Evaluation of the effects of photodynamic therapy on chronic central serous chorioretinopathy based on the mean choroidal thickness and the lumen area of abnormal choroidal vessels.

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Photodiagnosis and Photodynamic Therapy (2014) xxx, xxx—xxx

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Evaluation of the effects of photodynamic therapy on chronic central serous chorioretinopathy based on the mean choroidal thickness and the lumen area of abnormal choroidal vessels Rui Hua a, Limin Liu a, Chenyan Li b,c, Lei Chen a,∗ a

Department of Ophthalmology, First Hospital of China Medical University, Shenyang, China Department of Endocrinology, First Hospital of China Medical University, Shenyang, China c Key Laboratory of Endocrine Diseases in Liaoning Province, First Hospital of China Medical University, Shenyang, China b

KEYWORDS Enhanced depth imaging optical coherence tomography; Subfoveal choroidal thickness; Mean choroidal thickness; Lumen area; Chronic central serous chorioretinopathy

Summary Purpose: To evaluate the effects of photodynamic therapy (PDT) on chronic central serous chorioretinopathy (CCSC) by measuring the mean choroidal thickness (MCT) and the lumen area of abnormal choroidal vessels (LAACV). Methods: A total of 36 eyes of 18 patients with monocular CCSC were included in this study. The CCSC eyes received PDT with a half dose (3 mg/m2 ) of verteporfin and follow-up examinations were carried out for 3 months after PDT. The boundary of choroids and abnormal choroidal vessels (round or ovoid dark regions) were characterized using enhanced depth imaging optical coherence tomography. The MCT and LAACV were analyzed by two investigators masked to the diagnosis and the treatment of CCSC using the Image Pro Plus 6.0 software. Results: The MCT of CCSC eyes was significantly greater than that of normal eyes at baseline (P < 0.0001), but it significantly decreased at the last follow-up examination after PDT (P < 0.0001). The LAACV of the last follow-up examination was significantly smaller than that of the first follow-up examination (P < 0.0001). Moreover, the LAACV showed a significant correlation with the MCT in CCSC eyes. Conclusions: The MCT and LAACV are useful for quantitative evaluation of the effects of PDT on CCSC. © 2014 Elsevier B.V. All rights reserved.

∗ Corresponding author at: No. 155, Nanjingbei Street, Heping District, Shenyang, Liaoning Province, China. Tel.: +86 13 840583355; fax: +86 24 83282630. E-mail address: [email protected] (L. Chen).

http://dx.doi.org/10.1016/j.pdpdt.2014.07.005 1572-1000/© 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: Hua R, et al. Evaluation of the effects of photodynamic therapy on chronic central serous chorioretinopathy based on the mean choroidal thickness and the lumen area of abnormal choroidal vessels. Photodiagnosis and Photodynamic Therapy (2014), http://dx.doi.org/10.1016/j.pdpdt.2014.07.005


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Introduction Chronic central serous chorioretinopathy (CCSC) is characterized by serous detachment of the neurosensory retina and/or the retinal pigment epithelium (RPE) for over 6 months, which is often accompanied by extensive leakage caused by RPE damage [1]. The pathogenesis of CCSC remains controversial and two hypotheses have been proposed: the RPE dysfunction hypotheses (defects of the tight junctions between RPE cells [2]) and the choroid dysfunction hypotheses (increased inner-choroid permeability [3]). In the study performed by Guyer et al., diffused hyperpermeability around the active leakage sites was detected by indocyanine green angiography (ICGA) rather than fluorescein angiography (FA) [1]. Increased innerchoroid permeability that was considered as the primary abnormality of CCSC led to RPE elevation and disruption, and eventually caused serous macular detachment (SMD) [3]. Photodynamic therapy (PDT) could remodel the choroidal vessels, and reduce choroidal perfusion and choroidal exudation [4]. Moreover, it has been reported that PDT significantly reduced the dilated choroidal vasculature and relieved the congestion and leakage as early as 30 days after the first round of treatment [5]. However, studies have shown that standard dose of PDT might be associated with choriocapillaris hypoperfusion, resulting in decreased vision [6,7]. Jirarattanasopa et al. [8] and Karakus et al. [9] reported that the PDT with a half dose (3 mg/m2 ) of verteporfin was effective and safe for the treatment of CCSC with anatomical and functional improvements of choroids [10]. Since introduced by Spaide et al. [11] in 2008, the enhanced depth imaging optical coherence tomography (EDI-OCT) has been widely used for the analysis of choroidal parameters and the clinical evaluation of choroidal diseases. The most outstanding applications of EDI-OCT include etiological studies of CCSC [12], evaluation of PDT for the treatment of CCSC [13], and analysis of subfoveal choroidal thickness (SFCT) in Vogt—Kovanagi—Harada patients [14]. A Japanese study has recently reported that there was no significant correlation between SFCT and the total or subfoveal choroidal blood flow in healthy young subjects based on assessment of pulsatile ocular blood flow using the Langham ocular blood flow system (OBF) [15]. In some cases,

the ICGA staining areas do not correspond with thickened choroid detected by EDI-OCT [11]. The thickened choroid caused by leakage would be larger than regions where the hyperpermeability occurs. Therefore, additional parameters are necessary for the assessment of pathological changes of choroids. Here, we introduced two EDI-OCT parameters, the mean choroidal thickness (MCT) and the lumen area of abnormal choroidal vessels (LAACV), for the quantitative analysis of the SFCT of CCSC eyes. The MCT was defined as the choroidal area (CA) divided by the RPE length. CA was acquired by integrating the choroidal thickness (CT) at each point over a given scan line (Fig. 1). Thus, in addition to SFCT, the MCT represents the average CT over the entire OCT scan. To standardize the parameters and facilitate comparison, we referred the MCT to a certain EDI-OCT scanning line, and the MCT measurement was conducted under two conditions: involvement of the fovea and scanning through the relative maximum volume of the subretinal fluid (SRF). Recently, Wei et al. reported a thin inner choroidal layer with enlarged hyporeflective choroidal lumina in CCSC [16]. Similarly, in addition to the choroidal midphase hyperpermeability [17], LAACV can also be used directly for the assessment of permeability changes in CCSC patients. To minimum the influence of age as previously reported by Spaide [18], two eyes (a CCSC eye and a normal control eye) of the same patient were compared between before and after PDT therapy.

Materials and methods Patients This prospective study including 36 eyes of 18 CCSC patients (13 males and 5 females; mean age: 52.3 ± 11.56 years) was conducted in the Department of Ophthalmology Outpatient, First Hospital of China Medical University. The inclusion criteria were (1) subfoveal fluid accumulation based on EDI-OCT; (2) focal leakage in FA; (3) abnormally dilated choroidal vasculature and choroidal vascular hyper-permeability based on ICGA; and (4) the same refractive status and optic media condition bilaterally. Patients with systemic diseases such as hypertension and other ocular diseases such as tractional or exudative retinal

Fig. 1 The diagram of MCT. (A) In addition to SFCT, the randomly vertical distance between the RPE cells and the inner scleral border (a1, a2, a3, a4, a5, a6, a7, etc.) was measured by calculating the corresponding choroidal area (CA) shown in (B).



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Effects of photodynamic therapy on chronic central serous chorioretinopathy detachment, anisometropia, high myopia, and posterior sclera staphyloma were not included in this study. Longterm steroid users were also excluded from this study. All patients received examinations of best-corrected visual acuity (BCVA), indirect ophthalmoscopy, slit-lamp fundus biomicroscopy, EDI-OCT, FA, and ICGA. The diagnosis of unilateral CCSC with fovea involvement was based on ICGA [19] and EDI -OCT. In each case, the unaffected eye (without CCSC) was regarded as normal eye. The patients received one round of half-dose PDT (Carl Zeiss Meditec AG, Jena, Germany) with 3 mg/m2 of verteporfin [8]. MCT and LAACV were measured at four time points: I (one week before PDT), II (one day after PDT), III (2—3 weeks after PDT), and IV (2—3 months after PDT). This study adhered to the tenets of the Declaration of Helsinki, and was approved by the Medical Research Ethics Committee of First Hospital of China Medical University. Written informed consent was obtained from all participants.

Measurements of MCT and LAACV EDI-OCT (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany) with automatic real-time (ART) tracking was used to collect data with acquisition rate of up to 40,000 axial scans/second. Twelve routine EDI-OCT scanning lines covering 30◦ , and centered at the fovea were simultaneously generated. All measurements were conducted between 8 am and 10 am. Two independent reviewers who were blinded to the diagnosis and treatment of CCSC selected a single raster scan passing through the relatively maximum volume of SRF in CCSC eyes from the twelve scanning lines centered at the fovea and the symmetrical position in the corresponding normal eyes. The ART and eye tracking function facilitated ‘‘point-to-point’’ follow up. The functions of Heidelberg EDI-OCT ensured that the scan was exactly seen in the same B-scan plane at each visit. The retinal and choroidal sectional images were obtained through EDI-OCT scanning. The choroid boundary was defined as between the outer border of the original RPE and the inner scleral border based on EDI-OCT. The extended length of RPE detachment was not included in the length used. The integration of CT at each point and the RPE length were manually measured using the measurements function in Image Pro Plus 6.0 software (Media Cybernetics, America) by the two independent reviewers masked to the diagnosis

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and treatment of CCSC, and the average value of the CT integration was defined as CA. The MCT was calculated by dividing CA by the RPE length (Fig. 1). Based on the combination of EDI-OCT and ICGA, the abnormal choroidal vessels were detected as round or ovoid dark regions, corresponding to the hyperpermeability of multifocal areas of choroidal vessels in a point-to-point manner during the middle phase of ICGA [14,15] (Fig. 2). The LAACV in the PDT treated area was also manually calculated using the measurements function in Image Pro Plus 6.0 software. The SFCT and SRF were manually measured using the Heidelberg explorer software (Heidelberg, Germany).

Statistical analyses All statistical analyses were performed using the SPSS package (Version 19.0; IBM Inc., Chicago, IL). Data are presented as the median (Min—Max). The bilateral ocular differences of SFCT, SRF, and MCT at baseline were compared and analyzed using the Wilcoxon Matched-Pairs Signed-Ranks Test. Friedman test was used to analyze the differences of SFCT, SRF, MCT and LAACV between before and after PDT. In addition, the relationship between LAACV, MCT, and SFCT at each follow-up was evaluated using the Spearman’s rank correlation. The relationship between SRF, MCT, and SFCT at time point III was also analyzed using Spearman’s rank correlation. A probability (P) value of less than 0.05 was considered statistically significant.

Results The mean BCVA of 18 CCSC and 18 normal eyes was 18/60 (6/60—24/60) and 54/60 (42/60—60/60), respectively. The mean RPE length was 1260 (1247—1521) pixels for the CCSC eyes and 1271 (1132—1307) pixels for the normal eyes, respectively. The SRF of all CCSC eyes was completely absorbed at the last visit. At baseline, both SFCT and MCT in the CCSC eyes were significantly greater than those in the corresponding normal eyes (Z = 3.732, P < 0.0001) (Table 1). The MCT (2 = 46.067, P < 0.0001), SFCT (2 = 41.867, P < 0.0001), and SRF (2 = 46.322, P < 0.0001) at time point II were significantly higher than those observed at time point I, and these values gradually decreased at time points III and IV and became stable at the last visit (Table 1). Furthermore, no

Fig. 2 The pathological changes of the choroid of a 54-year-old female patient with CCSC (OS). (A) The fundus photograph. (B) The hyperpermeability of multifocal areas of choroidal vessels in the middle phase of ICGA. The green arrow indicated the direction of EDI-OCT scanning. (C) The corresponding dark round or ovoid regions (yellow triangles) in the EDI-OCT images.



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R. Hua et al. Table 1

SFCT, SRF and MCT for evaluating PDT in CCSC.

Examination time points

I. One week before PDT II. One day after PDT III. 2—3 weeks after PDT IV. 2—3 months after PDT

MCT (pixels)

SFCT (␮m)

SRF (␮m)

Study eyes

Corresponding normal eyes

Study eyes


Study eyes


143.3 (79.6—196.0) 154.3 (94.2—211.0) 125.5 (77.4—161.9) 101.9 (48.4—147.8)

117.6 (67.3—159.9)

470.0 (320.0—536.0) 469.0 (332.0—571.0) 364.0 (169.0—460.0) 381.0 (171.0—450.0)

316.0 (264.0—467.0)

233.0 (156.0—318.0) 349.5 (213.0—708.0) 92.0 (0.0—395.0) 0.0 (0.0—0.0)

0.0 (0.0—0.0)

Follow-up point I in study eyes vs. corresponding normal eyes: MCT. Z = 3.732, P < 0.0001; SFCT. Z = 3.732, P < 0.0001; SRF. Z = 3.739, P < 0.0001. In study eyes, I vs. II vs. III vs. IV: MCT. 2 = 46.067, P < 0.0001; SFCT. 2 = 41.867, P < 0.0001; SRF. 2 = 46.322, P < 0.0001; (study eyes, IV) vs. (normal eyes, I): MCT: Z = 1.593, P = 0.111 > 0.05; SFCT: Z = 0.415, P = 0.678 > 0.05.

significant differences of the MCT (Z = 1.593, P = 0.111) and SFCT (Z = 0.415, P = 0.678) were observed between the CCSC eyes at the last follow-up examination and the corresponding normal eyes at baseline (Fig. 3 and Table 1). A significant difference (2 = 45.267, P < 0.0001) of the LAACV was observed among different follow-up examinations. Specifically, the LAACV at time point IV was significantly lower than with that at time point I (Z = 3.732, P < 0.0001) (Fig. 3 and Table 2). The MCT exhibited a significant correlation with LAACV at time points II (r = 0.747, P < 0.0001) and III (r = 0.555, P = 0.017), other than at the time point IV (r = 0.091,

P = 0.721). In contrast, the SFCT only showed a significant correlation with LAACV at the time point IV (r = 0.598, P = 0.009). On the other hand, MCT showed a significantly negative correlation with SRF (r = −0.813, P < 0.0001) at the time point III, while SFCT exhibited no correlation (r = 0.109, P = 0.665).

Discussion CCSC is a relatively common eye disease causing visual impairment, but the pathogenesis of CCSC is poorly understood. Choroidal abnormalities and induced SMD may

Fig. 3 The dynamic results of vertical EDI-OCT scan of a female patient with CCSC (OD). (A) One week prior to PDT. (a) Inner scleral border (green arrows and red curve); (b) choroidal area; (c) subretinal fluid thickness; and (d) subfoveal choroidal thickness. (B) One day after PDT. (C) 2—3 weeks after PDT. (D) 2—3 months after PDT. The abnormal choroidal vessels underneath lesions were indicated as round or ovoid dark regions (yellow stars) at each checkpoint.



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Effects of photodynamic therapy on chronic central serous chorioretinopathy Table 2

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LAACV for evaluating PDT to CCSC (study eyes).

Examination time points

N

LAACV (pixels)

P value

I. One week before PDT

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77.7 (6.6—94.2)

2 = 45.267, P < 0.0001 IV compared with I, Z = 3.732, P < 0.0001

II. One day after PDT III. 2—3 weeks after PDT IV. 2—3 months after PDT

18 18 18

80.7 (6.9—94.2) 53.0 (5.4—79.4) 27.3 (4.5—74.8)

be involved in the pathogenesis of CCSC. For example, increased permeability of the choriocapillaris leads to the focal or diffuse dysfunction of RPE cells, causing a detachment of the neurosensory retina [20]. Moreover, damage in the outer blood—retinal barrier has been associated with choroidal ischemia [21]. The markedly increased SFCT in CCSC patients indicates enhanced choroidal permeability and elevated hydrostatic press, which may result in SMD [12]. Using swept-OCT, Razavi et al. demonstrated that the choroidal thickness in areas of angiographic abnormalities was increased to a greater extent in active central serous chorioretinopathy [22]. In addition, a 20% reduction of SFCT was observed after 1 year of half-dose PDT treatment [13,23]. Moreover, Shin and Lim [24] have reported that platelet-derived growth factor contributed to the development of CCSC. However, the role of vascular endothelial growth factor in CCSC is unclear and needs further investigations. It has been reported that PDT could narrow choriocapillaris to reduce the choroidal hyperpermeability [25]. Yannuzzi et al. successfully treated 20 CCSC eyes using ICGAguided PDT [17]. Furthermore, Uetani et al. reported that the choroidal thickness inside and outside the PDT-applied area was significantly reduced at baseline in half-dose PDT compared to one-third-dose PDT [26]. In contrast, Shinojima et al. [27] reported that the effects of half-dose PDT for the treatment of CCSC might be temporary because choroidal morphological changes still develop during the 1-year period after PDT. Herein, we concluded that PDT affects not only the treated area but also the neighboring areas, which is consistent with the results of a previous study [26]. In the present study, we investigated CCSC using EDI-OCT with two novel parameters: the MCT for choroidal quantification and the LAACV for tracing pathological changes of the choriocapillaris. While CT has been considered as an important parameter for choroidal evaluation based on EDI—OCT, only the mean value of several CTs at certain points was calculated and considered [28—31]. Apparently, the results from these methods do not reflect the actual CT. Extensive literature searches through MEDLINE and the Web of Science did not identify any methods using the MCT. On the other hand, Yang et al. found that central serous chorioretinopathy eyes had more hyporeflective and larger lumens than the control eyes based on measurements of the largest hyporeflective choroidal lumen [16]. However, the largest diameter is not always consistent with the lumen space, particularly for vessels of irregular shapes. In the present study, the two novel parameters provided supplemental information of SFCT for the characterization

of choroidal vascular abnormalities in CCSC patients subjected to PDT. Thus, through the comparison of the bilateral eyes in one patient, the influence of other factors could be avoided [32]. Recent studies have suggested a potential association between PDT and the alterations of choroidal thickness. Pryds and Larsen [33] demonstrated that PDT reduced the SFCT after 1 month of treatment of active central serous chorioretinopathy. However, Maruko et al. [13] reported that the mean SFCT was significantly increased after 2 days of PDT, which was followed by a rapid reduction of the SFCT after 4 weeks of PDT. Compared with the previous studies, the present study revealed four new findings. First, in addition to SFCT, we measured the entire choroidal thickness through the relatively longest SRF, providing more objective and representative data than SFCT. The MCT might be more significantly associated with SRF than SFCT during the early stages of PDT, which need to be further investigated. Second, we observed increased and decreased SRF, SFCT and MCT during the early stages of PDT, suggesting the occurrence of transitional reactive inflammatory choroidal vascular hyperpermeability and choroidal exudation. These changes were similar with the responses of choroidal neovascularization after PDT [34], suggesting a new aspect of the mechanism of PDT in the treatment of CCSC. Third, we detected and compared the pathological changes of target vessels based on the LAACV that correlated with MCT other than SFCT, suggesting that the abnormal choroidal vessels had influence on the CT. In particular, we found that the correlation between MCT and LAACV decreased gradually with the recovery of CCSC, and no statistical association was observed between MCT and LAACV after 2—3 months of PDT. We speculate that the effects of LAACV on the MCT were completely relieved at this stage. Fourth, Maruko [35] reported that the thickness of subfoveal choroid in CCSC temporarily increased after 2 days of PDT, but gradually decreased 1 month later. Similarly, we observed an early increase of the MCT, SFCT and SRF one day after PDT, which was inconsistent with the changes of LAAAV. These effects of PDT have not been previously reported in CCSC, however, studies with larger samples are necessary to confirm these results. To the best of our knowledge, the present study is the first report using the non-invasive LAACV to directly evaluate the effect of PDT on CCSC. The present study has some limitations. For example, no statistical evidence was collected to support the increase of MCT, SFCT and SRF at time point II. In addition, the MCT and LAACV within a certain scanning line rather than a region were measured. Moreover, given the high frequency of bilateral involvements of CCSC, another eye of the same subject



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may not be really non-CCSC, which may have influence on our results. In summary, we have developed two novel parameters, the MCT and LAACV, to supplement the quantitative assessment of SFCT in CCSC patients based on EDI-OCT. Our results confirmed the pathological alterations of CT in CCSC. The MCT and LAACV are useful for quantitative evaluation of choroidal diseases, particularly for fovea-spared diseases. However, these two parameters should be further tested based on larger samples.

Funding This study was supported by the Liaoning Science and Technology Project (Project #: 2011225014). The funders had no role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.

Acknowledgments We thank Dr. Yuedong Hu and Dr. Na Cai in the Department of Ophthalmology of the First Hospital of China Medical University for the diagnosis, treatment and follow-up of CCSC. In addition, Prof. Hongbo Liu, from the College of Public Health, China Medical University, assisted with statistical analyses.

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CHOROIDAL THICKNESS AFTER FULL-FLUENCE AND HALF-FLUENCE PHOTODYNAMIC THERAPY IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

Changes in choroidal thickness after photodynamic therapy in patients with central serous chorioretinopathy.

Changes in Choroidal Structures in Eyes with Chronic Central Serous Chorioretinopathy after Half-Dose Photodynamic Therapy.

Subfoveal Choroidal Thickness in Central Serous Chorioretinopathy: A Meta-Analysis.

The association between choroidal thickness variations and response to intravitreal bevacizumab in central serous chorioretinopathy.

PERIPAPILLARY CHOROIDAL THICKNESS IN CENTRAL SEROUS CHORIORETINOPATHY: Is Choroid Outside the Macula Also Thick?

Correlation of subretinal fluid volume with choroidal thickness and macular volume in acute central serous chorioretinopathy.

Change of regional choroid thickness after reduced-fluence photodynamic therapy for chronic central serous chorioretinopathy.

Optical density ratio in the subretinal fluid: differentiating chronic central serous chorioretinopathy and polypodial choroidal vasculopathy.

Half-dose Photodynamic Therapy for Chronic Central Serous Chorioretinopathy.

SUBFOVEAL CHOROIDAL THICKNESS CHANGES IN TREATED IDIOPATHIC CENTRAL SEROUS CHORIORETINOPATHY AND THEIR ASSOCIATION WITH RECURRENCE.

Photodynamic therapy for central serous chorioretinopathy.

Assessment of choroidal topographic changes by swept source optical coherence tomography after photodynamic therapy for central serous chorioretinopathy.

Flat irregular retinal pigment epithelium detachments in chronic central serous chorioretinopathy and choroidal neovascularization.

Photodynamic therapy in chronic central serous chorioretinopathy with subretinal fluid outside the fovea.

The effect of nicotine on choroidal thickness.

Effects of photodynamic therapy with verteporfin for the treatment of chronic central serous chorioretinopathy: An uncontrolled, open-label, observational study.

Effect of photodynamic therapy on short-wavelength fundus autofluorescence in eyes with acute central serous chorioretinopathy.

Punctate hyperfluorescence spot as a common choroidopathy of central serous chorioretinopathy and polypoidal choroidal vasculopathy.

Association of Choroidal Neovascularization and Central Serous Chorioretinopathy With Optical Coherence Tomography Angiography.

Changes of outer retinal microstructures after photodynamic therapy for chronic central serous chorioretinopathy.

Quantification of metamorphopsia in chronic central serous chorioretinopathy after half-dose verteporfin photodynamic therapy.

Unusual case of diffuse choroidal melanoma masquerading as atypical central serous chorioretinopathy.

Structural and Functional Outcomes in Chronic Central Serous Chorioretinopathy Treated with Photodynamic Therapy.