Papilledema or Pseudopapilledema? Sharpen Your Image Interpretation Skills

Lauren Ditta, MD
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Slideshow

  • Figure 1. An OCT image of this patient’s left eye, along with its corresponding infrared image, demonstrates an example of PHOMS.

  • Figure 2. A fundus photograph of the right eye with superficial drusen at the nasal border of the disc.

  • Figure 3A. An OCT scan shows the patient’s right eye with PHOMS.

  • Figure 3B. This fundus photograph shows the patient’s right eye, which demonstrates blurring of the nasal border of the optic nerve, correlating with PHOMS in that location on the OCT in Figure 3a.

  • Figure 4. This patient’s optic nerve shows high-grade edema. The cup of the disc is obliterated, and the size of the optic nerve itself is expanded. The margins of the disc are blurred, there is vessel obscuration and there are hemorrhages both on the optic nerve and surrounding the nerve. Macular exudates are present. Less obvious are the peripapillary folds seen on the temporal sign of the optic nerve, indicative of papilledema. Note how in this 2-dimensional photo, it is difficult to appreciate disc elevation.

  • Figure 5. A B-scan ultrasound image demonstrates buried drusen.

  • Figure 6. Buried drusen is also visible in the fundus photograph of this pediatric patient’s left eye.

  • Figure 7. In this example of a printout of a volumetric scan of optic nerves, all retinal layers are visible on the OCT image, not just the RNFL,. There is also a marked elevation of the optic nerve in the setting of papilledema.

  • Figure 8. This OCT image of a patient’s left optic nerve shows PHOMS at the nasal border as well as ODD, evidenced by the structure with a hyporeflective, signal-poor core with a complete or partial hyperreflective circumference located anterior to the lamina cribrosa within the nerve substance. Also, note the anomalous vasculature seen in the near infrared image at left.

  • Figure 9. These OCT volume scans demonstrate a reduction in the overall volume of the left optic nerve changes at a follow up visit. Less edema is noted in the left after treatment with a unilateral optic nerve sheath fenestration (ONSF) for high grade papilledema in the clinical setting of an afferent pupillary defect and monocular reduction in vision (image on bottom right). Also noted in this image is the subtle change in the orientation of Bruch’s membrane after the ONSF (bottom right). It is no longer bowed upwards (another possible indication of papilledema) but rather flattened (image bottom right) in comparison to the orientation of Bruch’s membrane in the other images, indicating a reduction in fluid pressure placed on the optic nerve.

  • Figure 10. This fundus autofluorescence image shows bilateral optic nerve drusen in a pediatric patient with bilateral, buried drusen. Drusen were not readily seen when evaluating the optic nerve.

  • Figure 11a. This fundus photograph demonstrates high grade, bilateral papilledema.

  • Figures 11b. This additional fundus photograph of the same eye also demonstrates high grade, bilateral papilledema.

  • Figure 11c. These early IV FA images portray the left and right eyes, respectively. Late IV FA images of the left and right eyes show leakage on the disc, consistent with papilledema.

  • Figures 11d. These early IV FA images portray the left and right eyes, respectively. Late IV FA images of the left and right eyes show leakage on the disc, consistent with papilledema.

  • Figures 11e. These early IV FA images portray the left and right eyes, respectively. Late IV FA images of the left and right eyes show leakage on the disc, consistent with papilledema.

  • Figures 11f. These early IV FA images portray the left and right eyes, respectively. Late IV FA images of the left and right eyes show leakage on the disc, consistent with papilledema.

  • Figures 12a. This early IV FA image of a patient’s right eye shows no leakage.

  • Figures 12b. A late IV FA image of the same patient’s right eye also shows no leakage.

  • Figures 12c. A similar pattern exists in the left eye without leakage. Only a staining defect can be seen at the temporal border of the disc.

  • Figures 12d. A similar pattern exists in the left eye without leakage. Only a staining defect can be seen at the temporal border of the disc.

Differentiating papilledema from pseudopapilledema is a crucial skill, although it can be a challenge. The appearance of mild papilledema can overlap greatly with that of pseudopapilledema, especially in cases of anomalous, pediatric optic nerves. In these situations, it is critical to minimize the risk of misdiagnosing papilledema, as this can result in ocular morbidity and have life-threatening consequences.1-4 At the same time, misdiagnosing pseudopapilledema as papilledema exposes the patient to invasive, expensive, and potentially unnecessary interventions and treatments. There is currently no gold standard algorithm to differentiate these entities; however, we continue to better understand and utilize diagnostic testing to help navigate this diagnostic dilemma. 

Papilledema describes a swelling of the optic nerve secondary to increased intracranial pressure. Pseudopapilledema, conversely, is a clinical situation where ‘apparent’ optic nerve swelling is present, secondary to other causes. Optic disc drusen (ODD), present in about 2% of the population, is widely considered the most common cause of pseudopapilledema.5 ODD are usually present as buried, noncalcified deposits early in life, and become more superficial and calcified with age. Because ODD causes elevation of the optic nerve and blur the optic disc margin, they can be mistaken for papilledema.6-8

Recently, the optical coherence tomography (OCT)-specific imaging phenomenon of peripapillary hyperreflective ovoid mass-like structure (PHOMS), has gained interest and is now considered a common cause of pseudopapilledema in the pediatric population.10,11 

PHOMS is a hyperreflective, ovoid-shaped, localized mass above and adjacent to the Bruch’s membrane opening, external to and extending circumferentially around the opening of the disc substance. PHOMS is visualized on OCT, in particular, enhanced depth imaging OCT (EDI-OCT) (Figure 1), which allows for a more detailed evaluation of the deeper structures of the optic nerve.12 PHOMS has been reported in a number of ophthalmic conditions, including papilledema and pseudopapilledema, often concomitant with drusen.13 Researchers believe PHOMS is a marker of axoplasmic stasis, although the exact pathophysiology remains unknown.13 Like the appearance of a disc with papilledema or ODD, PHOMS is associated with an elevation of the disc, as well as blurring of the disc margin; the disc margin blurring corresponds to the location of the PHOMS visualized on OCT. 

Much research has explored the best clinical diagnostic tests that can safely and reliably confirm papilledema with high specificity for entities of pseudopapilledema.14-19 With a variety of imaging technologies now at our disposal, ophthalmologists can better evaluate the optic nerve in detail and implement treatment strategies specific to imaging findings, and most importantly, individualized for each patient. 

Here, we summarize the use of those diagnostic tools used to better evaluate and differentiate patients with papilledema and pseudopapilledema, as well as offer practical management strategies to allow for optimal care of patients, using tools such as fundus photography, B-scan ultrasound, OCT, fundus auto-fluorescence, and fluorescein angiography.

Fundus Photography

Serial photos of the retina allow for better evaluation of the optic nerve and comparison of changes over time for both the adult and pediatric populations. Because subtle features of papilledema and pseudopapilledema can overlap, having the ability to scrutinize in detail is ideal. With ODD, PHOMS, and papilledema, the nerve can appear full, raised, and have blurred disc margins. To help differentiate, consider the following topographies. 

A disc with ODD may have an irregular, lumpy, bumpy appearance. If superficial, a visible refractive body may be present (Figure 2). In PHOMS, disc margins may appear blurred in a C-shaped partial torus surrounding the disc nasally, superiorly, and inferiorly, often sparing the temporal quadrant, corresponding to the location of the PHOMS on OCT (Figure 3a). The vasculature in a disc with pseudopapilledma can be anomalous, with arteriolar tortuosity, narrowing, or an increased number of vessels on the disc itself; but importantly in pseudopapilledema, the vessels should not be obscured (as obscured vessels are characteristic of true papilledema), and disc hemorrhages should be absent. Additionally, whereas in papilledema there may be concomitant exudate, cotton wool lesions, hemorrhages, or peripapillary wrinkles or retinal folds (Figure 4); these should not be seen in a disc with isolated drusen. Also, these findings have not been reported in isolated PHOMS. 

Finally, in all these entities, there will be elevation of the nerve. But the 2-dimensional nature of the fundus image may fail to capture the degree of elevation. It is, nonetheless, a valuable tool to consider.

B-Scan Ultrasonography

Another tool that can be used to evaluate characteristics of the optic nerve, including elevation, and for the presence of ODD, B-scan ultrasonography has long been the gold standard test for the diagnosis of ODD in adults. Superficial drusen, which is more common within the adult population, are easily seen as an identifiable, calcified lesion that is hyperechoic or hyperreflective with posterior shadowing, maintaining this hyper echogenicity at relatively low gain settings (Figure 5). Buried drusen, which are more commonly seen in children, are less readily seen and can appear nodular and less reflective (as they are not yet calcified) (Figure 6). For buried drusen, other diagnostic modalities may be useful.20

Elevation alone may not be enough to differentiate papilledema and pseudopapilledema by B-scan ultrasonography. But, other anatomic features may be indicative of papilledema — such as a narrow scleral canal, seen in congenitally crowded discs (pseudopapilledema), or fluid signs such as the crescent sign or a widened optic nerve sheath diameter.21 

Technically, image acquisition and diagnostic interpretation with this modality may prove challenging. B-scan ultrasonography has lower resolution than OCT, and investigators debate whether PHOMS can be identified using B-scan ultrasound images. Further research is required to validate this, and therefore OCT is currently the best modality to identify PHOMS.9,21

Optical Coherence Tomography 

Another noninvasive option, OCT allows for several aspects of the optic nerve and peripapillary area to be evaluated in a quantitative nature, including the circumpapillary retinal nerve fiber layer (cpRNFL) thickness — which is the most common measurement obtained when assessing for papilledema — volumetric scans of the optic nerve head (Figure 7), papillary height, and orientation of Bruch’s membrane opening.22 These measurements, either alone or in concert, can often be helpful in discerning papilledema from pseudopapilledema18,21 Additionally, investigators now recognize OCT as an excellent modality for detecting drusen and PHOMS (Figure 8).22

One of the most helpful features of OCT is that it allows for quantitative, longitudinal evaluation of the optic nerve over time, therefore allowing for assessment of disease progression as well as treatment efficacy (Figure 9). Both the cpRNFL thickness and optic nerve head volume are appropriate parameters to evaluate. The cpRNFL can increase with papilledema; however, there is significant overlap in the RNFL thickness measurements in papilledema and pseudopapilledema, and this measurement alone does not adequately discriminate papilledema from pseudopapilledema.23 When there is either marked disc edema or disc elevation, the OCT software has a hard time delimiting the RNFL, and “segmentation errors” arise. Therefore, it is key to be familiar with manual segmentation to get an accurate reading; and, more importantly, clinical decisions cannot be made on this clinical number alone without confirmation that the data acquisition is valid. 

OCT cannot readily differentiate situations where edema is present with concomitant optic atrophy, which is common in cases of chronic papilledema or in the setting of “elevation with atrophy,” known to occur in time with ODD. In these situations, a volumetric scan of the optic nerve head, or obtaining a ganglion cell thickness map, may be of additional value to indicate the health of the optic nerve. While OCT is tremendously useful, it is not yet the gold standard for differentiating papilledema from pseudopapilledema.

Fundus Autofluorescence and Fluorescein Angiography

Fundus autofluorescence (FAF) is a good modality to detect drusen, as it helps objectively establish whether ODD are present or not (Figure 10). However, it requires patient dilation and uses a bright light for image capture, which can be challenging for pediatric patients. If drusen are buried, FAF may not always detect them.

Fluorescein angiography (FA) (intravenous or oral), may be one of the most helpful tools in discriminating true papilledema from pseudopapilledema, especially when other modalities are equivocal. In papilledema, there should be leakage of the fluorescein into the optic disc. Leakage should occur early in the study with borders of leakage expanding and increasing in intensity throughout the study (Figures 11a to 11f). This pattern, combined with RNFL opacification and obscuration of the blood vessels, would confirm papilledema and prompt further diagnostic evaluation. ODD, on the other hand, may show early and late nodular staining without leakage. There should be no expansion of the borders of the dye, but rather, increased intensity of the dye confined within the same area as the study progresses (Figures 12a to 12d).23 

Note that drusen and edema can coexist. The advantage of FA is that, if there is an absence of leakage, superimposed optic nerve edema can often be excluded. However, FA, can at times, be hard to interpret, particularly differentiating mild leakage from staining patterns. This is, in part, due to the degree of optic disc leakage on FA, which corresponds to the grade of papilledema. In eyes with mild papilledema, leakage can be difficult to distinguish from staining.24 

In instances when clinical diagnostic testing fails to sufficiently provide an answer or at least some direction as to the next steps for diagnosis and treatment, or if in-office testing is limited, it may be beneficial to consult with a neuro-ophthalmology specialist or neurology colleague. In the absence of immediate concern for visual deficits, a good approach may be to closely follow changes in the optic nerve at sequential visits. This approach is practical and builds trust with your patient and patient families, if more invasive testing may be needed in the future. When close observation of the optic nerve in this manner is employed, a period of 6 months is usually the minimum amount of time needed to observe for any changes or confirm stability. However each case should be individualized, and when there is either a subjective or objective decline in vision, the emergence of subtle visual field defects, or a new afferent pupillary defect, immediate intervention is warranted to prevent permanent vision loss. 

Keep in mind that, in early papilledema, even when high grade, a patient’s visual acuity may be normal, and the patient may be asymptomatic. So, be cautiously aware of the 20/20 visual acuity patient who is at risk for permanent blindness. This is especially true of patients who may have a constricted visual field but remain with a 20/20 visual acuity.

Take A Multipronged Approach

Even with all these resources at our disposal, the final diagnosis and treatment plan is only as good as the clinician interpretation of the diagnostic testing and overall sense of the patient’s status. A combination of techniques, with some serving as more primary methods and others as confirmatory or serving in a trouble-shooting capacity, may offer the best sensitivity and specificity. However, such an algorithm has not yet been validated, and each technique needs to be able to be generalizable. Some have postulated artificial intelligence deep learning systems will be the tool that really changes how we identify and classify optic nerves.25 

Until then, ophthalmologists will continue to dutifully parse the nuances of the technologies that are available to make decisions in the best interest of our patients.

Lauren Ditta, MD, is a pediatric neuro-ophthalmologist with the Department of Ophthalmology at the University of Tennessee Health Science Center, Hamilton Eye Institute, Le Bonheur and St. Jude Children’s Research Hospitals.

References

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2. Shams PN, Davies NP. Pseudopapilloedema and optic disc haemorrhages in a child misdiagnosed as optic disc swelling. Br J Ophthalmol. 2010;94(10):1398–1399. doi:10.1136/bjo.2008.148700

3. Rigi M, Almarzouqi SJ, Morgan ML, Lee AG. Papilledema: epidemiology, etiology, and clinical management. Eye Brain. 2015;7(8):47–57. doi:10.2147/EB.S69174

4. Smith CG,  Ditta LC, Choudhri AF, Zhang J. Primary diffuse leptomeningeal glioneuronal tumor presenting as bilateral vision loss. J Neuroophthalmol. Published online August 4, 2021. doi:10.1097/WNO.0000000000001359 

5. Malmqvist L, Li XQ, Hansen MH, et al. Progression over 5 years of prelaminar hyperreflective lines to optic disc drusen in the Copenhagen Child Cohort 2000 Eye Study. J. Neuroophthalmol. 2020;40(3):315-321. doi:10.1097/WNO.0000000000000911

6. Braun A, Doniger SJ. Point-of-care ultrasonography for the identification of 2 children with optic disc drusen mimicking papilledema. Pediatr Emerg Care. 2014;30(7):505–507. doi:10.1097/PEC.0000000000000172

7. Sahin A, Cingu AK, Ari S, Cinar Y, Caca I. Bilateral optic disc drusen mimicking papilledema. J Clin Neurol. 2012;8(2):151–154. doi:10.3988/jcn.2012.8.2.151 

8. Rott D, Leibowitz D. Optic nerve head drusen mimicking papilledema and malignant hypertension. Eur J Intern Med. 2009;20:e112–e113. doi:10.1016/j.ejim.2008.09.019

9. Fraser JA, Sibony PA, Petzold A, Thaung C, Hamann S. Peripapillary hyper-reflective ovoid mass-like structure (PHOMS): an optical coherence tomography marker of axoplasmic stasis in the optic nerve head. J Neuroophthalmol. 2021;41(4):431–441. doi:10.1097/WNO.0000000000001203

10. Behrens C. Peripapillary hyperreflective ovoid mass-like structures (PHOMS) in a child cohort. In:Proceedings of the North American Neuro-Ophthalmology Society. Austin, Texas; 2022.

11. Mezad-Koursh D, Klein A, Rosenblatt A, et al. Peripapillary hyperreflective ovoid mass-like structures—a novel entity as frequent cause of pseudopapilloedema in children. Eye (Lond). 2021;35(4):1228–34. doi:0.1038/s41433-020-1067-x

12. Fraser JA, Hamann SA. 360-degree peripapillary hyper- reflective ovoid mass-like structure (PHOMS). Can J Ophthalmol. 2021;56(2):146. doi:10.1016/j.jcjo.2020.09.008

13. Ahn YJ, Park YY, Shin SY. Peripapillary hyperreflective ovoid mass-like structures (PHOMS) in children. Eye (Lond). Published online March 17, 2021. doi:10.1038/s41433-021-01461-w

14. Bassi ST, Mohana KP. Optical coherence tomography in papilledema and pseudopapilledema with and without optic nerve head drusen. Ind J Ophthalmol. 2014;62(12):1146–51. doi:10.4103/0301-4738.149136

15. Farazdaghi MK, Trimboli-Heidler C, Liu GT, Garcia A, Ying G-S, Avery RA. Utility of ultrasound and optical coherence tomography in differentiating between papilledema and pseudopapilledema in children. J Neuroophthalmol. 2021;41(4):488-495. doi:10.1097/WNO.0000000000001248

16. Chiu HH, Yang FP, VandenHoven C, Wan MJ. Utility of spectral domain OCT in differentiating optic disc drusen from papilledema in children. Can J Ophthalmol. 2021;56(4):250–255. doi:10.1016/j.jcjo.2020.12.003

17. Thompson A, Bhatti MT, El Dairi MA. Bruch’s membrane opening on optical coherence tomography in pediatric papilledema and pseudopapilledema. JAAPOS. 2018;22(1):38-43.e3. doi:10.1016/j.jaapos.2017.09.003

18. Chang MY, Velez FG, Demer JL, et al. Accuracy of diagnostic imaging modalities for classifying pediatric eyes as papilledema versus pseudopapilledema. Ophthalmol. 2017;124(12):1839-1848. doi: 10.1016/j.ophtha.2017.06.016

19. Chang MY, Binenbaum G, Heidary G. Imaging methods for differentiating pediatric papilledema from pseudopapilledema: a report by the American Academy of Ophthalmology. Ophthalmol. 2020;127(10):1416-1423. doi:10.1016/j.ophtha.2020.03.027

20. Kurz-Levin MM, Landau K. A comparison of imaging techniques for diagnosing drusen of the optic nerve head. Arch Ophthalmol. 1999;117(8):1045-1049. doi:10.1001/archopht.117.8.1045

21. Farazdaghi MK, Trimboli-Heidler C, Liu GT, Garcia A, Ying G-S, Avery RA. Utility of ultrasound and optical coherence tomography in differentiating between papilledema and pseudopapilledema in children. J Neuroophthalmol. 2021;41(4):488–95. doi:10.1097/WNO.0000000000001248

22. Malmqvist L, Bursztyn L, Costello F, et al. The Optic Disc Drusen Studies Consortium recommendations for diagnosis of optic disc drusen using optical coherence tomography. J Neuroophthalmol. 2018;38(3):299–307. doi:10.1097/WNO.0000000000000585

23. Pineles SL, Arnold AC. Fluorescein angiographic identification of optic disc drusen with and without optic disc edema. J Neuroophthalmol. 2012;32(1):17-22. doi:10.1097/WNO.0b013e31823010b8 

24. Hayreh SS. Pathogenesis of optic disc edema in raised intra- cranial pressure. Prog Retin Eye Res. 2016;50:108-144. doi:10.1016/j.preteyeres.2015.10.001 

25. Biousse V, Newman NJ, Najjar RP, et al. Optic disc classification by deep learning versus expert neuro-ophthalmologists. Ann Neuro. 2020;88(4):785–95. doi:10.1002/ana.25839

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