The distinction between papilledema and pseudopapilledema is important in clinical practice; however, differential diagnosis can be challenging, especially between incipient papilledema and occult optic disc drusen. Papilledema, defined as optic disc swelling secondary to elevated intracranial pressure, represents a potentially vision-threatening condition requiring urgent investigation and treatment.1,2 The pathophysiology involves transmission of elevated cerebrospinal fluid pressure through the optic nerve sheath, resulting in axoplasmic flow stasis and subsequent optic nerve head swelling. Untreated papilledema can lead to progressive visual field loss and irreversible blindness, making accurate and timely diagnosis critical.1–3

Pseudopapilledema, most commonly caused by optic disc drusen (ODD), mimics true disc edema but lacks the underlying elevated intracranial pressure. ODD are acellular calcified deposits occurring in up to 2.4% of the population, typically developing in small, crowded optic discs. In children, ODD are often buried within the optic nerve head tissue and uncalcified, making differentiation from true papilledema particularly challenging. Misdiagnosis can lead to unnecessary invasive investigations in cases of pseudopapilledema or delayed treatment of life-threatening conditions in true papilledema.4–6

Several diagnostic modalities are currently used to detect papilledema, including fundus examination, fluorescein angiography, autofluorescence, monochromatic filters, optical coherence tomography (OCT) and ocular ultrasound.6 Spectral-domain OCT has emerged as a valuable tool, with studies demonstrating that peripapillary retinal nerve fiber layer (RNFL) thickness, total retinal thickness, and optic nerve head volume are significantly increased in papilledema compared to pseudopapilledema.6,7 Enhanced depth imaging OCT (EDI-OCT) is particularly useful for distinguishing true optic disc edema from pseudopapilledema secondary to ODD, which appear as hyporeflective masses with hyperreflective borders.8

The presence of vascular abnormalities has been observed in both papilledema and pseudopapilledema.4,9 Classically, retinal vascularization has been studied by fluorescein angiography, but the recent introduction of optical coherence tomography angiography (OCTA) has allowed non-invasive assessment and quantification of macular and peripapillary retinal vessels. OCTA is a motion-contrast imaging technique that detects blood flow by analyzing the variable backscattering of light from moving erythrocytes, providing depth-resolved, high-resolution vascular images without the need for dye injection.10,11

Recent studies have demonstrated distinct OCTA patterns in papilledema versus pseudopapilledema. In papilledema, peripapillary capillary density is not significantly different from healthy controls when using customized software to remove major vessels.11 Conversely, in pseudopapilledema due to ODD, peripapillary capillary density is significantly reduced compared to both healthy controls and papilledema eyes, particularly in the nasal sector.11,12 The reduction in vessel density in ODD correlates with RNFL defects and visual field loss.12,13

This study aims to evaluate peripapillary vascular flow and perfusion using OCTA in the differential diagnosis of papilledema and pseudopapilledema.

We selected 76 patients, of whom 65 were finally included in the study, with a mean age of 36.5 years (SD 22.9) and with a predominance of women (41, 63.1%) (Fig. 1).

Fig. 1.

Flow diagram.

The papilledema group included 14 patients (28 eyes, mean age 37.1 years, 9 women): 11 idiopathic intracranial hypertension, 3 intracranial tumors (2 meningioma, 1 brain metastases). Frisen grades: grade 1 (n = 8 eyes), grade 2 (n = 14 eyes), grade 3 (n = 6 eyes). OCTA imaging was performed before the lumbar puncture and prior to receiving any treatment. The mean CSF pressure was 33.2 cmH2O (range 26–48). All patients underwent brain CT and MRI and 4 of them underwent angioMRI.

The pseudopapilledema group included 51 patients (95 eyes, mean age 36.4 years, 32 women): 36 patients with optic nerve head drusen (27 eyes with visible drusen and 41 eyes with hidden drusen) and 15 patients with other pseudopapilledema (24 pseudopapilledema without drusen, 2 eyes Bergmeister's papilla and 1 eye myelinated nerve fibers). Median follow-up was 8.2 months (range 6–18 months). During follow-up, no diagnoses changed, confirming diagnostic stability (Fig. 2).

Fig. 2.

Pseudopapilledema (occult optic disc drusen) (1): 20° Color retinography.(1A); OCT-HD Edi (1 B); ONH Angiography 4.5 × 4.5 mm, Angioplex RPC(1C). Papilledema (2): 20° Color retinography.(2A); OCT-HD Edi (2 B); ONH Angiography 4.5 × 4.5 mm, Angioplex RPC(2C).

No significant differences between the two groups were observed for age (p = 0.792) or gender (p = 0.916) (Table 1).

Results of diagnostic tests

ROC curve analysis of vascular flux index showed an area under the curve (AUC) of 0.683 for mean flow (95% CI 0.518–0.848), with a sensitivity (S) of 76.9% and a specificity (E) of 58.8%, and with a cut-off of 0.461 (Fig. 3). The sensitivity and specificity with the best Youden index for flow by sector were as follows: inferior flow (S = 71.4%; E = 62.7%), superior flow (S = 63.3%; E = 76.5%), nasal flow (S = 69.2%; E = 68.6%) and temporal flow (S = 50.0%; E = 78.4%) (Table 4A).

Fig. 3.

Receiver operating characteristic curve analysis of peripapillary vascular flow (flux index) (average, inferior, superior, nasal and temporal).

Table 4A.

Sensitivity and specificity of peripapillary flux index (flow) by OCTA. AUC = area under the curve. 95%CI = 95% confidence interval.

	ROC CURVE			Criteria cut point S > 80%		Criteria cut point Max I. Youden
Test Result Variable(s)	AUC	95%CI	Index	Value	95%CI	Value	95%CI
Average Flow	0.683	0.518- 0.848	Cut point	0.442		0.461
			Sensitivity	84.6%	54.6–98.1%	76.9%	46.2–95.0%
			Specificity	35.3%	22.4–49.9%	58.8%	44.2–72.4%
			Likelihood ratio (+)	1.31	0.96–1.78	1.87	1.20–2.91
			Likelihood ratio (-)	0.44	0.12–1.64	0.39	0.14–1.09
			Positive predictive value	25.0%	13.2–40.3%	32.3%	16.7–51.4%
			Negative predictive value	90.0%	68.3–98.8%	90.9%	75.7–98.1%
Inferior Flow	0.662	0.498- 0.827	Cut point	0.439		0.455
			Sensitivity	85.7%	57.2–98.2%	71.4%	41.9–91.6%
			Specificity	33.3%	20.8–47.9%	62.7%	48.1–75.9%
			Likelihood ratio (+)	1.29	0.96–1.72	1.92	1.18–3.12
			Likelihood ratio (-)	0.43	0.11–1.64	0.46	0.19–1.07
			Positive predictive value	26.1%	14.3–41.1%	34.5%	17.9–54.3%
			Negative predictive value	89.5%	66.9–98.7%	88.9%	73.9–96.9%
Superior Flow	0.676	0.516- 0.835	Cut point	0.429		0.460
			Sensitivity	85.7%	57.2–98.2%	64.3%	35.1–87.2%
			Specificity	35.3%	22.4–49.9%	76.5%	62.5–87.2%
			Likelihood ratio (+)	1.32	0.99–1.78	2.73	1.45–5.13
			Likelihood ratio (-)	0.41	0.11–1.54	0.47	0.23–0.96
			Positive predictive value	26.7%	14.6–41.9%	42.9%	21.8–66.0%
			Negative predictive value	90.0%	68.3–98.8%	88.6%	75.4–96.2%
NasalFlow	0.719	0.558- 0.881	Cut point	0.446		0.480
			Sensitivity	84.6%	54.6–98.1%	69.2%	38.6–90.9%
			Specificity	41.2%	27.6–55.8%	68.6%	54.1–80.9%
			Likelihood ratio (+)	1.44	1.04–1.99	2.21	1.28–3.80
			Likelihood ratio (-)	0.37	0.10–1.39	0.45	0.19–1.03
			Positive predictive value	26.8%	14.2–42.9%	36.0%	18.0–57.5%
			Negative predictive value	91.3%	72.0–98.9%	89.7%	75.8–97.1%
Temporal Flow	0.653	0.480–0.826	Cut point	0.459		0.500
			Sensitivity	83.3%	51.6–97.9%	50.0%	21.1–78.9%
			Specificity	43.1%	29.3–57.8%	78.4%	64.7–88.7%
			Likelihood ratio (+)	1.47	1.03–2.08	2.32	1.07–5.01
			Likelihood ratio (-)	0.39	0.11–1.42	0.64	0.36–1.14
			Positive predictive value	25.6%	13.0–42.1%	35.3%	14.2–61.7%
			Negative predictive value	91.7%	73.0–99.0%	87.0%	73.7–95.1%

Eyes with analyzable data ranged from 12–14 for papilledema and 51 for pseudopapilledema.

ROC curve analysis showed an AUC of 0.665 for mean perfusion (95% CI 0.492–0.838), with a sensitivity of 53.8% and specificity of 76.5%, and with a cut-off of 44.250% (Fig. 4). The sensitivity and specificity with the best Youden index for perfusion by sector were as follows: inferior (S = 35.7%; E = 88.2%), superior (S = 85.7%; E = 45.1%), nasal (S = 76.9%; E = 60.8%) and temporal (S = 50.0%; E = 70.6%) (Table 4B).

Fig. 4.

Receiver operating characteristic curve analysis of peripapillary vascular perfusion (average, inferior, superior, nasal and temporal).

Table 4B.

Sensitivity and specificity of peripapillary perfusion by OCTA. AUC = area under the curve. 95%CI = 95% confidence interval.

	ROC CURVE			Criteria cut point S > 80%		Criteria cut point Max I. Youden
Test Result Variable(s)	AUC	95%CI	Index	Value	95%CI	Value	95%CI
Average Perfusion	0.665	0.492–0.838	Cut point	42.650		44.250
			Sensitivity	84.6%	54.6–98.1%	53.8%	25.1–80.8%
			Specificity	35.3%	22.4–49.9%	76.5%	62.5–87.2%
			Likelihood ratio (+)	1.31	0.96- 1.78	2.29	1.13–4.63
			Likelihood ratio (-)	0.44	0.12- 1.64	0.60	0.33–1.11
			Positive predictive value	25.0%	13.2–40.3%	36.8%	16.3–61.6%
			Negative predictive value	90.0%	68.3–98.8%	86.7%	73.2–94.9%
Inferior Perfusion	0.595	0.414–0.777	Cut point	41.150		46.900
			Sensitivity	85.7%	57.2–98.2%	35.7%	12.8–64.9%
			Specificity	25.5%	14.3–39.6%	88.2%	76.1–95.6%
			Likelihood ratio (+)	1.15	0.88–1.50	3.04	1.08–8.49
			Likelihood ratio (-)	0.56	0.14–2.20	0.73	0.49–1.09
			Positive predictive value	24.0%	13.1–38.2%	45.5%	16.7–76.6%
			Negative predictive value	86.7%	59.5–98.3%	83.3%	70.7–92.1%
Superior Perfusion	0.635	0.481–0789	Cut point	40.950		40.950
			Sensitivity	85.7%	57.2–98.2%	85.7%	57.2–98.2%
			Specificity	45.1%	31.1–59.7%	45.1%	31.1–59.7%
			Likelihood ratio (+)	1.56	1.12–2.17	1.56	1.12–2.17
			Likelihood ratio (-)	0.32	0.08–1.18	0.32	0.08–1.18
			Positive predictive value	30.0%	16.6–46.5%	30.0%	16.6–46.5%
			Negative predictive value	92.0%	74.0–99.0%	92.0%	74.0–99.0%
NasalPerfusion	0.683	0.508–0857	Cut point	41.550		42.100
			Sensitivity	84.6%	54.6–98.1%	76.9%	46.2–95.0%
			Specificity	51.0%	36.6–65.2%	60.8%	46.1–74.2%
			Likelihood ratio (+)	1.73	1.20–2.48	1.96	1.25–3.09
			Likelihood ratio (-)	0.30	0.08–1.11	0.38	0.14–1.05
			Positive predictive value	30.6%	16.3–48.1%	33.3%	17.3–52.8%
			Negative predictive value	92.9%	76.5–99.1%	91.2%	76.3–98.1%
Temporal Flow	0.592	0.413–0772	Cut point	45.050		48.000
			Sensitivity	83.3%	51.6–97.9%	50.0%	21.1–78.9%
			Specificity	33.3%	20.8–47.9%	70.6%	56.2–82.5%
			Likelihood ratio (+)	1.25	0.91–1.72	1.70	0.84–3.45
			Likelihood ratio (-)	0.50	0.13–1.88	0.71	0.39–1.28
			Positive predictive value	22.7%	11.5–37.8%	28.6%	11.3–52.2%
			Negative predictive value	89.5%	66.9–98.7%	85.7%	71.5–94.6%

Eyes with analyzable data ranged from 12–14 for papilledema and 51 for pseudopapilledema.

The number of eyes with analyzable data ranged from 12–14 for papilledema and 51 for pseudopapilledema, depending on the specific flow and perfusion parameter analyzed (Table 4A and 4B).

The values of the predictive values, as well as the likelihood ratios, are shown in Tables 4A and 4B

The differential diagnosis between papilledema and pseudopapilledema is clinically important and often complex. Papilledema is a serious neurological condition that can be attributed to several causes including idiopathic intracranial hypertension.1–3

Pseudopapilledema encompasses several distinct entities that can mimic true optic disc edema. The most common cause is optic disc drusen (ODD), which may be visible on fundoscopy or buried (occult) and detectable only by ancillary testing.19 Other causes include: Tilted optic disc (oblique insertion of the optic nerve), Crowded optic disc (small scleral canal with crowded nerve fibers, common in hyperopia), myelinated nerve fibers (persistence of myelin anterior to the lamina cribrosa), Epipapillary glial tissue (Bergmeister's papilla) and optic disc hypoplasia with peripapillary elevation. Each of these entities has distinct structural characteristics and different probabilities of being confused with early papilledema.19–21

Optical coherence tomography, particularly enhanced depth imaging OCT (EDI-OCT), has become a highly sensitive and specific imaging modality for diagnosing optic disc drusen, with reported sensitivity of 87–100% and specificity of 83–100% in recent studies.8 The Optic Disc Drusen Studies Consortium recommends OCT as a key diagnostic tool, demonstrating characteristic hyporeflective cores with hyperreflective margins located anterior to the lamina cribrosa.22 However, the diagnostic approach should be multimodal, incorporating fundoscopy, B-scan ultrasound, and fundus autofluorescence, as each modality provides complementary information.19–21

The presence of vascular abnormalities has been described in both papilledema and optic disc drusen (ODD)4,9: dilatation of retinal veins, vascular tortuosity, capillary dilatation, leakage in fluorescein angiography (in papilledema); abnormal vascular branching, presence of cilioretinal vessels (in ODD). Classically, retinal vascularisation has been studied by fluorescein angiography. Recently, OCTA has been successfully applied to quantify the flow and density of macular and peripapillary retinal vessels in a reliable and reproducible manner, without the need for intravenous dyes.10,11

Previous OCTA studies have examined peripapillary vascular parameters in optic disc drusen and papilledema separately. Studies of ODD have consistently demonstrated reduced peripapillary perfusion density compared to healthy controls, attributed to mechanical compression of capillaries by drusen.23,24 In papilledema, the literature shows conflicting results, with some studies reporting decreased perfusion (possibly due to capillary dropout or compression)25–27 and others reporting increased perfusion (possibly due to vascular congestion and hyperemia).28,29

Few studies have assessed the diagnostic validity of peripapillary angiography in papilledema when compared with pseudopapilledema. Fard et al11, in a study of peripapillary vascularization similar to ours, using another commercial OCTA device (Angio Vue; Optovue Inc., Freemont, CA) found no differences between papilledema and pseudopapilledema. However, using custom software, they found significantly higher complete capillary and nasal sector peripapillary density in eyes with papilledema relative to pseudopapilledema.11 Using commercial equipment, we found higher flow and perfusion in papilledema when comparing with pseudopapilledema, with significant differences in nasal flow, mean perfusion and nasal perfusion.

In our study, subgroup analysis revealed that the reduced peripapillary perfusion in pseudopapilledema is primarily driven by eyes with optic disc drusen (ODD). The perfusion values in the NOODD pseudopapilledema subgroup (crowded discs, Bergmeister's papilla, myelinated nerve fibers) are almost identical to those observed in true papilledema. These findings suggest that OCTA may primarily detect the mechanical effect of optic nerve head drusen, which leads to a reduction in peripapillary vascularization, rather than accurately differentiating true papilledema from other forms of pseudopapilledema. In optic nerve head drusen, the marked reduction in the nasal flow index may be related to the direct mechanical compression exerted by the drusen.23,30 This compression could slow erythrocyte flow without immediately destroying retinal vessels. However, perfusion density shows the greatest reductions in the superior and inferior sectors. This decrease in vascular density may be associated with thinning of the retinal nerve fiber layer (RNFL) that occurs in eyes with drusen, similar to what is observed in glaucoma.

The diagnostic performance of OCTA parameters was moderate at best, with AUC values ranging from 0.592 to 0.719. These values indicate limited discriminatory ability and fall short of the threshold typically considered clinically useful (AUC >0.80–0.85).

A positive OCTA result (elevated nasal flow) increases the probability of papilledema from 21,5% to approximately 37,6%, while a negative result decreases it to 10,9%. These modest shifts in probability indicate that OCTA findings alone are insufficient for definitive diagnosis. In the high-stakes clinical context where missing papilledema is unacceptable, OCTA should be considered an exploratory adjunctive tool rather than a standalone diagnostic test.

The strengths of our study include the consecutive selection in clinical practice of mild and moderate papilledema and pseudopapilledema, which constitute the main diagnostic doubts.

The main limitations of our study are the small sample size (especially in the papilledema group), the heterogeneity of the pseudopapilledema group, and the interpretation of the results (without adjusting for other covariates such as age, gender, refractive error, etc.). External validation in an independent cohort is warranted to confirm the robustness, reproducibility, and generalizability of these findings before clinical implementation.

In conclusion, optical coherence tomography angiography provides quantitative, reproducible measurements of peripapillary vascular parameters that can aid in distinguishing papilledema from pseudopapilledema. In this study, OCTA reveals higher peripapillary vascular flow and perfusion in papilledema than in pseudopapilledema, particularly in the nasal region. These parameters showed moderate diagnostic accuracy, supporting OCTA as a valuable adjunct to conventional imaging modalities in the assessment of optic disc elevation. Further research with larger cohorts is required to validate these findings and establish clinically applicable diagnostic thresholds.

Financial support was provided by the Hospital Universitario Fundación Alcorcón