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HomemiophthalmologyRLRL: A New Myopia Control Strategy

RLRL: A New Myopia Control Strategy

Professor Mingguang He presents the evidence to support the Eyerising, a home-use device originally intended for amblyopia treatment in China, which is successfully being used to slow myopia progression.

‘Light therapy’ has gradually emerged as a new treatment category for myopia control, alongside optical and pharmacological treatments. It is relatively easy to adopt for children and teenagers. It employs a ‘lowlevel laser’ strategy to stimulate or increase blood flow and metabolism in the fundus, offering a novel approach to controlling myopia progression. Its efficacy is generally strong, supported by evidence from multiple randomised controlled trials.

Myopia is as common as 80% among junior high school graduates in urban Chinese populations.1 If it continues to progress, it will lead to high myopia and its related retinal damage, such as myopic maculopathy and an increased risk of developing glaucoma or even retinal detachment. An effective treatment to reduce the onset of myopia and control the progression among established myopic children is highly sought.

In 2015, we published a school-based randomised controlled trial (RCT) in the Journal of the American Medical Association (JAMA), reporting that a simple schoolbased intervention, adding one 40-minute outdoor class, would reduce or delay the onset of myopia by 20%.2 Subsequent work by colleagues in Taiwan demonstrated that the prophylactic effect of increased outdoor time on myopia onset is, in fact, secondary to exposure to bright light when a light meter was used in these studies.3 Since then, researchers have proposed further extending the duration of light exposure through classroom lighting systems or even ‘sunlight’ classrooms. However, these solutions are expensive and pragmatically challenging.

A NEW SOLUTION

Instead of increasing the duration or intensity of ambient light, we propose to deliver the light directly to the retina with relatively increased intensity but shorter duration and repetition, as a new method to enhance light exposure and blood flow to the retina and choroid. This work has resulted in a joint patent successfully granted in the United States, Australia, Europe, and many other countries. The technology is named Repeated Low-Level Red-Light (RLRL) therapy.

This technology is delivered through a homeuse device (Eyerising Myopia Management Device), originally intended for amblyopia treatment in China (Figure 1). The device comprises a semiconductor laser diode that emits low-level red laser at a wavelength of 650nm, providing an illuminance of 1,600 lux and 0.29mW through a 4mm pupil. The laser energy intensity in low-level red laser is significantly lower than that used for retinal photocoagulation, where energy levels of 200–3,000mW are typical.

The RLRL technology is administered via a home-use device composed of three components: 1) A laser diode emission system to generate 650nm visible red light; 2) A user interface connected to the internet, requiring login with an assigned username and password to control the light on and off; and 3) A backend system for login verification and compliance monitoring.

Users are required to take the device home and follow instructions to complete the treatment under parental supervision, twice a day, with an interval of at least four hours, and each treatment lasting exactly three minutes. The treatment should be repeated daily for five days a week.

Figure 2 (above and right). Efficacy on axial length changes and changes by baseline SER categories.

EFFICACY

The efficacy of RLRL in myopia control has been well-established. We published the first RTC evidence at the end of 2022, where we reported a 69.4% efficacy in controlling axial elongation (Figure 2) and 76.6% for spherical equivalent progression (Figure 3).4 The efficacy was even stronger among children with a higher degree of myopia, which is different from other treatment modalities.4 For example, atropine and orthokeratology (OK) are known to have poorer efficacy among children with a higher degree of myopia.

As expected, treatment efficacy is better among those with better compliance. When compliance was better than 75%, the spherical equivalent control was as high as nearly 90%. Since then, a number of clinical studies have been published. A recent systematic review and meta-analysis reported that as of 8 February 2023,5 13 studies have been published, including eight RCTs, three non-randomised trials, and two longitudinal studies. These consistently report strong treatment efficacy with a weighted mean difference of 0.68 dioptre and -0.35 mm axial elongation.

AXIAL SHORTENING

In any medical education program, myopia has been taught as a disease characterised by progressive and irreversible, excessive axial elongation. In the aforementioned 12-month RCT, we observed that substantial (> 0.05mm) axial shortening can be as common as 40% in one month and 20% in 12 months after the commencement of RLRL treatment (Figure 4).4 Clinically, the optical biometer measures the distance between the anterior surface of the cornea to the retinal pigment epithelium to represent axial length. Therefore, anatomically, the observed axial shortening can perhaps be explained by the choroidal thickening secondary to RLRL treatment.

In our post-hoc analysis, we further demonstrated that quantitatively, only one third of the axial shortening (mean = 0.20mm) can potentially be explained by choroidal thickening (mean = 0.056mm).6 In some extreme cases, axial shortening can be as much as 0.5mm, which could be greater than the full thickness of the choroid, particularly among highly myopic eyes (unpublished data). This suggests that the observed axial length shortening might be related to true scleral remodeling or shortening. Further investigation into the mechanism of scleral remodeling is underway by our research team and will be published soon.

REBOUND EFFECT

The rebound effect, referring to rapid myopia progression after stopping treatment, is common among various myopia treatment modalities, particularly in high-dose atropine treatment. To investigate the rebound effect of RLRL, we conducted a post-trial follow-up study, inviting participants who had originally completed the one-year RCT to return for a follow-up examination at the 24-month mark. This study demonstrated a modest rebound effect, with progression reaching a similar level as the control group during the first year when RLRL was discontinued in the second year (Figure 5).7

Figure 3 (above and right). Efficacy on spherical equivalent refraction changes

Figure 4. Proportion of axial length and SER hyperopic shift.

 

SAFETY

Emitting a laser beam onto the retina, repeatedly twice a day for three minutes per session, to treat myopia, a very common eye disease, might sound like a frightening idea. Fundamentally, we should understand the type of laser used for this treatment. First and foremost, it’s important to know that the red laser used in RLRL therapy has substantially lower energy levels than any laser modalities in ophthalmic clinical practice. We estimate that the laser energy passing through a 4mm pupil is 0.29mW, which is considerably lower than the laser energy (200–3,000mW) typically used in laser photocoagulation, where the primary treatment effect results from thermal effects. The treatment modality adopted in RLRL is often referred to as ‘low-level laser’.

The American National Standards Institute (ANSI) – Light Hazard Protection for Ophthalmic Instruments (ANSI Z80.21- 2020) is the global standard for assessing light safety for ophthalmic products. This testing is essential for any ophthalmic products seeking United States Food and Drug Administration (FDA) approval. In laboratory testing conducted by Laser Product Safety, an FDA-accredited lab in North Carolina, the device we used, the Eyerising Myopia Management Device, which employs a red visible laser source, was determined to be a Group 1 instrument. This designation indicates that the device poses minimal risk to the eyes when used as intended. In ANSI light hazard testing, the retinal photochemical light hazard measurement (E(A-R)) was 0.0797 uw/cm2 , well below the limit of 440 uw/cm2 . The retinal visible and infrared radiation thermal hazard was 0.1636 W/cm2 , meeting the limit of 0.7W/cm2 . Visible and infrared radiation thermal hazard weighting function R(λ) was determined to be 27.357 x 10-6 W/cm2 , also well below the limit of 0.7 W/cm2 . The device has received regulatory approval from CE marking in the Europe and, recently from the Therapeutic Goods Administration (TGA) in Australia, allowing it to be sold as a ‘home-use myopia management device’ in these countries.

In all the clinical trials mentioned above, side effects and complications have been closely monitored. Best-corrected visual acuity (BCVA) was adopted as a key outcome measure indicating functional damage, which has been shown to be comparable in treatment and control groups, suggesting no functional damage. More sensitive functional outcomes, such as multifocal electroretinogram and microperimetry, are challenging to measure in young children and, as a result, have not been included in most published RCTs. However, these studies are ongoing among teenagers aged 15–18 years.

Optical coherence tomography (OCT) has been widely used to measure possible structural changes or damage after RLRL treatment. In all reported RCTs, none of them reported OCT structural changes among the study participants.

Subjective symptoms are also important for possible side effect monitoring. The light is often felt to be stronger than expected by users at the commencement of treatment. As evidenced by two out of 117 children in the intervention group, they initially felt the light was too bright and withdrew from the study. Interestingly, none of the children withdrew from the study for the same reason after they were able to continue the treatment for a couple of days.4

Another important symptom that requires attention from users is afterimage. An afterimage refers to a visual perception that persists even after the original stimulus creating the image is no longer present. For example, if you stare at a bright red light for a period and then look at a blank white wall, you might continue to see a ghostly, red-coloured image of the object on the white wall. Afterimage is often considered a retinal adaptation or retinal fatigue, where photoreceptor cells become less responsive to the current stimulus, resulting in the perception of the original image (afterimage) instead of the current one. In more than 95% of RLRL users, the duration of afterimage is less than one minute. If the duration exceeds five minutes, it may indicate that the photoreceptors are oversensitive to red light and require special attention.

In May 2023, a case report on possible retinal damage after RLRL treatment was published. This report involved a 12-year-old girl who experienced possible retinal damage characterised by compromised BCVA acuity and foveal ellipsoid zone and interdigitation zone discontinuity in OCT.8 After three months of discontinuing RLRL therapy, the OCT structural and BCVA changes partially recovered in this paper and fully recovered in another Chinese literature with a longer follow-up on the same case.9 This case report is important for several reasons: 1) the complication is rare; so far, more than 150,000 children have used the RLRL device, and this is the only reported case of a side effect. Since this publication, many OCT scans have been performed among users, but no new cases have been reported to the best of my knowledge; 2) the child appears to be a super-responder to the red laser, as evidenced by substantial axial shortening and prolonged afterimage (>5 minutes); 3) the side effect appears to be symptomatic, with compromised BCVA; 4) it is detectable by OCT, featured by discontinued foveal ellipsoid zone; 5) it is recoverable when RLRL is discontinued. Additionally, two independent Japanese ophthalmologists published a discussion on this case, pointing out that this could be a preclinical Stargardt disease patient, given the ‘dark choroid phenomenon’ observed in OCT.8

Figure 5. Sustained and rebound effect

CLINICAL ADOPTION IN PRACTICE

For clinicians considering adopting RLRL in their practice, the first question would be patient selection: who should I recommend this newly available product to? Given the evidence mentioned above regarding strong treatment efficacy, a stronger effect among highly myopic individuals, axial shortening, and myopia regression, we would suggest that clinicians who are in the early phases of adopting this technology, in addition to the approved indication of the device (myopic children aged three to 16 years), may consider four types of patients in their practice: 1) Newly onset myopia, where the parents do not want their child to wear glasses. RLRL may be able to regress some of this low level of myopia, eliminating the need for glasses; 2) Highly progressive myopia, for example, greater than 0.5mm per year or greater than one dioptre per year, despite other currently available treatments; 3) Early onset high myopia where other existing treatment modalities may not be the best choice; 4) In combination with OK, so that the patient can be ‘glasses-off ’ and simultaneously maximise their myopia control effect.

In my opinion, in addition to routine clinical examination for refraction or myopia control clinics, an ocular biometric measurement is a ‘must-have’. This measurement allows you to demonstrate the effect of myopia control and, hopefully, axial shortening to your patients. Fundus photography and OCT scans are ‘goodto-have’ as they allow you to document baseline clinical features before starting treatment and, hopefully, monitor possible structural side effects, although they are extremely rare. In my clinical practice, I recommend that parents have a visual acuity chart at home, enabling them to self-test their child’s visual acuity with and without their current spectacles to monitor myopia progression or possible side effects.

Patients should, of course, follow the treatment protocol: twice a day, three minutes per session, with a four-hour interval, five to seven days a week. As mentioned, the device comes with an online log-on system to control the light on and off protocol. Parents are encouraged to accompany their child during treatment. The treatment should become a habit, just like brushing teeth before and after bedtime.

FUTURE OUTLOOK

RLRL has been expanding its indications, with a notable impact on highly myopic children, especially those with early-onset high myopia, which can be challenging to treat. RLRL often exhibits much better efficacy than other treatment modalities in these complex cases. Researchers in Japan are also using RLRL to increase choroidal thickness, with the hope of reversing or controlling choroidal thinning – a clinical feature strongly associated with diffuse, patchy, or even macular atrophy among highly myopic adults.

Clinical solutions that combine RLRL with existing treatment modalities, such as atropine, OK, or defocus spectacles, have been proposed and tested in several clinical trials, based on information available on clinical trial registration websites. In Shanghai, researchers demonstrated that RLRL was able to delay approximately half of ‘pre-myopia’ cases (defined as cycloplegic spherical equivalent refraction (SER) of -0.50 to 0.50 dioptre in the more myopic eye, with at least one parent having SER ≤ -3.00D) from progressing to myopia10 (Figure 2). This could potentially lead to a substantial reduction in myopia prevalence in the Chinese population.

We have been diligently working on mechanism studies, which will be published soon. With all these advancements, RLRL is increasingly becoming an alternative treatment option for myopia control. This holds the promise of reducing the prevalence of myopia and high myopia in communities while also preventing the development of myopic maculopathy in many highly myopic adults.

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Professor Mingguang He MD PhD FRANZCO is the Chair Professor of Experimental Ophthalmology at The Hong Kong Polytechnic University, where is also the Henry G. Leong Endowed Professor in Elderly Vision Health.

Before joining PolyU, Prof He was a National Health and Medical Research Council Leadership Fellow and Professor of Ophthalmic Epidemiology in The University of Melbourne and Centre for Eye Research Australia, as well as Director of the WHO Collaborating Centre for Prevention of Blindness (Australia).

References

  1. Wang, J., Li, J., et al., Prevalence of myopia and vision impairment in school students in Eastern China. BMC Ophthalmology. 2020 Dec;20:1-0.
  2. He, M., Morgan, I.G., et al., Effect of time spent outdoors at school on the development of myopia among children in China: a randomized clinical trial. JAMA. 2015 Sep 15;314(11):1142–8.
  3. Wu, P.C., Huang, J.C., et al., Myopia prevention and outdoor light intensity in a school-based cluster randomized trial. Ophthalmology. 2018 Aug 1;125(8):1239–50.
  4. Jiang, Y., He, M., et al., Effect of repeated low-level redlight therapy for myopia control in children: a multicenter randomized controlled trial. Ophthalmology. 2022 May 1;129(5):509–19.
  5. Tang, J., Wang, W., et al., Efficacy of repeated low-level red-light therapy for slowing the progression of childhood myopia: A systematic review and meta-analysis. American Journal of Ophthalmology. 2023 Apr 7.
  6. Wang, W., Yuan, Y., et al., Axial Shortening in Myopic Children after Repeated Low-Level Red-Light Therapy: Post Hoc Analysis of a Randomized Trial. Ophthalmology and Therapy. 2023 Apr;12(2):1223–37.
  7. Xiong, R., Xuan, M., et al., Sustained and rebound effect of repeated low-level red-light therapy on myopia control: A 2-year post-trial follow-up study. Clinical & Experimental Ophthalmology. 2022 Dec;50(9):1013–24.
  8. Liu, H., Zhao, P., et al., Retinal Damage After Repeated Low-level Red-Light Laser Exposure. JAMA Ophthalmology. 2023 May 25.
  9. Tian, Y., Zhigang, X., A case of recovery of retinal structural damage after repeated low-intensity red light treatment for high myopia [J]. Chinese Journal of Experimental Ophthalmology, 2023, 41(09): 853–855.
  10. He, X., Xun, X., et al., Effect of Repeated Low-level Red Light on myopia prevention among children in China with premyopia: A randomized clinical trial. JAMA Network Open. 2023 Apr 3;6(4):e239612.