Variability of the optic nerve sheath diameter on brain computed tomography in Turkish children based on sex and age

Optic nerve sheath diameter (ONSD) measurement is a noninvasive method that can be used for intracranial pressure monitoring. Several studies have investigated normal ONSD values in children, but no general consensus has been reached yet. The aim of our study was to reveal normal ONSD, eyeball transverse diameter (ETD), and ONSD/ETD values on brain computed tomography (CT) in healthy children aged 1 month to 18 years. Children admitted to the emergency department with minor head trauma and had normal brain CT were included in the study. The demographic characteristics of the patients (age and sex) were recorded, and the patients were divided into four age groups: 1 month to 2 years, 2 to 4 years, 4 to 10 years, and 10 to 18 years. The images of 332 patients were analyzed. When the median values of all measurement parameters (right and left ONSD, ETD, and ONSD/ETD) were compared between the right and left eyes, no statistically significant differences were found. When the same parameters were compared according to age group, the ONSD and ETD values differed significantly (values of males were found to be higher), but the ONSD proximal/ETD and ONSD middle/ETD values did not differ significantly. In our study, normal ONSD, ETD, and ONSD/ETD values were determined according to age and sex in healthy children. As the ONSD/ETD index did not statistically significantly differ according to age and sex, diagnostic studies for traumatic brain injuries can be performed using the index.


Introduction
Head trauma is a frequent cause of admission of children to the emergency department, and brain damage that may develop as a result can cause significant morbidity and mortality [1,2].Intracranial pressure monitoring is an important adjunct in the diagnosis and treatment of traumatic brain injury and is recommended in guidelines [1,3].However, the invasive methods used in follow-up examinations, such as catheter drainage, may cause undesirable complications such as bleeding and infection [4,5].The high incidence rate of complications of these invasive methods in pediatric patients has led to the search for easy, reliable, noninvasive methods of monitoring intracranial pressure [6].
Optic nerve sheath diameter (ONSD) measurement is a noninvasive method that can be used for intracranial pressure monitoring in cases of acute intracranial pressure increase and correlates with intracranial pressure and mortality [3,[7][8][9][10][11][12][13][14][15].The connections between the intracranial subarachnoid space and the dura mater and optic nerve sheath were demonstrated in 1870, and subsequent experimental studies have shown the enlargement of the ONSD in cases of increased intracranial pressure [16,17].ONSD measurement has gained popularity in intracranial pressure monitoring in the last 20 years (2 decades), and many studies have been conducted in various patient groups [18,19].
ONSD measurement can be performed using three methods: ultrasonography (USG), computed tomography (CT), and magnetic resonance imaging (MRI).In a meta-analysis that compared the usefulness of these three methods for ONSD measurement in cases of increased intracranial pressure, USG showed higher diagnostic accuracy than the other two methods [8].In addition, because USG does not cause ionizing radiation exposure and can be easily performed at bedside in a short time and can be repeated, it is considered more advantageous than the other methods and is preferred more often in diagnostic studies.
The gold standard imaging method for diagnosing traumatic brain injury in emergency departments is brain CT.Better-quality images can be obtained with MRI, but it requires sedation and is difficult to access.
The aim of our study was to reveal normal ONSD, ETD, and ONSD/ETD values on brain CT in healthy children aged 1 month to 18 years.

Materials and methods
A descriptive cross-sectional study was conducted prospectively between September 2020 and September 2021 in the pediatric emergency clinic of a university affiliated tertiary state hospital.The study was approved by the local ethics review committee (approval No. 2020/11-44).
Children admitted to the emergency department with minor head trauma and evaluated with non-contrast brain CT were included in the study.The characteristics of the patients included or excluded from the study are presented in Supplementary Tables 1 and 2. Patients were included and excluded from the study in accordance with the inclusion and exclusion criteria, respectively.
All patients who presented with head trauma were evaluated on the basis of the Pediatric Emergency Care Applied Research Network criteria, which we use in routine practice in our clinic, and brain CT was decided upon indication [36,37].
Patients who did not meet the appropriate criteria were excluded from the study (Supplementary Table 2).
The demographic characteristics of the patients (age and sex) were recorded, and the patients were divided into four age groups: 1 month to 2 years, 2 to 4 years, 4 to 10 years, and 10 to 18 years.Two radiologists (YP and EG) performed the ONSD and ETD measurements on the images, and the averages of the measurements were included in the statistical analysis.For each patient, the ONSD/ETD ratio was also calculated using the mean values.

Image analysis
Brain CT images were obtained in the axial plane with a 0.6-mm section thickness using a 64-slice spiral CT device (SOMATOM go.Up, Siemens) without intravenous contrast material.The ETD and ONSD values were calculated using a window level of 50 and a window width of 350.On the left and right ETD axial images, the diameter of the bulbus oculi was measured from retina to retina at the widest section.On the left and right ONSD axial images, thickness measurements were made at 3 mm (ONSD proximal) and 10 mm (ONSD middle; 8-12 mm) from the bulbus oculia.The middle measurement site of the ONSD was at half of the intraorbital optic nerve length.
The study excluded images with streak and movement artifacts, as well as images with pathologies that prevent measurement of the ONSD (intraorbital hematoma, multiple orbital wall fractures, intraorbital foreign body).

Statistical analysis
Statistical data analysis was performed using the IBM SPSS Statistics 25.0 package program (IBM Corp., Armonk, New York, USA).Descriptive statistics were given as number of units (n), percentage (%), median (M), 25th percentile (Q1), and 75th percentile (Q3).The normal distribution of the data of the continuous variables was evaluated using the Shapiro-Wilk test of normality and Q-Q graphs.Twogroup comparisons were made with the Mann-Whitney U test.Comparisons of more than two groups were performed using the Kruskal-Wallis analysis.In case of significant differences in the results of the Kruskal-Wallis analysis, the Dunn-Bonferroni test was used for multiple comparisons.A p value of < 0.05 was considered statistically significant.An S-curve model was created for each parameter to analyze the variation of the parameters according to age group.

Results
A total of 409 patients were included in the study.Measurements could not be made because of artifact in 77 of the images, which were thus excluded from the study.The images (for the right and left eyes separately) of 332 patients were analyzed.Of the patients, 59.6% were male and 40.4% were female.When the patients were evaluated according to age group, 91 (27.4%) were between 1 month and 2 years old, 67 (20.2%) were between 2 and 4 years old, 128 (38.6%) were between 4 and 10 years old, and 46 (13.9%) were between 10 and 18 years old (Table 1).
When the median values of all measurement parameters included in the study (right and left ONSD, ETD, and ONSD/ETD) were compared between the right and left eyes, no statistically significant differences in ONSD proximal (p = 0.39), ONSD middle (p = 0.14), ETD (p = 0.20), ONSD proximal/ETD (p = 0.23), and ONSD middle/ETD (p = 0.27) were found (Table 2).When the same parameters were compared according to sex, the ONSD proximal, ONSD middle, and ETD median values of the males were found to be statistically significantly higher than those of the female patients (Table 3).
When the parameters included in the study were compared according to age group, the ONSD and ETD values differed significantly, but the ONSD proximal/ETD (right eye, p = 0.60; left eye, p = 0.49) and ONSD middle/ETD values (right eye, p = 0.91; left eye, p = 0.21) did not differ significantly (Table 4).In the multiple comparison test (Dunn-Bonferroni analysis), the ONSD proximal, ONSD middle, and ETD values did not show statistically significant differences between the 4-to 10-year-old and 10-to 18-year-old age groups (ONSD proximal: right eye, p = 0.20 and left eye, p = 0.62; ONSD middle: right eye, p = 1.00 and left eye, p = 1.00;ETD: right eye, p = 0.12 and left eye, p = 0.24).The comparisons revealed statistically significant differences between all the other groups (p < 0.05).An S-curve model was created for each parameter according to age group (Fig. 1).The median and interquartile range values of all the parameters included in the study according to sex, age group, and right and left eyes are presented in Table 5.

Discussion
We measured CT images instead of USG images in our study for several reasons.Brain CT is performed especially for patients with severe head trauma to evaluate for possible hematoma and fracture and the need for emergency surgery.ONSD can also be measured objectively on brain CT performed as indicated, and USG measurement of ONSD may not be needed.Ultrasonographic measurements are dependent on the practitioner, require experience, and can provide subjective results.
Helmke and Hansen [17] reported that the maximum enlargement of the ONSD was 3 mm from the optic nerve head in patients with increased intracranial pressure.In most studies, measurements were based on this distance.However, the location and distance to the eyeball of the optic nerve also change because of eye movements [32].Thus, we thought that it would be appropriate to measure ONSD at two different distances, 3 and 8-12 mm from the bulbus oculi, as the children included in our study were less likely able to keep their eyes fixed during imaging.We used a second measurement site because studies have reported that measurements at 8-10 mm might be more reliable [31,32].The length of the intraorbital optic nerve usually range from 15 to 24 mm, and the middle ONSD measurement site in our study was the middle part of the intraorbital optic nerve [32].
We know that measurement is affected by many factors other than eye movements [32].Therefore, we carefully selected the patients included in our study, with preference for those who did not have any problems that could affect intracranial pressure and the eyeball; whose height, weight, and head circumference were in the appropriate ranges; and whose neurodevelopment was normal (Supplementary Tables 1 and 2).We considered it appropriate to exclude racial/ethnic differences to reduce diversity and     ensure standardization, so we included only Turkish patients.
The meta-analysis revealed that apart from all these factors, the altitude of the place where the measurement was made and the individual patient characteristics also affected the ONSD measurement values.A previous study reported that the ONSD measurement increased by 0.14 mm for every 1000-m increase in altitude [38].The hospital where our study was conducted and the CT images were obtained is located at an altitude of 8 m (26 ft).For this reason, we think that the normal median values we obtained are the smallest values, and it is important to keep this detail in mind when measuring at high altitudes.
Several studies have investigated normal ONSD values in healthy children [20][21][22][26][27][28][29][30].Most of these studies used USG for the measurements [20-22, 27, 30] and evaluated mostly patients in a control group [20-22, 29, 30].Normal ONSD values obtained using USG range from 1.9 to 3.5 mm for ages ≤ 4 years and between 2.2 and 4 mm for ages > 4 years [20][21][22]30].Unlike other studies, the study by Steinborn et al. [26] showed that the normal ONSD value was 5.75 mm in 99 healthy children.While the cutoff ONSD measurement value for predicting increased intracranial pressure was reported to be 4.5 mm in some studies [21][22][23]25], this value was reported as normal in another study [26].Similarly to our study, two studies investigated normal ONSD values on CT.Gupta et al. [28] reported that the mean ONSD value was 4.78 mm in people aged 7-71 years.In the study by Kayadibi et al. [9], the mean ONSD values were 3.25 mm for ages 0-3 years, 3.60 mm for ages 3-6 years, 3.80 mm for ages 6-12 years, and 3.85 mm for ages 12-18 years.In our study, the proximal ONSD values ranged from 4.89 to 5.33 mm in the youngest age group (1 month to 2 years old) and from 5.75 to 5.80 mm in the oldest age group (10-18 years old).The results we obtained are similar to those of the study by Steinborn et al. [26].However, their study was conducted with 99 healthy children with a mean age of 12 years and did not discriminate for sex [26].
In our study, statistically significant differences in ONSD and ETD values were found between the age groups.However, in the multiple comparisons, no statistically significant differences in all parameters were found between the 4-to 10-year-old and 10-to 18-year-old age groups.These results suggest that no significant changes in ONSD and ETD values occur from ages 4 to 18 years.Similar to our results, the ONSD values did not significantly change after the age of 4 years in another study [27].Contrary to these results, no significant changes were found after the age of 6 and 10 years in other studies [9,29,39].However, studies have also reported that ONSD values increase with age even in the adult age group [40,41].
In recent years, to resolve the dilemma arising from the variability of normal ONSD values, studies have investigated the ONSD/ETD ratio to create a constant value by proportioning the ONSD value to other measurements that vary with age [31][32][33][34][35].While the ONSD and ETD values we determined in our study differed significantly between the age groups, the ONSD/ETD ratio did not differ significantly between the age groups.This is one of our important findings that support that this ratio can be used in all age groups.Vaiman et al. [32] investigated ONSD measurements and ONSD/ETD ratios using brain CT in 400 healthy adults and found that the ONSD/ETD index for healthy adults is 0.19.Calculations were made from measurements made at 10 mm from the eyeball.In our study, the ONSD middle/ETD ratio (0.19-0.20) was similar to the value obtained in the previous study.Bartsikhovsky et al. [35] reported that an ONSD/ETD ratio of > 0.21 on brain CT in pediatric patients could predict patients with headache and papilledema with 82% sensitivity and 93% specificity.In the same study, 94 patients with a mean age of 11 years were specified as the control group, and their median ONSD/ETD ratio was 0.17.In the present study, ONSD was measured from the area where the ophthalmic vein crosses the optic nerve, and the middle ONSD approximately corresponds to the area where we made the measurement.In our study, the middle ONSD/ETD ratio (0.19-0.20) was higher than that obtained by Bartsikhovsky et al. [35].
Our study is the first to determine normal ONSD and ONSD/ETD values using brain CT in a completely healthy pediatric age group according to age and sex.When the parameters were evaluated according to sex, the ONSD and ETD values were found to be statistically significantly higher in the boys than in the girls.On the other hand, the ONSD/ETD ratio did not show a significant difference according to sex.A previous study conducted in the adult age group also supports our results [41].
We conducted this study because ONSD measurement is a method that correlates with intracranial pressure [3,[7][8][9][10][11].However, Biggs et al. [42] ultrasonographic ONSD measurement did not correlate with increased intracranial pressure in patients followed up in the pediatric intensive care unit.However, considering the variability of normal ONSD and ONSD/ETD values, future studies with more patients and diseases are needed to obtain a series of measurement values, not as a single measurement, to investigate whether measurement values change according to clinical situation.

Limitations
One limitation of this study is that the measurements were made using CT.The optic nerve and its sheath can be visualized in more detail using MRI.However, MRI access in pediatric emergency services is more difficult and requires sedation, which could delay diagnosis.
In our study, measurements were obtained from CT images taken with a single device.The values we obtained may differ from those obtained using different CT devices and other imaging modalities such as MRI.This warrants the conduct of a similar study with a larger population and other imaging methods.Evaluating normal values separately for each age group in a larger population may be more reliable.All measurements were performed by two radiologists with four and 15 years of experience, respectively.The outcomes were comparable.However, we did not account for intra-and inter-observer variability.This is yet another limitation of our research.Furthermore, our study was based on data from a single center and the ensuing results cannot represent the general Turkish population.

Conclusion
In our study, normal ONSD, ETD, and ONSD/ETD values were determined according to age and sex in healthy children.As the ONSD/ETD index did not statistically significantly differ according to age and sex, unlike the ONSD and ETD measurements, diagnostic studies for traumatic brain injuries can be performed using the index.It would be more accurate not only to act according to the determined normal values but also to evaluate each patient in terms of age, sex, and accompanying pathologies and to make treatment decisions based on a progression of measurements during the follow-up period instead of a single measurement.

Fig. 1 5
Fig. 1 Analysis of the distribution of measurement values (ONSD, ETD, and ONSD/ETD) according to age using the S-curve model

Table 1
Demographic characteristics of the patients

Table 2
Comparison of the median and IQR values of ONSD, ETD, and ONSD/ETD index between the right and left eyeballs

Table 3
Comparison of the median and IQR values of ONSD, ETD, and ONSD/ETD index according to sex IQR interquartile range, ONSD optic nerve sheath diameter, ETD eyeball transverse diameter * p < 0.05

Table 4
Comparison of the median and IQR values of ONSD, ETD, and ONSD/ETD index according to age group (Kruskal-Wallis analysis) IQR interquartile range, ONSD optic nerve sheath diameter, ETD eyeball transverse diameter *