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Pachychoroid pigment epitheliopathy in fellow eyes of patients with unilateral central serous chorioretinopathy
  1. M Giray Ersoz,
  2. Murat Karacorlu,
  3. Serra Arf,
  4. Mumin Hocaoglu,
  5. Isil Sayman Muslubas
  1. Istanbul Retina Institute, Istanbul, Turkey
  1. Correspondence to Professor Murat Karacorlu, Istanbul Retina Institute, Hakkı Yeten Cad. Unimed Center No: 19/7. Fulya – Şişli, Istanbul, Turkey; mkaracorlu{at}superonline.com

Abstract

Aims To investigate the prevalence of pachychoroid pigment epitheliopathy (PPE) in fellow eyes of patients with unilateral central serous chorioretinopathy (CSC) and to determine differences between patients with PPE, uncomplicated pachychoroid (UCP) and normal fellow eyes.

Methods We retrospectively reviewed 536 patients with CSC. Demographic and medical data, spectral domain optical coherence tomography scans with enhanced depth imaging mode, infrared reflectance images and fundus autofluorescence images were obtained from the patients’ medical records.

Results 254 (47.4%) of 536 patients had bilateral CSC. The female to male ratio was 1/2.8 in all patients with CSC. In patients with unilateral CSC (282 patients), 61% of fellow eyes had PPE, 30.8% had UCP and 8.2% were normal. There were no significant differences between patients with PPE, UCP and normal eyes in age, duration of disease, sex, presence of systemic hypertension, steroid use, psychopharmacological medication use, refractive error or central foveal thickness. Eyes with PPE and UCP did not differ regarding subfoveal choroidal thickness. In eyes with PPE (172 eyes), 77.3% had retinal pigment epithelium (RPE) bumps and 43% had pigment epithelium detachment.

Conclusion PPE is common in fellow eyes of patients with CSC. There is no difference between PPE and UCP regarding demographic characteristics and medical features.

  • choroid
  • retina

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Introduction

Central serous chorioretinopathy (CSC) is the fourth most common non-surgical retinal disease.1 It is characterised by serous retinal detachment of the neurosensory retina, often accompanied by detachment of the retinal pigment epithelium (RPE).2 3 The focal hyperpermeability of the choriocapillaris causes RPE damage that leads to subneurosensorial or sub-RPE fluid.4 Choroidal hyperpermeability around the leakage site, seen on indocyanine green angiography, confirms this.5 6Enhanced depth imaging (EDI) spectral domain optical coherence tomography (SD-OCT) revealed that the choroid is thick in eyes with CSC.7 It is also thicker in the unaffected fellow eyes of patients with CSC than in healthy subjects8 The thickening of the choroid in patients with CSC is related to dilatation of Haller layer vessels.9

Non-specific RPE changes have been reported in the unaffected eyes of patients with CSC.1 10 Warrow et al defined pachychoroid pigment epitheliopathy (PPE) as a forme fruste of CSC. Its characteristic findings are reduced fundus tessellation, pachychoroid phenotype, a variety of RPE abnormalities, including small pigment epithelium detachments (PEDs), absence of subretinal fluid, absence of a history of subretinal fluid and absence of drusen.11 12 Features of the pachychoroid phenotype are choroidal hyperpermeability, dilated choroidal vessels (pachyvessels) and focal or diffuse increase in choroidal thickness. Dansingani et al reported that choroidal thicknesses of eyes with pachychoroid phenotype are >300 µm or they have an extrafoveal focus exceeding the choroidal thickness of the fovea by at least 50 µm.13 Disorders that have these choroidal features are considered to be in the pachychoroid spectrum, which comprises uncomplicated pachychoroid (UCP), PPE, CSC, pachychoroid neovasculopathy and polypoidal choroidal vasculopathy.11–13 PPE may be isolated or in the fellow eyes of patients with CSC.13

We have previously reported outer nuclear layer thinning in eyes with PPE.14 In this study, we aimed to investigate the prevalence of PPE in the fellow eyes ofpatients with unilateral CSC. We also compared these patients with PPE, UCP and normal fellow eyes with regard to demographic characteristics and medical features.

Methods

The study was designed as a retrospective cross-sectional study. We reviewed 567 patients with CSC who had been referred to Istanbul Retina Institute from January 2009 to October 2016. The study protocol was approved by the institutional review board of Sisli Memorial Hospital, Istanbul. The study adhered to the tenets of the Declaration of Helsinki. Birth date, initial date of CSC, examination date, sex, detailed anamnesis, presence of systemic hypertension, steroid usage, antidepressant–anxiolytic drug usage, CSC type (acute or chronic), best corrected visual acuity (BCVA), intraocular pressure, refractive error, colour fundus photography, central foveal thickness, macular optical coherence tomography (OCT) scans, subfoveal choroidal thickness, maximal choroidal thickness, infrared reflectance images and fundus autofluorescence images were obtained from the patients’ medical records. Medical records of patients’ first visit were used for analysis. SD-OCT (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) was used for all OCT scans and standard OCT procedures of our clinic for patients with retinal diseases were applied. The macula was screened by taking 49 sections (512 A-scan) at 120 µm intervals within a 20° X 20° rectangular field. An average of nine images was obtained for each section. The fovea was evaluated by single vertical and horizontal scans, with an average of 100 images. Extramacular lesions seen on colour photography, infrared reflectance or fundus autofluorescence were evaluated by single OCT scans, with an average of 100 images. Single vertical and horizontal OCT scans of fovea, and single OCT scans of extramacular lesions were taken with EDI technique7 for visualisation of choroid and inverted images that were obtained from January 2009 to January 2011. Automated reversed EDI images could be possible with Spectralis 5.3 software. All OCT scans, including 20° X 20° macula screening, were performed with automated EDI mode after January 2011. OCT images of patients’ first visit were used for analysis.

Diagnosis of CSC, PPE or UCP

The diagnosis of CSC was based on the presence of subretinal fluid or subretinal fluid history, characteristic fundus autofluorescence findings such as gravitational tracts, zonal areas of hyperautofluorescence or geographic areas of speckled hyperautofluorescence, absence of drusen and absence of choroidal neovascular membrane.12 15 Although patients with CSC are referred to clinicians with visual symptoms due to macular (‘central’) involvement, some patients may have asymptomatic, extramacular subretinal fluid.2 Resolved CSC findings such as distinct interruption of the interdigitation zone (cone outer segment tips line), ellipsoid zone, external limiting membrane and distinct thinning of inner retinal layers at the lesion area16–19 were considered as CSC to avoid misdiagnosing this as PPE (figure 1). If the subretinal fluid resolved within 6 months and did not recur, the diagnosis was considered to be acute CSC.13 A diagnosis of pachychoroid was done based on findings of Dansingani et al 13 and we considered choroid as thick if choroidal thickness was >300 µm in any location or an extrafoveal focus exceeds the choroidal thickness of fovea by at least 50 µm. A diagnosis of PPE was based on the definition of Warrow et al 11 with using colour photography, multicolour imaging, fundus autofluorescence, infrared reflectance and EDI SD-OCT (figure 2). The localisation of RPE changes was assessed according to anatomical regions of the macula. The 1.5 mm centre of the macula was considered as fovea, the 0.5 mm ring surrounding the fovea was the parafovea and the 1.5 mm ring surrounding the parafovea was the perifovea. Lesions outside the perifovea were classified as macular lesions, and the lesions adjacent to or near the optic disc as juxtapapillary lesions. In the absence of RPE alterations, eyes with pachychoroid features were diagnosed as UCP. Eyes without pachychoroid features and RPE alterations were considered to be normal. Patients whose subfoveal choroidal thicknesses were <300 µm and extrafoveal choroid thickness could not be determined were not included. Eyes with shallow irregular PED underwent fluorescein and indocyanine green angiography and were excluded if a choroidal neovascularisation was found. In the absence of subretinal fluid or resolved subretinal fluid signs, eyes with >100 µm height serous PED were considered as CSC.

Figure 1

A 42-year-old man with central serous chorioretinopathy in his left eye. (A) Spectral domain optical coherence tomography scan shows subretinal fluid between the retinal pigment epithelium and ellipsoid zone and a shallow pigment epithelium detachment. (B) One year after resolution of subretinal fluid, the interdigitation zone does not appear and the ellipsoid zone is thinner in the area of former subretinal fluid than in the healthy retina. (C) Three years after resolution of subretinal fluid, in the area of former subretinal fluid, the ellipsoid has thickened. An irregular and thin interdigitation zone appears at the right side of this zone. Although 3 years have passed, the interdigitation zone does not resurface on the left side of the former subretinal fluid zone.

Figure 2

Left eye of a 52-year-old man with pachychoroid pigment epitheliopathy. (A) Multicolour images show retinal pigment epithelium (RPE) alteration (arrow) in the superior temporal area adjacent to the fovea. In this area, RPE alteration is shown by (B) hyporeflectance (arrow) on green reflectance imaging and (C) irregular hyper-reflectance and hyporeflectance (circle) on infrared reflectance imaging. (D) Slight hypoautofluorescence (arrow) appears in the fundus autofluorescence image (E) Spectral domain optical coherence tomography scan of the lesion reveals an RPE bump and choroidal thickening beneath the lesion.

Patients with previous ocular surgery other than uncomplicated cataract surgery, pre-existing ocular diseases such as uveitis, degenerative myopia and retinal disorders or a history of ocular trauma and patients having only one eye were excluded.

Statistical analyses

Statistical analyses were performed with the Statistical Packages for the Social Sciences (SPSS, version 15, Chicago, Illinois, USA). For comparison of groups, one-way analysis of variance test was used for continuous variables and Pearson χ2 test for categorical data. p<0.05 was considered statistically significant.

Results

Eight patients who had only one eye, 4 patients whose choroidal status could not be determined and 19 patients who had at least one other exclusion condition were excluded and 536 patients were included. Three hundred and ninety-five (73.7%) of 536 patients were men and 141 (26.3%) were women. Two hundred and fifty-four (47.4 %) of 536 patients had bilateral CSC and 282 (52.6 %) had unilateral disease. Of patients with bilateral CSC, only two patients (0.8%) had >100 µm height serous PED without subretinal fluid or resolved subretinal fluid signs in their fellow eyes. Of all patients with CSC, 32.1% (172 patients) had PPE, 16.2% (87) had UCP and 4.3% (23) had normal eyes. Of fellow eyes of unilateral CSC cases, 61% had PPE, 30.8% had UCP and 8.2% were normal.

There were no significant differences between patients with PPE, UCP and normal eyes in initial age, examination age, duration of disease, sex, presence of systemic hypertension, steroid usage, antidepressant–anxiolytic drug usage, BCVA, refractive error, intraocular pressure, type of CSC and central foveal thickness (tables 1 and 2). The subfoveal choroidal thickness in the PPE and UCP groups was significantly higher than in the normal group, as expected (both p<0.001). The subfoveal choroidal thickness in the PPE eyes did not significantly differ from that in the UCP eyes (p=0.94).

Table 1

Demographic features and drug usage of patients with unilateral central serous chorioretinopathy (CSC)

Table 2

Ocular features of fellow eyes of patients with unilateral central serous chorioretinopathy (CSC)

All eyes with RPE alterations had pachychoroid features and were diagnosed as PPE. Some patients with PPE had more than one type of lesion in more than one location. Of the 172 eyes with PPE, 133 (77.3%) had RPE bumps and 74 (43%) had PED (figure 3). Seventy-two eyes (41.9%) had foveal lesions, 62 (36%) had parafoveal lesions, 94 (54.7%) had perifoveal lesions, 17 (9.9 %) had macular lesions and 7 (4.1%) had juxtapapillary lesions.

Figure 3

Spectral domain optical coherence tomography scans of four different eyes with pachychoroid pigment epitheliopathy. (A,B) Retinal pigment epithelium (RPE) bumps. (C,D) Small (<100 µm) detachments of RPE. (C) Choroidal thickness of temporal side exceeds the choroidal thickness of fovea by 110 µm. (D) Choroidal thickening and Haller’s layer enlargement are seen beneath the RPE lesion.

Discussion

CSC has been reported to be bilateral in 4–40% of cases.20 In the present study, with a large sample size, 47.4% had bilateral CSC. Extrafoveal involvements and attacks with a small amount of subretinal fluid may be asymptomatic for a long time. We thought that the high rate of bilateral disease was dependent on detailed evaluation of infrared reflectance, fundus autofluorescence and OCT scans. Also, we carefully sought findings of resolved CSC in asymptomatic eyes. Our study revealed that the female to male ratio was 1/2.8 in Turkish patients with CSC. Other studies have reported that men have six times the incidence of women.2 Tsai et al found that 63.6% of Taiwanese patients with CSC were men.21

It is well known that choroidal hyperpermeability and choroidal thickening have a role in the pathophysiology of pachychoroid spectrum disease, but their relationship is still debated. Choroidal hyperpermeability has been reported in >90% of affected eyes of patients with CSC and 62–73% of unaffected fellow eyes.8 22 23 Maruko et al found that the choroid was thicker in fellow eyes of patients with CSC with choroidal hyperpermeability than those without choroidal hyperpermeability.8 Choroidal vascular dilatation is a reason for choroidal thickening, in addition to choroidal vascular hyperpermeability. Kim et al reported that choroidal vascular dilatation was present in 70% of CSC eyes and 60% of unaffected fellow eyes. They proposed that choroidal dilatation and hyperpermeability may be different stages of the disease. Also, they accepted 377.7 µm as the cut-off value for choroidal thickening but did not find significant difference between patients with a thick choroid and patients with normal choroid with regard to choroidal hyperpermability.23 In contrast to Kim et al, Maruko et al found a mean choroid thickness of 410±92 µm in fellow eyes of patients with CSC with choroidal hyperpermeability and 239±59 µm in those without choroidal hyperpermeability.8 This discrepancy may arise from the high cut-off value, 377.7 µm. We accepted >300 µm choroidal thickness as pachychoroid. Also, focal choroidal thickening was considered as pachychoroid, similar to the study of Dansingani et al, in which out of 33 patients with pachychoroid spectrum diseases, only one eye did not have pachychoroid.13 In our study, 91.8% of fellow eyes of patients with CSC had pachychoroid. This is the first study to evaluate fellow eyes according for PPE and UCP, so there is no comparative data in the literature. This present study supports the supposition that pachychoroid is a bilateral condition.

Gupta et al, with OCT, detected RPE alterations in 94% of fellow eyes of 17 patients with unilateral CSC.10 We detected RPE changes in 61% of 286 patients, which were diagnosed as PPE. In the study by Gupta et al, all patients with RPE alterations had RPE bumps and 11.8% had PED.10 In the present study, 77.3% of patients with PPE had RPE bumps and 43% had PED. The reasons for this discrepancy may be different sample sizes and different OCT imaging methods. The leakage site of active CSC was an RPE elevation in 19–68% and PED in 32–71%.2 Most leakage points are in the 2.5 mm zone centred on the fovea.24 In a case series study with 13 eyes with PPE, Dansingani et al reported that most RPE alterations were localised in fovea. In contrast to their study, we detected most RPE lesions in the perifoveal zone. Despite their risk of leaking, they were further from the fovea than the CSC lesions. Because of being asymptomatic and localised far from the fovea, to determine the real frequency of PPE in population is very difficult.

Warrow et al followed up eight patients with PPE for a mean of 70 months. They suggested that PPE might progress to CSC, but these eyes tended to remain stable and did not progress.11 In our study, the duration of disease and chronicity did not affect the development of PPE or UCP. Also, there were no differences between groups with regard to sex and age. PPE and UCP and normal choroid features in fellow eye of patients with CSC tend to remain stable. In this present study, all patients with RPE alterations had a thick choroid, but the choroidal thickness did not differ between PPE and UCP. Although the pachychoroid has a well-known role in CSC pathophysiology, no prospective study has proven that patients with thicker choroid have an increased incidence of CSC.20 Differences between patients regarding resistance of RPE to choroidal pressure may lead to development of different forms of disease.

The risk factors for CSC and PPE are believed to be similar.11 13 Steroid-induced CSC is associated with bilateral disease.25 We could not find any difference between groups with regard to steroid usage. Psychopharmacological medication use and systemic hypertension are other risk factors for CSC.20 Eyes with PPE, UCP and normal fellow eyes did not differ with regard to psychopharmacological medication use and presence of systemic hypertension. Myopia has been suggested as a protective factor for CSC.26 However, in our study, refractive error was not associated with development of different conditions in the fellow eyes of patients with CSC.

The findings of resolved CSC resemble PPE findings. Especially asymptomatic resolved CSC may be misdiagnosed as PPE. In active CSC, subretinal fluid accumulates between the ellipsoid zone and the RPE. Interdigitation zone, interdigitation between the apical processes of the RPE and the cone outer segments,27 is the primary and most affected zone from subretinal fluid. The findings of resolved CSC such as distinct disruption of the interdigitation zone, ellipsoid zone, external limiting membrane and outer nuclear layer should be considered as CSC.16–19

In conclusion, the PPE rate is 61% in the fellow eyes of patients with CSC. There is no difference between PPE and UCP regarding demographic characteristics and medical features. In normal fellow eyes, only difference from fellow eyes with UCP is the thinner choroid. Further studies are required for investigating all the factors influencing the conditions in the fellow eyes of CSC and isolated PPE cases.

References

Footnotes

  • Contributors MGE and MK were involved in the conception and design of the study. MGE, MK and SA were involved in the analysis, interpretation and critical revision of the article. MGE was involved in the drafting of the manuscript. MGE, MK, IBSM, MH and SA were involved in the final approval of the article. MH, IBSM and MGE were involved in the data collection and literature research.

  • Competing interests None declared.

  • Patient consent This is a retrospective study.

  • Ethics approval The institutional review board of Sisli Memorial Hospital, Istanbul.

  • Provenance and peer review Not commissioned; externally peer reviewed.