An explanation of RLRL, and questions about this new type of treatment

Note: Some articles cited here are only available in the Chinese language. Links to online versions of those studies will be provided where appropriate.

Repeated low-level red light (RLRL) has become a hot topic for myopia control, with several recent studies and more than 100,000 myopic children being treated with RLRL for myopia control in China (Link to Chinese source: bit.ly/om0823sohu ). With so much attention being paid to it, I wanted to review both the procedure’s background and my thoughts on current RLRL studies, including the areas where I think more research is needed or that can be improved.

Background of RLRL

RLRL became available as a procedure for amblyopia in 2008. The procedure later expanded its indication as adjunct treatment for myopia in 2021, with the approved age range of 3 to 16 years old. (Links to Chinese source: bit.ly/om0823cnqlr and bit.ly/om0823bjsupervision )

Despite the name “low-level red light,” the device consists of semiconductor low-energy laser diodes that deliver a red laser beam with a wavelength of 650±10 nm, rather than LED light. The output power of the device is 2 mW, with a fluctuation range of 0.5 mW. The estimated power reaching eye plane is 1.20-1.8 mW, with 0.29 mW entering a 4 mm pupil. The recommended dosing regimen is 3 minutes per session, twice a day, five days per week.¹

Multiple clinical trials have been published on the efficacy of RLRL for myopia control both in premyopic and already myopic Chinese children. In a one-year trial of premyopic children (baseline age 8.3±1.1 years), patients in the RLRL therapy showed slower myopic refractive change than the SV control group (cycloplegic spherical equivalent [SER] of -0.35±0.54 D and -0.76±0.60 D respectively) with an associated difference in axial length (AL) elongation (0.30±0.27 mm versus 0.47±0.25 mm for RLRL and control, P<0.001 for both).¹ In another one-year trial of myopic children (8.0-13.0 years), the mean AL elongation was 0.13 mm (95% CI 0.09-0.17 mm) and 0.38 mm (95% CI 0.34-0.42 mm) for RLRL treatment and SV control groups, respectively; and the mean SER progression was -0.20 D (95% CI -0.29 to -0.11 D) and -0.79 D (95% CI -0.88 to -0.69 D) for the two groups, P<0.001 for both AL and SER outcomes.²

However, there are still some concerns related to this treatment. Since its expanded use as a myopia therapy, multiple cases of serious maculopathy related to the treatment have been reported, including a recent case published in English.³ China NMPA (equivalent of United States’ FDA) is in active discussion to consider a recall of all red-light devices and to change RLRL from a Class 2 medical device to Class 3, which requires more rigorous clinical testing and approval at the state level. Below, I will review the areas where I think more data is needed.

1 The method of myopia control

While it has been hypothesized that RLRL could improve perfusion of the ocular posterior, which was consistent with the observed choroidal thickening after therapy, the exact signaling cascade has not been clearly demonstrated in either experimental or clinical settings. The devices works by thickening the choroid, for which part of the function is to vasodilate to dissipate the stress away from the macular area. However, just because the treatment thickens the choroid does not make it a myopia-control treatment.

Additionally, the claim that RLRL mimics the beneficial component of the sunlight for myopia inhibition is largely unfounded, as the exact mechanism of why outdoor exposure is protective against myopia development is still under investigation. Additionally, the energy and spectrum distribution of the red laser emitted from the device does not simulate the long wavelength component of the sunlight.

2 BCVA as the safety outcome

Despite the claim that the same treatment has been used to treat amblyopia since 2008, there has been no rigorously designed trials of the safety and efficacy of such therapy for amblyopia published in peer-reviewed journals. The more recently published trials of the same device used for myopia treatment utilized a primary safety outcome of “functional loss of vision or reduction of best-correctable visual acuity (BCVA),” which was neither sensitive nor specific enough to capture early signs of retinal or choroidal damage. (Link to Chinese source: bit.ly/om0823cnqlr )

3 Subclinical retinal/RPE changes

There has not been testing of any potential change at the molecular level in an experimental setting, nor through clinical testing, such as multifocal electroretinogram, electrooculogram, or adaptive optics scanning laser ophthalmoscopy, that allow better detection of possible subclinical retinal/RPE changes. With the redundancy of photoreceptors and RPE cells in the macular area, a long latency can exist between molecular and structural abnormality and any detectable decrease in BCVA, making it a poor safety measure for such treatment, especially considering the targeted patient population and the chronic use.

4 Masking methods

Despite the attempt of conducting the studies as single or double-masked, it was impossible to mask the patients or their parents of the treatment allocation due to the nature of the treatment and hallmark symptoms, such as blurry or dimmer vision, central scotoma, metamorphopsia, and prolonged afterimages, immediately after the exposure to laser. Masking the statistician but not the patients or the clinicians responsible for data collection did not provide sufficient protection against significant bias.

5 Risks of using class 3R laser

The laser source used in RLRL is categorized as class 3R, which has the output power between 1 mW and 4.99 mW, similar to that of a laser pointer. It has been well established that if handled improperly, 3R lasers may cause transient or irreversible damage to the eyes, hence the mandatory warning of “Do not look into the direct or reflected beam” on all 3R laser products.⁴ The intended use of RLRL is for the prolonged central fixation of 3 minutes, multiple sessions per day, and five days per week as a chronic treatment, which imposes significant risks of not only acute damages but also accumulative damages to the retina and RPE. Also note that comparing the power output of a laser source to that of an LED red light, as the RLRL manufacturers have done, carries little clinical value, as the energy directed to the macular area by the red laser beam is highly condensed in a very small area, rendering a much higher risk of damage than red LED of similar energy.

Additional data needed

Considering the long-term and repeated use of laser energy on the macular area, the young age of the targeted patients, and the lack of short-, intermediate-, and long-term safety testing, I would need to see more data to be comfortable recommending the use of RLRL either as a preventative treatment or intervention for myopic children. OM

References

1. He X, Wang J, Zhu Z, et al. Effect of Repeated Low-level Red Light on Myopia Prevention Among Children in China With Premyopia: A Randomized Clinical Trial. JAMA Netw Open. 2023;6(4):e239612. doi:10.1001/jamanetworkopen.2023.9612.
2. Jiang Y, Zhu Z, Tan X, Kong X, Zhong H, Zhang J, Xiong R, Yuan Y, Zeng J, Morgan IG, He M. Effect of Repeated Low-Level Red-Light Therapy for Myopia Control in Children: A Multicenter Randomized Controlled Trial. Ophthalmology. 2022 May;129(5):509-519. doi: 10.1016/j.ophtha.2021.11.023. Epub 2021 Dec 1. PMID: 34863776.
3. Liu H, Yang Y, Guo J, Peng J, Zhao P. Retinal Damage After Repeated Low-level Red-Light Laser Exposure. JAMA Ophthalmol. Published online May 25, 2023. doi:10.1001/jamaophthalmol.2023.1548
4. Laser Hazards. United States Department of Labor. https://www.osha.gov/laser-hazards/hazards . Accessed June 14, 2023.

DR. LIU is an associate professor at Herbert Wertheim School of Optometry & Vision Science, University of California Berkeley. She is also the founder of the Myopia Control Clinic, UC Berkeley Eye Center. She received her bachelor’s degree of Clinical Medicine from Peking University, her OD from Pacific University, and her PhD and MPH from UC Berkeley. She is a world-recognized clinical researcher in myopia. Dr. Liu is a consultant for Coopervision and Essilor China.