Role of Ocular Ultrasonography to Distinguish Papilledema From Pseudopapilledema

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Role of Ocular Ultrasonography to Distinguish Papilledema From Pseudopapilledema Anita A. Kohli, MD, Maxwell Pistilli, MEd, MS, Cesar Alfaro, MD, Ahmara G. Ross, MD, PhD, Imran Jivraj, MD, Sheila Bagchi, MD, Jessie Chan, BS, Dionne May, BS, Grant T. Liu, MD, Kenneth S. Shindler, MD, PhD, Madhura A. Tamhankar, MD Background: We prospectively evaluated the sensitivity and specificity of ocular ultrasonography (OUS) to distinguish papilledema from pseudopapilledema. Methods: Forty-nine study participants, with optic disc elevation, underwent neuro-ophthalmic evaluation, OUS, fundus photography, and optical coherence tomography (OCT) of the optic nerve head at the initial and follow-up visits (#6 months apart). Participants were classified as having papilledema if there was a change in optic nerve appearance on fundus photographs, as determined by a masked observer, between initial and follow-up visits #6 months apart. OUS was considered positive when the optic nerve sheath width was .3.3 mm and the 30° test was positive. Ocular ultrasonographic findings were correlated in patients who had papilledema vs patients who had pseudopapilledema. In a subanalysis, OUS findings were also correlated with change in peripapillary retinal nerve fiber layer thickness on OCT of the optic nerve head between initial and follow-up visits. Results: OUS was 68% (17/25) sensitive for papilledema and 54% (13/24) specific for pseudopapilledema. When using OCT parameters to define papilledema, the sensitivity Department of Ophthalmology and Visual Science (AAK), Yale University School of Medicine, New Haven, Connecticut; Department of Ophthalmology (MP), Center for Preventative Ophthalmology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Ophthalmology (CA), Icahn School of Medicine at Mount Sinai, New York, New York; Scheie Eye Institute (AGR, GTL, KSS, MAT), Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Ophthalmology (IJ), University of Alberta, Edmonton, Canada; Department of Medicine (SB), Temple University, Philadelphia, Pennsylvania; Rutgers Robert Wood Johnson Medical School (JC), Piscataway, New Jersey; Boston University Henry M. Goldman School of Dental Medicine (DM), Boston, Massachusetts; and Department of Neurology (GTL), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. This research was funded by Research to Prevent Blindness. The authors report no conflicts of interest. Address correspondence to Madhura A. Tamhankar, MD, Scheie Eye Institute, 51 North, 39th Street, Philadelphia, PA 19104; E-mail: [e-mail] 206 of OUS to diagnose papilledema decreased to 62%. Positive OUS correlated with elevated opening pressure on lumbar puncture and with signs of increased intracranial pressure on MRI. Conclusion: OUS alone was less sensitive in diagnosing papilledema than previously thought. Therefore, OUS may not be helpful in distinguishing between papilledema and pseudopapilledema. Journal of Neuro-Ophthalmology 2021;41:206–211 doi: 10.1097/WNO.0000000000000984 © 2020 by North American Neuro-Ophthalmology Society T he distinction between papilledema and pseudopapilledema can be challenging to make, especially in those individuals who have mild optic disc elevation. Although patients with pseudopapilledema require at most observation, one with papilledema requires further management with neuroimaging and lumbar puncture (LP). When the diagnosis is in question, ancillary tests such as ocular ultrasonography (OUS) (1,2), fluorescein angiography (3,4), optical coherence tomography (OCT) (5–7), opening pressure (OP) on LP (8), and MRI signs of raised intracranial pressure (ICP) (9,10) are often used to help diagnose papilledema, although there is no “gold standard.” In a previous retrospective study, OUS findings of the dilated optic nerve sheath (11) and shift of nerve sheath fluid, demonstrated by a positive 30° test, had a reported sensitivity and specificity of 90% and 79%, respectively (1). A more recent study showed that the use of the “crescent or doughnut” sign was 92% sensitive in diagnosing papilledema (12). However, these studies had an inherent bias of patient selection, had inadequate workup, and lacked strict objectives and precise criteria in distinguishing between papilledema and pseudopapilledema. Our objective was to assess prospectively the sensitivity and specificity of OUS for papilledema and pseudopapilledema in adults presenting with optic Kohli et al: J Neuro-Ophthalmol 2021; 41: 206-211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution nerve head swelling. Considering the popularity of OCT in such patients, we also looked for a correlation between OUS and a change in the peripapillary retinal nerve fiber layer (PPRNFL) thickness during the same study period. METHODS Adult patients referred for suspected papilledema were consecutively enrolled in the study and underwent neuroophthalmic evaluation, fundus photography, OUS, and OCT at the initial and follow-up visits. Optic nerve swelling was documented as per the Frisén grading scheme (13). A single experienced ultrasonographer performed OUS on all patients. OUS was considered positive when the optic nerve sheath width was greater than 3.3 mm (14), with a positive 30° test (decrease of the optic nerve sheath width by 10% on abduction of the eye by at least 30°) (15). OUS was performed using an Ellex Eye Cubed A/B System (Ellex Medical Pty Ltd, Adelaide, SA, Australia) equipped with a 10-MHz transducer in A-scan and B-scan modes. The B-scan mode was used to provide a two-dimensional cross-sectional image of the eye to identify optic disc elevation and look for a fluid (crescent) sign. The A-scan mode, which is standardized for tissue differentiation with 2 gates for measurement, was used to determine the optic nerve sheath width in the primary gaze. Digital fundus photography was performed by a trained technician using the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) protocol (16). A Zeiss FF450 camera was used with a 30° field angle. This fundus camera combined with Merge Healthcare software and a 5 megapixel backing camera allowed for photos taken with a resolution of 2,400 · 2,048 pixels. The photographs were uploaded to a Windows 7 Professional SP1 PC and contained within the WinStation version 11.4 program provided by Merge Healthcare. The images were visualized under dim room illumination by a masked neuroophthalmologist, who did not have access to any clinical data. The photographs contained an image centered on the optic disc at the retinal plane, on the plane of highest disc elevation, and on the papillomacular area. The photographs were viewed with stereoscopes to assess for the presence of stereo in the images during capture. All photographs were included with the exception of those containing artifacts or capture errors. Papilledema was defined as a change in optic disc appearance on fundus photographs (one or both eyes) between the initial and any follow-up visit up to and including the 6-month visit, whereas pseudopapilledema was defined as a lack of change in optic nerve appearance during the same time frame, on review of fundus photographs (both eyes) as determined by a masked neuro-ophthalmologist. In patients with papilledema, unless contraindicated, acetazolamide was started. OCT scan acquisition was performed with a Cirrus 5000 SD-OCT system (8.1.0.117), modeled after the IIHTT Kohli et al: J Neuro-Ophthalmol 2021; 41: 206-211 protocol (16,17). Five types of scans were performed, namely, two 200 · 200 optic disc cube scans, 2 macular cube scans 200 · 200 centered around the fovea, and 1 high-definition 5-line raster scan horizontally oriented and separated by 0.5 mm imposed on the optic disc. The cube scans were generated from a 6-mm2 grid composed of 200 horizontal lines containing 200 A-scans. A 3D segmentation algorithm using proprietary software from the University of Iowa (Department of Biomedical Engineering) (18) was used in this study. This software uses neighboring image information from multiple B-scans, which significantly reduces the rate of segmentation error and was successfully used in the OCT arm of the IIHTT (16,17). In secondary analyses, OUS findings were correlated with OCT PPRNFL parameters in all patients. A change in the average PPRNFL thickness of ± 5 mm was used to define papilledema, and a change in the average PPRFNL thickness of ,5 mm was used to define pseudopapilledema. Patients underwent standard workup including MRI and/or LP, as deemed necessary by the examining neuroophthalmologist. Findings suggestive of increased ICP on MRI were empty sella, flattening of the posterior globes, optic nerve sheath distension, and/or transverse sinus stenosis (19). An LP OP of $25 cm H2O was considered elevated. The results of OUS were then correlated with the change (papilledema) or lack of change (pseudopapilledema) on fundus photographs to assess the sensitivity and specificity of OUS for this diagnosis. Patients with optic neuropathies and obvious optic disc drusen were excluded from the study. Statistical analyses were performed with SAS. For categorical variables, P value was calculated using the Fisher exact test, and t tests were used to calculate the P value for continuous variables. 95% confidence intervals (CIs) are provided for continuous variables. The study design was approved by the University of Pennsylvania Institutional Review Board. RESULTS Forty-nine patients met the inclusion criteria and were enrolled in the study. The average age of this population was 36.5 years, and 45 (92%) were women (Table 1). Twenty-five patients were diagnosed with papilledema and 24 patients were diagnosed with pseudopapilledema, based on the change or lack of change of optic disc appearance on fundus photographs, respectively. The most common presenting symptoms were headache and blurred vision, followed by transient visual obscurations and ear ringing that statistically did not differ between the 2 groups (P = 0.08–1). However, more patients in the papilledema group had a history of weight gain (vs pseudopapilledema group, P = 0.04). The average BMI in the papilledema group was greater than that in the pseudopapilledema group, but this was not significant (P = 0.26). Of the 8 patients with papilledema who had negative OUS (32%), most had Grade 2 or more disc edema (Table 2). 207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographics and symptoms of the study population Mean, age (yrs) Women (%) History of weight gain Body mass index (BMI) Blurred vision Headache Whooshing Ear ringing Diplopia Transient visual obscuration All Papilledema (n = 25) Pseudopapilledema (n = 24) P value 36.5 92% 18/49 35.7 25 35 8 14 5 19 33.9 22 (88%) 13 (52%) 37.1 14 (56%) 18 (72%) 4 (16%) 7 (29%) 4 (16%) 13 (52%) 39.2 23 (95%) 5(21%) 34.2 11 (46%) 17 (71%) 4 (17%) 7 (29%) 1 (4%) 6 (25%) 0.16 (95% CI: 212.79 to 2.22) 0.61 0.04 0.26 (95% CI: 22.21 to 8.09) 0.57 1 1 1 0.35 0.08 Ninety-five percent CIs are provided in parentheses for continuous variables. CI, confidence interval. reported signs of increased ICP on MRI. In this cohort, there were 4 patients, all with pseudopapilledema, of whom 2 had positive OUS. The sensitivity of OUS to diagnose papilledema was 68% (17/ 25). Ultrasound was negative in 54% (13/24) of those with pseudopapilledema (Table 3). Correlation of OUS with a change in OCT PPRNFL thickness yielded a sensitivity of 62% (24/39) for papilledema and a specificity of 57% (4/7) for pseudopapilledema (Table 4). OUS was positive in 84% (16/19) of those with MRI findings of increased ICP in both groups (Table 5). Eighteen patients with papilledema underwent LP, and OP was elevated (average: 37.1 cm H2O) in 16. OUS was positive in 15 (94%) of these patients. Thirteen patients with pseudopapilledema underwent LP, and OP was elevated in 10 (average 29.8 cm H2O compared with the papilledema group average OP, P = 0.03, 95% CI [1.327–16.627]), of whom 8 (80%) had positive OUS. Although these 10 patients were classified as having pseudopapilledema according to the study definition, it is probable that they had true papilledema, based on elevated OP measurements. Of the 26 patients with elevated OP in both groups, 88% (23/26) had positive OUS, and 12% (3/26) had negative OUS, demonstrating a higher correlation between elevated OP and positive OUS. Because OUS correlated more strongly with OP than with our definition of papilledema, we looked at the OUS findings in patients who had normal OP on LP and no CONCLUSIONS Our study found that OUS was only moderately sensitive in diagnosing papilledema. Previous studies that assessed the sensitivity and specificity of ancillary tests for papilledema are often limited by the lack of adequate masking and examiner bias. This also underscores the fact that there is currently a lack of universal definition criteria for papilledema and the diagnosis is often made based on clinical judgment, presenting signs and symptoms, and supplementary testing. We acknowledge that a change in optic disc swelling between initial and follow-up visits is not a perfect method to diagnose papilledema because it may be difficult to detect a change in lower grades of disc swelling and/or mild papilledema may not change in the 6-month follow-up interval that was set for study purposes. Some patients, who had an undetectable change in disc swelling, could have been misclassified as having pseudopapilledema, especially when high OP and MRI signs of raised ICP were also observed in the pseudopapilledema group. It is also possible that patients were nonadherent or slow to respond to the treatment regimen, leading to a lack of change of optic TABLE 2. OUS results based on Frisén grading of optic disc swelling Papilledema Frisén Grade of Disc Edema 1 2 3 and above Pseudopapilledema Positive OUS (n = 17) Negative OUS (n = 8) Positive OUS (n = 11) Negative OUS (n = 13) 4/5 (80%) 4/9 (44%) 9/11 (82%) 1/5 (20%) 5/9 (56%) 2/11 (18%) 9/20 (45%) 2/4 (50%) 0% 11/20 (55%) 2/4 (50%) 0% OUS, ocular ultrasonography. 208 Kohli et al: J Neuro-Ophthalmol 2021; 41: 206-211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. OUS results for papilledema and pseudopapilledema Positive OUS Negative OUS Sensitivity of OUS for papilledema Specificity of OUS for pseudopapilledema Papilledema (n = 25) Pseudopapilledema (n = 24) P value 17 (68%) 8 (36%) 11 (46%) 13 (54%) 68% 54% 0.15 OUS, ocular ultrasonography. nerve appearance. Overall, we aimed to choose a definition of papilledema that relied on a feature of the examination alone and not on the results of other ancillary testing methods, which may be prone to bias and error and are not 100% sensitive to diagnose papilledema. In addition, it was important to have the treating neuro-ophthalmologist uninvolved in reviewing funduscopic or OUS data to exclude bias. Having a masked neuro-ophthalmologist view fundus images and correlate the ultrasonographic findings allowed us to reduce bias as much as possible. We agree, however, that interpretation of optic disc edema may also be subject to inconsistencies, even by neuroophthalmologists (20). Although the absence of a detectable change in disc swelling may not define pseudopapilledema during a discrete follow-up period, the presence of a change in disc swelling is perhaps more sensitive in diagnosing papilledema. In this cohort of patients, nearly one-third of patients with papilledema had negative OUS. Therefore, when there is mild disc swelling and the diagnosis of papilledema is the most in question, OUS may have limited utility to rule in or rule out this diagnosis. When a change in optic nerve appearance was noted, suggesting true papilledema, the sensitivity of OUS was lower than that previously reported (85%–92%) (1,2). Second, OUS was only 54% specific for the diagnosis of pseudopapilledema, when defined as no change in disc swelling between initial and follow-up visits. In this group, there were patients who had elevated OP and MRI findings of raised ICP. However, after excluding them, we were left with 4 patients with “true” pseudopapilledema, of whom 2 (50%) had positive OUS. This could be attributed to patulous optic nerve sheaths (21). There were 10 patients with pseudopapilledema who had elevated OP, and 8 of them had negative OUS, suggesting that OUS may have a limited ability to detect changes in the optic nerve sheath width, even in the setting of increased ICP. Overall, this suggests OUS has a low specificity for pseudopapilledema, although the numbers here are small. A previous prospective study of 44 patients, by Neudorfer et al, showed a higher degree of sensitivity (85%) and specificity (63%) of OUS for papilledema, using a similar OUS methodology as used in our study (2). However, the definition of papilledema was based on “earlier and current test results,” including LP and MRI, in addition to the measurement of optic nerve sheath width. This may have allowed clinical biases to impact the ultimate diagnosis. Over a third of patients (36%) with papilledema in our study had optic nerve sheath widths ,3.3 mm, suggesting that optic nerve sheath width alone may not be a reliable measure to indicate true papilledema. Although Neudorfer et al suggested that an optic nerve width cutoff of 3.0 mm increased the sensitivity of OUS for papilledema (2), we found that the average optic nerve sheath width in the pseudopapilledema group was greater than 3.3 mm, indicating that lowering the optic nerve width cutoff may not have increased the diagnostic accuracy of OUS in our study. Furthermore, there were 2 patients with $ Grade 3 optic disc edema, in whom OUS was negative. Change in PPRNFL thickness on OCT is now used with increasing frequency to diagnose and monitor changes objectively in optic disc swelling in those with papilledema. We hypothesized that OUS would be better correlated with a change in PPRNFL thickness. We were surprised to see that in those with .5 mm change in PPRNFL thickness, OUS was positive in only 62%. It is possible that a 5-mm TABLE 4. Sensitivity and specificity of OUS testing when $5-mm change in PPRNFLT by optical coherence tomography (OCT) was used to define papilledema Positive OUS Negative OUS Sensitivity of OUS for papilledema Specificity of OUS for pseudopapilledema Change in PPRNFLT $5 mm (n = 39) Change in PPRNFLT ,5 mm (n = 7) 24 (62%) 15 (37%) 3 (43%) 4 (57%) 62% 57% P value 0.42 OUS, ocular ultrasonography; PRNFLT, peripapillary retinal nerve fiber layer thickness. Kohli et al: J Neuro-Ophthalmol 2021; 41: 206-211 209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 5. Correlation between MRI findings of increased ICP and OP on lumbar puncture with OUS Positive OUS Negative OUS MRI Findings of Increased ICP (n = 19) Elevated OP (.25 cm H2O) (n = 26) 16 (84%) 3 (16%) 23 (88%) 3 (12%) ICP, intracranial pressure; OP, opening pressure; OUS, ocular ultrasonography. change in PPRNFL measurements was within the parameters for interexam variability and did not represent a true change, thereby lowering the correlation with OUS results. However, we used OCT data from the 3D-segmentation software (20), instead of proprietary software, to minimize this inherent variability. The 2 groups were well matched with respect to demographic data. Presence or absence of other ancillary signs and symptoms such as age, gender, BMI, blurred vision, headache, whooshing in ears, ear ringing, diplopia, or transient visual obscurations were not useful to distinguish between the 2 groups. The lack of differences in demographics and symptoms between the 2 groups may represent referral bias that often exists when patients with optic disc swelling are referred for neuro-ophthalmological evaluation. Therefore, presence of symptoms alone is insufficient to make the diagnosis of papilledema. The higher correlation of OUS seen with elevated OP on LP (88%) and with MRI signs of elevated ICP (84%) suggests that there may be a role for OUS in the emergency room and hospital setting to diagnose elevated ICP, although there is no consensus about the normal width of the optic nerve sheath. OUS measurements of optic nerve sheath distension (defined as .5.0 mm) have been used in the emergency department in adults (22) and children (23), as a surrogate for invasive ICP measurements (24,25). One study reported 100% sensitivity of OUS to diagnose pseudopapilledema, when 5.7 mm was used as the upper limit of normal for optic nerve sheath distension (26). There are limitations to our study, as discussed earlier. The small population can limit the generalizability of our data. Furthermore, using fundus photographs to establish a diagnosis of papilledema is also subject to human error and error from variability in the photographs themselves. Nevertheless, using a masked neuro-ophthalmologist to review fundus photographs and OCT data helped circumvent clinician bias that is often inherent in previous studies, secondary to a lack of an objective definition of papilledema. Finally, the effects of weight loss or treatment were not accounted for and may have created errors in classification of subjects into study groups. Overall, clinical judgment and combined results from the examination, ancillary testing, neuroimaging, and/or LP 210 remain the best approach for diagnosing papilledema. The use of OUS as a standalone test to distinguish papilledema from pseudopapilledema may not be as clinically useful as previously thought. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. A. Kohli, M. Pistilli, C. Alfaro, A. G. Ross, I. Jivraj, G. T. Liu, K. S. Shindler, and M. A. Tamhankar; b. Acquisition of data: A. A. Kohli, C. Alfaro, A. G. Ross, I. Jivraj, S. Bagchi, J. Chan, D. May, G. T. Liu, K. S. Shindler, and M. A. Tamhankar; c. Analysis and interpretation of data: A. A. Kohli, M. Pistilli, C. Alfaro, A. G. Ross, I. Jivraj, G. T. Liu, K. S. Shindler, and M. A. Tamhankar. Category 2: a. Drafting the manuscript: A. A. Kohli and M. A. Tamhankar; b. Revising it for intellectual content: A. A. Kohli, A. G. Ross, I. Jivraj, G. T. Liu, K. S. Shindler, and M. A. Tamhankar. Category 3: a. Final approval of the completed manuscript: A. A. Kohli, M. Pistilli, C. Alfaro, A. G. Ross, I. Jivraj, S. Bagchi, J. Chan, D. May, G. T. Liu, K. S. Shindler, and M. A. Tamhankar. REFERENCES 1. Carter SB, Pistilli M, Livingston KG, Gold DR, Volpe NJ, Shindler KS, Liu GT, Tamhankar MA. 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