Repeated low-level red light therapy: a look at safety and efficacy

Repeated low-level red light (RLRL) therapy has emerged as a promising new approach for myopia control. Spending more time outdoors has been widely recognized as an effective myopia strategy,^1-2 and is a key component of recommendations for myopia management. However, time spent outdoors for the purposes of myopia control appears to be dose-dependent.^3-4 RLRL leverages the therapeutic properties of red light within the visible spectrum to influence ocular growth and aims to be a time-effective alternative to time spent outdoors.⁵ You can read our head-to-head Science Summary on two recent RLRL treatment publications: here, we take a deeper dive into the research.

The exact mechanism at the molecular and cellular level of RLRL and influence on ocular structures is yet to be determined. In China, red light therapy has been used for decades as a treatment for amblyopia.⁶ Unpublished reports indicated potential benefits such as increased choroidal thickness, improved blood flow, and – notably – stabilization of axial elongation.⁵ These findings in amblyopes then led to the thought that RLRL may have potential applications to myopia. Structural changes that can occur in myopia include choroidal thinning and reduced blood flow leading to hypoxia.⁷ It is thought that RLRL can address these myopic structural changes at the retinal and choroidal level, which then reduces scleral hypoxia thus reducing risk of the development and progression of myopia.⁸

RLRL has gained a lot of clinical and academic interest, in part due to its innovative approach to myopia control. Like atropine, it is a non-optical intervention that can be used alongside optical treatments as a combination treatment or standalone as monotherapy. The interest in RLRL therapy is also attributed to its reported efficacy. Two randomized controlled trials in myopes^5,7,9 and one in pre-myopia⁸ have already been conducted in China using the device and have indicated high efficacy with RLRL.

The studies collectively demonstrate substantial reductions in the risk of myopia onset and rate of myopia progression in children aged from 6 to 15 years of age. In the first published, multi-centre randomized control trial, Chinese children aged 8-13 years with myopia of -1.00 to -5.00D, astigmatism up to 2.50D, anisometropia up to 1.50D and best-corrected visual acuity of 20/20 equivalent were recruited. The RLRL treatment protocol was 3 minutes of at-home, parent supervised device use, twice per day, separated by at least 4 hours, for 5 days per week.

The one-year data involving 264 children found a treatment effect (n=111) of 0.59D (66%) and 0.26mm (75%) less refractive and axial length progression, respectively, compared to the control group (n=114) who had no RLRL treatment. Both treatment and control groups wore single vision spectacles.⁵ The two-year data involving 114 children found 75% less refractive and axial length progression in the treatment group, who showed only 0.16mm and -0.31D myopia progression (n=11) compared to 0.64mm eye growth and -1.24D more refractive myopia in the control group (n=41).⁹ Importantly, no severe adverse events or structural damage as determined by OCT were observed.^5,9

The second randomized controlled trial, this time in a single centre in China, involved 112 Chinese children aged 7 to 12 years with myopia of at least -0.50D, astigmatism up to 1.50D and anisometropia up to 1.50D. This time the control group underwent a ‘sham’ treatment using a device with 10% of the original device’s power. The same protocol of 3 minutes per treatment, twice per day, with an interval of at least 4 hours was followed. After six months, refraction did not change in the RLRL group (mean +0.06D change) while the control group progressed -0.11D. The mean axial length increase was 0.02mm in the treatment group compared to 0.13mm in the control group (85% effect).⁷ It is important to note that shorter trials tend to give the most impressive results in myopia control - studies of at least 1-2 years allow for clearer comparison between treatment types.¹⁰ 

For children at risk of myopia, RLRL treatment reduced the incidence (onset) of myopia: over 12 months, 40.8% (49 of 120) in the intervention group became myopic compared to and 61.3% (68 of 111) in the control group. This relative 33.4% reduction in incidence increased to just over 50% in a subset of children whose treatment was not impacted by the COVID-19 pandemic.⁸

Perhaps most noteworthy of the RLRL clinical trials are the findings of axial length stability (no growth) and even shortening (reduction in measured axial length) in a subset of participants. In the multi-centre randomized controlled trial,^5,9 a subsequent analysis revealed that axial length shortening of >0.05mm, >0.10mm and >0.20mm was observed at 12 months in 22% (26/119), 15% (18/119) and 6% (7/119) respectively. No shortening >0.10mm was observed in controls, and only 2/145 (1.4%) showed >0.05mm shortening in the control group. Axial length shortening at 1 month was most pronounced and predicted stability of axial length thereafter to 12 months. Older baseline age, and female sex were correlated with axial length stability or shortening outcomes. Choroidal thickening only accounted for around 30% of the measured shortening - the authors suggested potential “scleral remodelling or shortening” as an additional explanation.¹¹

Retrospective clinical data from 434 children aged 3-17 years with at least one year of RLRL treatment showed 26.5%, 17.5% and 4.6% with axial length measures reduced by 0.05mm, 0.10mm and 0.20mm respectively.¹² 

What does this mean in practice? The repeatability of various optical biometers for measuring axial length in children has been shown to be in the order of 0.04-0.05mm,¹³ with findings ranging from around 0.02mm¹⁴ to 0.09mm.¹⁵ Taking the results conservatively and considering the 0.05mm category as indicative of axial length stability, rather than shortening, still yields these remarkable results in around 20-25% of children after 12 months.

The flip side of these findings are that of potential rebound on treatment cessation. Rebound has been defined as “greater progression after removal of a treatment than would have been observed at the same age in a child had treatment not been instigated.”¹⁰ In the second year of the multi-centre RLRL clinical trial, 52 children ceased treatment and showed 0.42mm mean axial length growth in that year (RLRL-SVS group in Figure 2), compared to a significantly lower 0.28mm axial length growth in the single vision corrected, no treatment group (n=41, SVS-SVS group in Figure 2). The authors noted that these children were only an average of 11.5 years at treatment cessation, and hence “continuation of therapy may confer further benefits for myopia control.”⁹

The Eyerising International RLRL device emits a wavelength of 650±10nm at a laser power of 0.29mW going through a 4-mm pupil and is used for 180 seconds at a time twice a day for 5 days per week. While the device complies with IEC 60825-1:2014 standard for laser products safety, there have been reports of adverse events after use of red-light therapy. A published case study reported on a 12-year-old female who presented with bilateral vision loss after using the Eyerising device for 5 months, with recovery to 20/25 OU three months after cessation.¹⁶ Read about this case study in our Science Summary, and read a response to this case study by Eyerising International, manufacturers and distributors of the RLRL device, via this link. 

Four other adverse events documented by Eyerising¹⁷ are all characterised by similar symptoms and signs: prolonged after-images lasting more than 5 minutes after device use, a decline in best corrected visual acuity and foveal ellipsoid zone disruption and interdigitation zone discontinuity revealed on optical coherence tomography. All reported full recovery of acuity and OCT-imaged structural changes 3-4 months after cessation of RLRL treatment.

Data supplied by Eyerising International indicates that the RLRL device has approximately 70,000-80,000 daily users in China: of those, these 5 cases are the only adverse events that have been reported to the company’s side-effect reporting centre, constituting a rare side effect rate of 0.0067%.¹⁷ The published case report cited several possibilities for this adverse outcome, such as the device's light power stability, extended exposure, or the patient's light sensitivity.¹⁶ The device does include a stringent control system whereby users must log in with specific credentials, and the system regulates the duration of light exposure, making prolonged exposure virtually impossible. A possible reason for adverse outcomes may be sensitivity to phototoxicity. While determining those that may be susceptible to this could be difficult, Eyerising International recommends that children who notice an afterimage persisting longer than 5 minutes should cease use and contact their clinician for further advice.

The series of studies on RLRL that reported on efficacy for myopia control also monitored for adverse events and reported no severe adverse events, functional visual loss, or structural damage.^5,7-9 These findings suggest a robust safety profile for RLRL therapy in children, with the important caveat of identifying children with prolonged afterimage (lasting more than 5 minutes) as unsuitable for continued treatment. Eyerising International also recommends against use of RLRL therapy in combination with atropine, due to its impact on pupil size and hence light transmittance to the retina. Monitoring children commencing RLRL treatment with measurement of best corrected acuity and OCT scans is recommended after one, three and six months, and every six months thereafter.¹⁷ 

Diligent myopia management requires parents and patients to be informed of potential treatment risks and side effects, along with providing advice on how to minimize risks.¹⁸ Eye care professionals are well versed in considering the risk-to-benefit balance with contact lens or atropine treatment, and RLRL is similar in this respect.

Repeated low-level red light (RLRL) therapy has emerged as a promising approach for myopia control, supported by a growing body of research, including three randomized controlled trials. While RLRL studies thus far have been conducted in China, more are underway in Australia, Japan, the USA, the UK and Singapore.
 
 The combination of clinical trial data with low frequency reports of adverse outcomes indicate that the RLRL therapy safety profile is robust, and underscores the significance of monitoring for persistent afterimage to ensure safety. The data on axial length stability and even shortening, observed in up to 12 months of treatment, has caught the collective eye of myopia researchers and clinicians alike. Questions of mechanisms, managing treatment cessation to avoid rebound, and how RLRL could potentially combine with optical treatments, will form the new wave of knowledge on this novel treatment.