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Outer Nuclear Layer as the Main Predictor to Anatomic Response to Half Dose Photodynamic Therapy in Chronic Central Serous Retinopathy.

1. Introduction

Central serous retinopathy (CSR) is characterized by macular serous detachment in the absence of other ocular abnormalities [1, 2]. Although most acute cases resolve spontaneously, the recurrence or persistence of serous subretinal fluid can lead to deterioration in vision [2, 3]. One definition of chronic CSR (cCSR) is characterized by persistent serous retinal detachment for more than 6 months [4]. Over the last decades, fluorescein angiography (FA) and indocyanine green angiography (ICG) have been used to confirm the diagnosis. However, these techniques remain insufficient for predicting visual outcomes [3]. The recent advances in spectral-domain optical coherence tomography (SD-OCT) have made it possible to detect changes in the retinal microstructure [2, 3]. The ability to evaluate changes in central macular thickness, submacular fluid, thickness of the outer nuclear layer (ONL), and thickness of the external retinal bands such as the external limiting membrane (ELM), the ellipsoid (EZ), and interdigitation (IZ) zones has increased our knowledge on the pathophysiology of CSR [2-10]. Subfoveal choroidal thickness (CT) has been reported to be thickened in CSR likely due to choroidal vascular dilation [11]. SD-OCT evaluation of the subretinal fluid has become an important tool for the management of the disease as it provides fast and innocuous characterization of disease activity, determining which patients require treatment due to persistent subretinal fluid, and it allows the anatomical evaluation of treatment response.

In cases of persistent subretinal fluid, half-dose photodynamic therapy (HD-PDT) with verteporfin has been widely used to treat CSR by inducing choroidal vascular remodeling and decreasing choroidal vascular permeability with a high anatomical success [4, 8, 12, 13]. However, there has been a discrepancy between anatomic success of the treatment, usually defined as absence of subretinal fluid, and visual recovery. This fact suggests that there may be prognostic factors that can predict anatomic and visual recovery [4, 12, 14]. The aim of our study is to identify baseline SDOCT characteristics that may predict the anatomic improvement after HD-PDT in patients with chronic CSR. We evaluated the CMT, ONL, ELM, EZ, IZ, subretinal fluid (SRF), and CT as prognostic factors for subretinal fluid resorption about 12 months after HD-PDT treatment.

2. Methods

Medical records of patients who had the diagnosis of cCSR that were submitted to HD-PDT between January 2015 and February 2018 were reviewed for this retrospective study. All investigations were performed in accordance with the principles of the Declaration of Helsinky and approved by the Ethics Committee of Hospital de Braga. All patients with a diagnosis of cCSR who performed HD-PDT during the reported period were included. Data were collected at baseline and 12 [+ or -] 2.6 months after treatment. No other treatments for cCSR including mineralocorticoid receptor antagonists or focal laser were performed during the study period. Patients with myopia [greater than or equal to] 6.0 diopters and macular disorders such as choroidal neovascularization, polypoidal choroidal vasculopathy, age-related macular degeneration, history of vitreomacular disease, intravitreal anti-VEGF (vascular endothelial growth-factor) or mineralocorticoid-receptor antagonists treatment, laser photocoagulation or prior PDT [less than or equal to] 6 months, cataract, or optical media opacity that restricted the examination of ocular fundus were excluded from this study.

Each study participant underwent a comprehensive ophthalmologic examination, SD-OCT, and FA (TRC-50DX, Topcon Medical Systems, Inc., Tokyo, Japan) and/or ICG (TRC-50DX, Topcon Medical Systems, Inc., Tokyo, Japan) evaluation. Demographic data collected included sex, age, time of diagnosis, laterality, and previous treatments. Ophthalmologic examination included best-corrected visual acuity (BCVA) and slit-lamp biomicroscopy. BCVA was assessed using the decimal scale chart and converted to logarithm of the minimum angle of resolution (log MAR).

Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany) was used to measure retinal thickness and evaluate the outer retinal layers. The OCT imaging technique consisted in obtaining a macular square (20 x 20[degrees]) composed of 25 horizontal B-scans, spaced at 240 [micro]m. Each B-scan was averaged 9 times (ART 9). Additionally, for each case, a single horizontal and a single vertical B-scan using the enhanced depth imaging mode, averaged 100 times (ART 100), and centered on the fovea was obtained.

The SD-OCTs were performed immediately before treatment and 12 [+ or -] 3 months later. The presumed foveal center was determined as the area lacking the inner retinal layers in the macular region. Data collected were: central macular thickness (CMT) and the following foveal parameters: outer nuclear layer (ONL) thickness, presence or absence of external limiting membrane (ELM), ellipsoid band (EZ), interdigitation band (IZ), subretinal fluid height (SRF), and choroidal thickness (CT). ONL was defined as the distance between the inner limiting membrane and the ELM at the central fovea. SRF was measured as the hyporeflective space from the IZ to the RPE. Choroidal thickness was measured subfoveally with enhanced depth imaging, from the outer portion of the retinal pigment epithelium (RPE) to the inner surface of the sclera. When there was any disruption of the central foveal millimeter of the ELM, EZ, and IZ bands, they were classified as absent; when these layers were preserved, they were classified as present. All measurements and evaluations were made by two independent investigators (K.S. and A.R.V.) on the horizontal high quality scans centered on the fovea. Any prominent difference between the two investigators was discussed with the senior author (M.F.), and the reconciled measurement was recorded.

PDT with verteporfin (Visudyne[R], Novartis, Basel, Switzerland) was performed using a half-dose protocol. Verteporfin at 3mg/[m.sup.2] dose was infused for 8 min; diode laser light (689 nm) was delivered (Visulas 690 D, Carl Zeiss Meditec Inc., Jena, Germany) for 83 s. The standard dose of laser intensity (600 mW/[cm.sup.2]) and fluence was used (50 J/[cm.sup.2]). The spot size was determined by the area size of the maximum leakage point on ICG or FA.

Two different groups of patients were created for the analysis. Patients were divided into anatomic responders (R) and nonresponders (NR) based on SRF resorption. Patients were classified as responders if the SRF improved equal or greater than 50% resorption of SRF measured on SD-OCT height.

All statistical analysis was performed using SPSS software version 25.0 (SPSS Inc., Chicago, IL), and p values <0.05 were considered statistically significant. All values were presented as mean ([+ or -]standard deviation (SD)) or median (interquartile range (IQR)). Nonparametric tests were applied after nonnormality of the sample was confirmed by the Shapiro-Wilk test. Wilcoxon signed-rank test was used to compare baseline and posttreatment visual acuity. Spearman's rho correlation was used to find the associations between anatomic response and baseline OCT characteristics. Mann-Whitney U or independent sample t-test was used to compare differences between groups. To identify factors affecting treatment success, we performed a binary univariate analysis and subsequently a multivariate regression using the backward conditional method to exclude possible confounders and analyzed the baseline variables to verify any predictive factors.

3. Results

Seventy eyes of 47 patients were selected. Nine eyes were excluded due to lack of complete follow-up. Sixty-one eyes of 42 patients were included. Mean age was 55.7 [+ or -] 12.6 years; 71.4% (n = 30) were male. Median time from diagnosis until treatment was 20 (IQR 26) months. Corticoid use was present in 27.9% (n = 11) of patients. Naive eyes were 44.3% (n = 27), and previous treatments, such as HD-PDT, mineralocorticoids, or anti-VEGF, were applied in 55.7% (n = 34) cases outside the study period and at least 3 months before the study. Table 1 shows demographic characteristics of our sample.

3.1. Anatomic Response and Visual Acuity. The samples were divided in two groups: R and NR, regarding the SRF improvement on SD-OCT. Forty-six patients (75.4%) were classified as R and 15 (24.6%) were classified as NR. Overall, the median baseline BCVA was 0.30 logMAR (IQR 0.40), and the final BCVA was 0.20 logMAR (IQR 0.30), which meant a significant visual improvement (z =- 2.85, p = 0.004). In the NR group, there was no significant variation in median BCVA throughout the study, from 0.70 (IQR 0.6) to 0.40 (IQR 0.50) (z =-0.12, p = 0.91). In the R group, the median baseline BCVA improved from 0.25 log MAR (IQR 0.20) to 0.20 log MAR (IQR 0.2) (z =-3.56, p < 0.001). Baseline visual acuity was not statistically different between both groups (U = 242, z =-1.75, p = 0.08). However, final BCVA was better in R (0.20 logMAR (IQR 0.20) than NR (0.40 logMAR (IQR 0.50)) (U = 156, z =-3.08, p = 0.002).

3.2. OCT Parameters. The baseline SD-OCT parameters evaluated in R and NR are shown in Table 2. The baseline ONL was thicker in the R group (43.5 [+ or -] 22.9 [micro]m) than in the NR group (23.9 [+ or -] 32.2 [micro]m, p < 0.01). The ELM integrity was more prevalent in the R group than in the NR group (67.2% vs. 16.4%), p = 0.04. The same was observed within the EZ (49.2% vs. 8.2%, p = 0.03) and the IZ (31.2% vs. 1.6%, p = 0.01).

3.3. Independent Correlations with Anatomic Response. The correlation between the baseline retinal layers and the anatomic response to HD-PDT was evaluated as shown in Table 3. The ONL thickness and the presence of the other outer retinal layers are significantly correlated with the final anatomic response (ONL (rs (59) = 0.416, p = 0.001*), ELM (rs (59) = 0.261, p = 0.04*), EZ (rs (59) = 0.278, p = 0.03*), and IZ (rs (59) = 0.318, p = 0.01*)). Overall, neither baseline BCVA and time from symptoms/diagnosis until treatment were correlated with the anatomic effect (rs (63) = 0.08, p = 0.54).

3.4. Binary Regression on Anatomical Response. A binomial multivariate logistic regression was performed to ascertain the effect of final BCVA, ONL, EZ, and IZ on the likelihood that patients will respond to HD-PDT. The logistic regression model was statistically significant ([chi-square](4) = 11.7, p = 0.002). The model explained 17.4% to 25.9% (Nagelkerke [R.sup.2]) of the variance of anatomical response and correctly classified 78.7% of cases. Of the four predictive values, only one was statistically significant, ONL (p = 0.02). The increase of 1 [micro]m of ONL thickness elevates 1.04 times the chance to anatomic response to HD-PDT. All other variables lost statistical significance in the multivariate logistic regression model as shown in Table 4.

4. Discussion

Due to the increasing costs of medical therapy, the decision to treat patients in clinical practice has led to an increasing concern over cost-effectiveness. Understanding which patients will benefit from treatment in expensive medications such as PDT is of paramount importance. Evaluating the anatomy of the outer retina before treatment may help predict the anatomic response. In our series, though all external layers had an independent significant correlation with the anatomical fluid resorption, we observed that patients with a thicker ONL had a higher likelihood to obtain an adequate anatomic response to HD-PDT in the dicotomic model. This could mean that ONL status might be the most important layer to predict the anatomic response.

Current advances in the SD-OCT technology have provided precious information regarding the importance of outer retinal layers in visual function in eyes with CSR [6,14,15]. Improvement in BCVA and SRF after HD-PDT is well documented [4, 14, 16-19] and was confirmed in this study. We also showed that when an anatomic response does not occur, we do not find a significant change in vision. Treatment effect based on SRF resorption and CMT reduction has been used to classify the response to PDT [18, 20]. Most of the studies reported an anatomical success of 60-85%, which was in line with our results of 75.4% of anatomical improvement [14, 18, 19]. In our study, we disclose that the anatomic responders had a final better median BCVA (with less improvement) as in the study of Matuskova et al. [4]. This could also be an indicator that using the PDT when the retina is not yet dysfunctional may lead to better SFR resorption, CMT improvement, and improved visual acuity. However, we did not find that time to treatment was an indicator of anatomic improvement after treatment. Chung et al. and Iacono et al. reported similar findings as they described that the duration of symptoms was not linked with subretinal fluid resolution [21, 22]. This could mean that retinal dysfunction in this disease may not be linked to the amount of time in which subretinal fluid is present and could be linked to other outer retinal changes that occur but are not time-dependent. It is possible that the biochemical characteristics of subretinal fluid may differ from patient to patient, and these differences may have different effects on the external retinal layers that have been described [2, 12, 21].

In our study, the R group had different baseline SDOCTs from NR. They had a thicker ONL, and the ELM, EZ, and IZ were more frequently intact. However, in our binary regression model, we found that the ONL thickness was the only predictor of SRF resorption. The ONL is the innermost retinal layer of the variables in our study. The ONL is composed by the nuclei of photoreceptors. Thinning of this layer could be a marker of definite retinal damage that may predict a poor response to PDT. When the subretinal fluid is present, the RPE is not able to absorb the tip of the outer segment. This may lead to both an elongation of photoreceptor outer segments and possibly photoreceptor cell apoptosis with subsequent thinning of ONL [9, 23, 24]. Other studies have reported that the ONL thickness could be an important predictor of visual acuity after one year of half-fluence PDT [8, 25]. However, these studies differ from the present studies because they had a lower number of eyes (22 and 36) and they used half-fluence PDT instead of half-dose PDT.

Other authors have reported other results but, in their studies, the ONL was not assessed, and therefore the importance of this layer could not be evaluated. A strong correlation between the disruption of the ellipsoid (previously denominated IS/OS) and low BCVA and a decrease in visual acuity when the ELM is disrupted was found in untreated chronic CSR [3]. One other study did not find any predictive factors with final BCVA, including ELM or the ellipsoid zone when low-fluence PDT was used [4]. When conventional PDT was used, a disruption of the EZ, longer duration of visual symptoms, and RPE atrophy negatively impacted on visual function [14]. Finally, Chung et al. used SRF resolution as a prognostic factor for visual acuity improvement for HD-PDT. They also observed that EZ was not a prognostic factor for SFR resorption, but they did not include other variables than the EZ as predictors [21]. These data suggest that evaluating the EZ as the sole predictive factor for visual function for chronic CSR might be reductionist and that all outer retinal structures, especially the ONL, should be taken into account as a predictive factor and in future evaluations of response to therapy.

Our study also has limitations. It is a retrospective study. There was an asymmetry between the number of patients in the two groups because the majority of patients had a good response. There were a significant number of patients who were followed-up for a long time, and other treatments have been performed before, which could explain the poorer results. Mean age was higher than usual, and it could be linked for the longer time of disease and due to 31.9% of patients that had cCSR linked to corticoid use. Patients were followed up in a regular clinical setting without strict followup protocols and treatment indications as clinical trials; however, it tries to reflect everyday clinical practice.

This is the first study to analyze the anatomic characteristics of all the outer retinal layers in a multivariable model to try and identify predictors of SRF resorption in patients treated with HD-PDT for cCSR with one year of follow-up. Anatomic recovery is usually proportional to visual acuity improvement [10, 14, 21]. That was the main reason to study predictors that may influence anatomic recovery. Evaluation of the outer retinal layers especially the ONL may help predict which patients may have an anatomical response to HD-PDT. Treating patients with a thin ONL may not have a good anatomical response and therefore will not obtain significant visual benefits.

5. Conclusion

HD-PDT is one treatment option for cCSR. Multiple studies used assorted variables trying to predict a better result of PDT in cCSR [25]. Most studies have evaluated single retinal layers using SD-OCT. We analyzed all the outer retinal layers, and in our model, a thicker ONL was the best predictor for better anatomic results.

Data Availability

The data used to support the findings of this study are restricted by the Ethics Committee of Hospital de Braga in order to protect patient privacy. Data are available for researchers who meet the criteria for access to confidential data.

Ethical Approval

All procedures were in accordance with the ethical standards of the institutional, document number 132/2017, and National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All data were used based on anonymized data, and none of the presented results can identify any patient.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


The authors acknowledge Andreia Magalhaes (OCT technique supervision); Gil Calvao-Santos, MD (proofreading and data collection); Rita Gentil, MD (data collection data); Luts Mendon^a, MD (data collection); Petra Gouveia, MD (writing assistance, technical editing, and proofreading); Nuno Gomes, MD (general supervision); Fernando Vaz, MD (general supervision).


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Keissy Sousa, (1,2) Ana Rita Viana, (3) Joana Pires, (1) Carla Ferreira, (1) Lara Queiros, (4) and Manuel Falcao [ID] (2,4,5)

(1) Ophthalmology Department, Hospital de Braga, Braga, Portugal

(2) Ophthalmology Department, Centro Hospitalar Universitario S. Joao, Porto, Portugal

(3) Medicine School, Universidade do Minho, Braga, Portugal

(4) Ophthalmology Department, Hospital Cuf Porto, Porto, Portugal

(5) Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal

Correspondence should be addressed to Manuel Falcao;

Received 6 June 2019; Accepted 23 September 2019; Published 13 October 2019

Academic Editor: Hong Liang
Table 1: Demographic characteristics and clinical data.

Variable                         (42 patients, n = 61)

Sex (male/female)                        30/12
Age (years)                        55.7 [+ or -] 12.6
Time until treatment (months)         20 (IQR 26)
                                         HD-PDT           16.4%
                                   Mineralocorticoid      1.6%
Previous treatments                       MPL             3.3%
                                       Anti-VEGF          4.9%
                                        Multiple          29.5%

values are presented as mean [+ or -] standard deviation in age
and as median (IQR = interquartile range) in time until treatment.

Table 2: Variables at baseline from responders and
nonresponders groups.

Variables                    Responders           Nonresponders

Best-corrected visual           0.25                   0.7
  acuity (log MAR)
Central macular              315.5 (183)            283 (95)
  thickness (pm)
Outer nuclear            43.5 [+ or -] 22.9    23.9 [+ or -] 32.2
  layer ([micro]m)
External limiting               41/5                  10/5
  membrane (present/
Ellipsoid zone           30/16 (65.2/34.8%)    5/10 (33.3%/66.7%)
Interdigitation zone     19/27 (41.3%/58.7%)    1/14 (6.7/93.3%)
Choroidal                304.2 [+ or -] 74.1   282.3 [+ or -] 47.8
  thickness ([micro]m)
Subretinal                   96.5 (201)              61 (89)


Best-corrected visual     U = 242, z =-1.75, p = 0.08
  acuity (log MAR)
Central macular           U = 417, z = 1.06, p = 0.29
  thickness (pm)
Outer nuclear              t(59) =-2.59, p = 0.01 *
  layer ([micro]m)
External limiting                 p = 0.04 *
  membrane (present/
Ellipsoid zone                    p = 0.03 *
Interdigitation zone              p = 0.01 *
Choroidal                   t(59) = -1.08, p = 0.29
  thickness ([micro]m)
Subretinal                U = 384, z = 0.66, p = 0.51
  fluid ([micro]m)

Variables at baseline included in the analysis from responders and
nonresponders groups. There was a significant difference between both
groups in outer nuclear layer, external limiting membrane, ellipsoid
zone, and interdigitation zone. * Statistically significant.

Table 3: Independent correlations between variables at baseline
and anatomic response.

Independent variables at baseline          Correlation with
                                           anatomic response

Best-corrected visual acuity           rs (59) = -0.23, p = 0.08
Time from diagnosis                    rs (57) = 0.05, p = 0.73
Central macular thickness              rs (59) = 0.15, p = 0.25
Outer nuclear layer                  rs (59) = 0.416, p = 0.001 *
External limiting membrane            rs (59) = 0.261, p = 0.04 *
Ellipsoid zone                        rs (59) = 0.278, p = 0.03 *
Interdigitation zone                  rs (59) = 0.318, p = 0.01 *
Choroidal thickness                   rs (59) = -0.098, p = 0.45
Subretinal fluid                       rs (59) = 0.085, p = 0.52

Independent correlations between the anatomic response and the
baseline retinal layers or baseline best-corrected visual acuity
(BCVA). There is an independent correlation between baseline outer
nuclear layer, external limiting membrane, ellipsoid zone, and
interdigitation zone. rs = Spear- man's rho correlation; p = p
value; * = statistically significant.

Table 4: Univariate and multivariate binomial regression to estimate
the probability of anatomic response.

Variable                     Univariate x      Univariate analysis
                             visual acuity       p-value, 95% CI

Baseline best-corrected          0.151       p = 0.04, 0.025--0.891 *
  visual acuity
Time until diagnosis             1.005        p = 0.73, 0.976-1.035
Central macular thickness        1.001        p = 0.76, 0.997-1.005
Outer nuclear layer              1.04        p = 0.02, 1.01 - 1.07 *

External limiting membrane       0.244        p = 0.05, 0.059-1.008
Ellipsoid zone                   0.267       p = 0.04, 0.078--0.915*
Interdigitation zone             0.102       p = 0.03, 0.012--0.839*
Choroidal thickness              1.005        p = 0.28, 0.996-1.014
Subretinal fluid                 1.001        p = 0.71, 0.996-1.005

Variable                     Multivariate        Multivariate
                              analysis,       analysis p-value,
                                Exp(B)              95% CI

Baseline best-corrected          0.49        p = 0.49, 0.065-3.66
  visual acuity
Time until diagnosis              X
Central macular thickness         X
Outer nuclear layer              1.04         p = 0.02, 1.007 -
                                                   10.071 *
External limiting membrane        X
Ellipsoid zone                   1.27       p = 0.76, 0.268-6.029
Interdigitation zone             0.16        p = 0.1, 0.018-1.43
Choroidal thickness               X
Subretinal fluid                  X

To estimate the probability of anatomic response of baseline
variables, a univariate analysis of each variable to exclude possible
confounders was performed initially, and subsequent multivariate
analysis was performed. Only the outer nuclear layer was a
significant predictor. *, statistically significant; X, not included.
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Title Annotation:Research Article
Author:Sousa, Keissy; Viana, Ana Rita; Pires, Joana; Ferreira, Carla; Queiros, Lara; Falcao, Manuel
Publication:Journal of Ophthalmology
Article Type:Clinical report
Geographic Code:4EUPR
Date:Oct 31, 2019
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