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This systematic review and meta-analysis compares the complications and effects of photobiomodulation (PBM) therapy with sham treatment in patients with age-related macular degeneration (AMD). AMD is a leading cause of visual impairment in older adults, with current treatments primarily focusing on symptom management. PBM therapy is emerging as a potential intervention to improve clinical and anatomical outcomes in patients with AMD, necessitating a comparative analysis with sham treatment to determine its efficacy and safety.
Methods
A systematic search was conducted across PubMed/Medline, Google Scholar and the Cochrane Library from inception to January 13, 2025. Randomised controlled trials (RCTs) meeting predefined inclusion criteria were selected. Meta-analysis employed random-effects models. The risk of bias in the included studies was assessed using Cochrane tools.
Results
A total of six studies, comprising 360 patients and 477 eyes, focused on PBM for dry AMD. Five studies were eligible for meta-analysis. Best-corrected visual acuity (BCVA) showed no significant improvement with PBM (SMD − 0.30, 95% CI − 0.85 to 0.26, p = 0.30), with high heterogeneity (I2 = 83%). Macular drusen volume also showed no significant change (SMD − 0.08, 95% CI − 0.52 to 0.37, p = 0.74), with moderate heterogeneity (I2 = 48%). A single study reported no significant effect on geographic atrophy (SMD − 0.28, 95% CI − 1.26 to 0.71, p = 0.58). Central subfield thickness (SMD 0.11, 95% CI − 0.25 to 0.47, p = 0.58) and microperimetry (SMD − 0.02, 95% CI − 0.48 to 0.44, p = 0.94) also showed no significant changes. The adverse events analysis indicated a statistically significant increase in adverse events in the sham group within 6 months (RR 0.48, 95% CI 0.29–0.82, p = 0.007), while the overall effect on adverse events was non-significant (RR 1.04, 95% CI 0.51–2.12, p = 0.91, I2 = 78%). Qualitative analysis suggested that PBM might enhance quality of life and clinical and anatomical outcomes compared to sham treatment.
Conclusion
This meta-analysis suggests that, to date, there are no significant clinical benefits of PBM therapy for patients with AMD. Further long-term studies are needed to establish its clinical relevance and safety profile.
Age-related macular degeneration (AMD) is a leading cause of visual impairment in older adults, with limited treatments focusing on symptom management.
Photobiomodulation (PBM) therapy is emerging as a potential intervention to improve clinical and anatomical outcomes in patients with AMD.
What did the study ask?
This study aimed to compare the efficacy and safety of PBM therapy with sham treatment in patients with AMD.
What was learned from the study?
Compared to sham treatment, PBM therapy did not significantly improve best-corrected visual acuity (BCVA), macular drusen volume, geographic atrophy, central subfield thickness, or microperimetry.
Although PBM therapy did not provide statistically significant clinical benefits, it may offer short-term quality-of-life improvements for patients with AMD.
The study indicates the need for further long-term research to establish the clinical relevance and safety profile of PBM therapy.
Introduction
Age-related macular degeneration (AMD) is a leading cause of blindness among older adults, affecting approximately one in eight individuals aged 60 years or more. Approximately 200 million people worldwide are affected by AMD, with projections suggesting an increase to nearly 300 million by 2040 [1]. AMD is a chronic progressive macular disease causing irreversible vision loss in older people and is the most common cause of blindness in developed countries, affecting about 7–8% of the population worldwide [2]. AMD is a multifactorial disease characterised by the deterioration of the macula, the central portion of the retina, due to a combination of ageing, genetic and environmental risk factors [3, 4]. The phenotype is classified into dry (non-exudative) AMD and exudative AMD, with three described stages: early, intermediate and late (neovascular and geographic atrophy, GA) AMD. Intermediate AMD represents the most crucial stage because it is still possible to slow disease progression to more severe forms [5]. Dry AMD accounts for 85–90% of cases and is marked by the presence of drusen (yellow deposits) between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM), leading to atrophy of the RPE. Wet AMD, although comprising only 10–15% of cases, is responsible for the majority of severe vision loss associated with AMD due to the growth of abnormal choroidal neovascularization [6]. Intermediate AMD is characterised by large drusen (> 125 μm) or medium drusen (> 63 μm) with pigmentary abnormalities [7]. The pathogenesis of AMD is complex and multifactorial, involving intrinsic and extrinsic stress factors leading to a progressive accumulation of waste materials, including extracellular deposits (drusen) and intracellular deposits (lipofuscin) [8]. Drusen contains pro-inflammatory factors that may stimulate inflammation through various pathways, such as the complement cascade. Lipofuscin, a waste metabolite from photoreceptors, is a major source of reactive oxygen species (ROS), and mitochondria, as key regulators of inflammatory and oxidative signalling pathways, are the major intracellular source of ROS [9]. With ageing, an excess of ROS production creates oxidative stress, causing further retinal damage and atrophy [10].
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Symptoms of AMD may include blurry or distorted vision, decreased colour brightness, difficulty recognising faces, trouble adapting to low light, and central vision loss, which can result in a central scotoma [11]. The diagnosis of AMD involves several clinical assessments, including fundoscopic examination, optical coherence tomography (OCT), OCT-A, fundus autofluorescence (FAF) and fluorescein angiography [12, 13].
Traditional treatment strategies for dry AMD include nutritional supplementation and lifestyle modifications. Current treatments for neovascular AMD include anti-vascular endothelial growth factor (VEGF) therapies ranibizumab, bevacizumab, aflibercept, brolucizumab and faricimab, while for GA, pegcetacoplan and avacincaptad pegol have been validated [14]. Unfortunately, therapeutic options for intermediate AMD are limited to a healthy lifestyle and nutritional supplements like the AREDS 2 formula. The Age-Related Eye Disease Study (AREDS) 2 revealed that patients with intermediate AMD who took these supplements experienced a decreased risk of developing advanced AMD [15].
High-dose nutrient supplementation with AREDS 2 formula (comprising vitamin C, vitamin E, copper, lutein, zeaxanthin and zinc) can reduce progression to advanced AMD [16]. A Mediterranean diet has been linked to a reduced incidence of advanced AMD [17]. Photobiomodulation (PBM), also known as low-level light therapy, is a noninvasive treatment that applies low-level lasers to the body’s surface. PBM is administered using devices that deliver light in the red to near-infrared spectrum to the retina, with sessions lasting up to a few minutes and often conducted multiple times per week over weeks to months. During PBM, particularly at 670 nm, light penetrates the retinal tissue and is absorbed by cytochrome c oxidase, a key enzyme in the electron transport chain in mitochondria [18]. An increase in proton gradient across the mitochondrial membrane upregulates ATP synthase activity, thereby enhancing ATP production [19]. In aging and AMD, mitochondrial dysfunction leads to excessive ROS accumulation, contributing to oxidative stress [20]. PBM modulates stress by increasing the activity of superoxide dismutase (SOD) and glutathione peroxidase, which neutralize superoxide anions and hydrogen peroxide, reducing mitochondrial DNA. Chronic inflammatory activation in AMD contributes to RPE degeneration, photoreceptor apoptosis and drusen accumulation. PBM mitigates inflammation by inhibiting NF-κB activation, suppressing the transcription of pro-inflammatory cytokines such as tumour necrosis factor (TNFα) and interleukin (IL)-6 [19]. It also downregulates complement activation and increases anti-inflammatory cytokines, such as IL-10 [20]. PBM upregulates neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which support photoreceptor and RPE survival [20].
PBM, gaining attention as a potential treatment for intermediate AMD, was initially discovered in the 1960s by Endre Mester, who observed that low-level laser light enhanced wound healing and hair regrowth in rodents [21]. Initially intended for tissue regeneration and pain management, it has since been used to treat conditions such as asthma, musculoskeletal injuries and neurodegenerative disorders [22]. The therapeutic effects of PBM on retinal health in AMD, while promising, remain under evaluation, requiring further understanding of its long-term safety and efficacy [23].
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Borrelli et al. conducted an RCT to investigate the EYE-LIGHT® PBM system, which employs 590 nm and 630 nm wavelengths, in patients with dry AMD [24]. The treatment plan consisted of two sessions per week for 4 weeks and outcomes were assessed at the end of the fourth month. LIGHTSITE I, LIGHTSITE II and LIGHTSITE III are sequential clinical trials investigating the effects of multiwavelength PBM therapy (590, 660 and 850 nm) for dry-AMD using the LumiThera Valeda® Light Delivery System [25‐27]. LIGHTSITE I lasted for 12 months, LIGHTSITE II for 10 months, whereas LIGHTSITE III was designed for 24 months, with a primary analysis conducted at 13 months. Both LIGHTSITE II and III studies involved nine sessions per series, repeated every 4 months. In the LIGHTSITE I study, PBM was delivered three times per week for 3–4 weeks in two series, 6 months apart. Inadequate sample size (46 eyes) and single-centre design were the limitations of this study [27]. Franceschelli et al. investigated the short-term effects of a new wearable LED PBM device for self-medication in patients with severe dry AMD [28]. The treatment group received 10-min stimulations over 10 sessions and outcomes were assessed in just 2 weeks. Robinson et al. examined the effects of low-level nighttime light therapy using an OLED sleep mask on early AMD progression over 12 months [29]. Participants wore Noctura 500 organic light-emitting diode (OLED) masks every night for 12 months.
This study aims to evaluate the clinical effectiveness and safety of PBM in patients with AMD by comparing visual and structural outcomes with sham or placebo treatments based on evidence from six RCTs. Additionally, this study’s novelty lies in its comprehensive assessment of adverse events, providing insights into PBM’s risk–benefit profile. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Methods
Search Strategy and Databases
The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [30]. Institutional review board approval was not required, given the nature of this investigation. Our research protocol was published in the Prospective Register of Systematic Reviews with registration number CRD42024619964. The study adhered to the tenets of the Declaration of Helsinki. An electronic search was conducted using PubMed/Medline from inception to January 13, 2025. The following search string was used: (Multiwavelength Photobiomodulation OR Multispectral light therapy OR Multiwavelength light-based therapy OR Broad-spectrum low-level light therapy OR LLLT OR Polychromatic light therapy OR Multi-spectrum phototherapy) AND (Nonexudative Age-Related Macular Degeneration OR Dry AMD OR Atrophic AMD OR Dry macular degeneration OR Non-leaking age-related macular degeneration OR Non-neovascular AMD OR Non-wet AMD). Additional relevant studies were identified through the references of previously published meta-analyses, cohort studies and review articles.
Study Selection Criteria
The study selection criteria for this systematic review and meta-analysis followed the PICOS framework, ensuring a thorough evaluation of relevant research. Patients included were those diagnosed with AMD. The intervention involved the application of multiwavelength PBM therapy, with control groups receiving sham or placebo treatments. The primary and secondary outcomes focused on comparing the effects of PBM therapy with control treatments, particularly in terms of visual and structural improvements in patients with AMD. Only randomised controlled trials (RCTs) were considered, as they provide robust evidence regarding the efficacy and safety of PBM therapy in AMD treatment. This stringent selection process ensured that only high-quality, relevant studies were included in the review. Exclusion criteria applied to studies that did not meet the PICOS framework, such as non-RCTs, observational studies, case reports, animal studies, reviews, editorials and those with irrelevant outcomes or interventions. These measures were taken to maintain the quality and relevance of the data analysed in the systematic review and meta-analysis.
Data Extraction and Quality Assessment
The search strategy was developed independently by two authors according to the specified criteria, and any discrepancies or misunderstandings were resolved through consensus with a third author. The electronic databases were screened, and studies were exported to EndNote Reference Library version 20.0.1 (Clarivate Analytics, London, UK). Duplicate articles were identified and removed. Two investigators entered the data extracted from the selected studies into a computer spreadsheet.
Quality and bias assessments were conducted using the Cochrane Collaboration Tool for clinical trials. Seven domains were evaluated: adequate sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and freedom from other biases. The individual domains and overall risk-of-bias judgments were categorised into three levels: high risk of bias, unclear risk of bias and low risk of bias. On the basis of these factors, the overall quality of evidence was classified as high, moderate or low risk of bias.
Statistical Analysis
Review Manager (version 5.4.1; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020) was utilised for all statistical analyses. Data from the included studies were pooled using a random-effects model to account for observed heterogeneity. The results were analysed by calculating the risk ratio (RR) and standard mean difference (SMD) with their respective 95% confidence intervals (CI). The chi-square test was employed to assess differences between subgroups. Sensitivity analysis was conducted to determine whether any individual study influenced the overall results and to investigate potential causes of high heterogeneity. According to the Cochrane Handbook, heterogeneity was categorised as follows: I2 = 25–60% (moderate), 50–90% (substantial) and 75–100% (considerable), with p values less than 0.1 indicating significant heterogeneity [31]. A p value of less than 0.05 was considered statistically significant by all analyses. Factors that could not be quantitatively assessed were examined qualitatively using a narrative approach. This allowed for a comprehensive interpretation of the data beyond statistical measures.
Results
Literature Search Results
This PRISMA flowchart (Fig. 1) outlines the systematic review process for study selection. A total of 218 records were identified through database searching, with no additional records from other sources. After removing duplicates, 184 records remained for screening. Of these, 158 records were excluded on the basis of title and abstract review. The remaining 26 full-text articles were assessed for eligibility, with 20 being excluded as a result of various reasons, including editorials, animal studies, reviews, case reports, case series, prior systematic reviews or meta-analyses, irrelevant outcomes, and exposures. Ultimately, six studies were included in the qualitative synthesis, of which five were eligible for inclusion in the meta-analysis. This step-by-step process ensures the rigorous selection of relevant studies for analysis.
The clinical and demographic details of the finalised studies are provided in Table 1 [24‐29]. Six RCTs conducted between 2018 and 2024 were included in the analysis, with a total of 360 patients and 477 evaluated eyes. Female participants accounted for 63.08%, and the mean age was 74.92 years. The studies originated from the USA, Italy, Germany, Spain, the UK, Canada and Turkey, reflecting a global effort to explore PBM interventions for dry AMD.
Table 1
Baseline demographic characteristics extracted from the included studies
Name
Year
Country
Study design
Intervention used
Total population (n)
Total patients in intervention group (n)
Female (%)
Mean age (years)
Factors present
Robinson et al.
2018
UK
RCT
Noctura 500 organic LED mask emitting 505 nm green light
60
30
57.1
77.6
Quality of life (VDF-25)
Markowiitz et al. (LIGHTSITE I)
2020
Canada
RCT
Valeda Light Delivery System emitting 590 nm (yellow), 660 nm (red) and 850 nm (near-infrared) wavelength
30 (46 eyes)
15 (24 eyes)
60
76
Best-corrected visual activity, adverse effects > 6 months, quality of life
Low-fluence PBM with a newly designed device emitting red light at 630 nm
50 (78 eyes)
31 (50 eyes)
56
77.85
Best-corrected visual activity, central subfield drusen thickness, microperimetry
N/A not available
The PBM devices utilised emitted light at wavelengths ranging from 505 nm (green) to 850 nm (near-infrared), with variations in single- and multi-wavelength systems. Participant numbers varied across studies, with sample sizes ranging from 30 to 100 patients. Most studies evaluated parameters such as best-corrected visual acuity (BCVA), macular drusen volume, central subfield drusen, quality of life and adverse effects within 6 months. These studies provide a comprehensive overview of PBM’s clinical efficacy and safety for managing dry AMD.
Publication Bias and Quality Assessment
The funnel plot (Fig. 2) examines the relationship between the standard error (SE) and the standardised mean difference (SMD) for various ocular outcomes, including BCVA, macular drusen volume, geographic atrophy, central subfield drusen thickness and microperimetry. Points are symmetrically distributed around the vertical dashed line at SMD = 0, indicating no evidence of publication bias. Most subgroups cluster near the central line with low SE values, reflecting small effects and higher study precision. The green square representing geographic atrophy is further from the cluster, suggesting greater variability or distinct effects in this subgroup.
Fig. 2
Funnel plot showing publication bias for clinical outcomes
The funnel plot (Fig. 3) shows the relationship between the SE of the logarithm of the relative risk (log RR) and relative risk (RR) for study durations (≤ 6 months and > 6 months). Points for studies lasting > 6 months, marked as red diamonds, cluster closer to the vertical dashed line at RR = 1, with slight asymmetry suggesting variability in longer-duration studies. The single circle for studies ≤ 6 months appears higher on the y-axis, indicating lower precision for shorter durations. The distribution suggests no significant publication bias, though heterogeneity between durations may require further investigation.
Fig. 3
Funnel plot showing publication bias for adverse events
The funnel plot (Supplement Fig. 1) displays SE (log RR) against RR for different adverse events (AEs), with symbols and colours corresponding to the legend. The dashed vertical line at RR = 1 indicates no effect. Points to the right suggest increased risk and points to the left suggest decreased risk. Most AEs cluster near RR = 1, suggesting no substantial difference in risk. A few points further from the line indicate potential variability in risk for specific AEs. The symmetrical distribution around RR = 1 suggests no significant publication bias, though a lack of points on one side could indicate reporting bias.
Overall, while most AEs do not show significant differences in relative risk, a few warrant further investigation due to their distance from the RR = 1 line.
Table 2 provides a quality assessment of several RCTs, highlighting different sources of bias. Robinson et al. [29] demonstrate low risk in most areas but show high risk in participant blinding and moderate risk in other sources, leading to a moderate overall risk. Markowitz et al. [27] and Burton et al. [26] exhibit low risk across most categories, with only moderate risk in other sources of bias, resulting in a low overall risk for both studies. Borrelli et al. [24] have low risk in most areas, though allocation concealment and outcome assessment have uncleared risks, still leading to a low overall risk. Boyer et al. [25] show low risk in most categories but have moderate risk in other sources and unclear risk in allocation concealment, resulting in a low overall risk. Franceschelli et al. [28] consistently show low risk across all areas except allocation concealment, which is unclear, yet maintains a low overall risk. Overall, the studies generally display a low risk of bias, with some variations in specific categories.
Table 2
Results of the quality assessment of the included RCT
The forest plot (Fig. 4) evaluates the efficacy of PBM therapy compared to a sham group across several outcomes. For BCVA, four studies reported a combined SMD of − 0.30 (95% CI − 0.85 to 0.26, p = 0.30), showing no significant difference between the groups. Heterogeneity was high (Tau2 = 0.26, I2 = 83%, p = 0.0005), indicating substantial variability among studies. The absence of a significant overall effect suggests PBM does not significantly improve BCVA compared to the sham group, although the considerable heterogeneity warrants cautious interpretation.
Fig. 4
Forest plot showing effect size clinical outcome between PBM and sham group
Regarding macular drusen volume, two studies reported an SMD of − 0.08 (95% CI − 0.52 to 0.37, p = 0.74), indicating no significant difference between the PBM and sham groups. Heterogeneity was moderate (Tau2 = 0.05, I2 = 48%, p = 0.17), reflecting some variability across studies. This result suggests that PBM therapy does not meaningfully reduce macular drusen volume. In the case of geographic atrophy, only one study reported an SMD of − 0.28 (95% CI − 1.26 to 0.71, p = 0.58), suggesting no significant impact of PBM therapy on the progression of geographic atrophy compared to the sham group. Since this outcome was derived from a single study, heterogeneity was not calculated and the findings should be interpreted cautiously.
For central subfield thickness, two studies provided an SMD of 0.11 (95% CI − 0.25 to 0.47, p = 0.58), slightly favouring PBM but not reaching statistical significance. Heterogeneity was low (Tau2 = 0.00, I2 = 0%, p = 0.68), indicating consistent findings between the studies. Overall, PBM therapy does not appear to significantly alter central subfield thickness compared to the sham group. When assessing microperimetry, a single study yielded an SMD of − 0.02 (95% CI − 0.48 to 0.44, p = 0.94), suggesting no significant effect of PBM therapy on this outcome compared to the sham group. The absence of additional studies limits the generalizability of this finding and underscores the need for further research.
The overall subgroup analysis revealed a Chi2 of 1.72 (p = 0.79, I2 = 0%), indicating no statistically significant differences between the outcomes assessed. This consistency across subgroups suggests that PBM therapy does not demonstrate a significant advantage over sham treatment for any of the evaluated outcomes.
The results emphasise that PBM therapy does not significantly outperform sham treatment in improving BCVA, reducing drusen volume, slowing geographic atrophy progression, altering central subfield thickness or enhancing microperimetry outcomes. While heterogeneity was considerable for BCVA, it was low for other outcomes, highlighting some consistency among those measures. In summary, the findings underscore the need for further research to address variability and confirm these results. The lack of significant benefits from PBM therapy across these visual and structural outcomes suggests its limited efficacy, though additional well-conducted studies may help clarify its role in ophthalmic care.
Risk Ratio Analysis of PBM Therapy Versus Sham Treatment Stratified by Follow-up Duration
This forest plot (Fig. 5) evaluates the risk ratio (RR) of outcomes associated with PBM therapy versus sham treatment, stratified by a follow-up duration of 6 months or less and greater than 6 months. For outcomes at 6 months or less, one study [24] reports an RR of 0.48 (95% CI 0.29–0.82, p = 0.007), favouring PBM therapy. This result is statistically significant, suggesting that PBM reduces the risk of adverse outcomes compared to the sham group within this timeframe. Heterogeneity is not applicable in this subgroup, as it includes only one study.
Fig. 5
Forest plot showing effect size adverse events between PBM and sham group
For outcomes at more than 6 months, three studies [25‐27] provide a pooled RR of 1.38 (95% CI 0.71–2.67, p = 0.34), favouring neither group. The result is not statistically significant, indicating no difference in risk between PBM and sham treatment for follow-ups exceeding 6 months. Heterogeneity within this subgroup is moderate (Tau2 = 0.20, I2 = 60%, p = 0.08), reflecting some variability among the included studies. The overall analysis yields a pooled RR of 1.04 (95% CI 0.51–2.12, p = 0.91), demonstrating no significant difference between PBM and sham therapy across all time points. However, heterogeneity is high (Tau2 = 0.40, I2 = 78%, p = 0.004), indicating substantial variability among studies. This variability is further supported by a significant test for subgroup differences (Chi2 = 5.91, p = 0.02, I2 = 83.1%), highlighting that the treatment effect varies according to follow-up duration.
The significant effect observed at 6 months or less (RR = 0.48) contrasts with the nonsignificant effect at more than 6 months (RR = 1.38), suggesting that PBM therapy may provide a short-term benefit that diminishes over time. However, the high heterogeneity in the overall analysis and the moderate heterogeneity within the more than 6 months subgroup underscore variability in study outcomes, warranting cautious interpretation of these findings. In summary, the forest plot suggests that PBM therapy might reduce risk compared to sham treatment in the short term (6 months or less), but this effect is not sustained over longer follow-up periods (more than 6 months). The overall analysis reveals no significant difference between the groups, and the substantial heterogeneity highlights the need for further studies to better understand the long-term effects of PBM therapy.
Assessment of Adverse Events and Safety Profile
The forest plot in Supplement Fig. 2 summarises the incidence of various adverse events (AEs) in patients receiving PBM therapy compared to a sham group. Each row represents an adverse event, with the risk ratio (RR) and corresponding 95% confidence interval (CI) plotted for each comparison. The horizontal lines represent the 95% CIs, and the vertical line at 1 indicates no difference between the PBM and sham groups. If the diamond (pooled estimate) crosses the vertical line, the effect is statistically insignificant for that adverse event.
Adverse events with reduced risk are particularly notable in this analysis. Photophobia demonstrates a pooled RR favouring the PBM group, indicating a reduced risk compared to sham therapy. Similarly, ocular pain shows a significant reduction in incidence, with a narrow CI highlighting consistency across the included studies. These findings suggest PBM may offer protective effects against specific ocular discomforts.
Conversely, adverse events with increased risk are also observed. Mild hyperemia shows a slight increase in risk associated with PBM therapy, although the CI does not indicate strong statistical significance. Transient visual blurring is noted to have a marginally elevated risk, possibly related to the temporary therapeutic effects of PBM. These outcomes might be therapy-related and warrant monitoring during clinical applications.
Most adverse events show no significant difference between PBM and sham groups. For example, the RRs for headache, tearing, foreign body sensation and dry eye symptoms are close to 1, with CIs crossing the vertical line. This indicates that PBM therapy does not substantially influence the risk of these common AEs compared to sham treatment.
The overall heterogeneity and summary findings indicate no significant overall difference between PBM and sham groups. The pooled estimate across all AEs at the bottom of the plot shows an RR close to 1, with the 95% CI including 1. High heterogeneity is observed in certain AEs, as reflected by broader CIs and varying study contributions, which suggests variability in trial populations, protocols or outcome definitions.
The clinical implications of this analysis are significant. The reduction in specific AEs, such as photophobia and ocular pain, highlights the potential therapeutic benefits of PBM. At the same time, the increased risk of mild hyperemia and transient visual blurring, while not severe, underscores the importance of patient counselling and monitoring during treatment.
In conclusion, this forest plot provides a comprehensive assessment of AEs associated with PBM therapy. While the therapy shows potential benefits in reducing symptoms like photophobia and ocular pain, clinicians should remain vigilant about mild side effects. Further studies are required to confirm these findings and explore long-term safety.
Sensitivity analysis was done by removing one study at a time and assessing the results. No study solely influenced the study and this showed how robust the results were.
Result of Qualitative Analysis
Three studies were utilised in performing qualitative analysis [24, 27, 29]. Markowitz et al. surveyed the change in the quality of life using the VDF-25 questionnaire. This study showed that PBM improved quality of life significantly at 3 months (p = 0.003), 7 months (p = 0.015) and 9 months (p = 0.003), whereas the sham group did not show significant improvement (p > 0.05) [27]. Robinson et al. demonstrated that PBM did not significantly improve disease progression as compared to the controls (odds ratio 0.763, p = 0.495). Additionally, a significantly larger delay of the cone was observed in PBM (mean time 1.66 min) than in the control group (mean time 0.66 min) [29]. Borrelli et al. compared the clinical and anatomical outcomes (BCVA, central subfield thickness, choroidal thickness and mean drusen volume) with the association of patients. All the parameters had non-significant differences between the two groups except mean drusen volume, in which the sham group showed a significant increase (p = 0.048) [24]. However, while analysing qualitatively, this study demonstrated that BCVA increased only in the PBM group as compared to the control, and choroidal thickness decreased in the PBM group as compared to the control. Hence, qualitatively, it is seen that PBM is superior in providing better quality of life and improving clinical and anatomical outcomes as compared to the sham treatment.
Discussion
The results of the meta-analysis highlighted the comparative safety and efficacy of PBM in dry AMD. The pooled data showed no statistically significant improvements in BCVA, macular drusen volume, central subfield drusen thickness, geographic atrophy or microperimetry when PBM was compared to sham treatment. The substantial heterogeneity across studies in BCVA highlights the variability in study designs, populations and treatment protocols, affecting the reliability of our results.
The subgroup analysis for adverse effects revealed mixed results regarding the safety of PBM. Within 6 months of intervention, PBM was associated with significantly fewer adverse effects compared to sham treatment. However, no significant differences were observed after 6 months, and the overall comparison across all time points was statistically non-significant. These findings suggest that PBM may have a favourable short-term safety profile but does not provide conclusive evidence for its long-term safety benefits.
PBM involves the absorption of specific light wavelengths by intracellular photoreceptors, triggering signalling pathways that lead to biological changes within cells [32, 33]. Unlike thermal photoablation caused by high-intensity lasers, PBM relies on low-intensity light to induce cellular reactions [34, 35]. Clinically, PBM has been widely used for decades to promote wound healing and alleviate pain and inflammation in conditions such as musculoskeletal disorders, sports injuries and dental treatments [36‐38]. Over the past two decades, growing experimental evidence has demonstrated PBM’s effectiveness in treating various retinal and ophthalmic conditions [34, 39]. Recently, preclinical research in ocular models has been successfully translated into clinical applications, showing encouraging outcomes [34, 39, 40].
The Toronto and Oak Ridge Photobiomodulation Study for Dry Age-Related Macular Degeneration (TOPRA) first evaluated the impact of PBM on patients with intermediate AMD with visual acuity of 20/20 and 20/200 and reported significant improvement in BCVA and contrast sensitivity [41]. The TOPRA II study found + 5.9 letter improvement on average and reduced drusen volume; however, despite the promising results, the significant limitations, including small sample sizes, short follow-up and nonrandomised design, limit the clinical acceptance of the study [42]. The LIGHTSITE clinical trials have significantly advanced PBM research. LIGHTSITE I, a randomised sham-controlled study, showed temporary BCVA gains, suggesting the need for repetitive treatments [27]. LIGHTSITE II demonstrated improved vision and slower geographic atrophy progression but faced challenges with small sample sizes and patient retention [26, 43]. LIGHTSITE III addressed these limitations, enrolling 148 eyes in a multicentre, randomised design over 24 months [25]. Results showed a significant BCVA gain (5.9 vs. 1.0 letters in controls) and reduced progression to geographic atrophy (1.1% vs. 9.1% in controls). However, the PBM group had a higher conversion rate to wet AMD (5.4% vs. 1.8%) [25].
PBM improves AMD by mitochondrial function, reducing oxidative damage and modulating complement expression, counteracting key mechanisms of AMD progression [44, 45]. Initially published literature, including Ivandic and Ivandic, demonstrated significant visual acuity and colour vision improvements in patients with early-stage AMD, though methodological details were limited [46]. Subsequent trials like TORPA 1, TORPA 2 and LIGHTSITE I expanded on these findings, reporting improved VA, contrast sensitivity and drusen reduction with 670 nm light treatments, though effects waned after 6 months, suggesting a need for consistent therapy [27, 41, 42].
Grewal et al. evaluate the effects of PBT in 42 eyes using a reproducible LED-based light source. Participants underwent daily 120-s exposures over 12 months, with the study focusing on functional and anatomical outcomes. They showed no notable improvements in visual acuity, contrast sensitivity, retinal structure or drusen volume. They used a different LED device, potentially emitting wavelengths or intensities less effective for therapeutic outcomes. Additionally, the study employed a higher cumulative dose and longer exposure duration, which may have diluted therapeutic effects or introduced unintended biological responses [18]. While current evidence supports PBT’s use in intermediate AMD, particularly for modifying oxidative stress and complement activity, its role in advanced stages, including geographic atrophy and exudative AMD, remains uncertain [20].
Godaert and Drame reported the results of a systematic review of the effectiveness of the PBM in older patients with neurodegenerative diseases. They reported that overall, PBM showed promising results for Binswanger’s disease, vascular parkinsonism, venous leg ulcer, chronic wound healing, and hyposalivation. They found the effect of PBM on macular degeneration. However, two included studies reported contrasting results [47]. They failed to present statistical evidence highlighting the effect of PBM on elderly patients.
Rassi et al. and Henein and Steel presented previous meta-analyses pooling the results of PBM therapy [48, 49]. Rassi et al. demonstrated statistically significant improvements in visual acuity and drusen volume; however, the clinical relevance of their results showed failure to meet the minimally clinically important difference. Similarly, our study observed short-term enhancements in visual function but underscored their limited clinical significance and inability to prevent GA progression. While Rassi et al. cited a small sample size as a limitation, our study included a larger cohort, although the short follow-up period remains a common constraint across both studies [49].
Henein and Steel, through their review of trials like LIGHTSITE I and ALIGHT, reported transient benefits in BCVA and contrast sensitivity, often diminishing within 6 months [48]. Our findings mirror this transient nature of PBM’s benefits, with significant early improvements failing to persist over time. They also highlighted discomfort and high withdrawal rates associated with PBM devices, whereas our study observed better tolerability and adherence, reflecting advancements in device design. However, like ALIGHT, our results failed to demonstrate any long-term impact on disease progression. Henein and Steel called for standardised dosimetric protocols and higher-quality evidence, a sentiment we echo despite implementing consistent dosing in our study.
Our qualitative analysis presents a contrasting result to the predominantly non-significant findings of the quantitative analysis. We found PBM significantly improved the quality of life at multiple time points, with no such benefits observed in the sham group. This underscores PBM’s capacity to enhance patient-perceived visual outcomes; objective clinical measures showed minimal change [27]. Additionally, the quantitative results showed PBM was associated with a significant improvement in BCVA and a reduction in choroidal thickness, whereas the sham group exhibited a significant increase in mean drusen volume, a critical marker of disease progression [24]. Robinson et al. reported no significant overall differences in disease progression and highlighted a notable delay in cone adaptation time in the PBM group [29]. These findings suggested it may confer qualitative benefits not highlighted by the statistical analysis. While quantitative results, such as those assessing BCVA and macular drusen volume, showed non-significant differences, the qualitative improvements observed in patient-centred outcomes and anatomical parameters highlight the potential for PBM to complement existing treatment modalities in managing dry AMD.
The results indicate that PBM may offer some short-term improvements in patient-reported quality of life in AMD, but they do not show statistically significant benefits in clinical outcomes such as BCVA, macular drusen volume or central subfield drusen thickness compared to sham treatments. The findings highlight the lack of consistency in clinical improvements and potential risks, particularly due to small sample sizes, variability in study designs and short follow-up durations.
The PBM devices used utilise different light wavelengths. The Noctura 500 organic LED mask emits 505 nm green light, offering a noninvasive approach. The Valeda Light Delivery System combines multiple wavelengths (590, 660 and 850 nm) for a more versatile treatment. The LumiThera Valeda Light Delivery System also uses multiwavelength PBM (590, 660 and 850 nm), showing promise across various populations. Additionally, the EYE-LIGHT PBM device uses 590 nm and 630 nm wavelengths in continuous and pulsed modes, potentially affecting treatment outcomes based on these modes. The low-fluence PBM device with a red light at 630 nm may offer a gentler treatment option, reducing the risk of adverse effects [24‐26, 28, 29, 50]. This variability in light wavelengths, devices and treatment modes suggests a growing interest in PBM for AMD but also presents challenges in directly comparing efficacy because of differing biological effects of the light parameters [51]. Table 1 reported the variation in PBM devices and wavelength used in the included studies.
Additionally, the variation in the sham group might influence the comparative efficacy of the outcomes across the studies. The sham treatments used in the LIGHTSITE studies were not true placebo treatments, as they delivered a significantly reduced fluence of selected wavelengths (590 and 660 nm) while omitting the 850 nm wavelength [25, 26]. This contrasts with studies like Franceschelli et al. and Borrelli et al., where the sham groups underwent identical procedures with devices that emitted either no light or a negligible power output, ensuring no biological effects on target tissues [24, 28]. Markowitz et al. also implemented a sham treatment delivering a noneffective dose with an approximate 100-fold fluence reduction [27]. Robinson et al. employed an untreated control arm rather than a sham intervention [29]. A potential limitation of this variability in sham treatment definitions is that studies using low-fluence PBM as a sham may still induce some biological effects, making it difficult to determine the true efficacy of the intervention compared to a completely inactive placebo.
Moreover, while PBM appears to be a safe adjunctive treatment, its efficacy remains uncertain, and publication bias could have influenced the results [52]. The current literature is limited to the role of PBM in dry AMD, neglecting the role of PBM in wet AMD [53]. Future high-quality, large-scale RCTs with standardised outcome measures and longer follow-up periods are needed to better understand PBM’s long-term clinical benefits and its role in managing AMD.
Conclusion
Our meta-analysis suggested that PBM may offer some short-term improvements in patient-reported quality of life, but it does not demonstrate statistically significant benefits in terms of clinical outcomes, such as BCVA, macular drusen volume and central subfield drusen thickness, when compared to sham treatment. The mixed results regarding adverse effects and the lack of long-term follow-up data make it difficult to assess the long-term safety and clinical benefit of PBM in AMD. Further high-quality RCTs with larger sample sizes and longer follow-up periods are required to fully elucidate the potential role of PBM in the management of AMD.
Declarations
Conflict of Interest
Kai Yang Chen, Kung Kuan Lee, Hoi-Chun Chan and Chi Ming Chan confirm that they have no conflicts of interest to declare.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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