Utility of Ultrasound and Optical Coherence Tomography in Differentiating Between Papilledema and Pseudopapilledema in Children

Differentiating between papilledema and pseudopapilledema in children presenting with mild-to- moderate optic nerve head elevation is challenging. This study sought to determine which B-scan ultrasonography (BSUS) and optical coherence tomography (OCT) features, individually or in combination, are best able to differentiate between papilledema and pseudopapilledema in children.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Utility of Ultrasound and Optical Coherence Tomography in Differentiating Between Papilledema and Pseudopapilledema in Children Marybeth K. Farazdaghi, MD, Carmelina Trimboli-Heidler, CDOS, Grant T. Liu, MD, Arielle Garcia, COT, Gui-Shuang Ying, PhD, Robert A. Avery, DO, MSCE Background: Differentiating between papilledema and pseudopapilledema in children presenting with mild-tomoderate optic nerve head elevation is challenging. This study sought to determine which B-scan ultrasonography (BSUS) and optical coherence tomography (OCT) features, individually or in combination, are best able to differentiate between papilledema and pseudopapilledema in children. Methods: Children presenting with optic nerve head elevation of unknown etiology were eligible if they underwent BSUS and OCT performed by the same investigator. The absolute optic nerve sheath diameter (in millimeter) along with the presence/absence of a hyperreflective nodule(s) at the optic nerve head (indicative of druse) from BSUS was determined. The average circumpapillary retinal nerve fiber layer (cpRNFL), diameter of Bruch membrane opening, maximum papillary height, and the presence/absence of hyper-/hyporeflective lesions at the optic nerve head were calculated. Sensitivity and specificity were calculated to evaluate which BSUS and OCT imaging features, individually and in combination, accurately classified children as having papilledema vs pseudopapilledema. Results: One hundred eighty-one eyes from 94 children (mean age, 11.0 years; range, 3.2–17.9) were included; 36 eyes with papilledema and 145 eyes with pseudopapilledema. Among BSUS features, optic nerve sheath widening (.4.5 mm) demonstrated the best sensitivity (86%; 95% confidence interval [CI], 64%–96%) and specificity (88%; 95% CI, 79%–94%) for papilledema. Among OCT measures, cpRNFL thickness of $140 mm demonstrated the best sensitivity (83%; 95% CI, 66%–93%) and specificity (76%; 95% CI, 66%–84%) to identify papilledema. The presence of Division of Ophthalmology (MKF), The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and Departments of Neurology (GTL, RAA), and Ophthalmology (MKF, G-SY, RAA), The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Supported by P30 EY001583. The authors report no conflicts of interest. Address correspondence to Robert A. Avery, DO MSCE, Division of Ophthalmology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Blvd, Philadelphia, PA 19104; E-mail: averyr@email. chop.edu 488 both optic nerve sheath widening (.4.5 mm) and cpRNFL thickness of $140 mm reduced the sensitivity (72%; 95% CI, 52%–86%) but increased specificity (95%; 95% CI, 88%– 98%). Conclusion: BSUS (optic nerve sheath widening [.4.5 mm]) and OCT (cpRNFL thickness $140 mm), individually and collectively, have good diagnostic accuracy for differentiating between papilledema and pseudopapilledema. The presence of druse does not exclude the diagnosis of papilledema. Journal of Neuro-Ophthalmology 2021;41:488–495 doi: 10.1097/WNO.0000000000001248 © 2021 by North American Neuro-Ophthalmology Society T he evaluation of children presenting with mild-tomoderate optic nerve head elevation can be challenging. Once confirmed, benign etiologies of optic nerve head elevation such as optic nerve head drusen (ONHD) and peripapillary hyperreflective ovoid mass-like structures (PHOMS) (1,2), frequently referred to as pseudopapilledema, do not require the patient to undergo further invasive or costly tests. On the other hand, children with optic nerve head elevation believed to be secondary to elevated intracranial pressure (ICP, termed papilledema) must be evaluated with brain MRI and, in most cases, a lumbar puncture. In the absence of distinctive features to help differentiate between these 2 etiologies (i.e., hemorrhage, cotton wool spots, visible druse), additional ophthalmic imaging is frequently performed. B-scan ultrasonography (BSUS) has been used for decades to help determine whether optic nerve head elevation is secondary to druse vs other etiologies (3–8). The absolute optic nerve sheath diameter (ONSD, in millimeter), presence/absence of hyperreflective nodules at the ON head, ON sheath accentuation, and the “crescent sign” have been reported as helpful in differentiating between ONH elevation secondary to pseudopapilledema and true Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution papilledema (3–8). Device accessibility and ease of acquisition regardless of patient cooperation makes BSUS an appealing imaging modality for children—although certain features of ONHD may impede diagnostic accuracy (6,9– 11). Spectral-domain optical coherence tomography (OCT) has been recently used to differentiate between ONHD and papilledema. The circumpapillary retinal nerve fiber layer (cpRNFL) thickness and other OCT measures have demonstrated mixed results in their ability to differentiate between papilledema and ONHD (12–20). Beyond the automated OCT segmentation software, the diameter of Bruch membrane opening (BMO), maximum papillary height, and Bruch membrane deformation have also demonstrated mixed results in differentiating between causes of optic nerve head elevation (12–20). The purpose of this study was to investigate which individual and/or combined features from BSUS and OCT are best able to differentiate between papilledema and pseudopapilledema in children. METHODS This study was approved by the Children’s Hospital of Philadelphia (CHOP) Institutional Board of Review. All data were collected and stored according to Health Insurance Portability and Accountability Act guidelines. Children evaluated in the outpatient Neuro-Ophthalmology clinic between January 2016 and May 2018 at CHOP were retrospectively identified if they presented with optic nerve head elevation of unknown etiology. When the attending pediatric NeuroOphthalmologist (G.T.L. or R.A.A.) could not determine whether the optic nerve head elevation was secondary to pseudopapilledema vs elevated ICP (i.e., papilledema) and there were no other diagnostic features on dilated examination (i.e., vessel obscuration, hemorrhage, cotton wool spots, visible druse), the child underwent both BSUS and OCT performed by the same investigator (C.T.-H.). A diagnosis of papilledema was confirmed by a combination of MRI and lumbar puncture results as well as resolution of optic nerve head elevation after treatment. Pseudopapilledema was confirmed by the absence of change in optic nerve head elevation on follow-up examinations. B-Scan Ultrasonography A 12-MHz ultrasound (Accutome B-Scan Plus; Accutome Inc., Malvern, PA; axial resolution of 0.015 mm) was used for all children. Axial scans were also performed, along with vertical transverse (para-axial) scans, to obtain ONSD measurements. Subjects were classified as having ONHD regardless of superficial vs buried location. Fluid signs were categorized as the crescent sign/donut sign or as sheath accentuation/optic nerve doubling (21). The donut sign, or crescent sign, has been described as a hypoechoic, crescentic Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 area surrounding the round hypoechoic focus, which represents the optic nerve (3). ONSD was measured in each eye at 3 mm behind the posterior retina perpendicular to the optic nerve head. The average of 3 unique measures was used to calculate the final ONSD (22). An abnormally widened ONSD was defined as greater than 4.5 mm based on parameters for normal/ abnormal ON sheath diameter set forth in previous studies (22,23). BSUS acquisition and analysis was performed by the same investigator (C.T.-H.). Optical Coherence Tomography Spectral-domain OCT (Heidelberg Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany) was acquired in all subjects using the same protocol by the same investigator (C.T.-H.). The average cpRNFL thickness, diameter of BMO, maximum papillary height, and the presence/ absence of hyper-/hyporeflective lesions at the optic nerve head were calculated from traditional and enhanced-depth imaging (EDI) OCT protocols, respectively. The EDI protocol used 24 radial line scans with each b-scan averaged 9 times (automatic real time = 9) centered over the optic nerve head. All scans were reviewed, and when necessary, segmentation errors were corrected. Measurements of BMO diameter and maximum papillary height, performed by a masked investigator (M.K.F.), were obtained at 6 clock-hour locations on an optic nerve radial scan. BMO diameter was defined as the transverse diameter of the neural canal at the level of the Retinal Pigment Epithelium/Bruch’s Membrane complex (Fig. 1). The average of the 6 BMO measurements yielded the mean BMO diameter for each eye. Maximum papillary height was defined as the perpendicular line from the highest point of the optic nerve head to the BMO diameter line (Fig. 1). Statistical Analysis We compared the BSUS and OCT imaging features between eyes with papilledema vs eyes with pseudopapilledema using generalized linear models that accounted for the intereye correlation through generalized estimating equations (24). We calculated the sensitivity, specificity, area-under-receiver operating characteristic curves (ROC), and their 95% confidence intervals (95% CIs) from logistic regression models to determine the ability of BSUS and OCT imaging features, individually and in combination, for discriminating eyes having papilledema vs pseudopapilledema. For calculating the 95% CIs of sensitivity, specificity, and area under ROC curve, the intereye correlation was accounted for generalized estimating equation (24). All statistical analyses were performed in SAS v9.4 (SAS Institute Inc., Cary, NC). RESULTS One hundred eighty-one eyes from 94 children (mean age, 11.0 years; range, 3.2–17.9) were included; 36 eyes from 20 489 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Example of measurements of BMO diameter and maximum papillary height. BMO, Bruch membrane open. subjects with papilledema and 145 eyes from 74 subjects with pseudopapilledema. There was no significant difference in patient sex (papilledema 64% female; pseudopapilledema 65% female) or patient age between subjects with papilledema and pseudopapilledema (mean, 9.9 vs 11.1 years, respectively; P = 0.18). All patients diagnosed as having papilledema underwent MRI imaging, and elevated ICP was secondary to an intracranial brain tumor in 4 subjects; the remainder met diagnostic criteria of pseudotumor cerebri syndrome after undergoing a lumbar puncture (25). All patients diagnosed with papilledema were followed until the papilledema resolved, confirming the diagnosis. Seventeen patients diagnosed as pseudopapilledema underwent MRI, 6 of whom also had a lumbar puncture all of which had opening pressure less than 25 cm of water. Subjects diagnosed with pseudopapilledema had follow-up visits (median = 2 months; range, 1–8 months) that typically occurred 2 months after their diagnosis (median = 2 months; range, 1– 68 months). B-Scan Ultrasonography All 4 BSUS features were significantly different between groups (Table 1). Among BSUS features, optic nerve sheath widening (.4.5 mm) demonstrated the best sensitivity (86%; 95% CI, 64%–96%) and specificity (88%; 95% CI, 79%–94%) for papilledema. Sensitivity and specificity did not improve when considering the presence of optic nerve sheath widening (.4.5 mm) along with the other 3 BSUS features. Given the importance of disease prevalence, optic nerve sheath widening (.4.5 mm) demonstrated modest positive predictive value (65%; 95% CI, 45%– 80%) and excellent negative predictive value (96%; 95% CI, 89%–99%) for papilledema. Drusen was detected in 50% of papilledema patients and 93% of pseudopapilledema patients. Optical Coherence Tomography Both mean values and distinct cut points for cpRNFL thickness and maximum papillary height, along with the presence of hyper-/hyporeflective nodules were significantly different between subject groups (Table 2). The mean values and percentages above distinct cut points for the mean BMO did not significantly differ between the groups (Table 2). When assessed as a continuous variable, cpRNFL thickness had the best diagnostic accuracy for discriminating between papilledema and pseudopapilledema (AUC = 0.87; 95% CI, 0.82–0.93), whereas mean BMO and maximum papillary height performed poorly based on the area under the ROC (AUC = 0.55; 95% CI, 0.43–0.67 and AUC = 0.66; 95% CI, 0.55–0.76, respectively). When considering different cutoff points, cpRNFL thickness $140 mm demonstrated the best sensitivity TABLE 1. Univariate analysis for the association of B-scan ultrasonography with papilledema vs pseudopapilledema Drusen present No Yes Sheath accentuation/optic nerve doubling No Yes Optic nerve sheath diameter . 4.5 mm No Yes Crescent/donut sign No Yes Papilledema, n = 36 Eyes (%) Pseudopapilledema, n = 145 Eyes (%) 18 (50.0) 18 (50.0) 10 (6.9) 135 (93.1)* 18 (50.0) 18 (50.0) 125 (86.2) 20 (13.8)* 5 (13.9) 31 (86.1) 128 (88.3) 17 (11.7)* 24 (66.7) 12 (33.3) 138 (95.2) 7 (4.8)* *P , 0.001, between groups. 490 Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Univariate analysis for the association of optical coherence tomography features with papilledema vs pseudopapilledema Papilledema, n = 36 Eyes Pseudopapilledema, n = 145 Eyes Circumpapillary retinal nerve fiber layer thickness (mm) Mean (SD) 164 (29) 123 (25) Median (min–max) 162 (121–261) 122 (69–192)* ,120 0 (0.0%) $120 36 (100%) 65 (44.8%) 80 (55.2%)* ,140 6 (16.7%) $140 30 (83.3%) ,160 18 (50.0%) 133 (91.7%) $160 18 (50.0%) 12 (8.3%)* No 10 (27.8%) 4 (2.8%) Yes 22 (61.1%) 128 (88.3%)* 110 (75.9%) 35 (24.1%)* Hyper-/hypo-reflective round nodules‡ Mean Bruch membrane opening§ Mean (SD) 1,384 (172) 1,404 (152) Median (min–max) 1,342 (1,090–1795) 1,396 (1,083–1,699) ,1,500 24 (66.7%) 98 (67.6%) $1,500 8 (22.2%) 39 (26.9%) ,1,600 28 (77.8%) 121 (83.5%) $1,600 4 (11.4%) 16 (11.0%) Maximum papillary heightk Mean (SD) 974 (125) 902 (143)† Median (min–max) 979 (672–1,223) 885 (565–1,387) ,900 6 (16.7%) 71 (49.0%) $900 24 (66.7%) ,1,000 17 (47.2%) $1,000 13 (36.1%) ,1,100 25 (69.4%) 129 (89.0%) $1,100 5 (13.9%) 8 (5.5%)† 66 (45.5%)* 106 (73.1%) 31 (21.4%)* *P , 0.001, between the groups. † P , 0.05, between the groups. ‡ Data unavailable (n = 17) due to patient cooperation and or inadequate image quality. § Data unavailable (n = 12) due to patient cooperation and or inadequate image quality. k Data unavailable (n = 14) due to patient cooperation and or inadequate image quality. NPV, Negative Predictive Value; PPV, Positive Predictive Value. (83%; 95% CI, 66%–93%) and specificity (76%; 95% CI, 66%–84%) for OCT measures to identify papilledema. Given the importance of disease prevalence, cpRNFL thickness of $140 mm demonstrated poor positive predictive value (46%; 95% CI, 31%–62%) and excellent negative predictive value (95%; 95% CI, 88%–98%) for papilledema. Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 Combined B-Scan Ultrasonography and Optical Coherence Tomography Features The combination of the best BSUS metric and best OCT metric (i.e., optic nerve sheath widening .4.5 mm AND cpRNFL thickness $140) reduced the overall sensitivity (72%; 95% CI, 52%–86%) but increased the specificity (95%, 95% CI, 88%–98%; Table 3), subsequently 491 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Sensitivity, specificity, and positive and negative predictive values for the best B-scan ultrasonography measure and optical coherence tomography measure alone or in combination for discriminating between papilledema and pseudopapilledema Optic nerve sheath diameter .4.5 mm Circumpapillary retinal nerve fiber layer thickness $140 (mm) Optic nerve sheath diameter .4.5 mm AND circumpapillary retinal nerve fiber layer thickness $140 (mm) Optic nerve sheath diameter .4.5 mm AND circumpapillary retinal nerve fiber layer thickness $120 (mm) Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI) NPV (95% CI) 86.1 (64.0–95.6) 88.3 (79.3–93.7) 64.6 (45.0–80.2) 96.2 (88.5–98.8) 83.3 (65.9–92.8) 75.9 (66.0–83.6) 46.2 (31.2–61.9) 94.8 (87.5–98.0) 72.2 (52.3–86.1) 95.2 (87.5–98.2) 78.8 (54.6–92.0) 93.2 (85.9–96.9) 86.1 (64.0–95.6) 91.0 (82.2–95.7) 70.5 (49.4–85.3) 96.4 (88.8–98.9) Analysis is at the eye level, with intereye correlation accounted for using generalized estimating equations. CI, confidence interval; PPV = positive predictive value; NPV = negative predictive value. improving the positive predictive value (79%; 95% CI, 55%–92%) with a slight reduction in the negative predictive value (93%; 95% CI, 86%–97%) relative to each individual metric. Reducing the cpRNFL thickness threshold to $120 mm in combination with the best BSUS metric demonstrated a small increase in sensitivity, along small reductions in specificity and positive and negative predictive values (Table 3). CONCLUSIONS By acquiring both BSUS and OCT metrics in a large cohort of patients with optic nerve head elevation, our study found that specific measures from unique modalities demonstrate varying degrees of diagnostic accuracy when differentiating between children with papilledema and pseudopapilledema. Although all BSUS tests showed a difference between the groups, ONSD of .4.5 mm demonstrated the best sensitivity and specificity in both detecting papilledema and in ruling it out. A cpRNFL thickness of $140 mm demonstrated the best combination of sensitivity and specificity compared with other cpRNFL thickness thresholds (i.e., $120 or $160 mm). The prevalence of hyper- or hyporeflective round nodules indicative of PHOMS and/ or drusen was different between the groups, but it did not have good diagnostic accuracy in differentiating between them. Using different cut points, the maximum papillary height also differed between the groups but had poor diagnostic accuracy (i.e., AUC = 0.66). Our study highlights the relative contribution, or lack thereof, of different BSUS findings believed to be present or absent in children with elevated ICP. Specifically, optic sheath accentuation and the crescent/donut sign have been reported to be strongly indicative of elevated ICP. Although 492 these signs were present in one-third to one-half of our papilledema subjects, they were also present in 5%–14% of those with pseudopapilledema. Although these false-positive signs may seem small, the much higher prevalence of pseudopapilledema results in a near equal number of patients with this sign from each group, producing a positive predictive value near chance. Although the positive predictive value of an ONSD of .4.5 mm is slightly better than chance (65%), its excellent negative predictive value is the most clinically helpful because in our study population, the incidence of pseudopapilledema is more than 3.5 times that of papilledema. Specifically, when the ONSD is below 4.5 mm and there are no concerning signs or symptoms, the clinician can be reassured that there is a 96% chance that the patient does not have elevated ICP and can subsequently avoid additional invasive or expensive tests (e.g., lumbar puncture or brain MRI). In 3 patients (5 total eyes) with papilledema who did not demonstrate an ONSD of .4.5 mm, other clinical features (i.e., visual acuity loss, headache) prompted the clinician to order a brain MRI. Individually, BSUS characteristics have been reported to be helpful in differentiating pseudopapilledema from papilledema. In agreement with our findings, multiple studies have found that increased ONSD has a high negative predictive value in the evaluation of optic nerve head elevation (5,7,8). The “crescent” or “doughnut” sign was not found to be a reliable indicator in our study due to the high number of falsepositive results. In an attempt to create simple guidelines for clinicians, we evaluated 3 different thresholds of cpRNFL thickness. We found that a cpRNFL thickness of $140 mm demonstrated the best overall performance providing an excellent negative predictive value. Despite this high negative Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Mixed hypo- and hyperreflective nodules on OCT B-scan (top middle panel) that are also hyperreflective on B-scan ultrasound (top right panel). Purely hyperreflective nodule on OCT B-scan (bottom left panel) that is also hyperreflective on Bscan ultrasound (bottom right panel). OCT, optical coherence tomography. predictive value, numerous factors could certainly influence the utility of such a cutoff, including the duration of elevated ICP, recent lumbar puncture, history of optic atrophy, and prior treatment of elevated ICP. As with all diagnostic tests used to evaluate elevated ICP, clinicians should not rely on one single value or measure to confirm or refute the diagnosis, but instead consider all clinical features (26). We found that our results were in agreement with several prior studies, which found that cpRNFL swelling is indicative of papilledema (12,14,27–30). In order to improve the clinical utility of these measurements, we considered the contribution of both BSUS and OCT and found that the combination of increased cpRNFL thickness on OCT and increased ONSD on BSUS were most helpful in differentiating pseudopapilledema from a true elevation in ICP. Our findings suggest that patients with thickened cpRNFL on OCT and widening of the optic nerve sheath on BSUS are more likely to have true elevations in ICP. Only one other study combined components of both BSUS and OCT, and based on 3 subjects with papilledema, the authors concluded that these tests were not sufficient to detect intracranial pathology (31). BSUS has long been the diagnostic modality of choice in identifying ONHD. However, as OCT technology has developed to include EDI, visualization of deeper drusen has improved (18). The prevalence of ONHD in children is estimated to be between 1% and 14.6%, depending on the morphologic definition used (10,32). The morphology of ONHD on OCT has been debated, with some studies describing hyporeflective masses with a hyperreflective margin (18,33–35), and some identifying hyperreflective structures (27,36,37). Recent consensus recommendations established that previously reported hyperreflective structures are likely PHOMS, whereas true ONHD are hyporeflective, with full or partial hyperreflective margins (1). Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 Although some have suggested that PHOMS may be precursors to ONHD (38), many features of PHOMS are inconsistent with ONHD and they appear to be a nonspecific finding in optic nerve head elevation, perhaps representing distended axons (1,2). In the present study, we classified the hypo- and hyperreflective round nodules visualized on OCT to be either present or absent (independent of cpRNFL thickness) because it has been our experience that the hyperreflective calcified borders of drusen are less commonly visualized in children compared with adults and that the lesions classified at PHOMS were also found to be hyperreflective on BSUS (Fig. 2). This finding is in contrast to other investigators who believe that PHOMS are not visible on BSUS (1). Although the debate about whether these lesions should be classified as PHOMS or drusen is important, it is somewhat irrelevant to the clinician attempting to determine whether this child’s optic nerve head elevation is due to papilledema and requires additional testing—especially because both PHOMS and drusen are frequently found in children with papilledema (39). Although PHOMS/ONHD were more prevalent in the pseudopapilledema group (88% and 93% respectively), diagnostic utility was poor. Our data reinforce the concept that the presence of PHOMS and or ONHD does not rule out true elevations in ICP. Some studies have found that, in cases of mild papilledema, cpRNFL thickness may not be significantly different between those with buried ONHD, as buried drusen may cause cpRNFL thickening without obvious hypo-/hyperreflective foci (16,17,20). Specifically, one study found no statistically significant difference in RNFL thickness between eyes with buried ONHD and mild papilledema (17). There are several possible explanations for these discrepancies, including small sample size and ambiguity on classification of ONHD. Our results demonstrated good diagnostic utility of cpRNFL 493 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution thickening to identify papilledema in our study population. In conclusion, we present the diagnostic utility of OCT and BSUS to differentiate between children with papilledema and pseudopapilledema. In patients with a reassuring clinical presentation and with an ONSD of ,4.5 mm on BSUS and cpRNFL thickness of ,140 mm on OCT, clinicians may feel comfortable foregoing further invasive testing, as the likelihood of papilledema in this population is low. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: R. A. Avery, C. TrimboliHeidler, G. T. Liu, and G.-S. Ying; b. Acquisition of data: M. K. Farazdaghi, C. Trimboli-Heidler, Garcia, G. T. Liu, and R. A. Avery; c. Analysis and interpretation of data: M. K. Farazdaghi, C. TrimboliHeidler, Garcia, G. T. Liu, G.-S. Ying, and R. A. Avery. Category 2: a. Drafting the manuscript: M. K. Farazdaghi, C. Trimboli-Heidler, Garcia, G. T. Liu, G.-S. Ying, and R. A. Avery; b. Revising it for intellectual content: M. K. Farazdaghi, C. Trimboli-Heidler, Garcia, G. T. Liu, G.-S. Ying, and R. A. Avery. Category 3: a. Final approval of the completed manuscript: M. K. Farazdaghi, C. Trimboli-Heidler, Garcia, G. T. Liu, G.-S. Ying, and R. A. Avery. REFERENCES 1. Malmqvist L, Bursztyn L, Costello F, Digre K, Fraser JA, Fraser C, Katz B, Lawlor M, Petzold A, Sibony P, Warner J, Wegener M, Wong S, Hamann S. The optic disc drusen studies consortium recommendations for diagnosis of optic disc drusen using optical coherence tomography. J Neuroophthalmol. 2018;38:299–307. 2. Malmqvist L, Sibony PA, Fraser CL, Wegener M, Heegaard S, Skougaard M, Hamann S. Peripapillary ovoid hyperreflectivity in optic disc edema and pseudopapilledema. Ophthalmology. 2018;125:1662–1664. 3. Bhosale A, Shah VM, Shah PK. Accuracy of crescent sign on ocular ultrasound in diagnosing papilledema. World J Methodol. 2017;7:108–111. 4. Boldt HC, Byrne SF, DiBernardo C. Echographic evaluation of optic disc drusen. J Clin Neuroophthalmol. 1991;11:85–91. 5. Carter SB, Pistilli M, Livingston KG, Gold DR, Volpe NJ, Shindler KS, Liu GT, Tamhankar MA. The role of orbital ultrasonography in distinguishing papilledema from pseudopapilledema. Eye (Lond). 2014;28:1425–1430. 6. Kurz-Levin MM, Landau K. A comparison of imaging techniques for diagnosing drusen of the optic nerve head. Arch Ophthalmol. 1999;117:1045–1049. 7. Mehrpour M, Oliaee Torshizi F, Esmaeeli S, Taghipour S, Abdollahi S. Optic nerve sonography in the diagnostic evaluation of pseudopapilledema and raised intracranial pressure: a cross-sectional study. Neurol Res Int. 2015;2015:146059. 8. Neudorfer M, Ben-Haim MS, Leibovitch I, Kesler A. The efficacy of optic nerve ultrasonography for differentiating papilloedema from pseudopapilloedema in eyes with swollen optic discs. Acta Ophthalmol. 2013;91:376–380. 9. Birnbaum FA, Johnson GM, Johnson LN, Jun B, Machan JT. Increased prevalence of optic disc drusen after papilloedema from idiopathic intracranial hypertension: on the possible formation of optic disc drusen. Neuroophthalmology. 2016;40:171–180. 10. Malmqvist L, Li XQ, Eckmann CL, Skovgaard AM, Olsen EM, Larsen M, Munch IC, Hamann S. Optic disc drusen in children: the copenhagen child cohort 2000 eye study. J Neuroophthalmol. 2018;38:140–146. 494 11. Malmqvist L, Lund-Andersen H, Hamann S. Long-term evolution of superficial optic disc drusen. Acta Ophthalmol. 2017;95:352–356. 12. Fard MA, Okhravi S, Moghimi S, Subramanian PS. Optic nerve head and macular optical coherence tomography measurements in papilledema compared with pseudopapilledema. J Neuroophthalmol. 2019;39:28–34. 13. Chang MY, Velez FG, Demer JL, Bonelli L, Quiros PA, Arnold AC, Sadun AA, Pineles SL. Accuracy of diagnostic imaging modalities for classifying pediatric eyes as papilledema versus pseudopapilledema. Ophthalmology. 2017;124:1839–1848. 14. Fard MA, Fakhree S, Abdi P, Hassanpoor N, Subramanian PS. Quantification of peripapillary total retinal volume in pseudopapilledema and mild papilledema using spectraldomain optical coherence tomography. Am J Ophthalmol. 2014;158:136–143. 15. Gampa A, Vangipuram G, Shirazi Z, Moss HE. Quantitative association between peripapillary Bruch’s membrane shape and intracranial PressureICP and peripapillary Bruch’s membrane shape. Invest Ophthalmol Vis Sci. 2017;58:2739– 2745. 16. Karam EZ, Hedges TR. Optical coherence tomography of the retinal nerve fibre layer in mild papilloedema and pseudopapilloedema. Br J Ophthalmol. 2005;89:294–298. 17. Kulkarni KM, Pasol J, Rosa PR, Lam BL. Differentiating mild papilledema and buried optic nerve head drusen using spectral domain optical coherence tomography. Ophthalmology. 2014;121:959–963. 18. Merchant KY, Su D, Park SC, Qayum S, Banik R, Liebmann JM, Ritch R. Enhanced depth imaging optical coherence tomography of optic nerve head drusen. Ophthalmology. 2013;120:1409–1414. 19. Thompson AC, Bhatti MT, El-Dairi MA. Bruch’s membrane opening on optical coherence tomography in pediatric papilledema and pseudopapilledema. J AAPOS. 2018;22:38– 43.e3. 20. Vartin C V, Nguyen AM, Balmitgere T, Bernard M, Tilikete C, Vighetto A. Detection of mild papilloedema using spectral domain optical coherence tomography. Br J Ophthalmol. 2012;96:375–379. 21. Green RL, Frazier SF. Ultrasound of the Eye and Orbit. 2nd edition. St. Louis, MO: Mosby Inc, 2002. 22. Le A, Hoehn ME, Smith ME, Spentzas T, Schlappy D, Pershad J. Bedside sonographic measurement of optic nerve sheath diameter as a predictor of increased intracranial pressure in children. Ann Emerg Med. 2009;53:785–791. 23. Ballantyne J, Hollman AS, Hamilton R, Bradnam MS, Carachi R, Young DG, Dutton GN. Transorbital optic nerve sheath ultrasonography in normal children. Clin Radiol. 1999;54:740– 742. 24. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42:121–130. 25. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81:1159–1165. 26. Avery RA. Interpretation of lumbar puncture opening pressure measurements in children. J Neuroophthalmol. 2014;34:284– 287. 27. Bassi ST, Mohana KP. Optical coherence tomography in papilledema and pseudopapilledema with and without optic nerve head drusen. Indian J Ophthalmol. 2014;62:1146–1151. 28. Johnson LN, Diehl ML, Hamm CW, Sommerville DN, Petroski GF. Differentiating optic disc edema from optic nerve head drusen on optical coherence tomography. Arch Ophthalmol. 2009;127:45–49. 29. Lee KM, Woo SJ, Hwang JM. Differentiation of optic nerve head drusen and optic disc edema with spectral-domain optical coherence tomography. Ophthalmology. 2011;118:971–977. 30. Sarac O, Tasci YY, Gurdal C, Can I. Differentiation of optic disc edema from optic nerve head drusen with spectral-domain optical coherence tomography. J Neuroophthalmol. 2012;32:207–211. Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 31. Dahlmann-Noor AH, Adams GW, Daniel MC, Davis A, Hancox J, Hingorani M, Ibanez P, McPhee B, Patel H, Restori M, Roberts C, Theodorou M, Acheson J. Detecting optic nerve head swelling on ultrasound and optical coherence tomography in children and young people: an observational study. Br J Ophthalmol. 2018;102:318–322. 32. Ghassibi MP, Chien JL, Abumasmah RK, Liebmann JM, Ritch R, Park SC. Optic nerve head drusen prevalence and associated factors in clinically normal subjects measured using optical coherence tomography. Ophthalmology. 2017;124:320–325. 33. Sato T, Mrejen S, Spaide RF. Multimodal imaging of optic disc drusen. Am J Ophthalmol. 2013;156:275–282.e1. 34. Slotnick S, Sherman J. Buried disc drusen have hypo-reflective appearance on SD-OCT. Optom Vis Sci. 2012;89:E704–E708. Farazdaghi et al: J Neuro-Ophthalmol 2021; 41: 488-495 35. Yi K, Mujat M, Sun W, Burnes D, Latina MA, Lin DT, Deschler DG, Rubin PA, Park BH, de Boer JF, Chen TC. Imaging of optic nerve head drusen: improvements with spectral domain optical coherence tomography. J Glaucoma. 2009;18:373–378. 36. Lee KM, Hwang JM, Woo SJ. Optic disc drusen associated with optic nerve tumors. Optom Vis Sci. 2015;92:S67–S75. 37. Lee KM, Woo SJ, Hwang JM. Morphologic characteristics of optic nerve head drusen on spectral-domain optical coherence tomography. Am J Ophthalmol. 2013;155:1139–e1. 38. Traber GL, Weber KP, Sabah M, Keane PA, Plant GT. Enhanced depth imaging optical coherence tomography of optic nerve head drusen: a comparison of cases with and without visual field loss. Ophthalmology. 2017;124:66–73. 39. Gospe SM, Bhatti MT, El-Dairi MA. Anatomic and visual function outcomes in paediatric idiopathic intracranial hypertension. Br J Ophthalmol. 2016;100:505. 495 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.