Pachychoroid Spectrum Research Articles

Choriocapillaris: Fundamentals and advancements.

The choriocapillaris is the innermost structure of the choroid that directly nourishes the retinal pigment epithelium and photoreceptors. This article provides an overview of its hemovasculogenesis development to achieve its final architecture as a lobular vasculature, and also summarizes the current histological and molecular knowledge about choriocapillaris and its dysfunction. After describing the existing state-of-the-art tools to image the choriocapillaris, we report the findings in the choriocapillaris encountered in the most frequent retinochoroidal diseases including vascular diseases, inflammatory diseases, myopia, pachychoroid disease spectrum disorders, and glaucoma. The final section focuses on the development of imaging technology to optimize visualization of the choriocapillaris as well as current treatments of retinochoroidal disorders that specifically target the choriocapillaris. We conclude the article with pertinent unanswered questions and future directions in research for the choriocapillaris.

Choroidal arteriovenous anastomoses: a hypothesis for the pathogenesis of central serous chorioretinopathy and other pachychoroid disease spectrum abnormalities.

The pachychoroid disease spectrum (PDS) includes several chorioretinal diseases that share specific choroidal abnormalities. Although their pathophysiological basis is poorly understood, diseases that are part of the PDS have been hypothesized to be the result of venous congestion. Within the PDS, central serous chorioretinopathy is the most common condition associated with vision loss, due to an accumulation of subretinal fluid in the macula. Central serous chorioretinopathy is characterized by distinct risk factors, most notably a high prevalence in males and exposure to corticosteroids. Interestingly, sex differences and corticosteroids are also strongly associated with specific types of arteriovenous anastomoses in the human body, including dural arteriovenous fistula and surgically created arteriovenous shunts. In this manuscript, we assess the potential of such arteriovenous anastomoses in the choroid as a causal mechanism of the PDS. We propose how this may provide a novel unifying concept on the pathophysiological basis of the PDS, and present cases in which this mechanism may play a role.

Pachychoroid spectrum disease and choriocapillary flow analysis in patients with Cushing disease: an optical coherence tomography angiography study.

To investigate the presence of pachychoroid spectrum disease (PSD) in patients with Cushing disease (CD) and to evaluate subfoveal choroidal thickness (SFCT) and choriocapillary flow using spectral domain OCT (SD-OCT) with the enhanced depth imaging (EDI) and optical coherence tomography angiography (OCT-A). Thirty-two patients with CD and 32 age- and sex-matched healthy volunteers were enrolled in this observational study. All participants had a complete ophthalmic examination including SD-OCT with EDI and OCT-A, and were subjected to the Perceived Stress Scale test (PSS). All patients with CD had hormone test including 24-h urinary-free cortisol (UFC) and plasma adrenocorticotropic hormone (ACTH). We compared SFCT and choriocapillary vessel density (CVD) between the two groups and evaluated the presence of PSD. We investigated the association of hormone level, SFTC, CVD with the presence of CD; the association between the hormone level, SFTC, CVD, the CD disease activity, and duration with the presence of PSD in CD patients; and the association between SFTC and CVD with the hormone level, the CD disease activity, and duration in CD patients. Higher values of SFCT and CVD were associated with CD (β: 0.028, 95% CI: 0.014; 0.041; β: 0.912, 95%CI: 0.205; 1.62, respectively). Twelve patients with CD (37.5%) reported a PSD in at least one eye, whereas no subject was found in control group (p < 0.001); in particular, 11 CD patients (34%) presented pachychoroid pigment epitheliopathy (PPE) and 1 CD patient (3%) presented polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization (PCV/AT1). In patients with CD, a significant positive association between SFCT and PSD was found (β: 0.010, 95% CI 0.001; 0.019). A chronic state of hypercortisolism may have direct implications on the choroid. Patients with CD had higher SFCT values and a significant change in the choriocapillary flow compared to healthy controls. Moreover, PSD was observed only in CD patients.

Prevalence of focal lamina cribrosa defects in eyes with pachychoroid disease spectrum.

To determine the prevalence of focal lamina cribrosa (LC) defect among patients with pachychoroid disease spectrum (PDS) in the absence of peripapillary retinoschisis. This retrospective, cross-sectional study comprised of 180 patients with PDS, including polypoidal choroidal vasculopathy (PCV), central serous chorioretinopathy, and pachychoroidal neovasculopathy. Medical records and optic nerve head evaluations conducted using spectral-domain optical coherence tomography with enhanced depth imaging were reviewed. As a control group, 236 patients who underwent ophthalmologic evaluation for vitreous floaters, without obvious ocular disease, were also included. The mean age of the PDS group, which included 118 male patients (65.6%), was 57.4±11.1y. There was no significant difference between the two groups in age (P=0.710) or sex (P=0.248). Six patients (3.3%) in the PDS group and none in the control group showed focal LC defect (P=0.318). Among the six patients with focal LC defect in the PDS group, four eyes had PCV, one eye was the fellow eye of a PCV eye, and one eye had pachychoroidal neovasculopathy. Focal LC defect can be defected in patients with PDS in the absence of peripapillary retinoschisis. However, the prevalence of focal LC defect was not different significantly between PDS patients and those who did not have PDS.

PERIPAPILLARY PACHYCHOROID SYNDROME

Available literature on peripapillary pachychoroid syndrome (PPS) is very limited. The purpose of this study is to evaluate features of PPS using multimodal imaging and shed further light on this entity. This is a retrospective case series at a tertiary eye-care center. Patients with features of pachychoroid with preferential choroidal thickening in nasal macula along with pachyvessels were identified and included for analysis. The patients underwent fundus photography, fundus autofluorescence, optical coherence tomography, fundus fluorescein angiography, and indocyanine angiography. Images were separately analyzed by two different retina specialists. A total of 27 eyes of 14 patients with mean age of 52.2 years were included. Seven patients had bilateral PPS, whereas six had unilateral; one patient had only one seeing eye. A total of 21 eyes with PPS were studied. 52.4% of the eyes revealed retinal pigment epithelium gravitational tracks, outer retinal atrophy, and serous PEDs. None of the eyes showed choroidal folds. Fundus fluorescein angiography showed late leakage at macula in 33% eyes. Fundus autofluorescence showed features of PPS to be similar to central serous chorioretinopathy in most cases. Peripapillary pachychoroid syndrome shares common findings with central serous chorioretinopathy and seems to be a subset of central serous chorioretinopathy than a separate entity in pachychoroid disease spectrum.

Central serous chorioretinopathy: Treatment.

Central serous chorioretinopathy (CSC) is a pachychoroid spectrum disease characterized by serous detachment of the neurosensory retina with subretinal fluid in young and middle-aged adults. The pathogenesis of CSC is not yet fully understood. However, it is considered a multifactorial disease that is strongly associated with choroidal dysfunction or vascular engorgement. Although there is no consensus on the treatment of CSC, photodynamic therapy has been effectively used to manage serous retinal detachment (SRD) in CSC. Moreover, micropulse diode laser photocoagulation and focal laser treatment have also been used. Recently, oral medications, including mineralocorticoid receptor antagonists, have been proposed for the management of CSC. Multimodal imaging plays a significant role in the diagnosis and treatment of CSC. Optical coherence tomography angiography (OCTA) has the advantage of detecting vascular flow in the retina and choroid layer, allowing for a better understanding of the pathology, severity, prognosis, and chronicity of CSC. In addition, early detection of choroidal neovascularization in CSC is possible using OCTA. This review article aims to provide a comprehensive and updated understanding of CSC, focusing on treatment.

Evaluation of Choroidal Thickness Using Optical Coherent Tomography: A Review.

The choroid is the main source of blood and nourishment supply to the eye. The dysfunction of the choroid has been implicated in various retinal and choroidal diseases. The identification and in-depth understanding of pachychoroid spectrum disorders are based on the tremendous progress of optical coherence tomography (OCT) technology in recent years, although visibility of choroid is challenging in the era of the time or spectral domain OCT. The recent rapid revolution of OCTs, such as the enhanced depth imaging OCT and the swept-source OCT, has greatly contributed to the significant improvement in the analysis of the morphology and physiology of the choroid precisely, especially to the choroid–scleral boundary and vasculature. The present review highlights the recently available evidence on the measurement methodology and the clinical significance of choroidal thickness in retinal or choroidal disorders.

Imbalanced choroidal circulation in eyes with asymmetric dilated vortex vein.

Asymmetric dilated vortex vein (ADVV) observed in eyes with pachychoroid spectrum diseases is thought to be due to congestion of choroidal blood flow. The purpose of this study was to quantitatively investigate the blood flow velocity of ADVV using laser speckle flowgraphy (LSFG). Retrospective case series. This was a retrospective case series with 23 eyes of 18 patients with ADVV on en-face OCT. A pair of choroidal veins from ADVV side (defined as ADVV vein) and non-ADVV side (defined as non-ADVV vein) was selected in each eye under the following criteria: (i) equivalent proximity to the deviated watershed, (ii) does not overlap with retinal blood vessels in the en-face OCT image, (iii) has approximately the same blood vessel diameter. Rubber bands were placed on the selected choroidal veins on the LSFG color map. Mean blur rate (MBR) values of ADVV and non-ADVV veins were statistically compared. The average MBR was 10.11 ± 1.9 in the ADVV veins and 13.49 ± 6.2 in the non-ADVV veins, showing significantly lower values in the ADVV veins (P = 0.03). The blood vessel diameter of the ADVV was 10.26 ± 3.0 and in the non-ADVV veins, 10.63 ± 2.9 pixels; not significantly different (P = 0.66). The distance from the deviated watershed to the ADVV was 53.3 ± 24.8 and to the non-ADVV veins, 46.80 ± 20.3 pixels; not significantly different (P = 0.41). In eyes with ADVV, the blood flow velocity in the ADVV veins was lower than in the non-ADVV veins, suggesting anatomical congestion of ADVV.

Pachychoroid disease spectrum: review article.

The aim of this article is to do a comprehensive literature review about the current understandings of the pachychoroid disease spectrum, describing its multimodal imaging analysis, pathophysiology, differential diagnosis, and current types of management. This comprehensive literature review was performed based on a search on the PubMed database, of relevant pachychoroid published papers according to our current knowledge. The pachychoroid disease spectrum, according to some authors, includes the following: pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CSC), pachychoroid neovasculopathy (PNV), polypoidal choroidal vasculopathy (PCV)/aneurysmal type 1 neovascularization (AT1), and more recently focal choroidal excavation (FCE) and peripapillary pachychoroid syndrome (PPS). Each one of these entities will be described and discussed in this article. Significant advances in multimodal imaging have enabled a better understanding of the typical choroidal changes in pachychoroid disease spectrum. The clinical knowledge and managing options about this disease significantly increased in the last years. However, it is still unclear why some eyes with typical pachychoroid disease phenotype show no evidence of RPE damage and subretinal fluid (uncomplicated pachychoroid) while others present progressive tissue damage, neovascularization, and atrophy.

Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium.

Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology.

A case of bilateral pachychoroid disease: polypoidal choroidal vasculopathy in one eye and peripheral exudative hemorrhagic chorioretinopathy in contralateral eye

BackgroundWe report a case of bilateral pachychoroid disease manifesting polypoidal choroidal vasculopathy (PCV) with punctate hyperfluorescent spot (PHS) in one eye, and peripheral exudative hemorrhagic choroidal retinopathy (PEHCR) with central serous chorioretinopathy (CSC) and PHS in the contralateral eye.Case presentation: A 51-year-old healthy woman presented with complaint of blurred vision in her right eye. Corrected visual acuity was 20/20 in the right and 24/20 in the left eye. Fundus examination was normal in the left eye. In the right eye, fundus finding of an orange-red nodular lesion and optical coherence tomography (OCT) finding of polypoidal lesions led to a diagnosis of PCV. Four aflibercept intravitreal injections were performed in her right eye. After treatment, indocyanine green angiography (ICGA) confirmed residual polypoidal lesions with branching vascular networks and PHS with choroidal vascular hyperpermeability. OCT showed PHS associated with small sharp-peaked retinal pigment epithelium (RPE) elevation in peripheral fundus and small RPE elevation in posterior fundus. Based on the above findings, PCV with PHS was finally diagnosed in the right eye. Posttreatment corrected visual acuity in the right eye was 20/20. She presented again 32 months later, with complaint of vision loss in her left eye. Left corrected visual acuity was 20/20, and fundus examination showed mild vitreous hemorrhage. Vitrectomy was performed. In temporal midperipheral fundus, fluorescein angiography revealed CSC, and OCT showed pachychoroid. ICGA depicted abnormal choroidal networks and PHS in peripheral fundus. Furthermore, polypoidal lesions were confirmed by OCT. Based on the above findings, PEHCR and CSC with PHS was finally diagnosed in the left eye. Postoperative corrected visual acuity in the left eye was 20/20, and aflibercept intravitreal injection was performed for prevention of recurrence of vitreous hemorrhage.ConclusionsThis is the first case report of PCV with PHS in one eye, and PEHCR with CSC and PHS in the contralateral eye. This case suggests that PCV, PEHCR, and CSC may be linked pathologies of pachychoroid spectrum disease.

This issue of ACTA

This issue of ACTA

Pachychoroid neovasculopathy: A comparative review on pathology, clinical features, and therapy.

There have been major changes in our understanding of choroidal diseases in the last decade owing to multiple retinal and choroidal imaging related advances. A major conceptual pivot is establishment of pachychoroid and its spectrum of clinical disorders: pachychoroid pigment epitheliopathy, central serous chorioretinopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization, peripapillary pachychoroid syndrome, and focal choroidal excavation. However, considerable overlaps in manifestations and therapeutics of these disorders make differentiation amongst them difficult. This review is focused on pathogenesis and clinical aspects of pachychoroid neovasculopathy (PNV). Since PNV was defined as a separate entity around 5 years ago, there have been numerous contrasting observations surrounding it. We review and summarize these studies, and also compare PNV with other disorders of the pachychoroid spectrum in detail. There are important differences between etiologies of neovascular age related macular degeneration and PNV. Yet the current treatment strategies for PNV have been extrapolated from the trials for the former. Future research needs to validate this assumption with long-term results.

Pulsation of anastomotic vortex veins in pachychoroid spectrum diseases

Accumulating evidence points to pachychoroid possibly being caused by vortex vein congestion which results in remodeling of choroidal drainage routes via intervortex vein anastomosis. This hypothesis prompted us to investigate vortex vein hemodynamics by studying videos of indocyanine green angiography (ICGA) in a retrospective case series of 295 eyes with pachychoroid spectrum diseases. In the early phase of the video-ICGA, pulsatile vortex venous flow was observed in 76 eyes (25.8%) at the vortex veins connected with anastomosis between superior and inferior vortex veins. The patients with pulsatile vortex venous flow were significantly older than those without pulsatile vortex venous flow (67.8 ± 13.2 vs. 63.9 ± 14.5 years, P < 0.05). Pulsatile vortex venous flow was 1.84 times more common in the inferior quadrants than in the superior quadrants. Interestingly, 14 of 76 eyes (18.4%) with pulsatile vortex venous flow showed retrograde pulsatile blood flow in the vortex veins. This retrograde pulsatile blood flow was 2.50 times more common in the inferior than in the superior quadrants. These findings indicate altered vortex vein hemodynamics due to vortex vein congestion in pachychoroid spectrum diseases.

Three-dimensional segmentation and depth-encoded visualization of choroidal vasculature using swept-source optical coherence tomography.

The choroid provides nutritional support for the retinal pigment epithelium and photoreceptors. Choroidal dysfunction plays a major role in several of the most important causes of vision loss including age-related macular degeneration, myopic degeneration, and pachychoroid diseases such as central serous chorioretinopathy and polypoidal choroidal vasculopathy. We describe an imaging technique using depth-resolved swept-source optical coherence tomography (SS-OCT) that provides full-thickness three-dimensional (3D) visualization of choroidal anatomy including topographical features of individual vessels. Enrolled subjects with different clinical manifestations within the pachychoroid disease spectrum underwent 15 mm × 9 mm volume scans centered on the fovea. A fully automated method segmented the choroidal vessels using their hyporeflective lumens. Binarized choroidal vessels were rendered in a 3D viewer as a vascular network within a choroidal slab. The network of choroidal vessels was color depth-encoded with a reference to the Bruch's membrane segmentation. Topographical features of the choroidal vasculature were characterized and compared with choroidal imaging obtained with indocyanine green angiography (ICGA) from the same subject. The en face SS-OCT projections of the larger choroid vessels closely resembled to that obtained with ICGA, with the automated SS-OCT approach proving additional depth-encoded 3D information. In 16 eyes with pachychoroid disease, the SS-OCT approach added clinically relevant structural details, including choroidal thickness and vessel depth, which the ICGA studies could not provide. Our technique appears to advance the in vivo visualization of the full-thickness choroid, successfully reveals the topographical features of choroidal vasculature, and shows potential for further quantitative analysis when compared with other choroidal imaging techniques. This improved visualization of choroidal vasculature and its 3D structure should provide an insight into choroid-related disease mechanisms as well as their responses to treatment.

PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY-A NEW ADDITION TO THE SPECTRUM OF PACHYCHOROID DISEASE?

Purpose: To demonstrate choroidal vascular changes and report a novel choroidal thickness contour in eyes with peripheral exudative hemorrhagic chorioretinopathy (PEHCR). Methods: Retrospective, observational, comparative case series. Fourteen eyes of nine patients with PEHCR and 14 eyes of 14 age-matched and sex-matched controls underwent swept-source optical coherence tomography. Choroidal thickness was measured from posterior edge of the retinal pigment epithelium–Bruch membrane to choroidoscleral interface at 11 points 1,000 µm apart. Large choroidal vessel thickness was also measured. Results: In PEHCR group, the choroid was thinnest at 3 mm nasal to fovea (mean 95.3 ± 33.5 µm) and thickest at 7 mm temporal to fovea (mean 272.7 ± 80.2 µm), with gradual increase in choroidal thickness from nasal to temporal periphery. The choroid was thickest subfoveally (259.7 ± 63.8 µm) in the control group. The choroid was significantly thicker in temporal periphery in PEHCR eyes as compared to controls (P = 0.0002). The mean large choroidal vessel thickness was 202.4 ± 50.8 µm in the PEHCR group and 160.6 ± 40.5 µm in the control group (P = 0.0235). Conclusion: Peripheral exudative hemorrhagic chorioretinopathy eyes showed progressively increasing choroidal thickness toward the temporal periphery, compared with age-matched and sex-matched controls. This gave rise to a club-shaped choroidal contour compared with the bowl-shaped contour seen in control eyes. Thicker choroid and pachyvessels favor inclusion of PEHCR in the pachychoroid disease spectrum.

Uniform classification of the pachychoroid spectrum disorders

Pachychoroid spectrum disorders are characterized by athickening of the choroid. The spectrum includes pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CCS), pachychoroid neovasculopathy (PNV), polypoidal choroidal vasculopathy (PCV)/aneurysmal type1 choroidal neovascularization (ACNV-1), focal choroidal excavation (FCE) and peripapillary pachychoroid syndrome (PPS). If the choroid is thickened and there is a pathological alteration in the retinal pigment epithelium, the diagnosis is PPE; if the thickened choroid is accompanied by subretinal fluid, the diagnosis is CCS; if choroidal neovascularization is present, the diagnosis is PNV; if accompanied by aneurysms, the diagnosis is ACNV‑1. The PPE, CCS, PNV and ACNV‑1 were formerly regarded as independent disease entities but can be classified into four forms of asingle disease family, pachychoroid macular disease.

A tale of two leaks – Pachychoroid spectrum

A tale of two leaks – Pachychoroid spectrum

A case of peripapillary pachychoroid syndrome treated with anti-vascular endothelial growth factor injections

Peripapillary pachychoroid syndrome (PPS) is a novel variant in the pachychoroid disease spectrum in which pachychoroid features are more prominent around the optic nerve head and are associated with intraretinal and/or subretinal fluid. The choroidal thickness in PPS is characterized by its atypical distribution with nasal macular choroid being thicker than the temporal counterpart. There are a few case reports of PPS in the literature that describe the morphological features of PPS but the management protocols are yet to be established. We hereby describe the clinical course of a 54-year-old gentleman who came to us with complaints of a gradual decrease in vision. On basis of multimodal imaging, a diagnosis of PPS was made. Since the patient was symptomatic, he was treated with intravitreal aflibercept which showed a favorable anatomical and functional outcome.

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