Photobiomodulation Therapy with Low‐Level Light in Chronic Central Serous Chorioretinopathy: A Pilot Study

Central serous chorioretinopathy (CSC) is a common retinal disorder characterized by the accumulation of subretinal fluid (SRF) and serous neurosensory detachment. It predominantly affects young to middle-aged adults, presenting a significantly higher prevalence in men. Stress and corticosteroid use are well recognized risk factors [1, 2].

The pathophysiology of CSC involves a complex interplay between choroidal circulation abnormalities, compromised retinal pigment epithelium (RPE) barrier dysfunction, and increased hydrostatic pressure within the choroid that leads to fluid leakage beneath the retina [1]. Although most acute CSC cases resolve spontaneously within 3–6 months, up to 50% of patients experience recurrence, and approximately 5–10% progress to a chronic form with persistent SRF lasting beyond 6 months [3, 4].

Chronic central serous chorioretinopathy (cCSC) can result in a progressive visual loss due to complications such as ellipsoid zone (EZ) damage, RPE atrophy, cystoid macular degeneration, choroidal neovascularization, macular scarring, and macular atrophy [5, 6].

Although photodynamic therapy (PDT) remains the gold-standard treatment for cCSC, alternative strategies—such as subthreshold micropulse laser, mineralocorticoid receptor antagonists, and intravitreal agents—are under active investigation [6,7,8,9,10]. Moreover, since 2021, the worldwide shortage of verteporfin emphasized the need for a more patient-tailored approach [11].

Low-level light therapy (LLLT), acting via photobiomodulation (PBM), is a nonthermal, noncoherent light therapy that enhances mitochondrial function, increases adenosine triphosphate (ATP) production, reduces inflammation, and supports photoreceptor (PR) and RPE repair [12, 13]. The proposed mechanisms involve the absorption of photons by cytochrome c oxidase (COX), leading to improved oxidative phosphorylation, ATP synthesis, and downstream antiinflammatory signaling [12, 13]. Preclinical studies have demonstrated that PBM can improve mitochondrial function, increase retinal ganglion cell survival, and reduce inflammation in models of retinal degeneration and ischemic optic neuropathy. In retinal applications, PBM typically employs irradiance levels of 10–100 mW/cm² and fluences ranging from 1 to 10 J/cm², which are considered safe for ocular tissues [14,15,16,17].

Clinical applications in retinal pathologies have yielded promising structural and functional improvements. PBM has been successfully employed for the resolution of a giant serous pigment epithelial detachment (PED) in a patient with cCSC [18].

On the basis of these findings, with the present study we evaluated the efficacy of PBM using the eye-light® system in patients with cCSC. We aim to assess both anatomical and functional outcomes over a 6-month follow-up.

Study Design

This retrospective pilot study, conducted at the Medical Retina Service of the Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Italy, analyzed data from consecutive patients with cCSC treated with PBM. This study was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. As per Italian regulations for retrospective studies, formal approval from an ethics committee was not required, but the institutional ethics committee was informed about the study.

All patients underwent a comprehensive ophthalmologic examination at baseline and at follow-up visit, including best corrected visual acuity (BCVA), intraocular pressure (IOP) measurement, and dilated fundus examination. All imaging, including color fundus photography (CFP), green fundus autofluorescence (FAF), tracked swept-source optical coherence tomography (OCT), and swept-source optical coherence tomography angiography (SS-OCTA), was performed using the DRI OCT Triton Plus (Topcon Medical Systems, Oakland, New Jersey, USA). Intraocular pressure (IOP) was measured using Goldmann applanation tonometry. Inclusion criteria were age ≥ 18 years and diagnosis of CSC with presence of subretinal fluid from at least 6 months confirmed by multimodal imaging. [19, 20]

Exclusion criteria included presence of cataract affecting image quality, previous vitrectomy or any other type of intraocular surgery, concurrent maculopathies including age-related macular degeneration (AMD) or diabetic retinopathy (DR), pathologic myopia defined as axial length greater than 26.5 mm or spherical equivalent exceeding −6.0 diopters, macular neovascularization resulting from other causes, pregnancy or nursing status, significant media opacities preventing high-quality imaging acquisition, and inability to provide informed consent or complete follow-up examinations.

Imaging Protocol

All patients underwent CFP, FAF, SS-OCT, and SS-OCTA at baseline and 3 and 6 months after treatment. Several OCT parameters were evaluated at baseline and at each follow up including: central retinal thickness (CRT), subretinal fluid height (SRH), subfoveal choroidal thickness (SCT), presence of intraretinal fluid (IRF), serous PED, and subretinal hyperreflective material (SHRM).

SRF Resolution Criteria

• Complete resolution: absence of any detectable subretinal fluid on OCT B-scans

• Partial resolution: reduction of subretinal fluid height by ≥ 50% compared with baseline

• No change: reduction < 50% or increase in subretinal fluid height

Measurement Approach

All OCT measurements (CRT, SCT, SRH) were performed manually using the device’s built-in caliper tool by two independent masked graders (initials C.I. and P.V.). The graders were blinded to the treatment timepoint and clinical information. For SRH, measurements were taken at the point of maximum fluid height perpendicular to the RPE. The average of the two measurements was used for statistical analysis.

Inter-Grader Reliability

Inter-grader reliability was assessed using the intraclass correlation coefficient (ICC) with a two-way random effects model for absolute agreement. The ICC values were: CRT = 0.94 (95% CI 0.86–0.98), SCT = 0.91 (95% CI 0.81–0.96), and SRH = 0.93 (95% CI 0.84–0.97), indicating excellent agreement between graders.

PBM Treatment Protocol

The possibility of PBM therapy was discussed with the patients. All patients received treatment with LLLT PBM using the eye-light^® system (Espansione Group, Bologna, Italy), a CE-certified class IIA medical device specifically developed for ocular PBM. Light was delivered through two distinct wavelengths, yellow (~590 nm) at 25 mW/cm² ± 20% and red (~625 nm) at 55 mW/cm² ± 20%. The treatment lasted approximately 12 min in total, 6 min with yellow light and 6 min with red light. In detail, each patient was instructed to keep the eyes closed for 5 min and opened for 1 min with either yellow and red light. The mask was placed at an approximate distance of 1–3 cm from the face, depending on the individual’s facial structure, and the eyelids were kept closed. The cumulative dose per session corresponds to the irradiance multiplied by exposure time. The system complies, among others, with international electrotechnical commission (IEC) standard IEC 60601–2-57.

All patients received one PBM treatment per week for four consecutive weeks, followed by one treatment per month for the subsequent 2 months, for a total of six sessions over 3 months. BCVA measurements and multimodal retinal imaging were performed at baseline and 6 months (Fig. 1).

Written informed consent was obtained from the patient for the publication of their images and any potentially identifiable information, in accordance with the journal’s policy.

Statistical Analysis

All data were collected and analyzed using IBM SPSS Statistics (version 30.0.0, IBM Corp., Armonk, NY, USA). Continuous variables are presented as mean ± standard deviation (SD) or mean with 95% confidence interval (CI), as appropriate. Categorical variables are expressed as counts and percentages.

To evaluate treatment efficacy, paired t-tests were applied to compare baseline and 6-month values of BCVA, CRT, SCT, and SRH, and effect sizes (Cohen’s d) with 95% confidence intervals were also calculated for these continuous outcomes. Normality of data distribution was verified using the Shapiro–Wilk test before performing parametric analyses. For categorical outcomes, such as the presence or resolution of SHRM and PED, differences between baseline and follow-up were assessed using the McNemar test.

Statistical significance was defined as a two-tailed p-value < 0.05. Given the exploratory and pilot nature of the study, no correction for multiple comparisons was applied.

A total of nine patients (ten eyes) with cCSC were included. The mean age was 45.37 years (range 35–56 years), with seven male patients and two female patients. The mean duration of disease prior to inclusion was 16.6 months (range 6–36 months). The mean CRT was 359 μm (range 255–445 μm), the mean SCT was 462 μm (range 367–551 μm), and the SRH thickness was 227.7 ± 51.5 µm, with a median of 219 µm [IQR 196–267.5]. SHRM was present in 30% of eyes, SRF in 100%, intraretinal fluid (IRF) in 0%, and PED in 40% of eyes (Table 1).

Prior to enrollment, six patients had received no previous laser treatment. One patient had been treated with eplerenone and nutritional supplements 1 year before for 4 months, and two others had received oral bromelain-based supplementation with no anatomical and functional improvements.

At baseline, mean BCVA was 67.12 ETDRS letters (±4.96). Following PBM treatment, BCVA improved progressively, reaching 77.87 ETDRS letters (±7.77) at 6 months (p = 0.0053). Treatment resulted in a significant reduction in CRT (mean difference 150.38 μm; p = 0.0005). No significant change in SCT was observed between pre- and post-treatment (mean difference 21.63 μm; 95% CI −30.58 to 73.83; p = 0.3893). A highly significant reduction in SRH was observed following treatment (mean difference 198.88 μm; 95% CI 142.89–254.86; p < 0.0001).

At 6 months, 70% of treated eyes showed a complete resolution of SRF (95% CI 40–100%), while 10% demonstrated a partial reduction and 20% showed no anatomical changes compared with baseline. Among the five eyes presenting with avascular serious PED at baseline, two PEDs completely flattened, one showed a partial reduction, and two remained unchanged throughout the follow-up period. Among the three patients with SHRM at baseline, two experienced complete resolution, while one showed a partial decrease (Table 2).

No adverse events or complications related to PBM therapy were observed during the treatment period or at any follow-up visits. Representative case of PBM treated eyes are shown in Figs. 2 and 3.

In this retrospective pilot study, we evaluated the anatomical and functional outcomes of patients with cCSC treated with PBM using the eye-light^® system. Over a 6-month follow-up period, PBM demonstrated a favorable safety profile and showed promising efficacy in improving both SRF resolution and BCVA.

Chronic CSC remains a therapeutic challenge, with limited consensus on optimal management strategies. Although half-dose PDT is widely regarded as the gold standard due to its ability to target choroidal hyperpermeability, its availability, cost, and potential side effects—such as RPE atrophy and secondary choroidal neovascularization—limit its widespread use [19].

Other pharmacologic approaches, including mineralocorticoid receptor antagonists and carbonic anhydrase inhibitors, have shown variable efficacy, and none are currently approved specifically for CSC [21,22,23,24].

In our cohort, several patients had previously received eplerenone or oral supplements including bromelain and curcumin without meaningful anatomical or functional improvement, highlighting the clinical need for alternative noninvasive options.

Although PDT is considered the standard of care in patients with cCSC [7, 19], it requires verteporfin injection, which has been missing in recent years and is not present in all retina service units.

PBM has recently gained interest in the field of retinal diseases due to its theoretical benefits in enhancing mitochondrial activity, modulating oxidative stress, and promoting PR and RPE repair [25, 26]. The biological rationale is supported by preclinical studies demonstrating that near-infrared light stimulates cytochrome c oxidase activity and ATP production, which may in turn support retinal homeostasis and antiinflammatory signaling. The absence of photothermal damage further differentiates PBM from other laser-based therapies, potentially allowing for repeatable and long-term application.

Our findings corroborate these theoretical benefits: 70% of eyes achieved complete SRF resolution at 6 months, while another 10% showed partial improvement. These results are in line with those shown in CSC eyes treated with yellow micropulse laser (YMPL) [27]. Nevertheless, despite sharing part of the mechanism of action with the YMPL, PBM treatment does not require any dye injection, including fluorescein and green indocyanine angiography to guide the treatment delivery.

Notably, BCVA improved significantly, with a gain of nearly 11 ETDRS letters on average due to the progressive resolution of the subretinal fluid.

The amount of subretinal fluid did not seem to influence the efficacy of the treatment. Indeed, recently Iovino et al. (2024) reported structural and functional recovery in a patient with cCSC and a huge pigment epithelial detachment treated with PBM [18].

The favorable response observed in cases with long-standing disease duration (mean: 18.2 months) suggests that PBM may be effective even in chronic stages of CSC. Additionally, the resolution or reduction of PED height in several eyes may reflect an improvement in RPE pump function rather than a direct choroidal structural change, as short-term subfoveal choroidal thickness did not significantly vary in our. Future studies integrating choroidal thickness metrics or vortex vein analysis via en face imaging may help further clarify these mechanisms.

Importantly, no adverse events or safety concerns emerged during treatment or follow-up, supporting the noninvasive and well-tolerated nature of PBM. This safety profile, coupled with the nonpharmacologic and repeatable characteristics of the therapy, may be particularly advantageous in chronic or recurrent disease, in patients with systemic contraindications to dye injection, or in cases where PDT is not accessible. Moreover, in patients with cCSC some PBM treatment sessions delivered bimonthly even after the resolution of the fluid, could be effective in reducing the recurrence rate, although this needs to be proven.

Limitations of this study include its retrospective analysis, small sample size, lack of a control group, open-label design, and that the SS-OCT measurement manually performed.

Although our data suggest improvements, randomized controlled trials with larger cohorts and placebo or standard-treatment arms are necessary to establish efficacy and to identify subgroups most likely to benefit from PBM. Moreover, the absence of long-term follow-up beyond 6 months precludes conclusions regarding the durability of response. Longer-term studies are needed to evaluate whether any structural remodeling occurs over time and to determine whether the visual benefits are durable.

Our findings support the potential role of PBM as a safe, noninvasive, and repeatable therapeutic modality for cCSC. While preliminary, the improvements in retinal structure and visual acuity observed in this series justify further investigation through controlled clinical trials to validate PBM as part of the therapeutic armamentarium for pachychoroid spectrum disorders.