Retinal sensitivity after selective retina therapy (SRT) on patients with central serous chorioretinopathy

Abstract

Purpose

To assess retinal sensitivity after selective retina therapy (SRT) in patients with central serous chorioretinopathy (CSCR).

Methods

Seventeen eyes of 17 patients with CSCR lasting longer than 3 months were treated with SRT (wavelength 527 nm Nd: YLF laser, 50–150 μJ/pulse, spot diameter 200 μm). Measurement of best-corrected visual acuity (BCVA), optical coherence tomography, fluorescence angiography, and microperimetry (MAIA™) were conducted before, and 1 and 3 months after treatment. Microperimetry was performed in the central 10° of the macula, and at the test spots applied near the vascular arcade for energy titration. In addition to the treatment effect, all test irradiation spots were thoroughly analyzed with regard to their sensitivity changes.

Results

The mean logMAR BCVA had improved from 0.06 to 0.02 after 1 month (p = 0.11) and to 0.03 after 3 months (p = 0.003). Eleven out of 17 eyes (64.7%) showed complete resolution of subretinal fluid after 3 months. Retinal sensitivity in the central 10° increased after 1 month (median: 25.9 dB) and 3 months (26.6 dB) as compared with that before treatment (23.0 dB) (p < 0.001). Analysis of the test spots revealed a slight decrease in retinal sensitivity after 1 month (ΔdB = −0.5 ± 2.1, p = 0.006), while there was no significant difference from baseline after 3 months (ΔdB = −0.3 ± 2.2, p = 0.09). No correlation was found between laser energy and the change in focal retinal sensitivity.

Conclusions

Results suggest that SRT is a safe and effective treatment for persistent CSCR and does not leave permanent scotoma regardless of irradiation energy in the therapeutic range.

Introduction

Selective retina therapy (SRT) has been developed as a novel and unique retinal laser treatment that enables non-thermal and neural retina-sparing irradiation limited to the retinal pigment epithelium (RPE) [13]. Microsecond laser pulses may induce a very short transient temperature increase only at the melanosomes within RPE cells, which generates micro-bubbles around them, followed by the mechanical disruption of RPE cells by temporal cell volume expansion, without inducing lethal temperature increase in the surrounding tissues [2, 4, 5]. Several clinical studies with SRT have been conducted to date, and it has been shown that SRT leads to positive clinical results in the treatment of different retinal disorders, such as central serous chorioretinopathy (CSCR) [69], diabetic macular edema [6, 7, 10], and persistent subretinal fluid (SRF) after retinal reattachment surgery for rhegmatogenous retinal detachment [11].

As well as its efficacy, the safety of SRT is of great interest as a sub-visible retinal laser treatment. Different from thermal laser treatments such as photocoagulation, SRT does not lead to thermal damage of the neural retina regardless of laser energy within the therapeutic window, and RPE restoration as well as functional recovery of the whole retina can be expected after treatment [2]. However, this point has not been clinically confirmed enough yet, and a careful investigation is also required to prove the safety of SRT with respect to avoiding scotoma.

CSCR is known as a retinal disorder that may spontaneously resolve, but on the other hand may be persistent and treatment-resistant [12, 13]. In this report, we present first the results of the clinical trial of SRT on Japanese patients with CSCR, suffering from subretinal fluid for longer than 3 months, and second the results of a detailed analysis of retinal sensitivity measured with an eye tracking system–integrated microperimetry. Not only the sensitivity in the treatment area, but also the focal retinal sensitivity of all test spots were assessed over 3 months after irradiation.

Methods

Subjects

Seventeen eyes of 17 patients (gender: 16 males and one female, age: average 47 years old, range 29–67 years old) with symptomatic CSCR with disease duration longer than 3 months were recruited in this study. The study was conducted in the eye clinic of Osaka City University Hospital during the study period from April 2012 until November 2013. This study protocol was approved by ethics committee of Osaka City University Hospital, based on the Declaration of Helsinki, and registered with UMIN; trial No.000005396. The written informed consent was obtained from all subjects after the nature and possible consequences of the study were explained. The basic clinical data of all patients are shown in the left part of Table 1.

Table 1 Clinical and ocular characteristics of all patients before and after treatment

Inclusion criteria

Inclusion criteria 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 CSCR [diagnosed with optical coherence tomography (OCT)], (4) presence of SRF on OCT, and (5) presence of active leakage in fluorescence angiography (FA).

Exclusion criteria

Ophthalmologic exclusion criteria were as follows: (1) macular diseases with SRF caused by the disease other than CSCR, and (2) history of other laser treatments for CSCR, such as photodynamic therapy (PDT). Systematic exclusion criteria were: (1) inflammatory disease, (2) bleeding tendency and anticoagulation therapy, (3) presence or possibility of pregnancy, (4) untreated hypertension and diabetes mellitus, and (5) taking of diuretic, such as acetazolamide or spironolactone.

SRT laser

A clinical prototype of a SRT laser (Medizinisches Laserzentrum Lübeck GmbH, Lübeck, Germany: frequency-doubled, pulse-stretched Nd: YLF laser: wavelength 527 nm, pulse duration 1.7 μs, radiation energy 50 μJ∼, repetition rate 100 Hz, 30 pulses) was used for the study. An Ocular® Mainster (standard) Focal/Grid Laser Lens (Ocular Instruments, Bellevue, WA, USA) with embedded ultrasonic transducer (Medizinisches Laserzentrum Lübeck GmbH) with a magnification of 1.05 was used, the spot size on the retina was fixed to 200 μm.

All SRT laser irradiations have been conducted by a single ophthalmologist. The treatment procedure of SRT is principally based on the previous study by Roider et al. [3], and briefly as follows; test irradiations are 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 4–6 different energies were used for two test lesions until the OA value (indicator of microbubble formation: detail described later) reached up to around 500. 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.

Real-time dosimetry with optoacoustic (OA) method

Since SRT laser spots are funduscopically invisible during and after irradiation, and further inhomogeneous fundus pigmentation may lead to a different laser energy requirement for microbubble formation, real-time dosimetry has been developed in order to display RPE cell disruption [4]. The microbubbles generated around the intracellular melanosomes lead to RPE cell disruption during laser pulse exposure [5]. Therefore, detection of microbubble formation is a useful method to ensure RPE cell disruption through SRT laser irradiation. Optoacoustic (OA) technique is used to detect the ultrasonic wave emitted by microbubble formation, expansion and collapse [14, 15]. With the use of an ultrasonic annular piezo transducer attached to the contact lens, OA transients for each pulse can be detected. By calculating the maximal pressure difference among all detected OA transients within the pulse train in one irradiation series (30 pulses) (= OA value), the probability that bubble formation has occurred, namely, the probability that the RPE cells were disrupted, can be surmised. Higher OA values may indicate the higher probability of the generation of transient bubble-induced pressure. According to our probit analysis of test irradiation spots, the effective dose (ED) 50 and ED 90 of the OA value for dye leakage in the FA directly after irradiation are 70 and 112 respectively. This indicates that if the OA value is shown to be 70 the probability of RPE disruption is 50%, and if the value is 112, it is 90%.

Clinical examinations

All patients had a complete clinical ophthalmic examination including measurement of the best-correlated visual acuity (BCVA), slit-lamp examination, funduscopy, spectral-domain optical coherence tomography (SD-OCT, SPECTRALIS®, Heidelberg Engineering, Heidelberg, Germany), color fundus photography, fundus autofluorescence (FAF), FA, and Indocyanine green angiography (IA) (SPECTRALIS®) before and 1 and 3 months after treatment. The decimal BCVA was converted to the logarithm of the minimal angle resolution (logMAR) units.

Measurement of retinal sensitivity

Retinal sensitivity was examined with a microperimeter (MAIA™; Macular Integrity Assessment, Topcon, Tokyo, Japan) coupled with its specific software. MAIA™ utilizes scanning laser ophthalmoscopy (SLO: 850 nm diode laser, 25 μm optical resolution) with a 25 Hz automated eye tracking system, which enables accurate repetitive tests of the same retinal point. For the measurement of retinal sensitivity, the target with the size of Goldmann III (26 arcmin ≈ 0.5°, diameter on the retina is supposed to be around 100-120 μm) is used. The background luminance is at 4 apostilb (asb), the maximum luminance at 1000 asb (=set as 0 dB), and the stimulus dynamic range is down to 0.25 asb (36 dB). The examination was conducted in a dark room, and all patients took the examination with pupil dilation using an eye drop containing 0.5% tropicamide and 0.5% phenylephrine hydrochloride (Mydrin-P®, Santen Pharmaceutical, Osaka, Japan). A single ophthalmologist conducted all measurements.

In this study, all patients underwent the following two different types of the sensitivity measurement with MAIA™ before and 1 and 3 months after treatment; (1) automated measurement of central 10° (37 points) with “expert exam mode” (Fig. 1a), and (2) manual measurement at the test irradiation spots with “manual grid mode” (Fig. 1b). In the expert exam mode for central 10°, the measured 37 points are automatically determined by the device through whole study period (before and 1 and 3 months after treatment). In addition, the measured points whose location is very close or almost identical to the irradiated site were picked up out of the measured 37 points, in order to investigate the influence of SRT laser irradiation of subsequent focal retinal sensitivity in the region with SRF.

Fig. 1
figure1

Measurement patterns of MAIA™ for (a) central 10° region and (b) test irradiation spot region. a For the central 10°, totally 37 points are measured with the presented pattern (“expert exam mode”). b For the test irradiation spots, retinal sensitivity at the randomly selected 10–12 points near the vascular arcade was measured before irradiation, and the mean value was referred as the pretreatment sensitivity of this region (= baseline). After irradiation, the focal sensitivity at the irradiated site was measured

Next, the sensitivity at test irradiation spots made near the vascular arcade were investigated as following; before irradiation, focal sensitivity of randomly selected 10 to 12 different points was measured with such interval, that they may cover the whole area of the test irradiation spots, as shown in Fig. 1b, and the mean value was utilized as the average baseline sensitivity of this area. After irradiation (at 1 and 3 months) the retinal sensitivity at the irradiated site was measured and compared with the average baseline sensitivity. The location of the irradiated site was often found by means of SLO (during microperimetry), or in case that no reflective change is detectable with SLO the notification made during irradiation was referred to decide the point to measure.

Overall, we conducted the analysis of (1) the mean retinal sensitivities of central 10° (37 points per patient for each measurement), (2) focal retinal sensitivity at the treatment spots in the central region (only available points from the measurement 1: 83 points in total), and (3) the retinal sensitivity of test irradiation spots (122 points in total).

Statistics

Statistical analysis of the change of logMAR BCVA was conducted using the Wilcoxon signed-ranks test. Analysis of retinal sensitivity in the central 10°, treatment spots, and test irradiation spots were conducted with paired t-test (under normal distribution), or Wilcoxon signed-ranks test (under non-normal distribution). Correlations between irradiation factors (energy, OA value) and the postoperative changes of retinal sensitivity (ΔdB) were analyzed using Spearman’s correlation coefficient by rank test. Correlation between individual factors (age, ΔBCVA after 1 month, ΔBCVA after 3 months, and the presence of residual SRF) and the postoperative changes of retinal sensitivity (ΔdB) was conducted with multiple regression analysis. All statistical analysis was performed using a statistical add-in software of Excel (Statcel 3, OMS Publishing, Saitama, Japan). A p-value smaller than 0.05 was indicated as significant.

Results

The clinical overview regarding pre- and post-operative BCVA, total number of treatment spots for each patient, and the presence of residual SRF at 3 months after treatment are shown in Table 1. The mean total number of treatment spots is 9.4 ± 4.0 (range: from 5 to 22, median: 8). Eleven out of 17 patients (65%) showed complete resolution of SRF after 3 months of treatment.

Case presentation

As a representative case, the images of color funduscopy, FA, IA, SD-OCT, and the measurement results of the retinal sensitivity in the central 10° of one patient (case.1) are shown in Fig. 2. In this case, SRF was completely resolved after 1 month, and this status remained until 3 months as shown in the SD-OCT image (Fig. 2a-f). Active fluorescence leakage was not observed after treatment (Fig. 2g-j), and the retinal sensitivity in the central 10° was significantly increased (Fig. 2k-m).

Fig. 2
figure2

Clinical course of case 1 (29 years old, male, pre-treatment logMAR BCVA is −0.079). af Color fundus images (a, c, e) and corresponding SD-OCT images (b, d, f) of before (a, b), 1 month after SRT (c, d) and 3 months after SRT (e, f). gj FA images (g, i) and IA images (h, j) of before (g, h) and 3 months after SRT (i, j). km Retinal sensitivity of central 10° region with MAIA™ of before (k), 1 month after SRT (l), and 3 months after SRT (m). In this case, SRF was completely resolved after 1 month, and this status remained until 3 months as shown in the SD-OCT image (af); active fluorescence leakage is undetectable after treatment (gj), and the retinal sensitivity in the central 10° was significantly increased (km)

Change of visual acuity

The logMAR BCVA (mean ± standard deviation (SD)) changed from 0.06 ± 0.18 preoperatively to 0.02 ± 0.20 and −0.03 ± 0.15 after 1 and 3 months respectively. There is no significant increase between preoperative BCVA and the one after 1 month (p = 0.11), whereas a significant difference was obtained between the preoperative BCVA and the one after 3 months (p < 0.01 ) (Fig. 3).

Fig. 3
figure3

Time course of change in logMAR BCVA from pre-treatment to 3 months after SRT. There is no significant improvement of BCVA after 1 month (0.06 ± 0.18 to 0.02 ± 0.20, p = 0.11), whereas significant improvement was shown after 3 months (−0.03 ± 0.15, p < 0.01)

Mean retinal sensitivity in the central 10° region

The mean retinal sensitivity in the central 10° of all 17 patients increased significantly after 1 month (1st quartile, median, 3rd quartile: 25.1 dB, 25.9 dB, 27.1 dB) and 3 months (25.6 dB, 26.6 dB, 27.6 dB), compared to the preoperative sensitivity (21.6 dB, 23.0 dB, 24.7 dB) (P < 0.01) (Fig. 4a). As shown in Table 1, some patients have remained SRF 3 months after treatment, and therefore we next compared the mean central retinal sensitivity of the groups with and without the residual SRF. The mean central retinal sensitivity of 11 eyes without residual SRF showed a significant increase both after 1 and 3 months (preoperative: 22.0 dB, 23.6 dB, 24.5 dB, whereas 1 month: 25.5 dB, 26.5 dB, 27.4 dB, and 3 months: 26.5 dB, 27.5 dB, 27.7dB, p < 0.01) (Fig. 4b). On the other hand, the six eyes with remaining SRF showed no statistical significant difference (preoperative: 20.6 dB, 22.4 dB, 24.9 dB, whereas 1 month: 21.8 dB, 23.6 dB, 25.8 dB, and 3 months: 22.8 dB, 25.6 dB, 26.4 dB, p = 0.11 and p = 0.12 respectively) (Fig. 4c).

Fig. 4
figure4

Boxplots of retinal sensitivity (dB) from pre-treatment to 3 months after SRT; the mean sensitivity in the central 10° region (ac) and focal sensitivity at the treatment spots (df). Middle line in the box represents the median, lower box bound the first quartile, upper box bound the third quartile, whiskers the 95% confidence interval of the mean, and the outliers are indicated by open circles. a and d show the results from all patients, whereas b and e are from the patients whose SRF has completely resolved, and c and f are from the patients with remaining SRF after 3 months. Except the central 10° in  the cases with the remaining SRF (c), mean retinal sensitivity at the central 10° region as well as the focal sensitivity at the treatment spots show the significant increase from 1 month after treatment, which remained until 3 months later. *p < 0.01

Focal retinal sensitivity at treatment spots

Change of focal retinal sensitivity of 83 treatment spots was individually analyzed, and the result shows that the focal sensitivity of the treated site was significantly increased after 1 month (22 dB, 25 dB, 27 dB, p < 0.01) and after 3 months (24 dB, 26 dB, 28 dB, p < 0.01) compared to the one before treatment (20 dB, 22 dB, 25 dB) (Fig. 4d).

The analyzed spots were then separated into two groups according to the existence of residual SRF at 3 months. The focal retinal sensitivity at the spots of the patients without residual SRF (in total 50 spots from 11 patients) showed a significant increase after 1 month (29 dB, 27 dB, 25 dB, p < 0.01) and after 3 months (29 dB, 27 dB, 26 dB, p < 0.01) compared to the preoperative sensitivity (25.6 dB, 23 dB, 21 dB) (Fig. 4e). Differently from the mean sensitivity of the central 10°, the focal sensitivity at the treated spots with residual SRF was also statistically significantly increased compared to the preoperative sensitivity at the spots, although the increased amount is not as large as in the case without SRF (in total 33 spots from six patients; pre: 18 dB, 20 dB, 24 dB, after 1 month: 20 dB, 22 dB, 25 dB, p = 0.01, after 3 months: 22 dB, 24 dB, 27 dB, p < 0.01) (Fig. 4f).

Figure 5 presents the distribution of the spot number sorted by the amount of change in retinal sensitivity (postoperative sensitivity − preoperative sensitivity: ΔdB) at the analyzed treatment spots. After 1 month of the treatment, 56 spots (67%) showed the increase more than +2 dB, where 15 spots (18%) showed an increased sensitivity more than +6 dB, and 14 spots (17%) no difference (ΔdB = 0). In 13 spots (16%) the sensitivity was decreased by either −2 or −4 dB after 1 month. After 3 months, the peak of the ΔdB shifted to the positive side; 63 spots (76%) increased by more than +2 dB, 31 spots (37%) by more than +6 dB. The number of spots which showed a decreased sensitivity had declined to ten (12%), among which 90% showed a decrease smaller than ΔdB = −4 dB, and one spot showed by −6 dB. There were no spots that showed the decreased sensitivity larger than −6 dB.

Fig. 5
figure5

Change in focal retinal sensitivity (ΔdB) after 1 and 3 months as compared to the pre-treatment at treatment spots (n = 83). In total, 56 spots (67%) after 1 month and 63 spots (76%) after 3 months showed a sensitivity increase of more than +2 dB. Ten spots (12%) showed a decrease of retinal sensitivity (–2 to –6 dB) after 3 months

Focal retinal sensitivity at test irradiation spots

Figure 6 presents the images of color fundus photography and FA from one patient, who underwent SRT treatment in this study. The test irradiations were performed near the upper vascular arcade as shown in Fig. 6a, with increasing energy from left to right in this region. As shown in Fig. 6b, mild fluorescence leakage is observed in FA from the site irradiated with higher energy, whereas no apparent whitening or scar formation is observed in color fundus photography up to 3 months after irradiation (Fig. 6c-e).

Fig. 6
figure6

Color fundus image (a, ce) and FA image (b) at the test irradiation spots. a Before irradiation, b and c directly after irradiation, d 1 month after SRT, e 3 months after SRT. a The sites of test irradiation spots are shown in the fundus image (from 1 to 11), whose output laser pulse energy and displayed OA values for each irradiation are shown in the table below. b In the FA directly after irradiation, fluorescence leakage is observed from some sites irradiated with higher energy. ce No apparent whitening or scars are observed at the irradiated site

A thorough examination of focal retinal sensitivities at all of those test irradiation sites was conducted. As in Fig. 7a, the mean value of retinal sensitivity of the test irradiation spots slightly declined after 1 month (25.0 dB, 27.0 dB, 28.0 dB) compared to the preoperative sensitivity (26.3 dB, 27.0 dB, 28.0 dB; mean ΔdB = −0.5 ± 2.1), which showed a statistical significance (p < 0.01 ), whereas there was no more significant difference after 3 months (25 dB, 27 dB, 28 dB; mean ΔdB = −0.3 ± 2.2, p = 0.09).

Fig. 7
figure7

Analysis of focal retinal sensitivity at the test irradiation spots. a Boxplot of the focal retinal sensitivity of test irradiation spots from pre- to 3 months after SRT: After 1 month, the focal retinal sensitivity was very slightly but significantly decreased (ΔdB = −0.5, p <0.01), whereas there was no significant difference between baseline sensitivity and after 3 months (ΔdB = −0.3, p = 0.09). b Distribution of the amount of the change in focal retinal sensitivity (ΔdB) at test irradiation spots after 1 and 3 months after SRT from the pre-treatment retinal sensitivity: Out of all investigated spots (122 spots), 36 (29.5%) and 35 (28.7%) spots after 1 and 3 months, respectively, showed no sensitivity change after irradiation, and the amounts of the change of 105 spots (86%) after 1 month and 102 spots (83%) after 3 months were in the range of −2 to +2 ΔdB. Eleven spots (9%) after 1 month and 12 spots (10%) after 3 months showed a decrease of 3 to 4 ΔdB

With regard to change in focal sensitivity (ΔdB: postoperative sensitivity − preoperative sensitivity), 105 spots (86%) and 102 spots (83%) was in the range of −2 dB and +2 dB, 11 spots (9%) and 12 spots (10%) by −3 or −4 dB at 1 and 3 months respectively (Fig. 7b).

Correlation between irradiation energy or OA value and change of focal retinal sensitivity at test irradiation spots

In order to investigate if the amount of the change in focal retinal sensitivity at test spots is correlated with the irradiated energy (μJ) or the OA value (theoretical indicator of the extent of RPE disruption), correlation coefficients between irradiation energy or OA value and the amount of change in retinal sensitivity (ΔdB) was investigated. In Fig. 8, ΔdB data of all test irradiation spots from 17 patients are plotted either with the irradiated energy (Fig. 8a, b) or with the OA value (Fig. 8c, d). As shown in the graphs, postoperative changes in focal retinal sensitivity (ΔdB) is distributed to a wide range of pulse energy and OA value, and statistically no correlation was found both at 1 and 3 months (energy vs ΔdB: rs (Spearman correlation coefficient) = 0.07 at 1 month, rs = 0.01 at 3 months, OA value vs ΔdB: rs = 0.06 at 1 month, rs = 0.02 at 3 months). These results suggest that neither pulse energy nor OA value are the determining factors of a change in subsequent retinal sensitivity after SRT.

Fig. 8
figure8

Correlation between the irradiation energy or OA value and the amount of changes in retinal sensitivity (ΔdB) of every test irradiation spot (n = 122); a correlation between irradiation energy and the amount of change in retinal sensitivity after 1 month, b correlation between irradiation energy and the amount of change in retinal sensitivity after 3 months, c correlation between OA value and the amount of change in retinal sensitivity after 1 month, and d correlation between OA value and the amount of change in retinal sensitivity after 3 months. All spots are plotted for the irradiated energy or OA value and the amount of change in retinal sensitivity. Different colors show for different patients. No correlation was detected between these parameters at any point of time [dashed lines: ED 50 OA value (70; orange line) and ED 90 OA value (112; blue line)]

Correlation between individual factors and the change in focal retinal sensitivity at test irradiation spots

In order to evaluate the correlation between individual factors and the change in focal retinal sensitivity at test irradiation spots, the correlation between mean ΔdB of test irradiation spots and the following clinical characteristics were investigated using multiple regression analysis: patient’s age, postoperative change in visual acuity (ΔBCVA after 1M and 3M), and presence of the postoperative remaining SRF. As a result, none of these factors had significant correlation with the postoperative change of focal retinal sensitivity at test irradiation spots [age vs ΔdB: r (regression coefficient) = 0.04 at 1 month (p = 0.51), r = 0.02 at 3 months (p = 0.62), ΔBCVA after 1 month vs ΔdB: r = −6.00 at 1 month (p = 0.34), r = −4.49 at 3 months (p = 0.54), ΔBCVA after 3 month vs ΔdB: r = 10.98 at 1 month (p = 0.20), r = 10.94 at 3 months (p = 0.28), remaining SRF vs ΔdB: r = −1.17 at 1 month (p = 0.19), r = −1.32 at 3 months (p = 0.21)] (Table 2).

Table 2 Correlation between individual factors and the amount of change in focal retinal sensitivity (ΔdB) at test irradiation spots (r: regression, coefficient)

Discussion

Irreversible scotoma in the central macula is the greatest concern of laser photocoagulation [16]. Selective retina therapy (SRT) selectively destroys the pigmented RPE without any thermal damage in surrounding tissues, and a rejuvenation of the RPE is expected through the RPE healing process. Therefore, it is considered to be a minimal-invasive laser treatment, which may be safely applicable in the macular region. However, since SRT is a new treatment option, it is important to gather clinical data to confirm its safety. The recent report by Kim et al. presented the preservation of retinal function with multifocal electroretinogram (mfERG) on rabbit eyes, suggesting that SRT may preserve retinal function after treatment [17]. With regard to the focal examination on the irradiated spots, the previous report by Roider et al. assessed the retinal sensitivity after SRT using microperimetry (however, without eye tracking system) where they showed no apparent sensitivity decrease at SRT laser spots [1]. In the current study, retinal sensitivity at the central macular region was significantly increased, which is considered to be largely due to the reduction of SRF. No case showed absolute scotoma or strong relative scotoma. Eye-tracking system-integrated microperimetry was first introduced commercially around the middle of the 2000s, by combining scanning laser ophthalmoscopy with an eye-tracking function and an automated full-threshold perimetry software [18, 19]. Since most of the laser spots of SRT are funduscopically invisible, it is difficult to follow the same point over time using a perimeter without eye-tracking system. A microperimetry with eye-tracking system enables and guarantees repeated measurement at the same retinal position. Therefore, its usefulness is particularly high in the assessment of the focal sensitivity at the irradiated sites of sub-visible laser treatments, like SRT, micropulse laser treatment [20, 21], or treatment using endpoint management [22].

The results of the current study showed that SRT may be a safe and effective treatment option for CSCR. The suggested therapeutic mechanisms to date is the re-absorption of SRF by the functionally recovered RPE [2]. In our current study, SRF remained 3 months after SRT in 35% (six eyes out of 17 eyes), showing a light tendency of increasing mean sensitivity after 1 and 3 months, although they were not significant. On the other hand, 65% (11 eyes out of 17 eyes) showed a disappearance of SRF after treatment, and retinal sensitivity in the central 10° and at the treatment spots were significantly increased. It should be noted that there is no significant decrease of retinal sensitivity in the central 10° after SRT in both groups with and without remained SRF.

A thorough analysis of the test irradiation spots was performed in order to see the influence of irradiation on retinal sensitivity, not being influenced by SRF. Test irradiation was performed near the vascular arcade with increasing energy, from the lowest to higher energy. Dye leakage was detected in FA directly after irradiation. The detailed sensitivity analysis of all test spots revealed a very slight but statistically significant decrease of the retinal sensitivity after 1 month (from 27.0 dB to 26.5 dB), whereas no more significant difference was shown after 3 months. These results suggest that SRT irradiation may temporarily decrease focal retinal sensitivity very slightly following irradiation, which had recovered 3 months later. Initially, it was assumed that stronger tissue destruction by higher energy may damage focal retinal function stronger and longer. However, statistical analysis revealed that there are no correlations in the change of retinal sensitivity (ΔdB) both with irradiated energy and with OA value after 1 and 3 months. These results suggest that the retinal sensitivity following SRT might be generally independent of the initial extent of RPE disruption, at least with the spot diameter of 200 μm.

In inter-individual analysis, most patients (15 out of 17) showed zero to mild changes in the mean sensitivity at the test irradiation spots (−2 dB to +2 dB) in 3 months after SRT; one patient showed a decrease of −4 dB, and one patient an increase of +4 dB. We attempted to find individual factors which might be responsible for these changes, such as patient’s age, postoperative visual acuity, or the presence of residual SRF (as one of the indicators of tissue response to laser irradiation); we found, however, no correlation. Therefore, it is still currently unknown whether there is a related individual factor for a tissue response to SRT. In order to avoid a sensitivity decrease at the treated retina, even very slight and temporal, elucidation of the factor that may affect the temporal sensitivity decrease would be important, and therefore, further investigation is desirable.

In addition, the functional potential of RPE cells is one of the important factors in RPE wound healing. In the wound-healing process after non-thermal RPE cell disruption, extension, migration, and proliferation of the surrounding RPE cells as well as scavenging the cell debris are required. Moreover, it is also required for the RPE to be closed as a monolayer in order to have a normal functionality. Therefore, the functionality of the restored RPE is mostly determined by the potential of surrounding non-damaged RPE cells and viable wound-healing environment during restitution. The previous study showed that 200 μm-diameter RPE wounds by SRT on fresh ex-vivo RPE could be covered as a monolayer in a few days, whereas in older RPE, the wound did not close properly, either with incomplete closure or closure with overproliferation, which would not be able to function properly [23]. These results suggest that the extent of excess damage, namely the excess amount of cell defect beyond the capacity of surrounding RPE cell functions, might induce inappropriate RPE wound healing, and eventually a retinal functional decrease at the irradiated site over a long period of time. Therefore, we need to pursue a minimal invasive and most effective treatment procedure, even if energy and OA value did not show any significant correlation to the sensitivity change in this study. Brinkmann and his colleagues have developed a new system with feedback-controlled energy ramping mode, which may control damage extent and eventually may reduce an undesirable too strong RPE disruption. The utility of the technique has been already proven in animal studies [24]. This development will widen the possibility to seek appropriate therapy conditions for the different pathological states with minimum invasiveness.

With regard to the treatment of CSCR, the most recent trend of laser-based therapy on CSCR, at least the most reported one, is the usage of reduced-dose PDT [25, 26]. Since hyperpermeability of choriocapillaris followed by the decrease of barrier and pump function of the RPE has been suggested as the main pathogenesis of CSCR [26], PDT, which has been suggested to contribute to the choriovascular remodeling [27], might be the meaningful method for CSCR. The biggest concern with PDT might be, even with the reduced dosage, the remaining possibility of photochemical tissue damage, which might lead to long-term apoptosis or atrophy of the choriocapillaris and adjacent choroid as well as the RPE [28, 29]. A previous report has shown that morphological and functional chorioretinal changes after PDT seem to be more likely to be related to the disease itself than to the treatment provided [30]. Nevertheless, comparative study between low-dose PDT and SRT in terms of long-term chorioretinal structure and function is needed.

Furthermore, as another type of fundoscopically subvisible (clinically subthreshold) retinal laser treatment, micropulse laser photocoagulation has also been introduced as a possible therapeutic method for CSCR [31, 32]. Koss et al. reported an increased retinal sensitivity in the automated central 10° measurement, and no significant sensitivity decrease after micropulse laser photocoagulation [31]. A crucial difference of micropulse laser treatment from SRT is the possibility of transient heat generation in the tissue around RPE cells, which is not the case in SRT. This treatment without thermal burn may serve as a safer laser treatment in the macular region. For the evaluation of long-term efficacy and safety of SRT, a further study with a longer investigation time period is required.

In summary, we showed the efficacy and safety of SRT on CSCR patients, and presented the results of retinal sensitivity analysis at the irradiated spots following SRT. Microperimetric results showed that SRT irradiation does not cause a significant decrease of retinal sensitivity in the long term. Moreover, we found no correlation between irradiation energy and a decrease of postoperative retinal sensitivity. As a whole, results of the current study might indicate that SRT is not likely to cause a clinically significant scotoma as may be observed after thermal laser photocoagulation.

References

  1. 1.

    Roider J, Brinkmann R, Wirbelauer C et al (1999) Retinal sparing by selective retinal pigment epithelial photocoagulation. Arch Ophthalmol 117:1028–1034

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Brinkmann R, Roider J, Birngruber R (2006) Selective retina therapy (SRT): a review on methods, techniques, preclinical and first clinical results. Bull Soc Belge Ophtalmol 302:51–69

    Google Scholar 

  3. 3.

    Roider J, Liew SH, Klatt C et al (2010) Selective retina therapy (SRT) for clinically significant diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 248:1263–1272

    Article  PubMed  Google Scholar 

  4. 4.

    Schuele G, Elsner H, Framme C et al (2005) Optoacoustic real-time dosimetry for selective retina treatment. J Biomed Opt 10:064022

    Article  PubMed  Google Scholar 

  5. 5.

    Neumann J, Brinkmann R (2005) Boiling nucleation on melanosomes and microbeads transiently heated by nanosecond and microsecond laser pulses. J Biomed Opt 10:024001

    Article  PubMed  Google Scholar 

  6. 6.

    Elsner H, Porksen E, Klatt C et al (2006) Selective retina therapy in patients with central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol 244:1638–1645

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Klatt C, Saeger M, Oppermann T et al (2011) Selective retina therapy for acute central serous chorioretinopathy. Br J Ophthalmol 95:83–88

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Kang S, Park YG, Kim JR, Seifert E, Dirk TK, Ralf B, Roh YJ (2016) Selective retina therapy in patients with chronic central serous chorioretinopathy: a pilot study. Medicine (Baltimore) 95:e2524. doi:10.1097/MD.0000000000002524

    Article  Google Scholar 

  9. 9.

    Framme C, Walter A, Berger L, Prahs P, Alt C, Theisen-Kunde D, Kowal J, Brinkmann R (2015) Selective retina therapy in acute and chronic-recurrent central serous chorioretinopathy. Ophthalmologica 234:177–188

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Park YG, Kim JR, Kang S, Seifert E, Theisen-Kunde D, Brinkmann R, Roh YJ (2016) Safety and efficacy of selective retina therapy (SRT) for the treatment of diabetic macular edema in Korean patients. Graefes Arch Clin Exp Ophthalmol. doi:10.1007/s00417-015-3262-1

    Google Scholar 

  11. 11.

    Koinzer S, Elsner H, Klatt C et al (2008) Selective retina therapy (SRT) of chronic subfoveal fluid after surgery of rhegmatogenous retinal detachment: three case reports. Graefes Arch Clin Exp Ophthalmol 246:1373–1378

    Article  PubMed  Google Scholar 

  12. 12.

    Yannuzzi LA, Shakin JL, Fisher YL, Altomonte MA (1984) Peripheral retinal detachments and retinal pigment epithelial atrophic tracts secondary to central serous pigment epitheliopathy. Ophthalmology 91:1554–1572

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Spaide RF, Campeas L, Haas A et al (1996) Central serous chorioretinopathy in younger and older adults. Ophthalmology 103:2070–2079, discussion 2079-2080

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Schule G, Huttmann G, Framme C et al (2004) Noninvasive optoacoustic temperature determination at the fundus of the eye during laser irradiation. J Biomed Opt 9:173–179

    Article  PubMed  Google Scholar 

  15. 15.

    Kandulla J, Elsner H, Birngruber R, Brinkmann R (2006) Noninvasive optoacoustic online retinal temperature determination during continuous-wave laser irradiation. J Biomed Opt 11:041111

    Article  PubMed  Google Scholar 

  16. 16.

    Dimitrakos S, Haefliger E, Robert Y (1985) Photocoagulation-induced macular scotoma and automated perimetry (Octopus). Klin Monatsbl Augenheilkd 186:506–509

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kim HD, Han JW, Ohn YH et al (2014) Functional evaluation using multifocal electroretinogram after selective retina therapy with a microsecond-pulsed laser. Invest Ophthalmol Vis Sci 56:122–131

    Article  PubMed  Google Scholar 

  18. 18.

    Kube T, Schmidt S, Toonen F et al (2005) Fixation stability and macular light sensitivity in patients with diabetic maculopathy: a microperimetric study with a scanning laser ophthalmoscope. Ophthalmologica 219:16–20

    Article  PubMed  Google Scholar 

  19. 19.

    Rohrschneider K, Springer C, Bultmann S, Volcker HE (2005) Microperimetry—comparison between the micro perimeter 1 and scanning laser ophthalmoscope--fundus perimetry. Am J Ophthalmol 139:125–134

    Article  PubMed  Google Scholar 

  20. 20.

    Inagaki K, Ohkoshi K, Ohde S et al (2015) Comparative efficacy of pure yellow (577-nm) and 810-nm subthreshold micropulse laser photocoagulation combined with yellow (561-577-nm) direct photocoagulation for diabetic macular edema. Jpn J Ophthalmol 59:21–28

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Malik KJ, Sampat KM, Mansouri A et al (2015) Low-intensity/high-density subthreshold micropulse diode laser for chronic central serous chorioretinopathy. Retina 35:532–536

    Article  PubMed  Google Scholar 

  22. 22.

    Lavinsky D, Sramek C, Wang J et al (2014) Subvisible retinal laser therapy: titration algorithm and tissue response. Retina 34:87–97

    Article  PubMed  Google Scholar 

  23. 23.

    Miura Y, Klettner A, Noelle B et al (2010) Change of morphological and functional characteristics of retinal pigment epithelium cells during cultivation of retinal pigment epithelium–choroid perfusion tissue culture. Ophthalmic Res 43:122–133

    Article  PubMed  Google Scholar 

  24. 24.

    Park YG, Seifert E, Roh YJ et al (2014) Tissue response of selective retina therapy by means of a feedback-controlled energy ramping mode. Clin Exp Ophthalmol 42:846–855

    Article  PubMed  Google Scholar 

  25. 25.

    Fujita K, Imamura Y, Shinoda K et al (2015) One-year outcomes with half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy. Ophthalmology 122:555–561

    Article  PubMed  Google Scholar 

  26. 26.

    Manabe S, Shiragami C, Hirooka K et al (2015) Change of regional choroid thickness after reduced-fluence photodynamic therapy for chronic central serous chorioretinopathy. Am J Ophthalmol 159:644–651

    Article  PubMed  Google Scholar 

  27. 27.

    Siaudvytyte L, Diliene V, Miniauskiene G, Balciuniene VJ (2012) Photodynamic therapy and central serous chorioretinopathy. Med Hypothesis Discov Innov Ophthalmol 1:67–71

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Tseng CC, Chen SN (2015) Long-term efficacy of half-dose photodynamic therapy on chronic central serous chorioretinopathy. Br J Ophthalmol 99:1070–1077

    Article  PubMed  Google Scholar 

  29. 29.

    Chuang LH, Hwang YS, Wang NK et al (2014) The chorioretinal damage caused by different half parameters of photodynamic therapy in rabbits. J Ocul Pharmacol Ther 30:642–649

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Vasconcelos H, Marques I, Santos AR et al (2013) Long-term chorioretinal changes after photodynamic therapy for chronic central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol 251:1697–1705

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Koss MJ, Beger I, Koch FH (2012) Subthreshold diode laser micropulse photocoagulation versus intravitreal injections of bevacizumab in the treatment of central serous chorioretinopathy. Eye (Lond) 26:307–314

    CAS  Article  Google Scholar 

  32. 32.

    Yadav NK, Jayadev C, Mohan A et al (2015) Subthreshold micropulse yellow laser (577 nm) in chronic central serous chorioretinopathy: safety profile and treatment outcome. Eye (Lond) 29:258–264, quiz 65

    CAS  Article  Google Scholar 

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Acknowledgments

Authors would like to thank Veit Danicke for his technical assistance, and Kerstin Schlott for her support in analytical work.

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Correspondence to Manabu Yamamoto.

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Yasui, A., Yamamoto, M., Hirayama, K. et al. Retinal sensitivity after selective retina therapy (SRT) on patients with central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol 255, 243–254 (2017). https://doi.org/10.1007/s00417-016-3441-8

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Keywords

  • Retinal sensitivity
  • Microperimetry
  • Central serous chorioretinopathy
  • Subvisible laser
  • Retinal pigment epithelium