Pachychoroid Neovasculopathy (PNV)

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Article initiated by:
Rohini Kaur Chahal, Jessica Tabary, Sanjana Jaiswal, Dina Abdelsalam, Nagham Al-Zubidi, MD
All contributors:
Dina Abdelsalam, Safa Ibrahim, MD
Assigned editor:
Review:
Assigned status Update Pending
.


Pachychoroid neovasculopathy (PNV) is a distinct form of type 1 macular neovascularization occurring within the pachychoroid disease spectrum.[1] First proposed in 2013 by Freund et al., PNV is separate from type 1, type 2, and type 3 macular neovascularization (MNV), as well as from polypoidal choroidal vasculopathy (PCV).[2][3] Unlike neovascular age-related macular degeneration (nAMD), PNV is not associated with drusen. Instead, it arises in eyes with structural and vascular abnormalities of Haller’s layer in the choroid. PNV is often misdiagnosed as wet AMD due to overlapping clinical presentations.[4] However, accumulating evidence demonstrates that PNV has a distinct pathophysiological basis, clinical profile, genetic background, and treatment response.

Disease Entity

Etiology

The etiology of PNV is controversial, namely due to its novel introduction as well as the supposed proportion of misdiagnoses of nAMD. In a review of 200 patients diagnosed with neovascular AMD, Mikaye et al. found 19.5% of the group to actually have PNV.[5] Subsequent cohort studies demonstrate approximately the same percentages of misdiagnosis. Observational studies on other clinical entities within the pachychoroid spectrum, namely CSC, have demonstrated these conditions could be inherited, potentially through dominant transmission.[6]

Risk Factors

Pachydrusen (PD) is a unique form of drusen associated with increased choroidal thickness. They are sub-RPE deposits with well-defined margins, and occur in isolation or in small groups. While previously described in patients with non-exudative age-related macular degeneration, Lee et al. have identified their presence in 49.3% of 169 eyes with polypoidal choroidal vasculopathy, and PD in these patients was associated with a thicker choroid. [7]In a retrospective analysis of 131 eyes of 79 patients with pachychoroid, Sheth et al. demonstrated that PD was identified in 53% of eyes, and on long-term followup, the presence of PD was associated with disease activity, in the form of leakage on digital fluorescein angiography (DFA) at the site of the PD. Sheth et al. conclude that PD in PNV is akin to the hard or soft drusen in AMD, meaning the PD are associated with damage to the RPE and underlying Bruch’s membrane. Therefore, PD can be a potential risk factor for disease activity in pachychoroid disorders including PNV.[8]

Keidel et al. identified increased anterior scleral thickness (AST) as another potential risk factor for PNV.[9]Anterior scleral thickness (AST) measured using swept source OCT in 46 eyes was significantly higher in the temporal segment in PNV eyes compared to control. The thickened AST may represent an ocular outflow restriction and secondary cause for venous overload. Chronic venous system overflow may cause anterograde filling delay of the choriocapillaris, resulting in thickening of Haller’s layer ultimately leading to the development of the pachychoroid phenotype.

Other risk factors have been identified for the pachychoroid disease spectrum including stress, corticosteroid exposure, and pregnancy.

Pathophysiology

The defining characteristic of PNV is the presence of pachyvessels, which are pathologically dilated choroidal vessels in the Haller’s layer.[3] These vessels are thought to develop in response to elevated venous pressure and choroidal congestion, which disrupts venous outflow and results in intervortex venous anastomoses.[10] Over time, this congestion reduces the viscoelasticity of the vessel walls and promotes structural remodeling of the choroidal vasculature. The altered hemodynamics lead to the upregulation of inflammatory cytokines and angiogenic factors, including interleukin (IL)-1a, IL-1B, IL-2, IL-4, IL-10, and vascular endothelial growth factor (VEGF).[11] These molecules have been found at significantly higher levels in eyes with PNV compared to control eyes, and their presence correlates with increased choroidal thickness, vessel dilation, and the number of polypoidal lesions. Among these, IL-4 showed the strongest association with the development of hallmark clinical features of PNV. The mechanical pressure exerted by these pachyvessels on Bruch’s membrane is believed to contribute to the development of neovascularization in the outer choroidal layers.[12] This type 1 choroidal neovascularization may gradually expand and eventually form polypoidal lesions.[12] [13]

Many studies have highlighted differences between PNV and neovascular AMD. VEGF levels are significantly lower in eyes with PNV compared to those with nAMD, suggesting a divergent pathophysiological mechanism.[14][15] Genetic studies have shown lower frequencies of high-risk alleles associated with AMD in PNV patients.[16] For instance, the frequency of the ARMS2 A69S risk allele is 46.7%, CFH I62V is 25.5%, and CFH Y402H is only 10.9%, compared to higher frequencies typically seen in AMD populations. These distinctions support the view that PNV is genetically and biochemically distinct from neovascular AMD.

Primary Prevention

Literature has yet to be published on the prevention of PNV, however given that it is possible to reduce exposure to some of the risk factors for pachychoroid neovasculopathy, namely stress and corticosteroid use, further research in this area is warranted.

Diagnosis

Clinically, PNV is most prevalent among elderly individuals presenting with macular neovascularization.[17] One study hypothesizes that nearly half of patients initially diagnosed with type 1 or type 2 MNV or PCV may have PNV upon re-evaluation.[4] Affected eyes typically display increased subfoveal choroidal thickness (SFCT), dilation of outer choroidal vessels (pachyvessels), and attenuation of the choriocapillaris and Sattler’s layer.[18] Additional findings include decreased fundus tessellation and hyperpermeability of the choroidal vasculature.

The diagnostic criteria for pachychoroid phenotype include four core elements[19]:

  1. Reduced fundus tessellation
  2. presence of pachyvessels that span the length of the vessel to the vortex vein ampullae as seen on OCT or ICGA
  3. Absence of soft drusen (although scattered pachydrusen may be present)
  4. Presence of CSCR characteristics, such as retinal pigment epithelium (RPE) abnormalities, choroidal vascular hyperpermeability (CVH), or a prior CSCR diagnosis

A key challenge in diagnosing PNV is the inconsistency in diagnostic criteria across studies. This has led to variability in how polypoidal lesions are classified. Some authors, such as Yamashiro et al., have proposed that pachychoroid-driven neovascularization with polypoidal lesions should be reclassified as PCV to maintain clearer diagnostic boundaries for PNV.

PNV can be further subtyped into CSC-dominant and MNV-dominant forms based on fluorescein angiography (FA) findings at baseline.[20] This classification holds prognostic significance. In comparative studies, patients with the CSC-dominant subtype demonstrated significantly greater improvement in best-corrected visual acuity (BCVA) one year after initial treatment, along with a lower recurrence rate (15.8% vs. 57.1%) during the maintenance phase compared to those with MNV-dominant PNV.

Imaging Modalities

Accurate imaging is crucial for distinguishing PNV from other chorioretinal diseases, particularly AMD. Historically, indocyanine green angiography (ICGA) has been considered the gold standard for diagnosing pachychoroid spectrum disorders and PCV.[21][12] ICGA can reveal choroidal hyperpermeability, pachyvessels, delayed choroidal filling, and focal hyperfluorescent areas corresponding to leakage points.[22] However, ICGA is invasive, time-consuming, and not widely available, and it carries the risk of systemic adverse reactions.[23] Moreover, while ICGA findings such as choroidal hyperpermeability usually correlate with increased choroidal thickness, this is not universally true.[22]

As a non-invasive and more accessible alternative, enhanced-depth imaging optical coherence tomography (EDI-OCT) has emerged as an effective tool for detecting pachychoroid features.[4] Optical coherence tomography angiography (OCTA) has also shown promise, particularly in detecting small, shallow lesions or irregular pigment epithelial detachments (PEDs) that may be missed by dye-based angiography.[1][24] OCTA has demonstrated superior sensitivity and specificity for identifying type 1 choroidal neovascularization (CNV) and offers better visualization of subtle capillary changes and vessel patterns in PNV.

Differential Diagnosis

PNV should be considered a critical differential diagnosis for type 1 AMD-related CNV.[4] Due to overlapping phenotypic features, many patients are misdiagnosed and inappropriately managed as having nAMD. In one cohort of 137 eyes, approximately 20% were initially misclassified. These patients with true PNV were statistically younger, had thicker choroids, and exhibited less subretinal fibrosis than their AMD counterparts. Despite overlapping features on OCTA, including CNV morphology and vessel density, EDI-OCT is considered to be an accurate, non-invasive, and accessible imaging modality for distinguishing PNV from typical AMD-CNV.

Management

The primary treatment options for PNV include anti-VEGF monotherapy, photodynamic therapy (PDT), or combination therapy.[25][26] Anti-VEGF agents, such as aflibercept, have shown excellent efficacy in improving vision, especially when used in a treat-and-extend regimen.[10] Visual gains are typically achieved during the first year and can be maintained over two years. Compared to AMD, PNV patients generally require fewer anti-VEGF injections annually.

Keidel et al. suggest using glucocorticoid-mineralocorticoid inhibitors such as spironolactone and eplerenone with anti-VEGF treatments for PNV. These medications facilitate subretinal fluid resolution and induce choroidal thinning through competitive inhibition of glucocorticoid receptors.[27]However, this addition is lacking evaluation in randomized, control trials.  

PDT has also proven beneficial, particularly in patients with CSC-dominant PNV.[20] PDT may be used alone or in combination with anti-VEGF therapy, with evidence showing that it reduces the number of required injections during the maintenance phase. However, concerns about photosensitivity reactions from verteporfin and the logistical burden of repeat treatments remain challenges.

Prognosis

PNV generally exhibits a more favorable visual prognosis and treatment response than nAMD.[16] One key prognostic factor is the presence of subretinal hemorrhage (SRH), defined as a hemorrhage measuring four or more disc areas. At baseline, there is no significant difference in BCVA between eyes with and without SRH. However, at follow-up, those with SRH have significantly worse vision outcomes and are more likely to have polypoidal lesions.

PNV also carries a risk of progression to pachychoroid aneurysmal type 1 CNV (PAT1) or PCV[28]. Based on Kaplan–Meier estimates, the risk of conversion increases over time: 0% at years one and two, 7.4% at year three, 13.6% at year four, and 30.7% at year five. This gradual evolution supports the hypothesis that PPE, CSC, PNV, and PAT1/PCV represent a continuous disease spectrum with overlapping features.

References

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  1. ↑ 1.0 1.1 Cheung CMG, Lee WK, Koizumi H, Dansingani K, Lai TYY, Freund KB. Pachychoroid disease. Eye (Lond). 2019;33(1):14-33. doi:10.1038/s41433-018-0158-4
  2. ↑ Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina. 2013;33(8):1659-1672. doi:10.1097/IAE.0b013e3182953df4
  3. ↑ 3.0 3.1 Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina. 2015;35:1–9. doi: 10.1097/IAE.0000000000000331.
  4. ↑ 4.0 4.1 4.2 4.3 Farvardin M, Amini A, Azizpourfard Y, Yasemi M, Mahdizad Z, Johari M. Pachychoroid neovasculopathy can mimic wet type age-related macular degeneration. Int J Retina Vitreous. 2022;8(1):78. Published 2022 Oct 23. doi:10.1186/s40942-022-00429-6
  5. ↑ Miyake M, Ooto S, Yamashiro K, Takahashi A, Yoshikawa M, Akagi-Kurashige Y, Ueda-Arakawa N, Oishi A, Nakanishi H, Tamura H, Tsujikawa A, Yoshimura N. Pachychoroid neovasculopathy and age-related macular degeneration. Sci Rep. 2015 Nov 6;5:16204. doi: 10.1038/srep16204. PMID: 26542071; PMCID: PMC4635432.
  6. ↑ Lehmann M, Bousquet E, Beydoun T, Behar-Cohen F. PACHYCHOROID: an inherited condition? Retina. 2015 Jan;35(1):10-6. doi: 10.1097/IAE.0000000000000287. PMID: 25046398.
  7. ↑ Lee, Junwon MD, PhD; Byeon, Suk Ho MD, PhD. PREVALENCE AND CLINICAL CHARACTERISTICS OF PACHYDRUSEN IN POLYPOIDAL CHOROIDAL VASCULOPATHY: Multimodal Image Study. Retina 39(4):p 670-678, April 2019. | DOI: 10.1097/IAE.0000000000002019
  8. ↑ Sheth J, Anantharaman G, Kumar N, Parachuri N, Bandello F, Kuppermann BD, Loewenstein A, Sharma A. Pachydrusen: the epidemiology of pachydrusen and its relevance to progression of pachychoroid disease spectrum. Eye (Lond). 2020 Sep;34(9):1501-1503. doi: 10.1038/s41433-020-0886-0. Epub 2020 Apr 23. PMID: 32327739; PMCID: PMC7608197.
  9. ↑ Keidel LF, Schworm B, Langer J, Luft N, Herold T, Hagenau F, Klaas JE, Priglinger SG, Siedlecki J. Scleral Thickness as a Risk Factor for Central Serous Chorioretinopathy and Pachychoroid Neovasculopathy. J Clin Med. 2023 Apr 24;12(9):3102. doi: 10.3390/jcm12093102. PMID: 37176543; PMCID: PMC10179194.
  10. ↑ 10.0 10.1 Matsumoto H, Kishi S, Mukai R, Akiyama H. Remodering of macular vortex veins in pachychoroid neovasculopathy. Sci Rep. 2019; 9:14689. doi: 10.1038/s41598-019-51268-9.
  11. ↑ Baba T, Koyama A, Uotani R, et al. Association of IL-4 with pachychoroid neovasculopathy. Sci Rep. 2023;13(1):1152. Published 2023 Jan 20. doi:10.1038/s41598-023-28108-y
  12. ↑ 12.0 12.1 12.2 Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol. 2008;146:496–500.
  13. ↑ Gupta P, Ting DSW, Thakku SG, et al. Detailed characterization of choroidal morphologic and vascular features in age-related macular degeneration and polypoidal choroidal vasculopathy. Retina. 2017;37:2269–80.
  14. ↑ Hata M, Yamashiro K, Ooto S, et al. Intraocular Vascular Endothelial Growth Factor Levels in Pachychoroid Neovasculopathy and Neovascular Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2017;58(1):292-298. doi:10.1167/iovs.16-20967
  15. ↑ Terao N, Koizumi H, Kojima K, et al. Distinct Aqueous Humour Cytokine Profiles of Patients with Pachychoroid Neovasculopathy and Neovascular Age-related Macular Degeneration. Sci Rep. 2018;8(1):10520. Published 2018 Jul 12. doi:10.1038/s41598-018-28484-w
  16. ↑ 16.0 16.1 Tagawa M, Ooto S, Yamashiro K, et al. Characteristics of pachychoroid neovasculopathy. Sci Rep. 2020;10(1):16248. Published 2020 Oct 1. doi:10.1038/s41598-020-73303-w
  17. ↑ Kuranami A, Maruko R, Maruko I, Hasegawa T, Iida T. Pachychoroid neovasculopathy has clinical properties that differ from conventional neovascular age-related macular degeneration. Sci Rep. 2023;13(1):7379. Published 2023 May 6. doi:10.1038/s41598-023-33936-z
  18. ↑ Balaratnasingam C, Lee WK, Koizumi H, Dansingani K, Inoue M, Freund KB. Polypoidal choroidal vasculopathy: a distinct disease or manifestation of many? Retina. 2016;36:1–8.
  19. ↑ Yamashiro K, Yanagi Y, Koizumi H, Matsumoto H, Cheung CMG, Gomi F, et al. Relationship between pachychoroid and polypoidal choroidal vasculopathy. J Clin Med. 2022;11 doi: 10.3390/jcm11154614.
  20. ↑ 20.0 20.1 Maruyama-Inoue M, Yanagi Y, Inoue T, Kitajima Y, Kadonosono K. Importance of fluorescein angiography as a predictor of treatment response in patients with pachychoroid neovasculopathy. Sci Rep. 2024;14(1):29157. Published 2024 Nov 25. doi:10.1038/s41598-024-79179-4
  21. ↑ Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. Idiopathic polypoidal choroidal vasculopathy (IPCV). Retina. 1990;10(1):1-8.
  22. ↑ 22.0 22.1 Mazzeo TJMM, Leber HM, da Silva AG, et al. Pachychoroid disease spectrum: review article. Graefes Arch Clin Exp Ophthalmol. 2022;260(3):723-735. doi:10.1007/s00417-021-05450-3
  23. ↑ Slakter JS, Yannuzzi LA, Guyer DR, Sorenson JA, Orlock DA. Indocyanine-green angiography. Curr Opin Ophthalmol. 1995;6(3):25-32. doi:10.1097/00055735-199506000-00005
  24. ↑ Su Y, Zhang X, Gan Y, Zeng Y, Wen F. Detection of pachychoroid neovasculopathy with optical coherence tomography angiography versus dye angiography imaging. Photodiagnosis Photodyn Ther. 2022;40:103126. doi: 10.1016/j.pdpdt.2022.103126
  25. ↑ Kitajima Y, Maruyama-Inoue M, Ito A, et al. One-year outcome of combination therapy with intravitreal anti-vascular endothelial growth factor and photodynamic therapy in patients with pachychoroid neovasculopathy. Graefes Arch Clin Exp Ophthalmol. 2020;258(6):1279-1285. doi:10.1007/s00417-020-04661-4
  26. ↑ Montero Hernández J, Remolí Sargues L, Monferrer Adsuara C, Castro Navarro V, Navarro Palop C, Cervera Taulet E. Two-Year Results of a Treat and Extend Regimen with Aflibercept in Caucasian Patients with Pachychoroid Neovasculopathy. Semin Ophthalmol. 2023;38(4):352-357. doi:10.1080/08820538.2023.2194983
  27. ↑ Leonie F. Keidel, Benedikt Schworm, Siegfried G. Priglinger, Jakob Siedlecki; Pachychoroid Neovasculopathy Disguising as Age-Related Macular Degeneration Treated by Spironolactone and Anti-VEGF Combination Therapy. Case Rep Ophthalmol 5 May 2021; 12 (1): 116–123. https://doi.org/10.1159/000510828
  28. ↑ Siedlecki J, Klaas JE, Keidel LF, et al. Progression of Pachychoroid Neovasculopathy into Aneurysmal Type 1 Choroidal Neovascularization or Polypoidal Choroidal Vasculopathy. Ophthalmol Retina. 2022;6(9):807-813. doi:10.1016/j.oret.2022.04.004
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