. According to the worldwide 10–20 system, the Oz, Cz, and Fz sites were utilized as ground electrodes, recording electrodes, and reference electrodes, respectively, making sure that each electrode’s impedance did not exceed 3 kΩ.

A pattern reversal checkerboard screen was used for monocular visual stimulation. Three different check sizes were utilized, corresponding to 60, 30, and 15 min of arc, respectively: 8 × 8, 16 × 16, and 32 × 32 checks. The center of the screen served as the fixation point. The stimulus’s brightness and contrast were continuously maintained during the test. The P 100 wave signals were amplified and filtered before their latencies and amplitudes were examined. There was an average of 100 responses from each side. P 100 latency and amplitude were assessed for both eyes to all study participants. From the previous peak of N75, the amplitude of the P 100 wave was recorded in μV, and the latency was recorded in millisecond (msec). “W” or bifid waves were interpolated, and the inter-side difference was measured.

According to Bäuerle and Nedelmann (2011) [18], TOS was done for all patients and controls Using Philips, IU22, California USA with 2.5–10 MHz linear probe. To prevent any strain on the eyes, the participants were tested while lying down with their upper bodies raised and their head angle maintained at a constant 20–30 degrees. To control the eye movements, it was requested that all participants maintain their eyes in the middle position. We lowered the mechanical index to 0.2 to lessen the potential biomechanical adverse effects on the subjects. Following the application of a thick coating of sonography gel. With the upper eyelid closed, the probe was positioned on the temporal portion of the lid. A transverse plane depiction of the ON was used, which showed the papilla and the nerve's longitudinal route at 3 and 5 mm bilaterally posterior to the eyeball. A total of three measurements were taken to determine the ONSD, which is the distance between the outer margins of the hyperechoic region around the ON [18]. To measure the relative myelination of the ON, researchers used the myelination index (MI), which is the ratio of ONSD at 3 mm (ONSD 3) from the eyeball to ONSD at 5 mm (ONSD 5) from the eyeball, to establish a relationship between ONSD and the thickness of the myelin covering of the ON [19].

A total of 120 eyes were examined: 60 eyes from the MS group and 60 eyes from the control group. In two sequential days, the VEP and TOS were carried out after the clinical and ophthalmological evaluation.

We used IBM SPSS software package version 20, (Redwood City, New York: IBM Corporation, 2016). The numerical and percentage statistics were applied to represent the categorical variables. To compare the two groups, the Chi-square test was applied. The Shapiro–Wilk test was employed to confirm whether the continuous data was distributed normally. Minimum and maximum values, as well as means, standard deviations, and medians, were used to convey quantitative data. When comparing two groups with normally distributed quantitative data, the student t test was applied, and when comparing two periods, the paired t test was utilized. The quantitative variables properly distributed are correlated by the Pearson coefficient. The findings were considered statistically significant at the 5% level.

The study enrolled 30 RRMS patients and 30 controls. The MS patients mean age was 29.1 ± 5.2 years (range 20–42), while the controls mean age was 28.3 ± 5.3 years (range 19–41); out of 30 patients with MS, 9 patients (30%) were males and 21 patients (70%) were females, while in the control group, 8 subjects (27%) were males, and 22 subjects (73%) were females. We examined a total of 120 eyes altogether (Table 1).

The mean duration of the disease was 8 ± 4.3 years, with a range of 2–17 years. The mean of the optic neuritis attacks was 2 ± 1.3, with a range of (0–4). The mean EDSS of patients was 2.6 ± 1.2, with a range of 1–5. The MRI black holes number had a mean of 2.6 ± 2.1, with a range of 0–6 (Table 2).

The average ONSD at 3 mm, 5 mm, and myelination index in the patients were 4.7 ± 0.3, 5.5 ± 0.3, and 0.86 ± 0.03, respectively. These values were significantly lower than those in the controls, which were 5.6 ± 0.3, 6.2 ± 0.4, and 0.90 ± 0.03, respectively (p < 0.001 for each) (Table 3). The mean p 100 latency was significantly delayed in the patients (125.5 ± 6.1 ms) than in 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) (Table 3).

The ONSD 3 was positively correlated with p 100 amplitude (r = 0.611, p < 0.001), and there were highly significant negative correlations between ONSD 3 and disease duration, number of optic neuritis attacks, EDSS, MRI black holes number, and p 100 latency (r = − 0.548, p < 0.001/r = − 0.517, p < 0.001/r = − 0.572, p < 0.001 r =− 0.569, p < 0.001 and r =− 0.419, p = 0.001), respectively (Table 4).

There were highly significant negative correlations between disease duration and ONSD 3, ONSD 5, myelination index, and P 100 Amplitude (r = − 0.548, p < 0.001/r = − 0.508, p < 0.001/r = − 0.525, p < 0.001 r = − 0.699, p < 0.001), respectively. There were highly significant positive correlations between disease duration and the number of optic neuritis attacks, EDSS, MRI black hole numbers, and p 100 latency (r = 0.676, p < 0.001/r = 0.603, p < 0.001/r = 0.556, p < 0.001 r = 0.424, p = 0.001), respectively (Table 5).

Numerous biomarkers have been studied over the years to see if they may aid in the diagnosis of multiple sclerosis or accurately predict different characteristics of the disease, including therapeutic response, progression, and prognosis [20].

The matched healthy controls and the relapse-free random MS group in this study did not differ significantly regarding age or sex, and the study found that 70% of MS patients were female, which is consistent with the well-known female predominance in multiple sclerosis [21].

Our study showed that the mean ONSD 3 and ONSD 5 for trans-orbital sonography in healthy controls were (5.6 ± 0.3 mm) and (6.2 ± 0.4 mm) and MS group were (4.7 ± 0.3 mm) and (5.5 ± 0.3 mm), while de Masi, R and his colleagues [19] found that the mean ONSD 3 and ONSD 5 in healthy controls were (6.5 ± 0.77 mm) and (7.3 ± 0.92 mm), and MS group were (4.9 ± 0.74 mm) and (5.7 ± 0.64 mm). the mean ONSD 3 in healthy controls was (5.2 ± 0.6 mm) in Elkholy and her colleague’s study [22] and it was (5.75 ± 0.52 mm) Steinborn and his colleague’s study [23].

Regarding ONSD, the MS group had a much smaller ONSD 3 and ONSD 5 than the controls. In addition, the MI was much higher in the healthy controls than in the patients, with results of 0.90 and 0.86, respectively, these findings are consistent with that found in de Masi, R and his colleagues [19], which can be explained by recurrent optic neuritis that causes nerve sheath damage, which may lead to a continuing lesser myelination process or even no myelination at all, which might explain the decrease in sheath diameter.

The ON directly posterior to the eyeball has either no myelination or a biologically decreased amount, making it easy to comprehend this occurrence considering the chronic axon depletion seen in multiple sclerosis. This investigation examined MI to confirm this. The physiologic basis for MI is provided by the nearly complete myelination of CNS nerve axons with diameters greater than 0.2 mm. The axon diameter ratio to the total fiber diameter (axon and myelin), which is kept at 0.90 regardless of axon diameter, is known as the “G ratio” and is frequently used [24].

In our study, MS patients had an MI of 0.86 which is much lower than the healthy controls 0.90 and this in agreement with de Masi and his colleagues [19] who reported that the MI in healthy controls was 0.89 and in MS patients was 0.84. The reduced ONSD in patients can be explained by axonal loss (95–96%) and demyelination (4–5%), because the MI in patients healthy was much lower than in controls (p = 0.001) [19].

By comparing the ONSD of the MS and control groups using TOS, we discovered that the MS group had much reduced diameters, leading to the idea that ONSD might be a useful complementary measure of disease progression in MS. These findings agreed with those in more recent research [19, 25, 26].

Studies have shown that MS patients' visual pathways experience trans-synaptic axonal degeneration, which implies that, in principle, the anterior visual system might be used to indirectly quantify axonal loss and other global brain parameters [27, 28].

The longer duration of the disease in our study, which predisposes to more ON demyelination and atrophy, may explain why our findings differ from those of Koraysha and his colleagues [29], who noted no statistically significant difference between ONSD measured by TOS in healthy and MS patients.

This study showed that other illness markers (disease duration, EDSS, and MRI black hole number) have a negative correlation with ONSD. Furthermore, prior research has shown a negative relationship between these variables [19, 26, 30]. This is not surprising given that atrophy persists throughout the disease's progression. While some studies have shown a correlation between OND and EDSS, others have found no link between OND and illness duration [31].

This study also showed significantly delayed P 100 latency and decreased P 100 amplitude of the VEP among patients than the controls, this can be explained by the recurrent inflammation and demyelination in the disease leading to axonal loss. The findings of de Masi and colleagues [19] and Raeesmohammadi and colleagues [31] are consistent with these results, which showed that the MS group had a delayed P 100 latency compared to the health group.

In our study also found that ONSD at 3 mm and 5 mm correlated inversely with VEP, while according to de Masi and colleagues [19], the neurophysiologic characteristics of P 100 did not correlate with ONSD, and neither did the clusters of P 100 with ONSD, also, in other studies, there was no significant correlation between ONSD and VEP but what can explain this correlation that T1-weighted black holes and delayed P 100 have been shown to correlate with disability in some studies [32].

Elkholy and her colleagues [22] who studied the accuracy of TOS in acute optic neuritis and showed its correlation with VEP, but its sensitivity and specificity are lesser than P-VEP, but this study was not specific to MS as the patients were examined during attack of optic neuritis irrelevant to the cause, but our patients were MS relapse free.

Our results prove that measurement of ONSD by trans-orbital B mode ultrasound is a relevant noninvasive cheap bed side helpful tool in follow up of ON affection in MS and as a tool of follow up of disability in MS, it also helps in assessment of brain atrophy.

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.

Our study has two limitations: a limited sample size and a cross-sectional design. Larger, longer-term studies in the future may enhance these. Furthermore, the fact that this was a single-center study could limit its broad applicability.