Factors Affecting Resolution of Subretinal Fluid After Selective Retina Therapy for Central Serous Chorioretinopathy

Abstract

The purpose of this study was to investigate the factors of clinical outcome of selective retina therapy (SRT) for central serous chorioretinopathy (CSC). This retrospective study included 77 eyes of 77 patients, who were treated with SRT for CSC and observed at least 6 months after the treatment. SRT laser (527 nm, 1.7 µs, 100 Hz) was used for treatment. The mean best-corrected visual acuity (BCVA) (logMAR), central macular thickness (CMT) and central choroidal thickness were changed from baseline to at 6-months follow-up with significant difference. The multivariate analyses found that the rate of change (reduction) in CMT was associated with focal leakage type on fluorescein angiography (FA) (p = 0.03, coefficient 15.26, 95% confidence interval 1.72 – 28.79) and larger baseline CMT (p < 0.01, coefficient -0.13, 95% confidence interval -0.13 – -0.05). Complete resolution of subretinal fluid was associated with nonsmoking history (p = 0.03, odds ratio 0.276, 95% confidence interval 0.086 – 0.887) and focal leakage type on FA (p < 0.01, odds ratio 0.136, 95% confidence interval 0.042 – 0.437). This result may be useful for predicting the therapeutic effectiveness of SRT.

Introduction

Central serous chorioretinopathy (CSC) is known to as a retinal disorder causing subretinal fluid (SRF) and resulting visual disturbances including metamorphopsia, central scotoma, reduced visual acuity and loss of contrast sensitivity. Most of SRF caused by CSC are self-limited and resolved spontaneously, but on the other hand, it may be persistent and treatment-resistant. After recurrent or prolonged SRF, some patients experience permanent visual impairment with retinal pigment epithelium (RPE) atrophy [1-4]. Several treatment methods were suggested for patients with prolonged SRF. Recently, because conventional laser photocoagulation may lead to irreversible scotoma in the central macula [5, 6], half-dose photodynamic therapy (PDT) and subthreshold microsecond-pulsed laser (SMPL) treatment were selected for persistent SRF with CSC [7-11].

Selective retina therapy (SRT) was developed as a novel and unique laser procedure in which the RPE is selectively broken down through a microbubble formation within RPE cells [12-14]. This treatment does not induce thermal diffusion in surrounding tissues, which enables selective RPE disruption without damaging the neural retina or choroid. Several reports have revealed that SRT was effective for CSC, diabetic macular edema (DME), persistent subretinal fluid after retinal detachment surgery, etc [15-23].

Previously, we reported the safety of SRT for CSC of Japanese patients using microperimetry after three months [18]. We also revealed the predictive factors associated with retinal thickness after SRT treatment for DME [21]. In this study, we carried out a retrospective investigation to evaluate the factors which may affect the therapeutic effectiveness of SRT on CSC after the treatment.

Methods

Subjects.
This study was approved by the Ethical Committee of Osaka City University Graduate School of Medicine (No. 2009 and 2421), carried out on the basis of the Declaration of Helsinki, and SRT was registered with University hospital Medical Information Network (UMIN) (No. 000005396 and 000010471). Written informed consent was obtained from all patients prior to enrolment. This study investigated 77 eyes in 77 CSC patients (61 eyes of 61 males and 16 eyes of 16 females), who underwent SRT in the Department of Ophthalmology at Osaka City University Hospital between June 2011 and December 2016 and were followed-up for at least 6 months. The mean age of patients was 51 years (range, 29–78 years). Table 1 shows baseline characteristics of the patients in this study.

SRT Inclusion and Exclusion Criteria.
Inclusion criteria for selection of patient treated with SRT were as follows:
1) minimum age of 20 years,
2) subjective symptoms of central scotoma, metamorphopsia, or decline of visual acuity,
3) history of more than 3 months with no sign of improvement of CSC diagnosed with optical coherence tomography (OCT),
4) presence of SRF on OCT, and
5) presence of active leakage in fluorescein angiography (FA).

Ophthalmologic exclusion criteria were as follows:
1) macular diseases with SRF caused by the disease other than CSC,
2) history of other laser treatments for CSC, such as conventional laser, PDT or SMPL.
3) absence of leakage in FA

Systematic exclusion criteria were as follows:
1) inflammatory disease,
2) bleeding tendency and anticoagulation therapy,
3) presence or possibility of pregnancy,
4) untreated hypertension and diabetes mellitus,
5) taking of diuretic, such as acetazolamide or spironolactone.

Clinical Observations.
All patients underwent the following ophthalmic observations at baseline and at 3 and 6 months after the treatment: the best corrected visual acuity (BCVA) measurement, slit-lamp microscopy, funduscopy, OCT (SPECTRALIS^®; Heidelberg Engineering GmbH, Heidelberg, Germany), color fundus photography, fundus autofluorescence, and FA (SPECTRALIS^®). For the BCVA analysis, decimal visual acuities were converted to logarithmic minimum angle of resolution (logMAR) values.

SRT Method
The SRT system utilizes a Q-switched frequency-doubled neodymium-doped yttrium lithium fluoride (Nd:YLF) laser, frequency doubled to a wavelength of 527 nm (Medical Laser Center Lübeck, Lübeck, Germany). In a single irradiation, a short 1.7 µs laser pulse is repeated 30 times at a repetition rate of 100Hz. The laser beam was adjusted such that the irradiation diameter on the retina was approximately 200 µm with a top hat beam profile under the use of a 1.05× magnification Mainster central field contact lens.
All SRT laser irradiations have been conducted by one ophthalmologist only. The treatment procedure of SRT is principally based on the previous study by Roider et al [20], and briefly as follows; test irradiations were conducted outside of the pathological central region, mostly near the vascular arcade. Beginning with the lowest energy (about 50–60 μJ), the irradiation energy was increased stepwise (every 10 to 20 μJ). In total, about 4–10 different energies were used for two test lesions to examine optoacoustic (OA) value (indicator of microbubble formation: detail described in previous reports [18, 21]. The OA value is a number which is calculated from the ultrasonic waves generated during microbubble formation leading to cell disintegration. The pressure waves are recorded by an ultrasonic transducer embedded in the contact lens [24]. According to the study, the OA value indicating 50% probability of RPE cell disruption (Effective Dose (ED) 50) is 70, and the one indicating 90% probability (ED90) is 112 as a result of calculating the leakage as positive on FA in the used system. Followed by the test laser irradiations, FA was conducted, and the treatment energy was determined, basically with FA findings and supplementarily with the OA value. In order to achieve RPE cell disruption with minimally-required energy, the energy, with which weakly positive leakage was detected in FA, was chosen as the initiation energy for the treatment. After deciding the treatment energy, the treatment was performed at and around the leakage point assessed with FA, giving an interval between spots of about one spot diameter.

Outcome Measures
BCVA, OCT, and FA were performed before treatment and 3 and 6 months after SRT. Central macular thickness (CMT), and central choroidal thickness (CCT) were also investigated. With regard to BCVA, changes of ≥0.2 in logMAR unit were considered significant. A change in CMT and CCT ≥15% compared with the pre-treatment baseline was regarded as significant as previously described [21]. SRT was considered effective if CMT decreased significantly compared to baseline, and as ineffective if this was not the case. As factors that might influence the rate of change in CMT and resolution of SRF 6 months after SRT, we evaluated sex, age, previous hypertension, smoking history, duration of symptom (months), number of episodes (first and second or more), history of medicine, leakage type on FA (focal or diffuse), baseline BCVA, baseline CMT and baseline CCT.

Statistical Analysis
Changes in BCVA (logMAR), CMT and CCT from baseline were assessed using a paired t-test with Bonferroni correction. In order to assess the associations between the changes of CMT after SRT treatment and clinical factors among SRT treated patients, we performed a univariable linear regression analyses with the change value of CMT at 6 months as the function of each clinical characteristic. The correlation between resolution of SRF and clinical factors was also assessed by using univariable logistic regression analysis. Factors showing p values <0.2 in univariate analyses were used for a multivariate analysis. IBM^® SPSS^® Statistics 24.0 (IBM Japan, Ltd., Tokyo, Japan) was used for statistical analysis, in which p values <0.05 were regarded as significant.

Results

Typical two cases of CSC treated with SRT are shown in Figure 1. The mean number of irradiations in one SRT was 12.0 ± 7.4 (range, 1-42). Per patient, the mean number of irradiations with <ED50 (OA <70) was 0.7 ± 1.3 (4.9% ± 8.7%), the mean number of irradiations with ³ED50 but <ED90 (70 £ OA < 112) was 2.2 ± 3.1 (13.9% ± 16.0%), and the mean number of irradiations with ³ED90 (OA ³112) was 9.0 ± 6.1 (81.1% ± 19.4%) (Fig. 2).

Clinical and morphological changes.
Changes of visual acuity and OCT findings during follow-up is shown in Table 2. Mean BCVA (logMAR) was 0.08 ± 0.28 before SRT, 0.04 ± 0.31 after 3 months, and 0.04 ± 0.29 after 6 months, with significant difference (3 months, p < 0.01; 6 months, p < 0.01). Individually, after 3 months BCVA had improved in 6.5% of patients, was unchanged in 92.2% and had worsened in 1.3%, and after 6 months had improved in 7.8%, was unchanged in 90.9%, and had worsened in 1.3% (Fig. 3a).
Mean CMT was 316 ± 89 mm before SRT, 246 ± 94 mm after 3 months, and 218 ± 82 mm after 6 months, showing a significant decrease after 3 and 6 months (3 months, p < 0.01; 6 months, p < 0.01). Individually, after 3 months CMT had decreased in 67.5% of patients, was unchanged in 20.8%, and had increased in 11.7%, and after 6 months had decreased in 72.7%, was unchanged in 15.6%, and had increased in 11.7% (Fig. 3b). Complete resolution of SRF was observed in 33 eyes (42.9%) 3 months after SRT and in 46 eyes (59.7%) 6 months after SRT.
Mean CCT was 342 ± 96 mm before SRT, 328 ± 93 mm after 3 months, and 329 ± 94 mm after 6 months, showing a significant decrease after 3 and 6 months (3 months, p < 0.01; 6 months, p < 0.01). Individually, after 3 months CCT had decreased in 7.8% of patients, was unchanged in 90.9%, and had increased in 1.3%, and after 6 months had decreased in 14.3%, was unchanged in 77.9%, and had increased in 7.8% (Fig. 3c).

Factors associated with retinal findings.
Univariate and multivariate regression analysis are showed in Table 3 and 4. The multivariate linear regression analysis found that the rate of change in CMT at 6 months after SRT was significantly associated positively with focal leakage type on FA (p = 0.03, coefficient 15.26, 95% confidence interval 1.72 – 28.79) and larger baseline CMT (p < 0.01, coefficient -0.13, 95% confidence interval -0.13 – -0.05) (Table 3). The multivariate logistic regression analysis found that the resolution of SRF at 6 months after SRT was significantly associated negatively with history of smoking (p = 0.03, odds ratio 0.276, 95% confidence interval 0.086 – 0.887) and positively with focal leakage type on FA (p < 0.01, odds ratio 0.136, 95% confidence interval 0.042 – 0.437) (Table 4). Figure 4 shows the decision tree classified by the factors associated with complete resolution of SRF used as the basis for the result of multivariate analysis.

Adverse events.
During this study, no patient developed intraocular inflammation, haemorrhage, or other event attributable to laser irradiation.

Discussion

In our current study, mean CMT in CSC patients was significantly decreased 6 months after SRT with an overall improvement rate of 72.7%. Complete resolution of SRF was seen in 59.7% of all cases. In the PLACE Trial, half-dose PDT was superior to SMPL treatment, with 67% of PDT-treated patients achieving a complete resolution of SRF, as compared to 29%of SMPL patients at 7-8 months after treatment [7]. Ho et al. reported that 87% of half-dose PDT patients and 50% of SMPL patients had complete resolution of SRF at 3 months after treatment [8]. SRT was reported in 19% to 74% of patients with chronic CSC achieved complete resolution of SRF after 3 months [17-19]. There are some differences in the inclusion criteria and the follow-up period, however, it is convincing that our result was as effective as the previous reports including PDT, SMPL and SRT.

Interestingly, CCT was also significantly decreased 6 months after SRT in this study. In PDT, there are many examinations reporting a choroidal thickness decrease after treatment [7-9]. In SMPL treatment, several reports showed no significant changes in choroidal thickness before and after treatment, while others showed a slight decrease [7, 8, 10, 11]. Park et al. reported no significant changes in choroidal thickness 3 months after SRT [19]. SRT affects only RPE cells causing rejuvenation and activation. In our results, the effect on choroidal thickness decrease seems to be less than that of PDT, but it is possible that those effects on RPE cells indirectly acted on the decrease of choroidal thickness in SRT.

Many reports have suggested various risk factors for developing CSC, such as endogenous or exogenous steroids, coagulation abnormalities, infection of Helicobacter pylori, males, pregnancy, hypertension, use of antibacterial agents, history of smoking, alcohol intake, sleep disturbance, oxidative stress, type A personality, etc [2, 25-30]. Matet et al. reported that risk factors of recurrence were significantly associated with thick subfoveal choroidal thickness and weak leakage on FA in CSC [31]. Bujarborua et al. revealed that 14.40% of CSC cases had smokestack leak, of which 70% occurred in first acute episode, 27.14% in acute recurrent episodes and 2.85% in chronic stage [32]. In the current study, according to classification of FA, the focal leakage type had a higher rate of CMT reduction and a higher rate of SRF resolution than the diffuse leakage type. CMT was decreased in 72.7% of all cases, and the decrease rate of CMT was associated with baseline CMT. These results suggest that diffuse leakage type and smaller baseline CMT may reflect high treatment resistance of chronic CSC also in treatment with SRT.

One of the important findings of this study is the fact that smoking history was associated with a poor SRF resolution. Smoking is not only associated with developing CSC, but poor visual prognosis and longer treatment needed in CSC patients [33]. Cotinine, the major nicotine metabolite, reduces RPE cell repair, wound healing ability and phagocytotic activity in vitro [34]. Fujihara et al. reported that chronic cigarette smoke develops evidence of oxidative damage with ultrastructural degeneration to the RPE and Bruch membrane, and RPE cell apoptosis [35]. Since functional mechanism of SRT is mainly derived from RPE cells, smoking, which can cause RPE dysfunction may strongly influence the therapeutic effect of SRT. As shown in the table 4, to investigate history of smoking and leakage type on FA may be informative for predicting visual function and anatomical effects after SRT.

In conclusion, our study showed that effectiveness of SRT was independently associated with smoking history, leakage type on FA and baseline CMT for CSC patients over 6 months of follow-up. This study was limited by the inclusion of only a small number of patients and by a non-randomized and retrospective study design. Further prospective studies with a larger number of patients may be useful to confirm these factors associated with the outcomes of SRT.

Declarations

Author contributions statement

Conceptualization: MY, Data curation: MY, AK and KH, Formal analysis: MY and YM, Funding acquisition: none, Investigation: MY, AK, KH and YM, Methodology: MY, YM and SH, Project administration: MY and SH, Resources: YM, TD and RB, Software: TD and RB, Supervision: TK, RB, YM and SH, Validation: none, Visualization: MY, AK and KH, Writing-Original draft: AK and MY, Writing-Review & Editing: All authors. All authors approved the final manuscript as submitted and have agreed to be accountable for all aspects of the work.

Competing Interests: The authors declare no competing interests.

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Tables

Table 1. Patient characteristics at baseline.

Table 2. Changes of visual acuity and optical coherence tomography findings during follow-up.

Table 3. Univariate and multivariate analysis of factors associated with the rate of change in central macular thickness at 6 months after selective retina therapy.

Table 4. Univariate and multivariate analysis of factors associated with complete resolution of subretinal fluid at 6 months after selective retina therapy.