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Abstract

Background

Our objective was to assess optic nerve sheath diameter (a marker of elevated intracranial pressure) and optic disc elevation (a marker of papilledema) in pseudotumor cerebri syndrome using transorbital sonography.

Methods

The study was a prospective case-control study. We included patients with new-onset pseudotumor cerebri syndrome and matched healthy controls. All had fundoscopy, lumbar puncture with opening pressure and transorbital sonography. Sonography was assessed by a blinded observer.

Results

We evaluated 45 patients and included 23 cases. We recruited 35 controls. Optic nerve sheath diameter was larger in pseudotumor cerebri syndrome compared to controls (6.3 ± 0.9 mm versus 5.0 ± 0.5 mm, p < 0.001) and so was optic disc elevation (0.9 ± 0.4 mm versus 0.4 ± 0.1 mm, p < 0.001). The optimal cut-off point for optic nerve sheath diameter was 6 mm with a sensitivity of 74% for prediction of pseudotumor cerebri syndrome and 68% for prediction of elevated opening pressure. Specificity was 94%. The optimal cut-off point for optic disc elevation was 0.6 mm. Sensitivity was 100% and specificity 83% for prediction of pseudotumor cerebri syndrome.

Conclusion

Optic disc elevation and optic nerve sheath diameter are increased in new-onset pseudotumor cerebri syndrome. Optic disc elevation achieved high specificity and excellent sensitivity for diagnosis of pseudotumor cerebri syndrome. Transorbital sonography (TOS) is a potential, non-invasive screening tool for pseudotumor cerebri syndrome in headache clinics.

Keywords

Pseudotumor cerebri diagnostic imaging intracranial pressure optic disk optic nerve

Introduction

Pseudotumor cerebri syndrome (PTCS) is the umbrella term for a neuro-ophthalmological disorder characterized by elevated intracranial pressure (ICP) without apparent brain pathology (1,2). Most frequently, PTCS occurs in an idiopathic form (idiopathic intracranial hypertension or IIH), but it can also be a rare side effect to medication or a complication to several conditions (2). The underlying disease mechanisms are unknown, but the idiopathic form is intricately linked with obesity, female sex and pre-menopausal age (2).

PTCS is diagnosed according to the revised Friedman criteria. Definite PTCS is defined as presence of papilledema and elevated lumbar puncture opening pressure (OP) ≥25 cm cerebrospinal fluid (CSF) with normal neuroimaging, CSF contents and neurological examination (1). Unfortunately, overdiagnosis occurs in up to 40% of cases (3), primarily due to difficulty in assessment of papilledema. Common optic disc anomalies, e.g. optic disc drusen, may be misinterpreted as papilledema (4). The gold standard for measuring ICP is via an intracranial probe, however this cannot be done routinely (5). OP measured by lumbar puncture (LP) is less invasive but does carry a risk of infection, bleeding and post-dural puncture headache, and to achieve reliable measurements the procedure should be standardized. Obesity further complicates the use of LP, and 47% of patients with IIH are anxious about future procedures (6).

Thus, there is an unmet need for valid, bedside diagnostic tests to assess PTCS, papilledema and ICP. These would be particularly relevant in emergency departments or headache clinics where neuroophthalmological or neurosurgical expertise may not be readily available. Transorbital sonography (TOS) is an ocular imaging technique, which is emerging as a safe, convenient, non-invasive test to investigate ICP and papilledema (7 –9). Located superficially, and filled with fluid, the eyes are well suited for sonography. The meninges and the CSF around the optic nerves are directly connected with the subarachnoid space surrounding the brain. Therefore, the diameter of the optic nerve sheath (ONSD) has been hypothesized to fluctuate with ICP (10). Furthermore, TOS allows visualization and quantification of the optic disc, including measurement of optic disc elevation (ODE), a marker for papilledema (7,9). For years TOS was also the gold standard for diagnosis of optic disc drusen, a common cause of pseudopapilledema (4). However, the existing studies on PTCS and TOS leave several key questions unanswered. The diagnostic value is highly variable between studies, the methodology varies in terms of exact cursor placement, timing of measurements in relation to OP and the use of matched controls (7,11 –16). ODE has only been investigated in few studies of PTCS, none of which investigated diagnostic cut-off points (7,12,14,17 –19).

Our objective was to validate TOS using a standardized technique in a well-defined cohort of new-onset PTCS (11). Uniquely, we included OP and fundoscopy in all participants. The primary outcomes were ONSD and ODE in PTCS compared to healthy controls. Secondary outcomes were correlation between ONSD and OP, correlation between TOS-ODE and OCT-ODE (ODE measured by optical coherence tomography [OCT]), changes in ONSD after LP and the diagnostic value of TOS in prediction of the correct diagnosis and elevated ICP.

Methods

Study subjects

Patients aged 18–65 years, with clinically suspected new-onset PTCS, were consecutively recruited at a tertiary referral center for PTCS (Danish Headache Center and Department of Ophthalmology, Rigshospitalet, February 2020–May 2021). Age, sex and BMI matched healthy controls were recruited via social media (Figure 1). Exclusion criteria were pregnancy, previous PTCS, ongoing treatment to lower ICP and headache disorders other than migraine and tension-type headache. Exclusion criteria in the control group were the same, but supplemented with no ophthalmological, neurological, or other significant disorders and ≤1 headache day per week.

Figure 1.

Inclusion of patients.

Patients and controls completed a standardized diagnostic work-up: structured medical interview, neurological examination, LP with CSF analysis and measurement of OP before and after CSF withdrawal. A standard issue manometer was used to measure OP in the relaxed participant, placed in left lateral decubitus position, legs and neck extended. Fundoscopy, using a scanning laser ophthalmoscope (SLO, Compass©, Padua, Italy), was used to exclude papilledema in controls. Patients underwent diagnostic neuroimaging (cerebral and orbital MRI and CT/MRI venography) and were examined by a consultant neuro-ophthalmologist (fundoscopy including photographs and Frisén grading (20), visual fields and acuity, OCT and Ishihara color plates). The final diagnosis was either confirmed PTCS (1), according to the diagnostic criteria, or PTCS was excluded, and an alternative diagnosis was made. Patients with confirmed PTCS were then compared to healthy controls.

The study was approved by Committee on Health Research Ethics, Capital and Southern Region of Denmark (H-19029542, S-20170058) and conducted in accordance with the Helsinki convention and Danish data laws. Participants gave written, informed consent before inclusion.

Transorbital sonography

Transorbital sonography was performed by a medical doctor (JJK) who had previous experience with sonography. Before the study JJK received 2 hours of training in TOS from an experienced physician (VVC) and completed 10 practice scans. A Logiq E9 (GE Healthcare, Chalfont St Giles, UK) machine was used (linear transducer, 4–15 MHz). Mechanical index was <0.3 and thermal index <1 to avoid temperature increase in the tissue (11). The probe was placed temporally on the upper eyelid, after application of water-based gel, to visualize the optic nerve sheath and the optic disc in the transverse plane. If necessary, the participant was asked to move their eye slightly to achieve the best possible alignment and reduce artifacts. Both eyes were examined with the participant in a supine position (headrest in a 30-degree angle) 10 minutes before and 30 minutes after LP. The operator selected and saved three images per eye before and after LP. Subsequently VVC measured the ONSD and ODE on all images according to pre-specified instructions (described below). VVC was blinded to participant identity and results of the diagnostic work-up. The mean of three measurements per eye was used. According to convention ONSD was measured 3 mm behind the globe at a perpendicular axis to the optic nerve (Figure 2) (11,18). The diameter was defined as the distance between the external borders of the subarachnoid space (Figure 2 depicts the hypoechogenic subarachnoid space with CSF, and the optic nerve, bordered by the hyperechoic dura mater and periorbital fat tissue) (11,18).

Figure 2.

Optic nerve sheath diameter in a patient with PTCS (before and after lumbar puncture) and in a healthy control. ONSD, optic nerve sheath diameter; CSF, cerebrospinal fluid; PTCS, pseudotumor cerebri syndrome.

The optic disc and retina appear hyperechoic on ultrasound, whereas the vitreous body is hypoechoic (Figure 2). TOS-ODE was defined as the distance between the retina and the dome of the optic disc measured at a perpendicular axis to the optic nerve. Maximum zoom was used to obtain a precise measurement of even small optic discs (Figure 3) (18).

Figure 3.

Measurement of optic disc elevation demonstrated in a patient with PTCS and a healthy control before lumbar puncture. PTCS, pseudotumor cerebri syndrome; ODE, optic disc elevation.

Optical coherence tomography

Spectral-domain OCT (Heidelberg Spectralis®, Heidelberg Engineering GmbH, Heidelberg, Germany) was performed in all patients with PTCS. The thickness map function was used to determine the maximum OCT-ODE measured from Bruch’s membrane to inner limiting membrane. The OCT-ODE was compared with TOS-ODE in PTCS patients. As OCT was not the main focus of the study, we did not measure OCT-ODE in controls.

Statistical analyses

The data was described using means with standard deviation (SD) for normally distributed data and medians with interquartile range (IQR) for non-normally distributed data. For comparison of cases and controls we used the Welch t-test (normally distributed data), Wilcoxon rank-sum (non-normally distributed data) or Fishers exact test (categorical data) Simple linear regression was used to evaluate the relationship between ONSD and OP, ODE and OP, TOS-ODE and OCT-ODE. R² and p-values were reported to assess variance, model fit and significance, Pearson’s r was used to assess the strength of the correlation. For determination of diagnostic potential receiver operating characteristic (ROC) curves were created and area under the curve (AUC) calculated. Optimal cut-off points were determined according to Youden weighing sensitivity and specificity equally (21). This was done for two predictions: PTCS diagnosis yes/no and OP ≥ 25 cm CSF yes/no.

Previous studies have shown significant results for our primary outcome with 15–22 participants in each group (7,12,13,19). We therefore planned to include at least 20 participants in each group. Significance level was determined as p < 0.05. Statistical analyses were performed using R software (version 3.6.0).

Results

Study subjects

In total 45 patients were evaluated, 6 were excluded and 39 included (Figure 1). We included 35 healthy controls. After the diagnostic work-up 23 patients were classified as PTCS with papilledema, 21 with IIH and 2 with PTCS secondary to tetracycline exposure and systemic lupus erythematosus (1). None had PTCS without papilledema, but 2/23 patients had probable PTCS (papilledema, OP < 25 cm CSF¹). In the remaining 16 patients PTCS was excluded (1). Sub-group analyses found that ONSD and ODE were similar to healthy controls in this group (ONSD 5.1 ± 0.5 mm, ODE 0.4 ± 0.2 mm, specific diagnoses listed in Figure 1). Patients with PTCS and controls were similar in terms of sex (100% versus 97% female, p = 1), age (30 versus 29 years, p = 0.6) and BMI (37 versus 37, p = 1) (Table 1). OP was higher in PTCS than in controls (40.5 ± 12.8 versus 19.5 ± 4.8 cm CSF, p < 0.001). Papilledema was present in all patients with PTCS. In 34.8% papilledema was mild (Frisén grade 1–2, worst eye) and in 60.9% it was moderate-severe (Frisén grade 3–5, worst eye) (20).

Table 1.

Participant characteristics.

	PTCS groupn = 23	Healthy controls (BMI, age, sex matched) n = 35	p value
Female sex, n (%)	23 (100)	34 (97.1)	1
Age, mean (SD)	30.1 (8.8)	29.1 (6.1)	0.6
BMI, mean (SD)	36.7 (6.8)	36.8 (6.5)	1
Opening pressure cmCSF, mean (SD)	40.5 (12.8)	19.5 (4.8)	<0.001
End pressure cmCSF, mean (SD)	17.2 (3.2)	13.9 (3.5)	<0.001
Papilledema present, n (%)	23 (100)	0 (0)	–
Frisén grade 1–2, worst eye, n (%)	8 (34.8)	–	–
Frisén grade 3–5, worst eye, n (%)	14 (60.9)	–	–
Grading not possible^a, n (%)	1 (4.3)	–	–
Optic disc elevation on OCT^b, μm, mean (SD)	1018.2 (237.6)	–

^aFunduscopy images not saved and specific grade not documented.

^bMeasured using the thickness map function (Heidelberg Eye Explorer) to determine the maximum elevation measured from Brüchs membrane to inner limiting membrane.

PTCS: pseudotumor cerebri syndrome; CSF: cerebrospinal fluid; OCT: optical coherence tomography.

Evaluation of ONSD and ODE

Pre-LP ONSD was larger in PTCS compared to controls (6.3 ± 0.9 mm versus 5.0 ± 0.5 mm, p < 0.001) and so was ODE (0.9 ± 0.4 mm versus 0.4 ± 0.1 mm, p < 0.001). Simple linear regression was done to test if ONSD significantly predicted OP. The correlation was moderate (r = 0.59, R² = 0.35, p < 0.001), Figure 4a). Likewise, we found a moderate correlation between ODE and OP (r = 0.77, R² = 0.59, p < 0.001, Figure 4b) as well as between TOS-ODE and OCT-ODE in patients with PTCS (r = 0.70, R² = 0.49, p < 0.001, Figure 4c). After LP a significant decrease in ONSD was observed in both groups, but it was three times larger in PTCS (14.0% versus 4.7%, p < 0.001) (Table 2). ODE was evaluated in relation to Frisén grade, and we found a significant increase in ODE with increasing Frisén grade (p < 0.001, Figure 5). There was no change in ODE after LP in either group.

Figure 4.

Relationship between sonographic measurements, OP and OCT-ODE. (a) Shows the linear relationship between ONSD, measured immediately before lumbar puncture, and opening pressure in patients and controls. (b) Shows the linear relationship between TOS-ODE, measured immediately before lumbar puncture, and opening pressure in patients and controls. (c) Shows the linear relationship between ODE as measured by TOS and OCT in patients with PTCS. ONSD, optic nerve sheath diameter, worst eye; CSF, cerebrospinal fluid; TOS-ODE, transorbital sonography, optic disc elevation; OCT-ODE, optical coherence tomography, optic disc elevation; PTCS, pseudotumor cerebri syndrome.

Table 2.

Measurement of ONSD and ODE (transorbital sonography).

	PTCS group n = 23	Healthy controls (BMI, age, sex matched) n = 35	p value
ONSD
Worst eye mm, mean (SD)	6.3 (0.9)	5.0 (0.5)	<0.001
Right eye mm, mean (SD)	5.9 (0.9)	4.8 (0.5)	<0.001
Left eye mm, mean (SD)	6.1 (0.9)	4.7 (0.6)	<0.001
Post-LP, worst eye mm, mean (SD)^a	5.3 (0.7)	4.7 (0.5)	–
Mean decrease in ONSD after LP, % (SD)	14.0 (10)	4.7 (8.4)	<0.001
ODE
Worst eye mm, median (IQR)	0.9 (0.4)	0.4 (0.1)	<0.001
Right eye mm, median (IQR)	0.8 (0.3)	0.4 (0.2)	<0.001
Left eye mm, median (IQR)	0.8 (0.4)	0.4 (0.2)	<0.001
Post-LP, worst eye mm, median (IQR)	0.9 (0.2)	0.4 (0.1)	<0.001

^aDifference after lumbar puncture is significant for comparison within both groups (paired t-test: p < 0.01 for controls and p < 0.001 for PTCS).

PTCS: pseudotumor cerebri syndrome; ONSD: optic nerve sheath diameter; ODE: optic disc elevation; LP: lumbar puncture.

Figure 5.

Relationship between TOS-ODE and degree of papilledema. TOS-ODE increases with increasing Frisén grade (Kruskal-Wallis test, p < 0.001). The median ODE is 0.4 ± 0.1 mm for no papilledema (grade 0), 0.8 ± 0.2 mm for grade 1–2 papilledema and 1.0 ± 0.2 mm for grade 3–5 papilledema. TOS-ODE, transorbital sonography, optic disc elevation.

Optimal cut-off points for ONSD and ODE

For ONSD a diagnosis of PTCS and ICP-elevation was best predicted by a 6 mm cut-off (Table 3, Figure 6). AUC was 0.88 (0.77–0.98) for prediction of diagnosis and 0.78 (0.63–0.92) for prediction of elevated OP. Sensitivity was 74% and 68% respectively. Specificity was 94%.

Table 3.

Optimal Cut-Off Points for ONSD and ODE.

	ONSD, worst eye	ODE, worst eye
Prediction of diagnosis PTCS with papilledema
AUC, 95% CI	0.88 (0.77–0.98)	0.98 (0.96–1)
Youden index	0.68	0.83
Optimal cut-off point, mm	6.0	0.6
Sensitivity, % (95% CI)	74 (52–90)	100 (85–100)
Specificity, % (95% CI)	94 (81–99)	83 (66–93)
Prediction of elevated opening pressure (≥25 cm CSF)
AUC, 95% CI	0.78 (0.63–0.92)	–
Youden index	0.61	–
Optimal cut-off point, mm	6.0	–
Sensitivity	68 (46–85)	–
Specificity	94 (80–99)	–

ONSD: optic nerve sheath diameter; ODE: optic disc elevation; PTCS: pseudotumor cerebri syndrome; AUC: area under the curve; CSF: cerebrospinal fluid.

Figure 6.

ROC curves for optic nerve sheath diameter and optic disc elevation. ROC, receiver operation curve; AUC, area under the curve; OP, opening pressure.

ODE best predicted PTCS at a cut-off of 0.6 mm (Table 3, Figure 6) and AUC was 0.98 (0.96–1). Sensitivity was 100% and specificity 83%.

Discussion

We present the first prospective case-control study of TOS in patients with new-onset PTCS which includes LP OP and fundoscopy in both patients and controls. Our results demonstrate that ONSD and ODE are significantly larger in PTCS than in controls. We found a moderate linear correlation between ONSD and OP, and a three times larger post-LP reduction of ONSD in patients versus controls. Based on these clear findings we propose diagnostic cut-off points and provide recommendations for use of TOS in suspected PTCS.

Our findings are in line with previous studies in which mean ONSD ranged from 5.2–6.8 mm in PTCS compared to 4.1–5.7 mm in controls (7,12 –19). Most studies place mean ONSD in PTCS above 6.0 mm (7,12,14,16 –19) and in healthy controls ≤5.5 mm (12,13,15 –18). Mean ODE in PTCS range from 0.6–1.3 mm, but these studies did not measure ODE in controls, and therefore could not provide measures of diagnostic accuracy for ODE (7,12,14,18,19).

While we found a highly significant linear correlation between ONSD and OP, the strength of the correlation was moderate (r = 0.59, R² = 0.35). This reflects a variation in OP, which cannot be explained by differences in ONSD, and is likely due to physiological and anatomical conditions. Even with a standardized technique, performed by the same person, as done in our study, OP remains a snapshot, surrogate measure of the true ICP. Studies of TOS-ONSD and ICP measured by intracranial devices has found stronger correlations (r = 0.73 (22)). The interval of 25–30 cm CSF is a grey zone as moderately elevated OP can be incidental, and has been reported in healthy individuals with obesity (2). This is also illustrated in our cohort as three healthy obese controls had OP > 25cm CSF despite our standardized approach and careful screening for symptoms of PTCS. Anatomical variations in the optic nerve sheath, or the trabeculated subarachnoid space, may also play a role, as some may withstand ICP fluctuations better than others, and as there is a maximum distensibility of the sheath (23). Likewise, bony structures and soft tissue tightly surround the optic nerves on their course to the orbit, and these anatomical limits may differentially restrict CSF-flow. Previous studies have shown conflicting results as to whether ONSD and OP correlate at all, which is likely explained by differences in study design (7,13,14). Studies which demonstrated no correlation either did not include OP in controls, included <20 measurements of OP in total, measured OP at separate time points from ONSD (e.g. ONSD measured one day after CSF withdrawal) or included patients with chronic PTCS (7,15 –19). Furthermore, up to four different marker positions for measurement of ONSD were described in a review of published studies (11).

The diagnostic value of TOS

We evaluated two diagnostic questions in relation to TOS – diagnosis of PTCS and elevated OP ≥ 25 cm CSF (ONSD). We demonstrate that ODE was the best predictor of diagnosis. The cut-off point was 0.6 mm and even though our cohort includes patients with mild papilledema, which can be difficult to spot using direct ophthalmoscopy (24), sensitivity was excellent. Specificity was high and AUC close to 1. ONSD achieved moderate sensitivity, but high specificity, for prediction of diagnosis and ICP elevation with a cut-off point of 6.0 mm. No previous studies have investigated prediction of elevated OP, as normal OP was assumed, but never measured, in controls (7,12,14,16,18,19). Likewise, we found no studies investigating cut-off points or the diagnostic significance of ODE in PTCS.

In previous studies ONSD cut-off points range from 4.8–6.3 mm, but most studies place them at 5.8–6.3 mm. Sensitivity ranges from 73–95% and specificity from 67–100%, with most studies placing both ≥80% (7,12 –19). This variation is also likely due to the heterogeneity of the study designs, and the methodological discrepancies in the sonographic technique, as described above. Additionally, control groups vary from patients with neurological/ophthalmological disease, e.g. migraine or nonarteritic anterior ischemic optic neuropathy (NA-AION), to healthy volunteers (7,13,14,17). Normal ICP in controls is assumed based on clinical evaluation, and only two studies match controls for age, sex and BMI (7,25). In previous studies the inclusion criteria for patients also vary considerably, e.g. in terms of length of disease, ongoing treatment for ICP-elevation and the timing of TOS and LP (7,12,14,17,19).

Recommendations for use of TOS in suspected PTCS

Based on our results we argue that TOS could potentially assist healthcare professionals in diagnosing PTCS. The excellent combination of high specificity and sensitivity, in patients with mixed degrees of papilledema, makes ODE a potentially ideal screening tool for PTCS. OCT-ODE has previously been shown to correlate with OP in IIH, and OCT of the optic disc is a well-recognized imaging modality used in the evaluation of papilledema. However, OCT is not readily available outside of ophthalmological clinics (26). In our study, TOS-ODE correlates well with OCT-ODE in PTCS patients (r = 0.70), and it can be done bedside, without pupillary dilation, and with minimal training, in settings where OCT is unavailable. The fact that superficial optic disc drusen, a common cause of pseudopapilledema, can often be revealed by TOS increases the relevance of this technique in suspected PTCS (4). It should be noted, however, that small, deeply lying optic disc drusen may be the source of considerable ODE, that cannot be detected by TOS (4).

ONSD is less sensitive and cannot be recommended as a single screening tool due to risk of underdiagnosis. However, measurement of ONSD can be a valuable addition in the work-up of PTCS. While ONSD is not a perfect marker for ICP, values above 6.0 mm strongly indicate elevated OP and PTCS, with only few false positives. It cannot be expected – regardless of study design – that ONSD and OP will show perfect linear correlation due to the previously described limitations of OP. This entails that clinical use of ONSD, like OP, must be interpreted relative to the patient’s history and clinical findings. With standardized training, TOS is easily learned by healthcare professionals with basic knowledge of anatomy and sonography (27). It is however strongly recommended that a specific protocol is followed to avoid variation caused by methodological discrepancies (11). This study exclusively used B-scan, as this technique is the most widely applied, and is easier to interpret for non-experts than A-scans. However, there is a lack of methodological studies regarding this, and further comparison of these methods and their reliability are needed (28,29).

TOS cannot replace neuro-ophthalmological assessment, and despite the high specificity of ONSD, it cannot replace diagnostic LP. Both remain crucial in the investigation of differential diagnosis, e.g. NA-AION, papillitis or infections (2). Furthermore, TOS cannot assess functional visual impairment or identify patients who need surgical interventions to save visual function (2). We did not include PTCS without papilledema or patients with optic disc atrophy after previous PTCS. ONSD is theoretically less likely to be affected by optic disc atrophy than ODE, as transmission of CSF to the subarachnoid space may not be affected by optic nerve axonal loss, making ONSD a possible target in patients with post-papilledema optic disc atrophy. Further longitudinal studies in large, unselected samples are needed.

ONSD and follow-up

Our demonstration that ONSD is dynamic and responds to fluctuations in OP, particularly in PTCS, is potentially useful in monitoring ICP-changes non-invasively. Despite a better correlation with OP ODE was not dynamic. This is in line with the fact that papilledema, once developed, can take weeks to resolve even after surgical interventions to reduce ICP (30). Furthermore, we did not include patients with optic disc swelling caused by other conditions than elevated ICP (e.g. inflammatory). Thus, the correlation between ODE and OP in this study should be interpreted in the context of patients with papilledema due to elevated ICP.

Strengths and limitations

An important strength is inclusion of a well-defined group of patients, diagnosed by experts at a tertiary care center after a standardized work-up. All participants were scanned by the same operator, according to recent methodological recommendations (11), at a specific time point: time of diagnosis, prior to commencement of ICP-lowering therapy and LP. Measurements were done by a blinded observer. BMI, age, and sex matched healthy controls had a fundoscopic examination and a LP.

Previous studies have demonstrated excellent interobserver and interrater reliability (29,31,32) for TOS. Interestingly, studies have shown a fast learning curve with just 10–25 exams needed depending on previous sonography experience (27,33,34). Our study supports this as the operator had no previous experience with TOS and only had few hours of training. Nevertheless, the literature is sparse, and further methodological studies are needed.

Limitations include lack of patients with optic nerve atrophy, PTCS without papilledema and follow-up investigations. Patients were included from a tertiary center. While referral of all suspected PTCS cases is encouraged we cannot exclude that severely affected patients were referred more consistently. The specificity of TOS-ODE for diagnosis of PTCS decreases if the control group includes patients with ODE due to other conditions. Sensitivity remains high (supplementary material, Table 1, Table 2). Thus, TOS-ODE can screen for papilledema but, much like OCT, cannot differentiate the underlying cause and should not replace neuro-ophthalmological evaluation or CSF studies. Generalizability is probably highest in tertiary care headache centers and may also be affected by ethnicity (91% of patients in this study were of Caucasian descent). Studies of acute ICP-elevation, e.g. traumatic brain injury, find similar diagnostic accuracy estimates for ONSD (cut off 4.8-6.4 mm, sensitivity and specificity >85%) (8). However, due to the differences between acute and chronic ICP-elevation, our findings should primarily be interpreted in terms of chronic ICP-elevation. The anatomy of the subarachnoid space and the optic disc is not necessarily equally affected in chronic versus acute ICP elevation and papilledema is less frequent, or delayed, in acute ICP-elevation (35).

Conclusion

Convenient, non-invasive, bedside tests to investigate papilledema and ICP are needed to improve diagnosis of PTCS and patient care. TOS-ONSD and TOS-ODE has been investigated for this purpose, but cut-off points vary considerably, and the literature is sparse. We confirm that ODE and ONSD are significantly larger in PTCS compared to healthy controls and demonstrate a linear correlation between ONSD and OP, ODE and OP as well as OCT-ODE and TOS-ODE. The best predictor was ODE achieving high specificity and sensitivity for diagnosis of PTCS. ONSD achieved high specificity, but only moderate sensitivity, for diagnosis of PTCS and prediction of OP. Further, ONSD was highly dynamic and decreased after lumbar puncture. TOS cannot replace neuroophthalmological evaluation or diagnostic lumbar puncture, but ODE is potentially highly valuable as a screening tool for PTCS, particularly in settings without immediate access to neuroophthalmological expertise. ONSD can be used as a supplementary test in the diagnostic work-up for PTCS and is a promising non-invasive follow-up tool in PTCS.

Key findings

Optic nerve sheath diameter (ONSD) and optic disc elevation (ODE) measured by transorbital sonography are larger in PTCS than in matched controls.

The optimal cut-off point for ONSD was 6.0 mm and for ODE 0.6 mm.

ODE is highly sensitive and specific for PTCS and is a potential screening tool in settings without access to neuro-ophthalmological expertise.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024221094293 - Supplemental material for Transorbital sonography: A non-invasive bedside screening tool for detection of pseudotumor cerebri syndrome

Supplemental material, sj-pdf-1-cep-10.1177_03331024221094293 for Transorbital sonography: A non-invasive bedside screening tool for detection of pseudotumor cerebri syndrome by Johanne Juhl Korsbæk, Snorre Malm Hagen, Henrik W Schytz, Vlasta Vukovic-Cvetkovic, Elisabeth Arnberg Wibroe, Steffen Hamann and Rigmor H Jensen in Cephalalgia

Supplemental Material

sj-pdf-2-cep-10.1177_03331024221094293 - Supplemental material for Transorbital sonography: A non-invasive bedside screening tool for detection of pseudotumor cerebri syndrome

Supplemental material, sj-pdf-2-cep-10.1177_03331024221094293 for Transorbital sonography: A non-invasive bedside screening tool for detection of pseudotumor cerebri syndrome by Johanne Juhl Korsbæk, Snorre Malm Hagen, Henrik W Schytz, Vlasta Vukovic-Cvetkovic, Elisabeth Arnberg Wibroe, Steffen Hamann and Rigmor H Jensen in Cephalalgia

Footnotes

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JJK, SMH, HS, EAW, SH have no conflicts of interest to disclose. VVC has given lectures for Novartis. RHJ gave lectures for Pfizer, Eli-Lilly, ATI, Merck, TEVA, Novartis, Lundbeck and Allergan. Investigator in clinical trials with ATI, Eli-Lilly, Novartis and Lundbeck. Director of Danish Headache Center, Lifting the Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen. Received research funding from University of Copenhagen, Rigshospitalet, ATI, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Lundbeck Foundation [R-276-2018-403-4]; and Candys Foundation [grant number 2015-146].

ORCID iDs

Johanne Juhl Korsbæk

Snorre Malm Hagen

Supplemental material

Supplemental material for this article is available online.

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