Variability Within Optic Nerve Optical Coherence Tomography Measurements Distinguishes Papilledema From Pseudopapilledema

To report a linear risk score obtained using clock-hour optical coherence tomography (OCT) data from papilledema and pseudopapilledema nerves that differentiates between the 2 diagnoses with high sensitivity and specificity.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Variability Within Optic Nerve Optical Coherence Tomography Measurements Distinguishes Papilledema From Pseudopapilledema Alexis M. Flowers, MD, Reid A. Longmuir, MD, Yuhan Liu, MS, Qingxia Chen, PhD, Sean P. Donahue, MD, PhD, Background: To report a linear risk score obtained using clock-hour optical coherence tomography (OCT) data from papilledema and pseudopapilledema nerves that differentiates between the 2 diagnoses with high sensitivity and specificity. Methods: Patients presenting to a single neuroophthalmologist with papilledema or pseudopapilledema were included for a retrospective review. The absolute consecutive difference in OCT retinal nerve fiber layer (RNFL) thickness between adjacent clock hours and the mean magnitude of thickness for clock hours 1–12 were compared between the 2 groups using mixed-effect models adjusting for age and clock hour with a random intercept for subjects and eyes (nested within subject). The area under the curve (AUC) for the receiver operating characteristics curve and a separate calibration curve was used to evaluate potential clinical usage. Results: Forty-four eyes with papilledema and 72 eyes with pseudopapilledema, 36 of whom had optic nerve drusen met criteria. The papilledema group had a higher mean RNFL thickness (papilledema = 163 ± 68 mm, pseudopapilledema = 82 ± 22 mm, P , 0.001). The papilledema groups also had more variability between consecutive clock hours (papilledema = 57 ± 20 mm, pseudopapilledema = 26 ± 11 mm, P , 0.001). A linear combination of each patient’s averaged values separated the 2 groups with an AUC of 98.4% (95% CI 95.5%–100%) with an optimized sensitivity of 88.9% and specificity of 95.5% as well as good calibration (mean absolute error = 0.015). Department of Ophthalmology and Visual Sciences (AMF, RAL, QC, SPD), Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Biostatistics (YL, QC), Vanderbilt University Medical Center, Nashville, Tennessee. Supported by an unrestrictive departmental grant from Research to Prevent Blindness to Vanderbilt Eye Institute. The authors report no conflicts of interest. Application pending for patent of the linear model. Address correspondence to Alexis M. Flowers, MD, Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, 2311 Pierce Avenue, Nashville, TN 37232; E-mail: alexis.flowers009@ gmail.com. 496 Conclusions: Patients with papilledema have higher intrinsic variability and magnitude within their OCT, and this finding reliably distinguishes them from those with pseudopapilledema. Journal of Neuro-Ophthalmology 2021;41:496–503 doi: 10.1097/WNO.0000000000001137 © 2020 by North American Neuro-Ophthalmology Society D ifferentiating patients with papilledema from those with pseudopapilledema has been a long-standing dilemma for not only the comprehensive ophthalmologist but also for well-established neuro-ophthalmologists (1). It is important to be able to correctly diagnose and distinguish these 2 conditions because failure to recognize true papilledema can have serious life-threatening and visionthreatening complications (2) while misclassifying pseudopapilledema can lead to multiple unnecessary and invasive tests (1). There has been much research into diagnostic tools to aid the clinical examination in this regard (3–6). Previous studies have evaluated ultrasonography (7,8), optical coherence tomography (OCT) (8–16), OCT angiography (17), and fluorescein angiography (18). Although all these tests have utility, each has advantages and disadvantages in the clinical setting. OCT is user friendly, accessible in most ophthalmology practices, and can be used for both young and elderly patients. The development of clock-hour data from OCT measurements has allowed increased sensitivity to detect conditions that might have asymmetric involvement of the optic nerve head. Based on clinical observation, patients with pseudopapilledema either from drusen or a congenital anomaly often have only part of the nerve that is elevated. This is in contrast to patients with papilledema who have clock-hour elevation that varies relatively linearly based on the magnitude of the normal nerve fiber layer thickness. Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Optical coherence tomography (OCT) from 3 patients with elevation of bilateral optic nerves on examination. A. A patient with mild disc edema due to idiopathic intracranial hypertension. B. The baseline OCT of a patient with anomalous nerves. OCT measurements stable over 8 months and unchanged with trial of acetazolamide. C. A patient with pseudopapilledema from buried optic nerve drusen confirmed with ultrasonography. This patient had been referred by a community provider to the emergency department for urgent papilledema evaluation. The clock-hour measurements are elevated in one localized area in B and C, whereas multiple clock hours in the papilledema patient are elevated. This is the basis of the hypothesis that more clock hour variability would be seen in papilledema patients than pseudopapilledema patients. RNFL, retinal nerve fiber layer. Figure 1 illustrates this observation with an example of an OCT scan from patients having mild disc edema, optic nerve drusen, and congenitally anomalous nerves. All 3 patients had been referred with a concern for papilledema from community eye doctors. Based on the above observation, we hypothesized that patients with papilledema would have more variability in their individual clock-hour measurements than those with pseudopapilledema and that this variability in the OCT clock-hour data could be used to distinguish patients with papilledema from those with pseudopapilledema. We devised a linear risk score using those data to separate the 2 groups, and we present this model here. METHODS Institutional prospective IRB approval was obtained through the Vanderbilt University Medical Center, and the Declaration of Helsinki was adhered to. A retrospective review was conducted of patients who presented to a single fellowship-trained neuro-ophthalmologist (RL) with clinically elevated optic nerves over a 4-year period. Patients were included if they had a diagnosis of papilledema or pseudopapilledema, which included optic disc drusen. Both eyes of every patient were included for analysis. The diagnosis of papilledema required a documented lumbar puncture with opening pressure greater than 24 cm H2O and appropriate neuroimaging. Further inclusion criteria were age .18 years and reliable Cirrus OCT optic nerve head measurements (Carl Zeiss Meditec, Inc, Dublin, CA). Both eyes had to have some degree of disc edema but Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 they could be asymmetric. Exclusion criteria included Grade 5 papilledema due to presumably unreliable OCT scans, intracranial or ocular pathology (e.g., masses, ischemic lesions, and panretinal photocoagulation) that may have a confounding effect on the RNFL because of anterograde or retrograde axonal degeneration (19), and other co-existing optic nerve pathology. Inclusion criteria for pseudopapilledema were patients with clinically elevated optic nerves who had been referred to neuro-ophthalmology. Any questionable diagnoses from the neuro-ophthalmologist were excluded. Etiologies for pseudopapilledema included optic disc drusen and congenital anomaly; other etiologies were excluded. A lumbar puncture was not required as the standard of practice at our institution does not routinely order lumber punctures for these patients. Data collected included age of patient, diagnosis, and lumbar puncture opening pressure if performed. Collected OCT data included the mean RNFL thickness, the 4 quadrant RNFL thickness measurements, and the 12 clockhour RNFL thickness measurements that are all readily available in the standard OCT report. The clock hours on the right eye were labeled clockwise and the left eye was labeled counterclockwise to maintain consistency with temporal and nasal sides. The mean of the 12 clock-hour RNFL thickness and the mean absolute consecutive difference for clock hours 1–12 (MACD1-12) were compared between papilledema and pseudopapilledema groups using a mixed-effect model adjusting for age and clock hour with a random intercept for subjects and eyes (nested within subject). This accounted for within-patient and inter-eye 497 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution correlations. Sex was not controlled for because it has not been showed to affect the RNFL (20). MACD1-12 was defined as AbsDiff ¼ ðjOCThour12OCThour12j þjOCThour22OCThour1j þ . þ jOCThour12 2OCThour11jÞ=12. A linear risk score of RNFL and MACD1-12 was developed to distinguish papilledema from pseudopapilledema with their coefficients derived from a logistic regression model. The area under the curve (AUC) for the receiver operating characteristics (ROC) curve and calibration curve was used to evaluate potential clinical usage. The calibration curve was developed using R 3.6.1 with the rms package (Regression Modeling Strategies. R package version 5.1-3.1. https://CRAN.R-project. org/package=rms). The ROC was plotted for sensitivity against 1-specificity. The worse eye (larger linear combination) was used to calculate the ROC. The AUC confidence interval (CI) was calculated using a bootstrap method (2000 replicates). Four criteria were used to find the optimal cutoff (Youden (21), Closest to the top left (22), Index of Union (22), and the Concordance Probability Method (23)). A 2-sided P value less than 0.05 was considered statistically significant. RESULTS One hundred sixteen eyes (58 patients) were found that met the criteria for analysis (Table 1). Forty-four eyes (22 patients) had papilledema, and 72 eyes had pseudopapilledema; of the 72 eyes, 36 eyes had optic disc drusen and 36 had anomalous nerves. Of the eyes that had optic nerve drusen, 20 eyes were visible on examination. The rest were buried and diagnosed by ultrasonography or seen on OCT. The average age of the papilledema group was 28.3 years (range = 19–49 years, SD = 7.5 years), and all were women. Twenty-one of the 22 patients were diagnosed with idiopathic intracranial hypertension (IIH). The remaining patient had hydrocephalus from a ventricular plexus choroid papilloma. Of the 44 eyes, 26 eyes had Frisen Grade 1 papilledema, 13 eyes were Grade 2, 3 were Grade 3, and 1 was Grade 4. Twenty-one of the 22 patients had a documented opening pressure by lumbar puncture. The mean opening pressure was 36.8 cm H2O, (range = 25.7–55 cm H2O, SD 8.0 cm H2O). The one patient with hydrocephalus had an external ventricular drain placed with an intracranial pressure of 25 cm H2O. The average age of the patients with pseudopapilledema without drusen was 40.6 years (range = 18–89 years, SD = 19.7 years), and the average age of the patients with pseudopapilledema with optic nerve drusen was 53.9 years (range = 29–80 years, SD = 12.7 years). Twenty-seven of the 36 patients with pseudopapilledema were women. The average RNFL thickness for the papilledema group was higher than that for the pseudopapilledema group (papilledema = 163 ± 68 mm, pseudopapilledema = 82 ± 22 mm, P , 0.001). As can be seen in Figure 2, the papilledema group overall had thicker RNFLs; however, there was notable overlap between the 2 groups. The papilledema group also had higher MACD1-12 (papilledema = 57 ± 20 mm, pseudopapilledema = 26 ± 11 mm, P , 0.001). The papilledema group had more variability from 1 clock hour to the next, but there was still overlap between the 2 groups (Fig. 3). From these data, we created a linear risk score with an outcome metric (termed the Optic Disc Edema Index [ODEI]) to better stratify papilledema nerves from pseudopapilledema (Fig. 4). When the linear combination of the average values for covariates 1) the RNFL thickness and 2) the mean absolute consecutive difference were used to classify the 2 groups, we achieved the AUC of 98.4% (95% CI 95.5%–100%) (Fig. 5). As can be referenced in Figure 6, good calibration was obtained for this linear combination (the mean absolute error = 0.015). With different cut-off values as shown in Figure 5, sensitivity ranged from 86% to 100% and specificity from 86% to 100%. Table 2 shows the distribution of the linear combination results for this data set. This was developed using the worst eye from each patient. Nearly all the papilledema eyes had a value of greater than 14.8; 4 eyes were less than 14.8. Nearly all the pseudopapilledema eyes had a linear combination value of less than 13.2; 4 eyes were greater than 13.2. Figure 7 graphically shows how there is a separation between the 2 groups with only a small area of overlap. TABLE 1. Demographic information of the papilledema and pseudopapilledema groups Total number (eyes) Age, yr (range, SD) Gender (female/total) Diagnosis Frisen grade Lumbar puncture, cm H2O (range, SD) 498 Papilledema Pseudopapilledema 22 (44) 28.3 (19–49, 7.5) 22/22 21/22 IIH 1/22 hydrocephalus Frisen Grade 1: 26 Frisen Grade 2: 13 Frisen Grade 3: 3 Frisen Grade 4: 1 36.8 (25.7–55, 8) 36 (72) 40.6 (18–89, 19.7) 27/36 18/36 drusen (10 visible drusen) 18/36 anomalous N/A N/A Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Mean retinal nerve fiber layer (RNFL) thickness for the papilledema and pseudopapilledema groups. The papilledema group has a larger RNFL, although there is significant overlap between the 2 groups. OCT, optical coherence tomography. The opening pressures on lumbar puncture for the 4 patients with papilledema with an ODEI ,14.8 were 27, 33, 34, and 39 cm H2O. Three of the 4 were described to have mild disc elevation only in the nasal quadrant. The fourth had Frisen Grade 2 disc edema in one eye and Grade 1 in the second eye. All 4 patients had been started on acetazolamide by outside providers before presentation. Four patients with pseudopapilledema had an ODEI of greater than 13.2. One of these 4 had a lumbar puncture with normal opening pressure. Two patients had stable pseudopapilledema over a 2-year period. One patient was a 49-year-old obese woman who had sleep apnea and inter- mittently experienced pulsatile tinnitus but no headache. Clinical examination and OCT were noted consistent with pseudopapilledema with no true papilledema. The examination and OCT were stable over a 2-month period. DISCUSSION The importance of recognizing papilledema cannot be overestimated because it typically indicates a visionthreatening and often life-threatening problem. Accordingly, recognizing pseudopapilledema and being able to distinguish it adequately from true papilledema are similarly FIG. 3. Absolute consecutive differences for the papilledema and pseudopapilledema groups. The papilledema group showed more variability, although there is overlap between the 2 groups. Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 499 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Optic Disc Edema Index. Linear combination formula for covariates 1) the mean retinal nerve fiber layer (RNFL) thickness and 2) the mean absolute consecutive difference. b 1 = 0.1007, b 2 = 0.0493, OCT= average RNFL thickness, AbsDiff= mean absolute consecutive difference. important. Unfortunately, it often remains difficult to determine true vs pseudopapilledema (1). Previous investigators have used measurements of RNFL thickness from OCT readings to separate true from pseudopapilledema. Carta et al (10) compared the 4 quadrant measurements and found that RNFL thickness was greater in papilledema, particularly the inferior quadrant. Another study observed that the average RNFL thickness was greater in papilledema for all 12 clock-hour segments than that in pseudopapilledema in younger patients (11). Bassi and Mohana also found that papilledema nerves had a thicker RNFL than pseudopapilledema, but the highest AUC that they achieved for stratification was 0.79 using the nasal quadrant (14). Lee confirmed these findings with an AUC of the nasal quadrant of 0.86 (15). Our results agree with these observations, but we report a higher AUC of 0.98 using our linear model. We observed an overlap of the RNFL thickness with the 2 groups and believed this metric was limited in its ability to reliably and accurately separate them. Kulkarni et al did not find a difference in RNFL thickness between papilledema eyes and buried optic nerve drusen (16) further supporting the notion that RNFL thickness alone is not a sufficient biomarker to separate these groups. In 2018, Costello et al (1) published a review of different OCT modalities used to compare papilledema and pseudo- papilledema, including the subretinal hyporeflective space (9,12) and the angle of the Bruch membrane. The study by Johnson et al compared optic disc edema with optic nerve head drusen. They again found that the disc edema nerves had thicker RNFLs than the drusen nerves, agreeing with the above. The ROC for RNFL thickness was able to differentiate the 2 with sensitivity ranging from 65% to 80% and specificity from 70% to 80%. This was limited by the overlap of the 2 groups, similar to our results. The ROC for the subretinal hyporeflective space was able to give a sensitivity of 75% and specificity of 90%. Our linear model had higher sensitivity and specificity. Some have analyzed the angle of the Bruch membrane in papilledema nerves before and after lumbar puncture (24,25) and in comparison to disc edema from other etiologies (26). However, as Costello et al (1) point out, this has not been reproducible in every study (16) and has been seen in normal optic nerves (27). Carter et al reported a large cohort of 407 patients who underwent ultrasonography (7). They reported a sensitivity of 90% and specificity of 79% for the 30° test. Although these results seem promising, it does require specialized staff to perform the test. Chang et al reported a high accuracy rate of 97% for fluorescein angiography to detect drusen vs optic disc edema (6). However, this is an invasive test requiring an intravenous line, skilled staff, is more time intensive than OCT, has medication related side effects, and is contraindicated in pregnancy. These negatives are contrasted with the relatively few negatives of the OCT. Our clinical observation that the variability in the clockhour data seemed to differ between the patients with papilledema and pseudopapilledema gave rise to the hypothesis tested in this article. Our analysis found that patients with papilledema have an increase in the mean FIG. 5. Area under the curve (AUC) for the receiver operating characteristics (ROC) curve using the worst eye to calculate a linear combination. Covariates were 1) the mean retinal nerve fiber layer thickness and 2) the mean absolute consecutive difference. 500 Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 6. Calibration curve plot for the linear combination model. This demonstrates good calibration for the linear model. The mean absolute error = 0.015. RNFL thickness than patients with pseudopapilledema. However, these distributions overlap; thus, we were unable to separate the 2 groups exclusively using this variable with high enough sensitivity and specificity. We also found that an increase in absolute consecutive clock-hour variability was seen in both pseudo and true papilledema; these distributions also had a significant overlap and were not sufficient to separate the 2 groups. We therefore devised a linear model to best fit the variables of 1) the overall thickness of the retinal nerve fiber layer and 2) the absolute consecutive difference between clock-hour segments. The outcome metric, which we term the ODEI, distinguished between the 2 conditions with high sensitivity and specificity. Our data show that an ODEI .14.8 was associated with papilledema, whereas ,13.2 was associated with pseudopapilledema. Accordingly, one can use this outcome metric to determine the likelihood of optic disc edema. The AUC for this model was 0.98, which indicates an excellent fit of this linear model. In our series of 116 eyes, only 4 papilledema eyes had optic nerve edema indexes less than 14.8 and 4 pseudopapilledema eyes greater than 13.2. Thus, there remains a small but important area of overlap using this metric. To the best of our knowledge, we are the first to report this method. Conveniently, the clock-hour data are readily available with current software, and the OCT machine is widely accessible, making clinical implementation of this method practical. This makes the linear model attractive to not only neuro-ophthalmologists but also referring comprehensive ophthalmologists to better triage and manage these patients. TABLE 2. Frequency distribution of the linear combination formula values for papilledema and pseudopapilledema groups Linear Combination Value #13.2 13.2–13.4 13.4–13.6 13.6–13.8 13.8–14.0 14.0–14.2 14.2–14.4 14.4–14.6 14.6–14.8 .14.8 Papilledema N = 22 0.05 0.05 0.05 0.00 0.00 0.00 0.00 0.00 0.05 0.82 (1)* (1) (1) (0) (0) (0) (0) (0) (1) (18) Pseudopapilledema N = 36 0.89 0.00 0.03 0.00 0.03 0.00 0.03 0.00 0.03 0.00 (32) (0) (1) (0) (1) (0) (1) (0) (1) (0) The worst eye was used from each patient to calculate a risk score. Most papilledema eyes had values greater than 14.8, whereas most pseudopapilledema eyes had values less than 13.2. *Numbers after proportions are frequencies. Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 501 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 7. Frequency plot of the outcome values, or Optic Disc Edema Indices, for the linear combination formula applied to this data set. There is little overlap between the 2 groups. There are several limitations to our data. First, the linear model was validated on the same data set from which it was derived and was performed only with Cirrus OCT. Accordingly, additional validation needs to occur on independent data sets before incorporation into clinical practice. Second, because this model was derived from data obtained mostly from patients with optic disc edema secondary to IIH, it is currently applicable only for these patients. Validation in patients with increased intracranial pressure from other etiologies is needed. Third, patients who have atrophic disc edema will likely have less of a difference in their RNFL thickness, and therefore in their ODEI and so this model may not be valid in this cohort. Fourth, although the diagnosis of papilledema was supported by a lumbar puncture, this was not true for the pseudopapilledema group in whom the diagnosis was based on clinical examination and ancillary testing by a fellowship-trained neuro-ophthalmologist; therefore, it is possible that some of the patients with pseudopapilledema were misclassified. As this was a retrospective review (and our institution does not routinely perform lumbar punctures in all patients with pseudopapilledema in accordance with the standard of care practices) we did not have that supportive data. Frisen Grade 3 and 4 nerves were included in this study because the authors felt it is important to create and validate the linear model on all grades 1–4, instead of just Frisen Grade 1 and 2. Despite this, most of the papilledema eyes were Frisen Grade 1 and 2, and none of the Grade 3 and 4 nerves had an ODEI below 14.8. Finally, the data set we used for this linear model was derived from adults, and therefore this model is not currently applicable to children with suspicious optic discs. We aim for this tool to be applicable not only for neuro-ophthalmologists but also for community providers to aid in the decision of timing for neuro502 ophthalmologic or emergency department referral. We look forward to publishing our independent validation of this linear model and developing a similar linear model for use in children. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. M. Flowers, C. Chen, R. A. Longmuir, and S. P. Donahue; b. Acquisition of data: A. M. Flowers; c. Analysis and interpretation of data: A. M. Flowers, Y. Liu, C. Chen, R. Longmuir, and S. P. Donahue. Category 2: a. Drafting the manuscript: A. M. Flowers; b. Revising it for intellectual content: C. Chen, R. A. Longmuir, S. P. Donahue, and Category 3: a. Final approval of the completed manuscript: A. M. Flowers, Y. Liu, C. Chen, R. A. Longmuir, and S. P. Donahue. REFERENCES 1. Costello F, Malmqvist L, Hamann S. The role of optical coherence tomography in differentiating optic disc drusen from optic disc edema. Asia-Pacific J Ophthalmol. 2018;7:271–279. 2. Rigi M, Almarzouqi SJ, Morgan ML, Lee AG. Papilledema: epidemiology, etiology, and clinical management. Eye and brain. 2015;7:47. 3. Hoyt WF, Pont ME. Pseudopapilledema: anomalous elevation of optic disk: pitfalls in diagnosis and management. JAMA. 1962;181:191–196. 4. Freund P, Margolin E. Pseudopapilledema. In. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2019. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK538291/. 5. Chiang J, Wong E, Whatham A, Hennessy M, Kalloniatis M, Zangerl B. The usefulness of multimodal imaging for differentiating pseudopapilloedema and true swelling of the optic nerve head: a review and case series. Clin Exp Optom. 2015;98:12–24. 6. 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. 7. Carter SB, Pistilli M, Livingston KG, Gold DR, Volpe NJ, Shindler KS, Liu GT, Tamhankar MA. The role of orbital Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. ultrasonography in distinguishing papilledema from pseudopapilledema. Eye. 2014;28:1425. Saenz R, Cheng H, Prager TC, Frishman LJ, Tang RA. Use of A-scan ultrasound and optical coherence tomography to differentiate papilledema from pseudopapilledema. Optom Vis Sci. 2017;94:1081–1089. 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. Carta A, Mora P, Aldigeri R, Gozzi F, Favilla S, Tedesco S, Calzetti G, Farci R, Barboni P, Bianchi-Marzoli S, Fossarello M. Optical coherence tomography is a useful tool in the differentiation between true edema and pseudoedema of the optic disc. PLoS One. 2018;13:e0208145. Martinez MR, Ophir A. Optical coherence tomography as an adjunctive tool for diagnosing papilledema in young patients. J Pediatr Ophthalmol Strabismus. 2011;48:174–181. 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 Neuroophthal. 2012;32:207–211. Pardon LP, Cheng H, Tang RA, Saenz R, Frishman LJ, Patel NB. Custom optical coherence tomography parameters for distinguishing papilledema from pseudopapilledema. Optom Vis Sci. 2019;96:599–608. 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. 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. 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. Fard MA, Sahraiyan A, Jalili J, Hejazi M, Suwan Y, Ritch R, Subramanian PS. Optical coherence tomography angiography Flowers et al: J Neuro-Ophthalmol 2021; 41: 496-503 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. in papilledema compared with pseudopapilledema. Invest Ophthalmol Vis Sci. 2019;60:168–175. Pineles SL, Arnold AC. Fluorescein angiographic identification of optic disc drusen with and without optic disc edema. J Neuroophthalmol. 2012;32:17. Jindahra P, Petrie A, Plant GT. The time course of retrograde trans-synaptic degeneration following occipital lobe damage in humans. Brain. 2012;135:534–541. Budenz DL, Anderson DR, Varma R, Schuman J, Cantor L, Savell J, Greenfield DS, Patella VM, Quigley HA, Tielsch J. Determinants of normal retinal nerve fiber layer thickness measured by Stratus OCT. Ophthalmology. 2007;114:1046– 1052. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–35. Perkins NJ, Schisterman EF. The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am J Epidemiol. 2006;163:670–675. Liu X. Classification accuracy and cut point selection. Stat Med. 2012;31:2676–2686. Gampa A, Vangipuram G, Shirazi Z, Moss HE. Quantitative association between peripapillary Bruch’s membrane shape and intracranial pressure. Invest Ophthalmol Vis Sci. 2017;58:2739–2745. Sibony P, Kupersmith MJ, Honkanen R, Rohlf FJ, Torab-Parhiz A. Effects of lowering cerebrospinal fluid pressure on the shape of the peripapillary retina in intracranial hypertension. Invest Ophthalmol Vis Sci. 2014;55:8223–8231. Kupersmith MJ, Sibony P, Mandel G, Durbin M, Kardon RH. Optical coherence tomography of the swollen optic nerve head: deformation of the peripapillary retinal pigment epithelium layer in papilledema. Invest Ophthalmol Vis Sci. 2011;52:6558–6564. Kardon R Optical coherence tomography in papilledema: what am I missing? J Neuroophthalmol. 2014;34(suppl):S10–S17. 503 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.