Efficacy of Repeated Low-Level Red Light (RLRL) therapy on myopia outcomes in children: a systematic review and meta-analysis

Myopia is the most prevalent form of refractive error [1] which has a major negative impact on visual function and causes blurring of vision. It is estimated that the number of myopic patients will be 4.7 billion in the world by 2050 [2, 3]. Myopia prevalence in children aged 6 to 8 years increased 1.4–3 times during COVID-19's social isolation [4]. High myopia is linked to a significant risk of disorders that permanently impair vision, such as myopic maculopathy, glaucoma, staphyloma, and retinal detachment [5‐7]. As a result myopia is a significant public health issue, and there is an urgent need for a strategy to stop its progression.

Myopia is most frequently characterized by an increase in the axial length of the eyeball [8] and can be brought on by both environmental [9] and hereditary causes [10, 11]. The threshold for myopia progression is a spherical equivalent refraction (SER) of -1.00 diopters (D) or less is [12]. The primary characteristic of high myopia-related irreversible vision loss is choroidal thinning [13]. Research on both animals and human indicates that the choroid is crucial for controlling the development of the eye's refractive system [14, 15]. As potential indicators of treatment response, axial length (AL), spherical equivalent refraction (SER), and macular choroidal thickness (mCT) have all been identified [16].

Several techniques have already been proven to be efficient preventative elements for the growth of myopia in children. Increased exposure to bright light outdoors [3, 17] is used with myopia. Increased time outdoors has been shown to prevent or delay myopia onset in several studies. Furthermore, increased outdoor time has been shown to have a protective effect on the cumulative incidence rate of myopia in children enrolled in randomized clinical trials in China and Taiwan. On the other hand, increased near-work time and reduced outdoor activities have been suggested to be at the origin of the increased myopia prevalence in older children [18]. A previous review mentioned that several studies conducted in various countries concluded that greater average daily light exposure is associated with a reduced axial elongation during childhood. For example, a study cluster-randomized intervention-controlled trial showed that exposure to outdoor light leads to less myopic shifts, reduced axial elongation and a 54% lower risk of myopia progression [19]. Additionally, single vision spectacle lenses (SVS), refractive procedures, and implantable collamer lens (ICL) are all frequently used to treat myopia. Additional methods such as orthokeratology, various contact lens options, peripheral defocus-modifying spectacle lenses, pharmacy therapy in the form of atropine eye drops, and orthokeratology were also used [20‐23]. However, all of these methods have disadvantages being potentially difficult and harmful in administration. For example, the risk of adverse events associated with orthokeratology, such as infective keratitis, is well recognized [24]. Photophobia, among other side effects, is possible with atropine eye solutions [25]. Thus, there is a pressing need for more effective and practical treatments for halting myopia progression.

While increasing exposure to outdoor light levels can successfully be implemented through national outdoor programs, implementation remains suboptimal in some circumstances. On the other hand, the optimization of architectural lighting or development of light-therapy devices requires a holistic understanding of the benefits and side effects of light characteristics on ocular growth and neurophysiology [19]. The characteristics of wavelength, intensity, and other variables all have an impact on how light affects the refractive power of lenses [26]. According to research, red light has been shown to be more efficient than other wavelengths in slowing the progression of myopia in rhesus monkeys [27]. Studies have shown that repeated low-intensity red light (RLRL) can slow the progression of myopia in children [12, 25, 28] Laser therapy induces various molecular, cellular, and tissue effects [29]. Differentiating from high-power laser therapy, RLRL utilizes low doses of red and near-infrared light, with an output ranged from 1 to 500 mW, and a wavelength ranging from 600 to 1100 nm. As a result, it is described as a sort of phototherapy that emits low energy to cause tissue response [30].

Clinical studies that compared RLRL to single-vision glasses over a six-month period discovered that it significantly delayed the development of myopia and axial elongation (SVS) [28]. Several randomized clinical trials including children showed that RLRL therapy was more effective than SVS in reducing myopia, and no structural or functional impairment was detected [12]. To accurately assess the effects, it was necessary to do a meta-analysis collectively with RCT which is much better than using non-RCT. Potential biases are likely to be greater for non-randomized studies compared with randomized trials when evaluating the effects of interventions. Additionally, randomization provides a rigorous tool to examine cause-effect relationships between an intervention and outcome. Therefore, we conducted this systematic review to determine the potential benefits of RLRL treatment for childhood myopia. Our research objectives include understanding how RLRL influences the development of myopia, spherical equivalent refraction (SER), axial length (AL), and sub foveal choroidal thickness (SFCT).

This review followed the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [31]. The filled checklist is attached in the supplementary data (Additional file 1). This systematic review was registered in PROSPERO (registration ID: CRD42023410702).

This is a systematic review specifically conducted to investigate whether repeated low-level red light (RLRL) therapy can control the progression of myopia in children. The efficacy of the RLRL can introduce an alternative which seems at least competitive with other treatment methods. Our results showed that RLRL can better control axial length (AL) elongation, spherical equivalence refraction (SER), and subfoveal choroidal thickness (SFCT) better than single vision spectacles (SVS) within 3, 6, 12 months when compared to wearing single-vision glasses. All the outcomes were reported at 6 months follow up; however, AL was reported in 3 months and SER was reported in 12 months additionally. AL was defined as the distance from the corneal vertex to the retinal pigment epithelium, representing myopia. AL was improved compared to baseline values at 3 month follow up and 6 month follow up periods. SER was improved after using RLRL compared to baseline at 3 months follow up, 6 months follow up, and 12 months follow up. SFCT was increased compared to baseline at 6 months follow up.

The heterogeneity was significantly high when pooling all studies. To investigate the heterogeneity, we couldn’t do subgroup analysis due to limited data. However, we excluded from the quantitative analysis the studies that were responsible for heterogeneity by conducting sensitivity analysis. Sensitivity analysis showed changes in the heterogeneity, however, there was still a statistically significant difference. The studies removed by leave one out may have some limitations due to the design, sample size, or the procedures. For example, we removed the data of Xiong 2021 due to significant heterogeneity detected in all outcomes except AL of 3 months. This study was of low quality according to the quality assessments tool which may have resulted from the methods of randomization and allocation. Additionally, the laser power was very different in this paper compared to other papers (Additional file 3). Another example, we removed the data of Dong 2023 also due to significant heterogeneity detected in all outcomes without exception. The heterogeneity of this study could be related to using sham device that used 10% of the original device’s power compared with the SVS control group which improved the cases to an extent. Sensitivity analysis showed solving of some heterogeneity however, the significant differences were still found between the two groups.

Our results are consistent with a recently published systematic review and meta-analysis (Tang et al. 2023) [47] discussing the RLRL therapy effectiveness. Tang et al. 2023 concluded that the weighted mean difference (WMD) for myopia progression between RLRL and the control group was 0.68 D per 6 months for SER change, -0.35 mm per 6 months for AL elongation and 36.04 μm per 6 months for SFChT change. However, this recently published study included non-randomized controlled trials as cohort and post-hoc analysis studies that may affected the heterogeneity and validity of the results.

No severe adverse events, such as scotoma that occurred during the trial linked to the intervention or sudden vision loss by 2 lines happening over the course of a few seconds or minutes to a few days, were reported in any of the included studies. This is consistent with Tang et al. 2023 which reported that none of the studies in their meta-analysis reported vison-threatening events and no structural damage was observed in the photosensory layers. However, a recent case report of 12-year-old female mentioned the possibility of retinal damage after RLRL exposure [48]. Based on the findings of the short-term follow-up, RLRL intervention has a promising control impact on myopia. Contrarily, the risk of adverse events associated with orthokeratology, such as infective keratitis, is well recognized [24]. Photophobia, among other side effects, is possible with atropine eye solutions [49‐51].

Currently, much empirical evidence suggests that oxidative stress and inflammation may be responsible for the altered regulatory pathways in myopia, and that oxidative damage of hypoxic myopia can change how nitric oxide and dopamine are neuromodulated during eye development [52, 53]. It may be feasible to protect patients from the effects of oxidative stress and reduce inflammation associated with myopia by investigating the potential mechanisms underlying the inhibitory effects of RLRL treatment [54]. In both animal research [55] and clinical studies [28, 56], RLRL has the greatest effects on the nitric oxide system and reduces the intensity of oxidative stress. By inhibiting inflammatory cytokines like interleukin-1 (IL-1) and tumor necrosis factor-α, RLRL may lower their amounts [57]. Additionally, severe myopia may substantially raise IL-1 and IL-6 levels, which may be related to the myopic control mechanism [58, 59]. According to a generally accepted theory, bright light causes the retina to produce and release more dopamine [60]. In the development of refractive eyes, dopamine functions as a termination signal [61].

The choroid has a variety of functions, including nourishing the retina [62] and can affect the refractive state [63, 64]. Furthermore, the choroid has a crucial role in relaying signals derived from the retina to the sclera, further altering the synthesis of scleral extracellular matrix and changing the ocular size, resulting in refractive changes that have a vital function in the etiology of myopia [65, 66]. Additionally, the release of nitric oxide from the retina or choroid by the dopamine in the retina may cause choroidal thickening and inhibit ocular growth [67, 68]. After 650 nm RLRL treatment, previous research found a significant increase in choroidal thickness. Similarly, Gawne et al. [69] noted a refractive shift brought on by a decrease in vitreous chamber depth and a rise in choroid thickness. Two of the included studies [12, 41] hypothesized that RLRL may control myopia by increasing choroidal blood flow and reducing oxidative stress and inflammation [70, 71], and thus ameliorating scleral hypoxia.

Other presently available non-invasive interventions, such as more outdoor exercise, orthokeratology, and atropine eye drops, may not have the same myopia-controlling effects as 650 nm RLRL. Over the past few years, outdoor time has drawn a lot of focus. According to He et al. [72], spending more time outside did reduce the progression of myopia compared to the control group. Despite an extra 40 min of outdoor activity being added to each school day, children still on average underwent a -1.42 D myopic shift and a 0.95 mm elongation of AL during the 3-year follow-up. Outdoor exercise, in contrast, appeared to be less effective than 650 nm RLRL, let alone the difficulty of implementing an extra 40 min of outdoor exercise given the demands of students' academic work.

In terms of clinical implication from this review, repeated low-level red-light intervention was needed twice daily, 3 min per session, five days per week which is the same procedure for treating amblyopia. The investigators of one of the included studies (Jiang 2022) gave parents the device to allow this daily treatment schedule so they could carry out this treatment at home. Users must log in to the system using a specified username and password given to start treatment because the device is connected to the internet. The research coordinator will be able to watch, record, and keep track of treatment adherence when using devices. Jiang et al.'s study [12] showed that greater treatment compliance greatly increased treatment efficacy. This significant dose response effect may further support the effectiveness of RLRL in controlling myopia, but it also emphasizes the importance of putting up a suitable incentive system to motivate kids to use the device and to maximize treatment efficacy. This potent dose–response relationship also suggests that treatment efficacy may be enhanced by increasing the treatment duration from 3 min to an extended treatment time per session.

However, there were some limitations in our review. First, the number of studies included in this meta-analysis was limited. Because of the limited number of included studies and hence limited statistical power, publication bias test was not performed in our review according to Begg’s and Egger’s recommendation [73]. Second, considering the significant methodological heterogeneity among included studies, we couldn't conduct subgroup analysis due to limited data. Third, the follow up periods were short to evaluate the potential dose–response relationship and the optimal power intensity of the RLRL treatment for myopia control. Fourth, all the published studies were limited to centers in China. Thus, we recommend further studies with long-term follow-up involving various centers in different countries to confirm our findings. Furthermore, we do not know whether there is a rebound effect like atropine eye drops once treatment is stopped, which is a knowledge gap for future study.

In summary, this is the first systematic review and meta-analysis investigating only RCTs evidence supporting the efficacy of 650 nm RLRL for myopia control in the short term of 3, 6, and 12 months follow up. The present review revealed the clinical significance of RLRL for myopia control in terms of AL, SER, and SFCT. It has slowed down and reversed the myopia progression in a large proportion of children. RLRL therapy is an effective new alternative treatment for myopia control with good user acceptability and no documented functional or structural damage. However, the effect of long-term RLRL treatment and the rebound effect after cessation require further investigation.