O R I G I N A L P A P E R
Macular ganglion cell complex thickness in acute
and chronic central serous chorioretinopathy
Gu¨lizar Demirok.Fatih Kocamaz.Yasemin Topalak.Yes¸im Altay.Ahmet Sengun
Received: 16 February 2016 / Accepted: 10 June 2016 / Published online: 20 June 2016 Ó Springer Science+Business Media Dordrecht 2016
Abstract Central serous chorioretinopathy (CSCR) is characterized by neurosensory retinal detachment. Because the retina pigment epithelium and choroidal pathology is the current mechanism in CSCR, many studies in the literature focused on the outer retinal layers. There is little information about the functional or histological structure of the detached retina. In this study, we assess the ganglion cell complex (GCC) thickness using optical coherence tomography (OCT) in patients with acute and chronic CSCR. The medical records of 16 acute and 19 chronic CSCR patients which have no other disorders that cause a serous macula detachment were analyzed. Chronic cases were also divided into two subgroups: chronic active and chronic nonactive CSCR. The eyes with extra-macular involvement or cystoid degeneration and cases which developed choroidal neovascularization were excluded from the study. The mean, minimum, superior-nasal, superior, superior-temporal, inferior-nasal, inferior, and inferior-temporal GCC values
obtained using OCT were used for analysis. The duration from the onset was 7.8 ± 4.5 weeks and the mean age was 45.0 ± 10.7 years in acute CSCR, and in chronic cases the values were 36.0 ± 6.2 weeks and 52.9 ± 10.5 years, respectively. There were no significant differences in sex distribution. The chronic cases were statistically significantly older than acute cases (p = 0.02). While there was no difference between the acute and chronic cases, there were statistically significant differences between the chronic CSCR and control group in all values of GCC. Additionally, there were statistically significant differences between the acute CSCR and control group in mean, minimum, and superior-temporal GCC thicknesses. Although choroid and outer retinal layers play an important role in the pathogenesis of CSCR, there is scant information about the functional or histological structure of the detached retina in CSCR. Our results showed that GCC was significantly reduced in both acute and chronic CSCR compared to healthy subjects. Analysis of ganglion cell helps us understand the etiology of the patients which healed anatomically but had limited visual improvement in CSCR.
Keywords Acute central serous chorioretinopathy Chronic central serous chorioretinopathy Ganglion cell complex thickness Optical coherence
tomography Serous macula detachment G. Demirok (&) Y. Altay
Ophthalmology Department, Ankara Training and Research Hospital, Kızılırmak Street, 1425, Avenue, Hayat Sebla Apartment Number 30/37, C¸ ukurambar, Ankara, Turkey
e-mail: gsoyugelen@yahoo.com F. Kocamaz Y. Topalak A. Sengun
Ophthalmology Department, Ufuk University Faculty of Medicine, Ankara, Turkey
Introduction
Central serous chorioretinopathy (CSCR), which is characterized by detachment of the neurosensory retina in the macular area, is a common clinical diagnosis, particularly in young to middle-aged adults [1]. Several hypotheses have been suggested regarding the pathogenesis of CSCR, but none have been definitively proven. The most eligible mechanisms are focal lesions in retinal pigment epithelium (RPE) and disturbances of choroidal circulation resulting in serous detachment of the neurosensory retina [2]. Although patients affected by CSCR often have higher levels of glucocorticoids and the actions of glucocor-ticoids such as suppression of the collagen synthesis and the inhibition of fibroblastic activity may be the probable mechanism [3], clarifying the pathogenesis of CSCR alone is not sufficient. Here, a new opinion presented that an acute increase in the environmental light intensity may induce focal damages of choroidal vessels, leading to a focal leakage, and a high level of glucocorticoids decelerates the repairing process. Therefore, glucocorticoids may be a persistence factor rather than a trigger of the leakage [4]. According to the result of an electrophysiological study, in which it was hypothesized that CSCR involves not only a leak but also a diffuse RPE transport dysfunction, the electrooculogram did not demonstrate any abnormal-ities in patients with CSCR [5]. Therefore, it may be clearly stated that the role of RPE in the pathogenesis of CSCR remains unclear.
Although many studies in the literature focused on the outer retinal layers and choroidal structures in connection with CSCR [6–9], there is little informa-tion about the funcinforma-tional or histological structure of the detached retina.
The aim of this study was to assess and compare the thicknesses of the ganglion cell complex (GCC) between CSCR patients and healthy individuals, to determine if there are any differences in the inner retinal layers between the two groups.
Methods
This retrospective, comparative study was approved by the Ethical Review Committee and adhered to the provisions of the Declaration of Helsinki for research involving human subjects. The medical records of 16
acute and 19 chronic CSCR cases diagnosed at our retinal disease section between May 2012 and March 2015 were analyzed. The exclusion criteria were as follows: any other disorders that can cause serous macula detachment; a history of eye surgery, including laser therapy or intravitreal injections; cases that developed choroidal neovascularization (CNV); and cystoid degeneration. Because the current ganglion cell analysis (GCA) algorithm uses 6 9 6 mm portion of the retina around the fovea to measure the ganglion cell thickness, the eyes with extramacular involvement were excluded. Patients with uveitis, glaucoma, and diabetes and those using medications such as plaque-nil, immunosuppressive drugs, and steroids that may impact the ganglion cells were also excluded. There-fore, only the effect of the disease on the ganglion cell was evaluated. Only unilateral cases were included, to avoid any statistical errors. In addition, recurrent cases were excluded to eliminate the possible repetitive effect on ganglion cells. Fundus fluorescein angiogra-phy (FFA) was used to clarify the diagnosis in appropriate cases.
We used the GCC thickness data of 20 age- and sex-matched eyes of 20 healthy subjects in the control group. For inclusion, subjects were required to have refractive errors less than 1D spherical equivalent, should not have any ocular and retinal disease, should be free of systemic disease that could likely influence ganglion cells (such as diabetes and hypertension), and must be nonsmokers.
The macula 200 9 200 acquisition protocol was used to view the macula, and the ganglion cell analysis algorithm (Cirrus OCT, Carl Zeiss Meditec, Inc., Dublin, CA) was used to measure the macular ganglion cell–inner plexiform layer (GCIPL) thick-ness with optical coherence tomography (OCT). The mean, minimum, nasal, superior, superior-temporal, inferior-nasal, inferior, and inferior-tempo-ral GCIPL values were used for analysis (Fig.1).
Acute CSCR was defined as the detachment of the neurosensory retina that became symptomatic within 6 months. Chronic CSCR was defined as the duration of decreased visual acuity, residual symptoms, and RPE changes persisting for at least 6 months [10]. Chronic cases were then divided into the following two subgroups: chronic active CSCR, which was defined as cases with apparent neurosensory retinal detachment, and chronic nonactive CSCR or sequelae
of CSCR, defined as cases with no neurosensory detachment [11] (Fig.2).
Treatment was considered only in the chronic active group for those who have persistent serous detachment after 6 months, as irreversible photoreceptor atrophy may occur thereafter. Photodynamic therapy was administered to patients, but it was not accepted because of high cost and possible side effects. Argon laser photocoagulation was performed using minimal laser power to the extrafoveal leakage sites which were determined by FFA, as the treatment. All the values that were used in this study were obtained before the treatment session to rule out the effect of laser treatment on ganglion cell analysis and symptoms. All CSCR patients underwent routine psychiatric consultation and blood pressure regulation.
Central macula thicknesses, inner segment–outer segment (ISOS) continuity, pigment epithelium detachment occurrence, and border appearance (dis-tinct/indistinct) of the CSCR cases were also recorded from the OCT data.
Statistical analysis was performed using the Statis-tical Package for Social Sciences (version 17.0, SPSS Inc., Chicago, IL, USA), and the values are presented as the mean ± SD. The Shapiro–Wilk test was used to determine the normal distribution of all variable
groups, and the Mann–Whitney U test was used for comparison of the variables that were not normally distributed. p values\0.05 were considered to be statistically significant. Bonferroni correction was used for multiple comparisons to control type 1 errors.
Results
The acute CSCR group consisted of 12 (75 %) male and 4 (25 %) female cases, with a mean age of 45.0 ± 10.7 (27–66) years, whereas the chronic CSCR group consisted of 11 (57.9 %) male and 8 (42.1 %) female cases, with a mean age of 52.9 ± 10.5 (33–72) years. The mean age of the control group was 48.6 ± 8.5 (29–68) years. The chronic cases were statistically significantly older than the acute cases (p = 0.02). The mean age of the control group matched well with both the CSCR groups (p [ 0.05, for both).
Table 1 reports all the descriptive and statistical information in terms of initial demographics, exam-ination, treatments, and OCT findings, for the acute and chronic CSCR groups.
The duration of acute CSCR from disease onset was 7.8 ± 4.5 weeks (mean ± SD, range 2–16 weeks), whereas the duration of chronic CSCR from disease Fig. 1 Ganglion cell segmentations in optical coherence tomography of acute central serous chorioretinopathy (upper) and normal subjects (bottom)
onset was 36.0 ± 6.2 weeks (mean ± SD, range 26–50 weeks).
In the acute cases, ISOS continuity on OCT was statistically significantly preserved compared with the chronic cases (p = 0.005). Overall, the cases with preserved ISOS integrity had better visual acuity (0.73 ± 0.17, decimal) than the unpreserved cases (0.56 ± 0.18, decimal) (p = 0.004).
Table 2 shows the GCC thicknesses in the acute CSCR, chronic CSCR, and control groups at the time of diagnosis (Fig.3). Although there were no statis-tically significant differences between the acute and chronic cases, there were significant differences between the chronic CSCR and control groups for all of the GCC values. In addition, there were statistically significant differences between the acute CSCR and Fig. 2 Subgroups of central serous chorioretinopathy (CSCR): a acute CSCR, b chronic active CSCR, and c chronic nonactive CSCR
control groups in the mean, minimum, and superior-temporal GCC thicknesses.
The chronic cases consisted of 11 chronic active CSCR and 8 chronic nonactive CSCR cases. There were no statistically significant differences in terms of the GCC thickness values between the two subgroups (p [ 0.05).
Discussion
CSCR, which is characterized by the accumulation of fluid between the RPE and the neurosensory retina, is a
poorly understood disease [12]. Previous studies attempting to determine the pathogenesis of the disease have focused on the RPE and choroidal dysfunction. FFA has been used to reveal focal leakage sites in the RPE, and it has been suggested that this leakage causes the RPE or neurosensory retinal detachment [13, 14]. In contrast, choroidal vascular hyperpermeability has been suggested as the primary cause of damage to the RPE in some reports, and this increased permeability has been demonstrated using indocyanine green angiography [15]. As a support for the choroidal hyperpermeability, the Table 1 Comparison of demographic characteristics and examination findings of the central serous chorioretinopathy cases
Parameters Acute CSCR Chronic CSCR p
Number of cases (n) 16 (45.7 %) 19 (54.3 %) –
Gender, n (%) M; F
12 (75.0 %); 4 (25.0 %) 11 (57.9 %); 8 (42.1 %) 0.288
BCVA (decimal) 0.82 (0.60–1.00) 0.53 (0.30–0.70) 0.004*
Refractive error (SE)(D) 1.41 ± 2.06 1.54 ± 1.23 0.325
IOP (mmHg) 16.5 (±3.4) 17.6 (±2.8) 0.456
Central fovea thickness (lm) 346.1 (±103.6) 278.1 (±95.9) 0.005* ISOS continuity ±
(OCT)
14/2 7/12 0.005*
Borders (distinct/indistinct) (OCT) 14/2 2/17 \0.001*
PED ± (OCT) 4/12 8/11 0.476
Smoking± 6/10 7/12 0.621
Treatment (Laser)± 0/16 8/11 0.003*
BCVA best-corrected visual acuity, CSCR central serous chorioretinopathy, D diopter, IOP intraocular pressure, ISOS inner segment– outer segment, OCT optical coherence tomography, PED pigment epithelial detachment, SE spherical equivalent
*p \ 0.05 was considered statistically significant
Table 2 Comparison of ganglion cell complex thicknesses of all cases and controls Acute CSCR median (min–max) Chronic CSCR median (min–max) Control group median (min–max) p
Mean GCC thickness (lm) 75.5 (28–112)a 77.0 (39–85)b 88.0 (74–102)a,b \0.001 Minimum GCC thickness (lm) 62.5 (11–91)a 73.0 (10–83)b 85.5 (71– 98)a,b \0.001 Superior-nasal GCC thickness (lm) 85.5 (30–112) 79.0 (25–108)b 89.0 (73–106)b 0.025 Superior GCC thickness (lm) 80.0 (21–96) 77.0 (30–100)b 89.5 (75–102)b 0.002 Superior-temporal GCC thickness (lm) 76.0 (21–94)a 77.0 (33–85)b 87.5 (75–104)a,b \0.001 Inferior-nasal GCC thickness (lm) 79.0 (31–112) 76.0 (39–90)b 89.0 (74–106)b 0.001 Inferior GCC thickness (lm) 82.0 (24–114) 75.0 (26–84)b 87.5 (70–103)b 0.002 Inferior-temporal GCC thickness (lm) 83.5 (25–105) 79.0 (28–90)b 90.0 (75–103)b 0.002 According to the Bonferroni correction, p < 0.017 was considered statistically significant
CSCR central serous chorioretinopathy, GCC ganglion cell complex
a Statistically significant difference between the acute CSCR and control groups b Statisticalyl significant difference between the chronic CSCR and control groups
plasma levels of plasminogen activator inhibitor 1 concentrations were found to be significantly higher in patients with CSCR as compared with normal sub-jects. This protein downregulates fibrinolysis and causes thrombotic occlusion in the choroidal veins [16].
OCT is a noninvasive and relatively new method for defining serous detachments of the RPE and retina. Using OCT, elongation of the outer segments of the photoreceptors and narrowing of the outer nuclear layer were demonstrated by Matsuma et al. [17]. In addition, visual recovery rates were markedly lower in patients with a disrupted outer photoreceptor layer on OCT [18]. Although most studies have shown that visual prognosis in CSCR is associated with the outer retinal layer, there is still not enough information in the literature about the inner layers of the retina and GCC, which have important roles in the visual pathway. Therefore, we aimed to gain knowledge about the structure of the innermost layers of the retina in CSCR patients using the GCC thicknesses obtained using OCT.
Our results show that GCC is significantly reduced in both acute and chronic CSCR subjects compared with healthy subjects. It is unclear whether this result is secondary to the deteriorated circulation of the detached retina or the psychogenic factors that con-tribute to the etiology of the primary disease (CSCR). One can hypothesize that psychological factors may also play an important role in ganglion cell loss in CSCR because ganglion cell numbers have been found to be lower in patients with type A personality, which is known to be related to stress levels [19]. However, the reduction of ganglion cells in all the segments of the chronic cases compared with acute cases, which had fewer ganglion cells in only three segments, suggests a relationship between ganglion cell loss and duration of the disease. The chronic CSCR patients were older than the acute patients. Medeiros et al. found a rate of retinal ganglion cell loss of 7877 cells per year [20]; therefore, this could be the reason for the reduction of the ganglion cell numbers in the chronic cases in the present study. However, the mean age of the control group matched well with those of the two Fig. 3 Graphic of ganglion cell complex (GCC) thicknesses of all cases
patient groups, which suggests that age-related loss of ganglion cells is unlikely in this study population.
Numerous studies have demonstrated that patients affected by CSCR often have higher serum and urinary cortisol levels than healthy subjects [21,22]. Although the exact pathomechanism is not completely under-stood, the mineralocorticoid receptor (MR) affinity of glucocorticoids is the most important topic. MRs are present in vascular smooth muscle and endothelial cells, and excessive MR activation inhibits vascular relaxation that results in vessel inflammation and fibrosis [23,24]. In addition, various mechanisms of steroids, such as increased capillary permeability, production of nitric oxide, prostaglandins, and free radicals, and inhibition of collagen production, which is the primary component of Bruch’s membrane, may be responsible for the etiopathogenesis of CSCR [25]. In addition, steroids can cause circulatory disturbances [26]. Thus, one can hypothesize that this circulatory problem could cause the reduction of ganglion cells observed in CSCR patients. Furthermore, Chandra et al. showed delayed retinal circulation times using FA in only nine patients in their study, which evaluated retinal circulation in various macular disor-ders [27]. Six of these nine patients were affected by CSCR, with more than 6 months’ duration of the disease. Despite the small number of patients, these data may be valuable and may be associated with the decreased thickness of the GCC, which receives its blood supply from the retinal circulation.
Consequently, in patients with CSCR, the analysis of ganglion cells helps us understand the etiology of patients who have healed anatomically but still have limited visual improvement. We acknowledge that our study has a number of shortcomings, including the relatively limited number of patients and the absence of a longitudinal follow-up to assess possible long-term changes in the GCC.
In conclusion, this study demonstrates that eyes with acute and chronic CSCR exhibit reduced GCC thickness. Further studies are warranted to provide a better understanding of factors affecting the ganglion cell layers and their value in patients with CSCR. Compliance with ethical standards
Conflict of interest The authors report no conflict of interest in this work.
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