Differentiating between papilledema and pseudopapilledema is a common and difficult clinical conundrum. Although the conditions appear similar on fundoscopy, the systemic implications are vastly different. Papilledema is a sign of increased intracranial pressure, and workup involves neuroimaging and/or lumbar puncture, which frequently require sedation in children. Pseudopapilledema is typically isolated and does not necessitate neurologic workup. Most children who are initially referred for papilledema are ultimately diagnosed with pseudopapilledema. Differentiating between pediatric papilledema and pseudopapilledema relies on a careful history, thorough examination, and use of ancillary diagnostic tests such as fundus photography, autofluorescence, ultrasonography, fluorescein angiography, and optical coherence tomography.
Key points
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Papilledema and pseudopapilledema can be difficult to differentiate in children, but correct diagnosis is critical to ensure appropriate workup and timely identification of any underlying neurologic condition.
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Ancillary ophthalmic imaging tests such as fundus photography, autofluorescence, ultrasonography, fluorescein angiography, and optical coherence tomography have varying accuracy in differentiating pediatric papilledema and pseudopapilledema.
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Neuroimaging, lumbar puncture, and longitudinal follow-up may be required for definitive diagnosis.
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Artificial intelligence shows promise as an adjunctive tool in the diagnostic workup for pediatric papilledema and pseudopapilledema.
Background
Papilledema is defined as pathologic swelling of the optic nerve due to increased intracranial pressure (ICP). Papilledema can signify life-threatening disorders such as brain tumors or meningitis, as well as vision-threatening disorders such as pseudotumor cerebri syndrome [ ]. The diagnostic workup for suspected papilledema includes neuroimaging and lumbar puncture, which may require sedation in young patients [ ]. Pseudopapilledema, on the other hand, has a similar optic disc appearance, with elevation of the optic nerve head and/or blurring of the margins ( Fig. 1 A, B). However, pseudopapilledema has different clinical implications than papilledema, as it is usually due to structural conditions such as optic disc drusen (ODD), which are not associated with an underlying neurologic disorder [ ]. More than half of children who are referred for papilledema ultimately are found to have pseudopapilledema [ ]. While distinguishing papilledema from pseudopapilledema can be challenging, it is critical to differentiate the 2 diagnoses because (1) misdiagnosing papilledema as pseudopapilledema may lead to a failure to identify a life-threatening diagnosis and (2) misdiagnosing pseudopapilledema as papilledema may subject children to unnecessary and invasive testing.
Pseudopapilledema can be caused by ODD, tilted optic nerves as seen in myopia, small crowded optic nerves (especially in hyperopic eyes), myelinated retinal nerve fiber layers, anomalous optic nerves, and prior (resolved) papilledema, which can cause gliosis [ ]. The most common cause of pseudopapilledema in children is ODD, which are proteinaceous deposits that calcify and migrate superficially within the optic nerve head over time [ ]. Buried ODD cannot be directly visualized due to obscuration by overlying tissue, and they are more likely to be mistaken for papilledema than superficial ODD [ ]. Non-calcified ODD are more difficult to detect because some ophthalmic imaging techniques (such as B-scan ultrasonography) rely on the presence of calcium to identify ODD. Compared to adults, ODD in children are more difficult to distinguish from papilledema because they are more frequently buried and non-calcified. This review will focus on pseudopapilledema due to ODD, since this is the most common clinical scenario.
Significance
Differentiation of papilledema and pseudopapilledema in children begins with a careful history and ophthalmologic examination. Ophthalmic imaging techniques, including fundus photography, autofluorescence, ultrasonography, fluorescein angiography (FA), and optical coherence tomography (OCT), may aid in distinguishing the diagnoses. Ultimately, some children may require definitive workup including neuroimaging and lumbar puncture. To avoid the sedation required for these tests, close observation is an option for children with a low suspicion of true papilledema.
History
Symptoms of increased ICP and papilledema include postural headaches, nausea, vomiting, pulsatile tinnitus, diplopia, and transient visual obscurations or visual graying episodes. Clinicians should ask about risk factors for pseudotumor cerebri syndrome, including weight gain, conditions that lead to hypercoagulability, and use of medications associated with secondary pseudotumor cerebri syndrome [ ]. Other neurologic symptoms suggestive of a neurologic condition causing papilledema include ataxia, weakness, and loss of sensation [ ]. In children, the majority of intracranial tumors are located infratentorially [ ]; therefore, clinicians should specifically ask about symptoms of cerebellar dysfunction such as discoordination and gait abnormalities.
Most children with pseudopapilledema do not have symptoms from their condition since pseudopapilledema is not associated with an underlying neurologic diagnosis. However, some children with ODD experience transient visual obscurations [ , ]. Headaches frequently are reported by children with pseudopapilledema, because they are a common and nonspecific symptom [ ]. Therefore, the presence of headaches alone is insufficient to differentiate papilledema from pseudopapilledema.
Fundus examination
Papilledema presents with a variety of mechanical and vascular signs including elevation of the optic nerve head, blurring of the disc margin and retinal vessels, venous engorgement, and capillary leakage [ , ]. In a study primarily including adults with suspicious optic nerves, Carta and colleagues [ ] identified 4 clinical features that had the greatest accuracy in identifying papilledema on fundoscopy: (1) swelling indicating thickening of the peripapillary retinal nerve fiber layer (RNFL), (2) peripapillary hemorrhages, (3) elevation of the optic nerve head anteriorly, and (4) congestion of the arcuate and peripapillary venous vessels. The combination of these features had an accuracy of 93%, a sensitivity of 95%, and a specificity of 89% for detecting papilledema. Retinal and choroidal folds seen were considered pathognomonic for papilledema because they were not seen in cases with pseudopapilledema (100% specificity), but sensitivity was low (23%). However, the constellation of these findings is less reliable for identifying papilledema in a pediatric cohort, since buried ODD, which are more common in children, are typically associated with elevation of the optic nerve head [ ] and also may be associated with hemorrhages and vascular abnormalities.
Fundoscopic signs of ODD include excessive branching and coiling of the retinal vessels and a ‘lumpy bumpy appearance’ in the case of superficial ODD [ , ]. It may be possible to detect buried ODD with oblique illumination on ophthalmoscopy, but this has varying success [ ]. ODD may be associated with peripapillary, subretinal, intraretinal, pre-retinal, or vitreous hemorrhages. However, multiple intraretinal or vitreous hemorrhages occur more frequently in papilledema than pseudopapilledema [ ].
Spontaneous venous pulsations (SVPs) are another distinguishing feature between papilledema and pseudopapilledema. It is hypothesized that increased ICP causes loss of SVPs due to the collapse of the central retinal vein within the optic nerve sheath, where ICP from the subarachnoid space is transmitted. Levin examined 146 subjects (aged 20–90 years) without signs or symptoms of increased ICP, and 87.6% were noted to have SVPs. 100% of the subjects with elevated ICP were found to have no SVPs. He reported that these pulsations stop with ICP levels greater than 190 to 195 mmH 2 O [ ]. The presence of SVPs suggests that true papilledema is highly unlikely, whereas the absence of SVPs may be associated with either papilledema or pseudopapilledema.
Fundus photography
Some children may only cooperate with a brief ophthalmoscopic examination; in such cases, fundus photography may be helpful to obtain a more detailed assessment of the optic nerve appearance. However, fundus photography alone has limited utility in distinguishing between pseudopapilledema due to buried ODD and true papilledema in children. A prospective, multi-modal imaging study found that the accuracy of masked expert examiners in differentiating these 2 diagnoses in children using isolated fundus photographs was low (53%) [ ]. However, documenting the optic nerve appearance with fundus photography may be useful to identify longitudinal changes.
Fundus autofluorescence
On autofluorescence, superficial ODD appear as irregular hyperautofluorescent lesions on the optic nerve head ( Fig. 2 ) [ ]. Buried ODD may not be detectable on autofluorescence because of attenuation caused by overlying tissue [ ]. In a study of children with ultrasound-positive ODD (indicating calcification), autofluorescence was positive in 94% of cases [ ]. However, because ODD are frequently buried and non-calcified in children, the overall accuracy of detecting pediatric ODD is lower (62% in 1 study) [ ]. Positive fundus autofluorescence is suggestive of ODD as a cause of pseudopapilledema, but negative autofluorescence may be seen in either pseudopapilledema or true papilledema.
Ultrasonography
Ultrasonography has been used in various ways to differentiate papilledema from pseudopapilledema. A-scan ultrasonography can measure optic nerve sheath diameter (ONSD), which is increased in papilledema due to fluid in the subarachnoid space around the optic nerve. Additionally, A-scan and B-scan ultrasonography may be used to perform the 30° test, in which the change in width of the ONSD is measured at 30° of lateral gaze. In papilledema, there is a reduction in the ONSD with eccentric gaze due to the redistribution of fluid in the setting of edema. Finally, B-scan ultrasonography may be used to detect calcified ODD.
Although the average ONSD is higher in papilledema than pseudopapilledema, there is overlap and the optimal cutoff to be used in the diagnosis of papilledema in children is unknown. Ballantyne and colleagues [ ] suggested a threshold of 4 mm in infants (aged 1 year and younger) and 4.5 mm in older children [ , ]. Padayachy and colleagues [ ] recommended a threshold of 5.16 mm in infants and 5.75 mm in older children. Fontanel and colleagues [ ] published evidence for thresholds of 4.1 mm in children 4 to 10 years of age and 4.4 mm in children 11 to 18 years of age. A literature review by Cannata and colleagues [ ] concluded that it was difficult to establish a reliable ONSD cutoff for elevated ICP due to variability among the published studies in ultrasonographic measurement techniques and methodological approaches.
In the 30° test, a reduction of ONSD by more than 10% from the primary position to 30° of eccentric gaze is considered a marker of elevated ICP. The 30° test has not been specifically studied in children with suspected papilledema. However, in a study of older individuals with papilledema and pseudopapilledema (mean age 29 years), Saenz and colleagues [ ] reported that there was a larger percent reduction in ONSD on the 30° test in patients with papilledema (22%) than in pseudopapilledema (8.6%). They reported that the 30° test had a sensitivity of 91.3% and a specificity of 71.4% in detecting papilledema.
Finally, B-scan ultrasonography may be used to detect ODD, the most common cause of pseudopapilledema [ ]. Calcified ODD on ultrasonography appear as hyperechoic structures on the optic nerve head with posterior shadowing ( Fig. 3 ). However, in pediatric patients, ODD are often non-calcified, appearing on B-scan ultrasonography as elevation of the optic nerve head without hyperechogenicity or posterior shadowing, similar to papilledema. In a study of B-scan ultrasonography for differentiating papilledema and pseudopapilledema in children based on hyperechogenicity of the optic nerve head, ultrasonography achieved an accuracy of 74%. The investigators found that 60% of eyes with papilledema were misinterpreted as pseudopapilledema [ ], whereas 12% of eyes with pseudopapilledema were misinterpreted as papilledema.
Overall, the advantage of ultrasonography in young children is that less cooperation is required, and identification of calcified ODD on B-scan ultrasound is suggestive of a diagnosis of pseudopapilledema rather than papilledema. Additional studies are required to determine the optimal cutoff for ONSD to differentiate between papilledema and pseudopapilledema in children, and to assess the accuracy of the 30° test in this population.
Fluorescein angiography
On FA, eyes with papilledema have the appearance of early and late hyperfluorescence that increases in area over time, indicating leakage [ ]. The degree of optic disc leakage corresponds to the severity of papilledema [ ]. In eyes with superficial ODD, early and late nodular staining of the optic nerve occurs. Buried ODD may be characterized by the absence of hyperfluorescence or late circumferential peripapillary staining [ ].
Chang and colleagues [ ] found that FA had the greatest accuracy in differentiating papilledema from pseudopapilledema in a study comparing B-scan ultrasound, autofluorescence, fundus photography, and OCT. In their study of 19 pediatric subjects, 5 had papilledema, 11 had pseudopapilledema secondary to buried ODD, and 3 had pseudopapilledema secondary to superficial ODD. FA was found to have 97% accuracy in distinguishing papilledema from pseudopapilledema, and no cases of papilledema were misinterpreted as pseudopapilledema. However, this study did not assess papilledema grade, and it is unknown if FA has similar accuracy when evaluating milder cases of papilledema [ ].
FA also can identify optic disc edema superimposed on ODD. Pineles and colleagues [ ] reported that the FA characteristics of eyes with both diagnoses were late nodular hyperfluorescence in addition to leakage. In children with demonstrable ODD as well as symptoms of increased ICP, FA may assist in clarifying whether superimposed edema is present.
The preceding studies utilized intravenous FA (IVFA), which may be difficult to obtain in children. Oral FA (OFA) is easier to administer but has lower image quality. Elhusseiny and colleagues [ ] reported that the accuracy of OFA in differentiating pseudopapilledema and papilledema in children was 62% to 69%. Sensitivity improved as Frisen grade increased. These findings suggest that OFA may be inferior to IVFA in differentiating papilledema from pseudopapilledema in children.
Given the high accuracy but invasive nature of IVFA, this test may be most useful if the diagnosis remains uncertain after other ophthalmic imaging techniques are performed. Clinicians must be aware that the absence of leakage on IVFA does not completely rule out the possibility of true papilledema, especially in cases of apparently mild swelling.
Optical coherence tomography
Various OCT measures have been investigated for differentiating papilledema from pseudopapilledema in children. Initial studies focused on the thickness of the peripapillary RNFL, which is increased in papilledema. However, pseudopapilledema may be associated with decreased, normal, or increased RNFL thickness (typically decreased in superficial ODD and increased in buried ODD), so measurements overlap between papilledema and pseudopapilledema [ ]. The Optic Disc Drusen Studies (ODDS) Consortium has noted that the thickness of the RNFL on OCT is unreliable in differentiating between papilledema and pseudopapilledema [ ]. Other OCT parameters that have been used to distinguish between papilledema and pseudopapilledema include (1) identification of ODD on OCT line scans, (2) the presence of retinal or choroidal folds, which are suggestive of papilledema, and (3) changes to Bruch’s membrane (BM), which includes anterior bowing and increased width of BM opening at the optic nerve head in papilledema.
The ODDS Consortium has defined the OCT appearance of ODD as hyporeflective structures with a partial or full hyperreflective margin, with hyperreflectivity most commonly seen superiorly ( Fig. 4 ) [ ]. With the use of enhanced depth imaging (EDI)-OCT, even buried ODD may be detected. Studies primarily in adults suggest that EDI-OCT has the highest sensitivity and accuracy of ophthalmic imaging modalities for identifying ODD [ ]. Youn and colleagues [ ] found that the accuracy of EDI-OCT was 97% for ODD detection, which was higher than fundus autofluorescence (92%), ultrasonography (86%), and fundus photography (66%).
