Fluorescein angiography patterns and subretinal hyperreflective material predict subthreshold micropulse laser response in chronic central serous chorioretinopathy

Abstract

Background

To investigate predictors of navigated subthreshold micropulse laser (SML) treatment in chronic central serous chorioretinopathy (cCSC).

Methods

In this single-center prospective consecutive case series, patients with cCSC were treated with 577 nm SML and followed up for 12 months. A complete ophthalmological evaluation including spectral optical coherence tomography (SD-OCT), fluorescein angiography (FA) and microperimetry (MP) was performed. FA hyperfluorescence patterns and SD-OCT features were investigated.

Results

Overall, 38 eyes from 38 patients affected by cCSC with a mean age of 48.20 ± 5.95 years were included. Thirty-one eyes (81.6%) demonstrated a significant subretinal fluid (SRF) reduction after treatment at 3 months. Complete SRF resolution was achieved by twenty-three patients (60.5%) at 3 months and attained by an additional patient (24 in total, 63.2%) at 6 months. Twenty-two (57.9%) of such individuals were confirmed with no SRF at the end of the follow-up. Best-corrected visual acuity improved significantly and progressively at all timepoints from baseline, in parallel with macular sensitivity (all p: <0.005). Logistic regression analysis revealed that the presence of subretinal hyperreflective material (SHRM, p: 0.044; OR: -0.225; 95% CI: -0.448 - -0.003) and focal hyperfluorescence pattern on FA (p < 0.001; OR: 0.438; 95% CI: 0.196–0.632) predicted poorer and better treatment response, respectively.

Conclusions

FA hyperfluorescence pattern and presence of SHRM may predict SML treatment response in cCSC patients.

Background

Central serous chorioretinopathy (CSC) is a chorioretinal disease characterized by a serous neurosensory retinal detachment, usually featured by pigment epithelial detachments (PEDs), retinal pigment epithelial (RPE) dysfunction, choroidal thickening and hyperpermeability [1].

CSC is usually classified into acute (aCSC) and chronic (cCSC), albeit there is no consensus on the exact definition and duration on the chronicity of this condition [2]. Patients with acute CSC are likely to have a spontaneous subretinal fluid (SRF) resorption shortly after the onset of symptoms [3], whereas patients with cCSC tend to have persistent SRF over time, often associated with RPE atrophy and permanent photoreceptors impairment [4, 5].

Treatment should be recommended in patients with cCSC in order to minimize the permanent harmful effects of a long-standing neurosensory retinal detachment [2, 4, 6].

Photodynamic therapy (PDT) and subthreshold micropulse laser (SML) have demonstrated promising results in managing cCSC, with the first displaying significantly better anatomical and functional outcomes when compared to the latter [7–9].

PDT and SML have different mechanisms of action [8, 10]. The therapeutical effect of the PDT is believed to result from the occlusion, thrombosis, and choroidal hypoperfusion of the treated choroidal areas, whereas SML stimulates the RPE to reabsorb the SRF [8, 10].

Nevertheless, in the last few years, because of the dramatic verteporfin shortage worldwide, SML has been gaining ground over PDT, which is still a relatively invasive procedure requiring verteporfin injection [11]. Moreover, although rare, the risk of possible foveal RPE and outer retinal damage following PDT has been reported in several studies [12]. For such reasons, SML can be considered as a competitive, efficient, and safe alternative treatment option for cCSC, with no potential retinal tissue damage [12].

However, the reason why some eyes do not show a good response to SML treatment is still unknown. Considering the spread of this treatment modality, it would be of great value to identify possible predictors of good response to SML.

Therefore, the aim of this study was to investigate the potential influence of optical coherence tomography (OCT) and fluorescein angiography (FA) features in cCSC patients treated with SML.

Methods

In this single-center prospective consecutive case series, patients with cCSC and SRF were treated with SML and followed up for 12 months at the Eye Clinic of the University of Campania “Luigi Vanvitelli”, Naples, Italy. This study complied with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the University of Campania “Luigi Vanvitelli” (37768/2022).

All patients signed an informed consent for participation in the study.

Study population

Inclusion criteria were patients aged ≥ 18 years with an active cCSC, defined by multimodal imaging findings consisting of unresolved serous macular detachment lasting more than 4 months and evidence of thick choroid and mottled RPE changes, highlighted with spectral domain (SD)-OCT and fundus autofluorescence (FAF) [4, 10].

Exclusion criteria were any previous surgical or parasurgical procedure, such as laser photocoagulation and cataract or vitrectomy within the last 6 months in the study eye; high refractive error (i.e., greater than − 6 D or + 3 D); presence of other concomitant diseases, such as: diabetic retinopathy, retinal vascular occlusions, uveitis, vitreoretinal interface pathologies [13, 14].

Eyes who had previously received anti-vascular endothelial growth factor (VEGF) injections before the first SML application were also excluded.

All eyes with low quality SD-OCT scans due to poor compliance with testing or media opacities that prevented high resolution imaging of the retina and/or choroid were excluded from the study as well.

The success rate in the overall cohort and the possible predictors of positive treatment response were evaluated. A successful response was defined, as previously published [15], as the percentage of responders displaying decrease of both SRF maximal height and central subfield thickness (CST) at 3 months after treatment.

Best corrected visual acuity (BCVA), SRF height, and CST changes over the 12-month follow-up visits (1-3-6-12 months) were also evaluated.

Clinical examination

Data collected included patients’ demographics, medical history, and BCVA.

SD-OCT (Heidelberg Spectralis HRA + OCT, Heidelberg Engineering, Germany) was performed at baseline and after 1, 3, 6 and 12 months after treatment. The OCT acquisition protocol set for the analysis consisted of an enhanced depth imaging (EDI) 30°x 20° dense horizontal 49-scan with follow-up function [16].

SD-OCT measurements included SRF, CST, presence of intraretinal cysts and subretinal hyperreflective material (SHRM).

SRF height and SHRM presence were recorded at baseline and each follow up. Additionally, patients with SHRM were further evaluated with OCT-angiography to exclude the presence of eventual macular neovascularization (MNV).

CST was defined as average retinal thickness of the circular ETDRS area with 1-mm diameter around the foveal centre.

All patients underwent FA (Carl Zeiss Meditec, Dublin, CA) with an intravenous injection of 5 ml of 20% sodium fluorescein solution at the baseline visit and the pattern of hotspots (single vs. multiple) and the hyperfluorescence morphology (focal or diffuse) were recorded.

Macular sensitivity was investigated with a MP-3 microperimeter (Nidek Technologies, Italy), at baseline, 6 and at 12 months. The assessment was carried out with a 31.4 apostilibs white background, with a Goldmann V stimulus (34 dB dynamic range) through a 4 − 2 strategy and a single cross 2° red fixation target [17].

The mean macular sensitivity was automatically calculated from the 24 measured points in the foveal-centered 12º polygon, from the fixation stability evaluation within the 2º and 4º central foveal areas and the bivariate contour ellipse areas of the 68.2%, 95.4%, and 99.6% standard deviations (SD) of the total fixations.

Treatment procedure

Navigated yellow 577-nm SML (NAVILAS®; OD-OS GmbH, Teltow, Germany) was employed for treatments. The FA image was imported in the NAVILAS system and overlapped on the color picture acquired with the embedded software to specifically target the leaking area/s.

The power energy was adjusted after titration for each patient.

Once the whiteish point was visualized, the power energy was lowered of 30%. A 5% duty cycle treatment, with 200 ms and 100 μm diameter spots, with no inter-spot spacing, was delivered. SLM average power and number of spots delivered was recorded for each treatment session.

Statistical analysis

Continuous variables were reported as mean ± standard deviation (SD), and categorical features were reported as count (frequency). The normal distribution of variables was verified with the Kolmogorov–Smirnov test. Changes in BCVA, CST and SRF from baseline compared to 1, 3, 6 and 12 months and variations of macular sensitivity from baseline at 6 and 12 months were tested by a paired t- test. Univariate analysis for outcome measures (CST and SRF decrease) was done using a t-test for continuous variables and Fisher’s Exact Test for binary variables as previously adopted [15], including: (1) eye, (2) gender, (3) CST, (4) SRF height, (5) presence of SHRM, (6) presence of intraretinal cysts, (7) FA hyperfluorescence morphology (focal or diffuse), (8) FA hotspots pattern (e.g., single or multiple), (9) number of SML delivered spots, (10) average SML power used and (11) subfoveal choroidal thickness (SCT), manually determined as the subfoveal vertical distance between the Bruch’s membrane interface and the sclerochoroidal junction. Predictors with a double-sided p-value ≤ 0.05 in univariate analysis were included in the final multiple regression analyisis model. Statistical analysis was conducted with SPSS statistical package version 28.0.

Results

A total of 38 eyes from 38 patients affected by cCSC were included in the study. All the patients completed the follow-up. Mean age at baseline was 48.20 ± 5.95 years, 36 patients (94.7%) were male and 2 (5.3%) were female. SHRM was present in 15 patients (39.5%) at baseline, in line with the literature [18], and none of them exhibited any sign of MNV.

Thirty-one eyes (81,6%) demonstrated successful response to treatment showing a reduction of both SRF and CST after 3 months.

A total of 23 patients (60.5%) achieved a complete SRF resolution at 3 months, 24 (63.2%) at 6 months and 22 (57.9%) at 12 months.

CST and SRF height demonstrated significant changes (p < 0.001) at all timepoints (Table 1), exhibiting a progressive reduction during the first 6 months after treatment, with a relative stabilization at the 12-month visit (Table 1).

Table 1.

Structural OCT-based changes from baseline following yellow subthreshold laser treatment

	CST	p	SRF	p
B.	398.34 (SD 146.05)		180.21 (SD 139.32)
1MO	-101.40 (SD 146.79)	< 0.001	-121.03 (SD 146.11)	< 0.001
3MO	-110.50 (SD 147.74)	< 0.001	-144.04 (SD 148.64)	< 0.001
6MO	-141.06 (SD 149.19)	< 0.001	-155.54 (SD 149.40)	< 0.001
12MO	-118.59 (SD 141.12)	< 0.001	-143.65 (SD 152.90)	< 0.001

B.: baseline; CMT: central macular thickness; CST: central subfield thickness; MO: months; p: p-value; SD: standard deviation; SRF: subretinal fluid

Table 2 summarizes functional features in terms of BCVA and mean macular sensitivity changes following SML treatment. Specifically, BCVA constantly improved at all timepoints from baseline (p < 001), in parallel with macular sensitivity (6 months: +1.69 dB (SD 3.09), p: 0.002; 12 months: +1.99 dB (SD 3.38), p < 0.001).

Table 2.

BCVA and MS changes from baseline following yellow subthreshold laser treatment

	BCVA	p	MS	p
B.	52.13 ETDRS letters (SD 12.57)		24.22 dB (SD 4.08)
1MO	+ 4.79 ETDRS letters (SD 8.20)	< 0.001	/
3MO	+ 5.26 ETDRS letters (SD 8.85)	< 0.001	/
6MO	+ 8.28 ETDRS letters (SD 11.12)	< 0.001	+ 1.69 dB (SD 3.09)	0.002
12MO	+ 7.69 ETDRS letters (SD 13.35)	0.004	+ 1.99 dB (SD 3.38)	< 0.001

BCVA: best-corrected visual acuity; MS: macular sensitivity

Multivariable regression analysis revealed that eyes with SHRM on SD-OCT were characterized by significantly smaller chance of achieving treatment success (p: 0.044; OR: -0.225; 95% confidence interval: -0.448 - -0.003) (Fig. 1).

Fig. 1.

Multimodal imaging of the left eye of a 56-year-old man with chronic central serous chorioretinopathy at baseline and after yellow SML treatment. A. Intermediate-late-phase fluorescein angiography showing diffuse hyperfluorescence with multiple hotspots along the superior vascular temporal arcade. B. Color picture showing the caution zones as yellow circles on the macula and optic disc and in blue the confluent 100 μm spots of the treated YSML area. C. Baseline MP performed with a 4 − 2 strategy showing a mean retinal sensitivity of 24.2 Db. D. Six month follow up MP reveling a stable mean retinal sensitivity of 24.9 Db. E. Baseline SD-OCT and the near infrared (inset) with the horizontal foveal B-scan revealing SRF and SHRM. F. Six-month tracked follow-up SD-OCT B-scan showing only a slight reduction of the SRF with persistent SHRM

The FA hyperfluorescence morphology was also demonstrated to affect the treatment result, as focal leakages were significantly associated with a better response compared to a diffuse pattern (p < 0.001; OR: 0.438; 95% confidence interval: 0.196–0.632) (Figs. 1 and 2).

Fig. 2.

Multimodal imaging of the right eye of a 45-year-old man with chronic central serous chorioretinopathy at baseline and after yellow SML treatment. A. Intermediate-late-phase fluorescein angiography showing a focal hyperfluorescence with a single hot spot and surrounding focal area of leakage nasal to the fovea. B. Color picture showing the caution zones as yellow circles on the macula and optic disc and in blue the confluent 100 μm spots of the treated SML area. C. Baseline MP performed with a 4 − 2 strategy showing a mean retinal sensitivity of 26.1 Db. D. Six month follow up MP reveling a stable mean retinal sensitivity of 29.5 Db. E. Baseline SD-OCT and the near infrared (inset) with the horizontal foveal B-scan revealing SRF. F. Six-month tracked follow-up SD-OCT B-scan revealing a complete reabsorption of the SRF

Treatment success was independent from the following baseline parameters: BCVA (p: 0.883); SRF (p: 0.424); CST (p: 0.794); SCT (p: 0.374); MP3 (p: 0.068); intraretinal fluid presence (p: 0.786); single or multiple FA hotspots (p: 0.604); number of delivered SML spots (p: 0.434); average SML delivered power (p: 0.272).

Discussion

Recent evidence suggests that SML is a safe and effective treatment option for cCSC patients with longstanding SRF [8]. Nevertheless, although the same therapeutic protocol is adopted, the inter-individuals’ responses can vary significantly. Therefore, determining which anatomical or imaging parameters may affect SML efficacy could be of utmost importance in successfully identifying candidates who may benefit from the treatment.

In this prospective study, we evaluated the treatment success of navigated SML in patients with cCSC and investigated imaging features that may influence the therapeutical outcomes.

Our results confirmed the data reported in the recent literature and demonstrated a successful treatment response in the vast majority of patients (31 eyes, 81.6%), who reported significant reduction of SRF height and CST, associated with higher improvement of BCVA and macular sensitivity from baseline compared to non-responding patients [8].

Moreover, 21 out of 31 (67.7%) responder patients were characterized by a complete SRF resorption at 3 months that persisted throughout the entire follow-up (12 months), which is rather in line with the observations reported in the recent literature [19–21].

The anatomical treatment success was also accompanied by significant functional benefits as showed by BCVA and macular sensitivity improvements over time.

Moreover, the significant mean macular sensitivity gain at 6- and 12-months further confirms that SML can be considered a safe therapeutic approach not leaving any outer retina or RPE damage impairing the retinal sensitivity.

Kiraly et al. reported in a prospective, single-center study assessing 31 consecutive patients with cCSC that the lower baseline maximal height of SRF was associated with a better SML response, claiming that the amount of SRF might predict the treatment outcome [22]. Conversely, our data did not confirm any of such observations as SRF at baseline was demonstrated to not predict patients’ responses to SML, highlighting that the sole serous SRF presence would not impair the efficient stimulation and restoration of viable RPE pumping mechanism.

Similarly, Singh et al. showed that thicker choroid underneath the fovea was associated with a complete macular SRF reabsorption in patients on eplerenone regimens [23], albeit this association has never been confirmed in CSC patients treated with SML. Indeed, our study did not demonstrate any significant correlation between SCT and treatment response, in agreement with the experience of Kiraly et al. [22]

To this regard, we supposed that the choroidal congestion, significantly contributing to the choroidal tissue thickening, would not necessarily imply the RPE dysfunction, and thus it would not be of any help in predicting the SML efficacy.

Moreover, Iovino et al. showed the significant reduction of the SCT and specifically the luminal area of the choroid following PDT [10]. Conversely, Van Rijssen et al. demonstrated that SML does not significantly affect the choroidal vasculature, and therefore a choroidal vascularity change may not be primarily responsible for the treatment effect [24].

Interestingly, our findings highlighted the role of FA leakage morphology in forecasting the SML efficacy. In particular, focal leakages were associated with better outcomes, whereas diffuse hyperfluorescence patterns characterized worse responses to the therapy in both anatomical and functional terms (Figs. 1 and 2).

Similarly, Amoroso et al. reported the presence of a hotspot on FA and a focal choroidal hyperpermeability on indocyanine green angiography to be predictors of good response of SML at month [25].

In this light, it may be speculated that the diffuse hyperfluorescence patterns might represent a more advanced disease stage, featuring severe choroidal dysfunction and hyperpermeability that ultimately lead to RPE-outer blood retinal barrier compromission.

Accordingly, the consequent extensive RPE failure would explain the poor morpho-functional recovery after SML, which in turn would not stimulate enough target tissue to efficiently reabsorb the SRF, resulting in recalcitrant chronic neurosensory retinal detachment.

Of note, the presence of SHRM was found to be significantly associated to worse treatment outcomes among our patients. One possible empirical explanation could be that the subretinal hyperreflective material, representing fibrin or photoreceptors shedding, would be the expression of advanced outer retina-RPE degeneration, as RPE cells beneath the subretinal fibrin were found to lose their normal, epithelial, morphologic features and pump functions [26]. Moreover, Sahoo and coauthors demonstrated that the ELM damage at resolution of the fluid in cCSC patients with SHRM correlates with a poor visual acuity outcomes [27].

Another possible explanation could be that the hyperreflective material itself could physically shield the underneath RPE layer, preventing the SML to exert its effect over its target tissue.

Our study has several limitations, including the relatively small cohort size and the absence of a control group. In addition, SML was delivered based on the FA results. Indocyanine green angiography-based-SML may have led to different areas to target, although which of the two imaging modalities is to be preferred for micropulse laser treatment is yet to be proven. Moreover, we used a 577-nm yellow navigated laser, but treatment protocols and strategies may vary from different laser devices [8].

Conclusion

In conclusion, the results of our study showed that SML may be considered as a valid treatment option for patients with cCSC. Moreover, it highlighted the importance of FA hyperfluorescence pattern and presence of SHRM in predicting the functional outcomes. However, further prospective randomized studies with longer follow-ups on larger cohorts are warranted to better target the causes halting the effective treatment response, standardize the therapeutical algorithms, define precise inclusion criteria and understand the real treatment outcomes of this promising treatment strategy.

Abbreviations

BCVA

Best Corrected Visual Acuity

CSC

Central Serous Chorioretinopathy

CST

Central Subfield Thickness

FA

Fluorescein Angiography

FAF

Fundus Autofluorescence

MNV

Macular Neovascularization

PDT

Photodynamic Therapy

PED

Pigment Epithelial Detachments

RPE

Retinal Pigment Epithelial

SD-OCT

Spectral Domain-Optical Coherence Tomography

SHRM

Subretinal Hyperreflective Material

SML

Subthreshold Micropulse Laser

SRF

Subretinal Fluid

VEGF

Anti-Vascular Endothelial Growth Factor

Author contributions

C.I. and F.S. designed the study. L.D. and D.P. acquired the data. C.I. and C.M.I. analyzed and interpreted the data. C.I. and C.M.I. drafted the manuscript. C.I., C.M.I., F.T., S.R. and F.S. critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of the work.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

The datasets generated during and/or analyzed during the study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study complied with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the University of Campania “Luigi Vanvitelli” (37768/2022). Additionally, all patients signed an informed consent for participation in the study.

Consent for publication

Not applicable.

Competing interests

C.I is an Editorial Board member of BMC Ophthalmology. The rest of the authors declare no competing interests.