Optic Nerve Sheath Diameter and Retinal Artery Resistive Index Measurements with Bedside Ophthalmic Ultrasound in Pediatric Patients with Pseudotumor Cerebri Syndrome

Abstract

Pseudotumor cerebri syndrome (PTCS) is characterized by raised intracranial pressure (ICP) with no neuroradiological abnormalities. Ocular ultrasound has been in use to measure optic nerve sheath diameter (ONSD), and retinal artery Doppler indices have been used for indirect assessment of ICP by pediatric intensivists. Here, we aimed to evaluate the correlation of the lumbar puncture (LP) opening pressure with the ultrasonographic ONSD and retinal resistive index (RRI) measures in patients with PTCS. And we wanted to find an answer to the following question: Can ultrasonographic ONSD measures serve as a follow-up tool in patients with PTCS? A prospective, single-center, case–control study was performed by pediatric intensive care and pediatric neurology departments. A total of 7 patients with PTCS were evaluated as patient group and 15 healthy children were evaluated as control group. The mean age of patient group was 138.8 ± 43.7 months. The mean right ONSD was 6.7 ± 0.5 mm and the mean left ONSD was 6.7 ± 0.6 mm. The mean right RRI value was 0.73 ± 0.03 and the mean left RRI was 0.73 ± 0.09. For the patient group, ONSD and RRI values of both eyes were statistically significant higher values than for the control group. The mean LP opening pressure was 56.57 ± 16.36 cmH ₂ O. We detected strong, positive, and statistically significant correlations between the LP opening pressure and ONSD baseline measures for both the right eye ( r  = 0.882, p  = 0.009) and the left eye ( r  = 0.649, p  = 0.004). There was no correlation between opening pressure in LP and RRI measurements. We detected a statistically significant decrease in the right ONSD and left ONSD values and visual analog scale scores at the third-month follow-up. Our study results demonstrate that ultrasonographic ONSD measurements can be used as a noninvasive tool for assessment of the ICP at first admission and can be used as a follow-up tool in PTSC patients.

Introduction

Idiopathic intracranial hypertension (IIH) is commonly known as pseudotumor cerebri syndrome (PTCS), which is characterized by raised intracranial pressure (ICP) with no neuroradiological abnormalities. ¹ Patients with PTCS typically present with persistent severe headache, nausea, blurred vision, and vomiting. Both cranial computed tomography (CT) and magnetic resonance imaging (MRI) findings and the composition of cerebrospinal fluid are normal. Increased opening pressure in lumbar puncture (LP) with normal cerebrospinal fluid composition supports a diagnosis of PTCS. ²

The use of bedside ultrasonography by clinicians other than radiologists is becoming increasingly common. ³ Pediatricians commonly utilize ultrasound imaging especially in emergency and intensive care departments. ^{3 4} Ocular ultrasound has been in use to measure the optic nerve sheath diameter (ONSD) for the indirect assessment of ICP. ⁵ The subarachnoid space around the optic nerve is continuous with the subarachnoid space. ⁶ Because of the direct communication, pressure changes in the intracranial compartment are readily transmitted to the intraorbital subarachnoid space around the optic nerve. ⁷ It has been demonstrated that dilatation of the optic nerve sheath is an early manifestation of ICP rise. ⁴ Ultrasound technology allows taking noninvasive, repetitive, and radiation-free images of the optic nerve sheath. ^{8 9}

Doppler ultrasound waveform indices of the ophthalmic and central retinal arteries can be utilized to evaluate any increases in ICP instead of performing a transcranial Doppler ultrasound imaging. ⁹ With ultrasonography, the central retinal and ophthalmic arteries can be readily visualized deep in the orbital cavity, in the area where they cross the optic nerve. ¹⁰ The resistive index is a widely used measure of resistance to arterial flow and is calculated using the color Doppler images. ¹¹

The primary aim of our study was to evaluate the correlation of the LP opening pressure with the ultrasonographic ONSD or retinal resistive index (RRI) measures at admission. The secondary aim was to compare ophthalmic ultrasound measurements with a healthy control group. Finally, the third aim was to evaluate the correlation of the ultrasound parameters and clinical signs of patients after treatment, and to find an answer to the following question: Can ultrasonographic ONSD measures serve as a follow-up tool in patients with PTCS?

Materials and Methods

Patients

This prospective, single-center, case–control study was performed by pediatric intensive care and pediatric neurology departments. A total of 7 pediatric patients with PTCS were prospectively enrolled in the study over a 5-month period. Fifteen children without increased ICP symptoms were enrolled from the general pediatric policlinic. Patients were diagnosed with PTCS according to the current diagnostic criteria. ¹² Each participant underwent general medical, ophthalmological, and neurological examinations, basic and advanced laboratory investigations, and an MRI or a CT scan of the brain. Demographic information about age, gender, weight, height, and body mass index (BMI) of the patients was collected. The presence of papilledema was recorded. LP was performed in all of the patients by the same pediatric neurology fellow in the lateral decubitus position (N.O.). The diagnosis of PTCS was made when the cerebrospinal fluid opening pressure was 25 cm or greater. The intensity of the headache of the patients was recorded using the visual analog scale (VAS) (the intensity of headache was scored in the range from 0 to 10). ¹³

The study was approved by the ethics committee of Faculty of Medicine, Çukurova University (January 2019; 84). The study was performed in compliance with the ethical standards of the 1964 Declaration of Helsinki. Written informed consents were obtained from the parents of the patients.

Ophthalmic Ultrasonography Method

Ophthalmic ultrasound was performed by one of the investigators when the patients were in the supine position. The examining investigator was a pediatric intensive care fellow (N.A.) who was trained for point-of-care ultrasound use by Turkish Pediatric Intensive Care Society and experienced in ophthalmic ultrasound with more than 300 measurements. The ultrasonographic evaluation of ONSD and Doppler indices of the retinal vessels were performed with an L14-6s linear 5.1 to 12.5 MHz probe (Resona 7; Mindray Bio-Medical Electronics Co., Ltd., China). B-mode ultrasound was used for the evaluation. Both the left and the right eyes of all patients were evaluated to assess ONSD and the resistive indices of the central retinal arteries by using axial images for both the two groups. Measurements were performed 30 minutes before LP for patient group. The ONSD was measured 3 mm posterior to the disc when the lens was positioned centrally ( Fig. 1 ). At least two repeated measurements were taken for both right and left ONSDs and the mean value was reported.

Fig. 1.

Ultrasonographic optic nerve sheath diameter measurement method.

Doppler ultrasonographic assessments of the central retinal artery and the ophthalmic artery were performed using spectral waveforms ( Fig. 2 ). The central retinal artery and the vein were identified in combination inside the optic nerve using color Doppler sonography. The peak systolic velocity (PSV) and the end-diastolic velocity (EDV) values were measured and the RRI value was calculated automatically by the sonography machine (RRI = [PSV − EDV]/PSV). ^{7 14}

Fig. 2.

Doppler ultrasonographic assessments of the central retinal artery and the ophthalmic artery.

All of the patients were followed up monthly by the pediatric neurology department. The following parameters were recorded: headache intensity, BMI, currently received therapies and the third-month values of the ultrasonographic ONSD measurements, and the RRI.

The ultrasound system controls acoustic output not to exceed a mechanical index (MI) level of 1.9, a spatial-peak temporal average intensities (I _SPTA.3 ) of 50 mW/cm ² , or a thermal index (TI) value of 1.0. ^{15 16}

Statistical Analysis

IBM SPSS Statistics, version 20.0 statistical software was used to analyze the data. The categorical variables, such as the descriptive data and the ultrasonographic measurements, were summarized as number and per cent. The numeric data were summarized as mean and standard deviation (median and minimum–maximum values were used where appropriate). Comparisons between the baseline and follow-up data were assessed with the nonparametric Wilcoxon's signed-rank test. Correlations were assessed with the Spearman's test. The level of statistical significance was set at p  < 0.05.

Results

The mean age of our patients was 138.8 ± 43.7 (84–204) months. The mean BMI was 21.18 ± 8.23 kg/m ² . The demographic characteristics of the patients are shown in Table 1 . The mean right ONSD was 6.7 ± 0.5 mm and the mean left ONSD was 6.7 ± 0.6 mm. The mean right RRI value was 0.73 ± 0.03 and the mean left RRI was 0.73 ± 0.09. The patient group ONSD and RRI values of both eyes were statistically significant higher values than for the control group ( Table 2 ). The mean opening pressure in LP was 56.57 ± 16.36 (43–88) cmH ₂ O. In a correlation analysis, we detected a strong, positive, and statistically significant correlation between the opening pressure at LP and ONSD baseline measures for both the right eye ( r  = 0.882, p  = 0.009) and for the left eye ( r  = 0.649, p  = 0.004). There was no correlation between opening pressure in LP and RRI measurements. Ophthalmological examinations showed papilledema in four patients (57.1%) and blurred optic disc margins in the other three (42.9%) patients. The mean VAS score of the patients at baseline was 8.43 ± 0.97 (7–10). The most common complaint at admission was severe headache, which was present in all of the patients. Other complaints included diplopia in two patients, pain behind the eye in two patients, and tinnitus in one patient. Bradycardia was detected in the patient with the highest recorded opening pressure. The most commonly administered first-line treatment option in our patients was acetazolamide. Five patients needed repeated LPs for withdrawing the cerebrospinal fluid as a therapeutic maneuver. Then, topiramate was added to the treatment regimen in these five patients due to the presence of refractory symptoms and recurrent LP requirements. Two patients required the placement of lumboperitoneal shunts because their symptoms were resistant to medical treatment. There was a statistically significant correlation between VAS at admission and LP opening pressure in the patient group ( r  = 0.662, p  = 0.005). We detected a statistically significant decrease in the right ONSD values, left ONSD values, and VAS scores at the third-month follow-up. The differences between the baseline and third-month follow-up values of the ultrasonographic measurements and VAS scores are listed in Table 3 . The findings from the cranial CT scans and MRI were normal in the study patients.

Table 1. Demographic characteristics of the patients.

n  = 7	Mean ± SD Median (min, max)
Age (y)	11.57 ± 3.64
	11 (7–17)
Weight (kg)	45.08 ± 22.41
	38 (24–88)
Height (cm)	145.50 ± 10.76
	149.50 (125–155)
BMI (kg/m 2 )	21.18 ± 8.23
	21.20 (10.8–36.6)

Abbreviations: BMI, body mass index; max, maximum; min, minimum; SD, standard deviation.

Table 2. Comparison of ultrasonographic measurements of PTCS patients and control group.

	PTCS group n  = 7 Mean ± SD Median (min, max)	Control group n  = 15 Mean ± SD Median (min, max)	p -Value
Age (mo)	138.8 ± 43.7	118 ± 55.7	0.548
	132 (84–204)	132 (30–204)
Right ONSD (mm)	6.7 ± 0.5	5.3 ± 0.2	<0.001
	6.8 (6.1–7.9)	5.4 (4.8–5.7)
Left ONSD (mm)	6.7 ± 0.6	5.2 ± 0.3	<0.001
	6.7 (6.0–8.1)	5.3 (5.2–5.7)
Right PSV (cm/s)	18.12 ± 6.31	18.47 ± 10.2	0.503
	15.2 (13.51–31.52)	13.4 (7.7–36.97)
Left PSV (cm/s)	24.91 ± 13.92	17.31 ± 3.89	0.483
	19.52 (15.2–55.92)	17.4 (15.5–26.46)
Right EDV (cm/s)	4.81 ± 1.92	6.54 ± 3.4	0.481
	4.5 (3–9)	6 (2.8–12.76)
Left EDV (cm/s)	6.41 ± 3.76	6.26 ± 1.9	0.332
	5.25 (3.38–13.89)	6.19 (3.38–8.70)
Right RRI	0.73 ± 0.03	0.63 ± 0.86	0.008
	0.73 (0.7–0.8)	0.64 (0.51–0.79)
Left RRI	0.73 ± 0.09	0.66 ± 0.08	0.042
	0.75 (0.53–0.82)	0.65 (0.52–0.80)

Abbreviations: EDV, end-diastolic velocity; max, maximum; min, minimum; ONSD, optic nerve sheath diameter; PSV, peak systolic velocity; PTCS, pseudotumor cerebri syndrome; SD, standard deviation.

Note: Bold represents statistically significant values ( p  < 0.05).

Table 3. Baseline and follow-up ultrasonographic measures and VAS scores.

n  = 7	Mean ± SD Median (min, max) Baseline	Mean ± SD Median (min, max) Third month follow-up	Mean difference ± SD	p -Value
VAS scores	8.43 ± 0.97	1.71 ± 2	6.71 ± 2.56	0.018
	8 (7–10)	1 (0–6)
Opening pressure at LP (cmH 2 O)	56.57 ± 16.36 48 (43–88)	–
Right ONSD (mm)	6.7 ± 0.5	6.0 ± 0.7	0.07 ± 0.04	0.017
	6.8 (6.1–7.9)	5.6 (5.5–7.7)
Left ONSD (mm)	6.7 ± 0.6	6.0 ± 0.8	0.07 ± 0.04	0.018
	6.7 (6.0–8.1)	5.8 (5.2–7.9)
Right PSV (cm/s)	18.12 ± 6.31	20.76 ± 8.8	−2.64 ± 8.88	0.398
	15.2 (13.51–31.52)	18.01 (11.26–37.34)
Left PSV (cm/s)	24.91 ± 13.92	19.31 ± 3.89	5.59 ± 15.34	0.463
	19.52 (15.2–55.92)	18.4 (15.5–26.46)
Right EDV (cm/s)	4.81 ± 1.92	6.34 ± 2.27	−1.5 ± 3.313	0.176
	4.5 (3–9)	5.63 (3.75–10.32)
Left EDV (cm/s)	6.41 ± 3.76	6.56 ± 1.9	−0.14 ± 4.98	0.310
	5.25 (3.38–13.89)	6.19 (3.38–8.70)
Right RRI	0.73 ± 0.03	0.69 ± 0.05	0.04 ± 0.06	0.128
	0.73 (0.7–0.8)	0.67 (0.62–0.78)
Left RRI	0.73 ± 0.09	0.65 ± 0.08	0.07 ± 0.08	0.063
	0.75 (0.53–0.82)	0.64 (0.52–0.80)

Abbreviations: EDV, end-diastolic velocity; LP, lumbar puncture; max, maximum; min, minimum; ONSD, optic nerve sheath diameter; PSV, peak systolic velocity; RRI, retinal resistive index; SD, standard deviation; VAS, visual analog scale.

Note: Bold represents statistically significant values ( p  < 0.05).

Discussion

PTCS is a clinical condition, which is diagnosed by excluding other neuro-ophthalmological diseases. The modified Dandy criteria are used for making the diagnosis of PTCS. ¹² In the revised diagnostic criteria of PTCS, Friedman et al ¹² suggested that patients can be subdivided into two groups: primary and secondary PTCSs. They determined IIH to be a subset within primary PTCS, while secondary PTCS includes patients with identifiable causes such as venous sinus thrombosis, medications, and medical conditions. The etiology of PTCS has not been completely clarified yet. LP is very important for both the diagnosis and treatment of this syndrome. ¹⁷ Increased opening pressure with normal cerebrospinal fluid composition in LP supports the diagnosis of PTCS. ¹²

Headache, nausea, blurry vision, and vomiting are the common clinical symptoms of PTCS. ¹⁸ Headache is the most common presenting symptom of PTCS in children and found in 57 to 87% of pediatric patients. ¹⁹ Headache can be constant or episodic, and it can be diffuse or focal. ¹⁷ In our study population, headache was detected in all of the seven patients.

Acetazolamide is started in most PTCS cases after the initial diagnosis as a first-line treatment. ²⁰ Topiramate might be effective and should be used for refractory PTCS cases before surgical treatments. ²¹ Both acetazolamide and topiramate are the inhibitors of the choroid plexus carbonic anhydrase. In medical treatment-refractory patients, surgical treatments are considered, including lumboperitoneal shunt placement. ²² Acetazolamide was the most preferred first-line therapy in our study. In five patients, who had refractory symptoms requiring repeat LPs, we added topiramate to the treatment regimen. A lumboperitoneal shunt was placed in two patients because their signs and symptoms were resistant to medical treatment.

Neuroimaging is required to confirm that the brain parenchyma is normal in patients with suspected PTCS. ²² In the cranial CT scans and MRI of the patients, we did not detect any lesions, which might cause the increased ICP. We did not observe any abnormal findings in the composition of the cerebrospinal fluid in none of our study patients.

When ICP is increased, the ONSD increases initially even before papilledema occurs. ¹¹ As a rapid and noninvasive method, the ultrasonographic ONSD measurement has become a new tool in monitoring elevated ICP for pediatricians in emergency and intensive care departments. ⁷ It is already well known that ocular ultrasound has been used for the indirect assessment of ICP by measuring ONSD. ⁵ In previous studies, children younger than 10 years with >4 mm ONSD and children older than 10 years with >5 mm ONSD were considered to have signs of raised ICP. The sensitivity and specificity of ONSD in detecting an elevated ICP vary widely in the literature from 36 to 100 and from 38 to 100%, respectively. ^{5 23} In one pediatric study, Rehman Siddiqui et al ²⁴ reported the threshold of ultrasonographic ONSD values of >4.0 mm in infants, > 4.71 mm in children of 1 to 10 years, and >5.43 mm in adolescents older than 10 years to identify the raised ICP with sensitivity and specificity values of 100 and 60 to 66.7%, respectively. In another study, Irazuzta et al ²⁵ evaluated 13 pediatric patients with PTCS, reporting that the mean ONSD in the right eye was 5.5 ± 1.2 mm and the mean ONSD in the left eye was 5.4 ± 1 mm. Padayachy et al ²⁶ reported that the ONSD measurement with the best diagnostic accuracy for detecting an ICP ≥ 20 mm Hg over their patient population was 5.5 mm with a sensitivity of 93.2% and a specificity of 74%. Additionally, they concluded that transorbital ultrasound measurement of the ONSD is a reliable technique that demonstrated both a good relationship with ICP and high diagnostic accuracy for detecting raised ICP. In a similar study, Kerscher et al ²⁷ evaluated 72 pediatric patients who had invasive ICP catheters placed following ultrasound ONSD determination, and found that the optimal ONSD cutoff values were 5.28 mm for detecting ICP >15 mm Hg and 5.57 mm for ICP >20 mm Hg. In our study, we detected that mean value of right ONSD was 6.7 ± 0.5 mm and the mean left ONSD was 6.7 ± 0.6 mm. When we compared our patient group with a healthy control group, we detected statistically significant higher levels of ONSD and RRI measurements in the patient group for both eyes.

Our first aim in this study was to evaluate the correlation between ONSD and the opening pressure of LP in pediatric patients. We aimed to study this issue because of the small number of pediatric studies which use ultrasonographic ONSD measures in PTCS patients. One similar adult study included 22 PTCS patients with a mean age of 33 ± 11 years and the authors reported that they did not detect a correlation between ONSD and the opening pressure in LP at admission. ²⁸ In a study conducted on pediatric PTCS patients, the authors reported a correlation between ONSD and the opening pressure in LP. ²⁵ Although the number of patients in our study is small, we detected a strong, positive, and significant correlation between the opening pressure in LP and the ONSD measures of both the right and left eyes.

In recent years, the Doppler ultrasound assessment of ophthalmic arteries is one of the options for evaluating patients with increased ICP. ¹⁰ The anatomy of the central retinal vessels is well suited for Doppler sonography because the ultrasound probe is easily positioned parallel to the axis of the blood flow in the anterior portion of the optic nerve. ²⁹ After visualizing the arteries, the PSV and EDV can be measured with the color Doppler imaging. Then, the ultrasonography machine calculates an RRI value automatically. ¹⁴ It should be noted that the effect of elevated ICP on the ophthalmic vessel parameters has not been established yet because of the conflicting reports in the current literature. Ebraheim et al ³⁰ performed color Doppler ophthalmic ultrasound in 24 adult PTCS patients. However, they did not detect any significant differences in the parameters between the patient and healthy control groups. Furthermore, the observed changes in the patient group at the follow-up were insignificant. Following this study, Zweifel et al ³¹ and Tarzamni et al ¹⁰ reported similar results to those of Ebraheim et al's study. In contrast, Karami et al ³² demonstrated significant elevations in the transorbital Doppler parameters in PTCS patients. In the present study, we evaluated Doppler ultrasound waveform indices of the central retinal artery to detect increased ICP with PTCS patients. But we did not detect a significant correlation between the RRI values and the opening pressure of LP. Based on our findings, we did not find this method accurate enough, particularly compared with sonographic ONSD measurements.

There are only limited data in the literature about the use of ONSD measurements as a monitoring tool in PTCS. ³³ Lochner et al ²⁸ reported that ocular ultrasonography could be an additional diagnostic tool to monitor ICP in patients with PTCS and might be useful to measure the success of ICP treatment. In our study, we detected a statistically significant reduction in ONSD values in both eyes of the patients. However, the baseline and follow-up RRI values of the patients were not significantly different. Based on our study results, we would like to suggest that ophthalmic ultrasound can be an additional diagnostic tool for monitoring and follow-up of ICP and may be a useful tool to measure the success of treatment in patients with PTCS.

In the literature, there are many studies investigating the accordance of patients in pediatric age groups to pain scales. ^{34 35 36} Some authors find the VAS to be an appropriate measure for use by children aged 7 years and older, ³⁴ while others including Bailey et al ³⁵ reported problems with the accuracy of using VAS in children. Le May et al ³⁶ compared three self-reported pain scales in the pediatric emergency department and suggested that VAS, Faces Pain Scale-Revised, and Color Analog Scale all have strong psychometric properties in children aged between 6 and17 years presenting with a musculoskeletal injury, and therefore, can all be recommended for use in daily clinical practice. In this study, we used VAS for determining the intensity of headache. All of our patients in the study were older than 6 years (7–17 years) and all of them were able to correctly mark their responses.

For ophthalmic diagnostic applications, the U.S. Food and Drug Administration (FDA) has set maximum recommended exposure levels of MI, TI, and I _SPTA.3 . ¹⁵ These are very significant limits to provide safety of evaluation and protect the optic globe. There are different maximum limits for different types of ultrasonographic methods determined by FDA. In an article about safety consideration of ophthalmic ultrasound, Harris ¹⁶ recommended the safety limits for use of ophthalmic ultrasound. When applying the ophthalmic ultrasound to the patients, we have paid attention to the FDA's maximum recommended acoustic output levels and technical characteristics of our device.

We are aware that the major limitations of our study are the low number of patients. Although the limited number of patients, we have tried to improve our study in many aspects. We did not evaluated just ultrasonographic ONSD measurements. In addition to ONSD, we measured central retinal artery Doppler indices (RRI, PSV, end-diastolic velocity) and compared these measurements with a healthy control group's ultrasonographic measurements. We evaluated the correlation of the LP opening pressure with the ultrasonographic ONSD or RRI measures at admission. And we have given results about third-month follow-up of patients with PTCS. Therefore, we currently continue to carry out this present study. In the meantime, we have been aware of a limited clinical study in the literature about ONSD and RRI measurements with ophthalmic ultrasound especially in pediatric patients with PTCS. Thereby, we would like to draw attention to this noninvasive and useful imaging tool by presenting our preliminary results as a pilot study for pediatric age group.

To the best of our knowledge, the current study is one of the limited studies in the literature, examining the benefits of combined ultrasonographic ONSD measurements and Doppler indices of central retinal arteries in pediatric PTSC patients. In our study, we found a strong and positive correlation between the ONSD measures and the opening pressure of LP despite the small number of patients. Furthermore, our study results demonstrate that ultrasonographic ONSD measurements can be used as a noninvasive follow-up tool in PTSC patients. Also, we evaluated the central retinal artery Doppler indices, but we did not detect a correlation of the resistive indices with the opening pressure at admission or we did not find a significant difference in the resistive indices during the follow-up of the patients. Further large-scale studies are required to confirm our findings.