Optical coherence tomography-based misdiagnosis and morphological distinction in pachychoroid neovasculopathy vs. polypoidal choroidal vasculopathy

The present study indicates that a relevant percentage of eyes diagnosed with PNV in a clinical real-world setting might in reality suffer from aneurysmatic PAT1/PCV. Among 49 eyes with a clinical diagnosis of PNV in this study, we found that 7 (14.3%) showed clinical signs of aneurysmal disease on both OCT and FA/ICGA at first diagnosis but had not been correctly identified.

Whereas ICGA remains the gold standard for diagnosing PAT1/PCV, specific OCT-based diagnostic criteria for PAT1/PCV have recently been suggested [17, 22]. The establishment of such OCT criteria is important for two reasons. First, although most hospitals and private practices can readily offer OCT, FA is lacking in some, and ICGA is unavailable in many clinical institutions. Second, OCT is by far the most widespread and recognized retinal imaging method, and clinicians nowadays seem to devote most of their time to the interpretation of OCT. For these two reasons, a better definition of PAT1/PCV diagnostic criteria on OCT has become an important undertaking in order to improve clinical care [17, 22].

Pachychoroid spectrum has become a popular diagnosis, reflected in an almost exponential increase in pubmed.gov listed articles referencing this keyword, ranging from its first description by Warrow and colleagues in 2013 [23] to 44 articles in the year 2018 and 97 in 2021. However, the definitive diagnosis of pachychoroid phenotype and its distinct maculopathies might be more complex than initially thought and require far more than the single denominator of choroidal thickness [24].

In this context, our study suggests several OCT features in a real-world cohort that might greatly aid in the differentiation between PNV as a non-aneurysmatic pachychoroid related maculopathy and PAT1/PCV as an aneurysmatic pachychoroid related maculopathy. Although we found that SFCT and age did not differ between both entities, PED height, the presence of SHRM above the PED peak, sub-RPE fluid, and a SRRLS strongly suggested PAT1/PCV. These data are in good agreement with a recent study by Cheung et al. [17] who consider that the presence of a sharp-peaked PED and of SRRLS is of great diagnostic importance. Whereas we have been unable to examine the importance of a “complex RPE elevation” as mentioned in the Cheung et al study [17], because of the absence of a macular scanning pattern allowing an en-face reconstruction, our data indicate the presence of SHRM above the PED peak and the presence of sub-RPE fluid as novel additional biomarkers. At 42.9%, sub-RPE fluid was significantly more frequent in PAT1/PCV eyes than in PNV eyes (7.7%). The same applies for SHRM, which was significantly more frequent in eyes with PAT1/PCV (71.4%) than with PNV (28.6%).

Furthermore, we performed a ROC analysis to provide a value of height above which a PED could be interpreted as “peaking PED”. From our data, we found 158 µm to be an optimal cutoff for defining “peaking PED”, with an area under the curve of 0.975, a sensitivity of 1.0 (95% CI: 0.59–1.0), and a specificity of 0.95 (95 CI: 0.84–0.99). Although such a simplified approach is not intended to trivialize a differential diagnosis that sometimes represents a diagnostic conundrum, the value of 158 µm might be of use as a first indicator of PAT1/PCV, following which further imaging, especially ICG, can be recommended.

With regard to therapeutic approaches, the differentiation between PNV and PAT1/PCV harbours implications for the potential use of photodynamic therapy (PDT) with Verteporfin. Although PDT has also been described for PNV in smaller studies [25,26,27,28], high level evidence from randomized controlled trials is available for PDT in PAT1/PCV [19, 29]. The presence of polypoidal lesions particularly seems to favour the addition of PDT to intravitreal anti-VEGF therapy, as their regression seems to occur more often with combination therapy, resulting in better visual acuity outcomes [29]. Moreover, in the presence of polypoidal lesions, full-dose PDT should be preferred over reduced dose or fluence settings.

Also, differentiation between PNV and PAT1/PCV bears prognostic implications. PAT1/PCV is regarded as a more aggressive form of pachychoroid neovascularization with sometimes unpredictable exudation dynamics. Yoon et al. for example found that PAT1/PCV eyes presented more frequently with aggressive OCT biomarkers of disease like intraretinal fluid (38.2 vs. 12.2%) or macular haemorrhage (51.4 vs. 12.2%) than eyes with PNV [30]. Especially the higher incidence of macular haemorrhage in PAT1/PCV (30–63.6% [31] vs. 20.2% in PNV [32]) seems to impact long-term prognosis, with vitreous breakthrough haemorrhage often requiring pars plana vitrectomy [31]. Therefore, eyes with PAT1/PCV on average receive more annual anti-VEGF injections than eyes with PNV [30]. In this context, data from the EVEREST II trial suggest that the benefit of anti-VEGF/PDT combination therapy over anti-VEGF monotherapy mainly lies in a closure of PAT1/PCV polypoidal lesions, which was associated with higher gains in visual acuity [29] and might reduce the risk of haemorrhage.

Our study is limited by its small size and retrospective nature. Larger studies with longer follow-up are necessary, in particular to establish the definition of “peaking PED” as PED exceeding 158 µm. Concerning the rate of misdiagnosis, the cases and diagnoses included in our study span 2017 until 2021. From a 2022 perspective, recent efforts undertaken to improve the characterization of pachychoroid spectrum might already have led to clinicians distinguishing between non-aneurysmatic and aneurysmatic pachychoroid disease, thereby yielding a lower rate of misdiagnosis. A further important limitation is that our cohort exhibited primarily a pachychoroid phenotype. The OCT signs analysed in this study should therefore not be generalized to PCV in patients with an age-related macular degeneration phenotype, which presents at an older age with soft or reticular pseudodrusen and thinner choroid [33].

In conclusion, a relevant percentage of eyes clinically diagnosed with PNV might in reality suffer from aneurysmatic PAT1/PCV. In addition to the importance of ICG, which still represents the gold standard for diagnosing PAT1/PCV, our data further corroborate OCT as a suitable imaging method for differentiating between PNV and PAT1/PCV. A peaking PED exceeding 158 µm in height and the presence of SRRLS, sub-RPE fluid, and SHRM above the PED peak all suggest the presence of aneurysms and the diagnosis of PAT1/PCV instead of PNV.

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