In this episode of Evidence-Based Retina, Dr. Rishi Singh, MD, FASRS, speaks with Grace Baldwin, MD, a third-year ophthalmology resident at Harvard Ophthalmology, Massachusetts Eye and Ear, to discuss the role of photobiomodulation in managing retinal diseases.
What is photobiomodulation?
Photobiomodulation (PBM) is the application of low-level laser energy to treat medical conditions. PBM has shown applications across almost every field of medicine, including retinal diseases and neurocognitive conditions.1
History and underlying mechanism
Drs. Baldwin and Singh discuss in brief the history of photobiomodulation. She states that in the 1970s, Dr. Endre Mester discovered that LED light improved wound healing in rats.2 Subsequently, early PBM research at NASA led to the development of one of the first FDA-approved PBM devices, WARP 10, which was shown to improve wound healing.3 Since then, there has been an explosion of animal and clinical research in PBM.
The biochemical basis suggests that PBM boosts mitochondrial function, thereby reducing inflammation and improving tissue regeneration.4 Red light penetrates the cell membrane and activates cytochrome c oxidase in the mitochondria, leading to the production of ATP. ATP is believed to trigger a signaling cascade that reduces inflammation and promotes the recruitment and growth of stem cells.
These effects have been observed in cellular models of retinal disease and injury.4,5 For example, an early study by Eells et al. published in 2003 revealed that PBM attenuated the retinotoxic effects of methanol in a rat model.6
Applications of PBM in ophthalmology
To date, PBM has been studied in:
- Myopia progression prevention: PBM appears to prevent axial length progression with evidence from 17 randomized controlled trials (RCTs)—the largest included 336 children.7,8
- Age-related macular degeneration (AMD): There have been 18 studies total, including six RCTs evaluating PBM for AMD suggesting modest improvement or stabilization of visual acuity (VA) and possible improvement or stability of optical coherence tomography (OCT) markers.9
- Diabetic retinopathy (DR): There have only been six studies total in DR, with just one RCT that did not show improvement, although this was limited by a short follow-up time.10,11
- Inherited retinal diseases (IRDs): There have been three case series total in retinitis pigmentosa and Stargardt disease, the results are promising, but difficult to interpret without a control group.12,13
- Retinopathy of prematurity (ROP): There has been one RCT in ROP with 86 neonates, the study was not powered to detect a difference in ROP, which would require 700 neonates, but did not show any adverse effects.14
Figure 1: A graphic illustrating the highest level of published evidence on PBM efficacy for each retinal disease. The disease type, number of randomized controlled trials (RCTs), if any, and the size of cohorts are included (CSCR = central serous chorioretinopathy).
Figure 1: Courtesy of Grace Baldwin, MD.
Figure 2: A graphic illustrating all the clinical studies that have been done using PBM for AMD, including the article type and the PMID for the respective studies.
Figure 2: Courtesy of Grace Baldwin, MD.
Dr. Baldwin notes that across all studies, no serious adverse effects have been reported, and overall, there is a positive trend toward improved visual acuity and structural markers of retinal disease.
The LIGHTSITE III STUDY
The LIGHTSITE trials are arguably the most notable RCTs for PBM in AMD, utilizing the LumiThera Valeda Light Delivery System, the first FDA-approved benchtop PBM device for AMD. The device emits light at 590, 660, and 850nm.4
Figure 3: Summary of the LIGHTSITE trials (pts=patients, mos=months).
Figure 3: Courtesy of Grace Baldwin, MD.
LIGHTSITE III is the most recent trial, which included 10 US centers and had a modest sample size of 91 eyes receiving PBM and 54 eyes receiving a sham treatment.4
Key features of LIGHTSITE III include:
- Primary endpoint: The trial met its primary endpoint of mean change in visual acuity, showing an average improvement of six letters after 13 months of treatment.4
- Secondary outcomes: Eyes that received PBM had statistically significant reduced drusen volume compared to the sham group and a significantly reduced rate of progression to geographic atrophy.4
- Treatment schedule: The treatment was intensive, administered in nine sessions spanning 3 to 4 weeks, and repeated every 4 months.4
- Limitations: The main limitation was the small sample size.4
Figure 4: Summary of the LIGHTSITE III trial.
Figure 4: Courtesy of Grace Baldwin, MD.
To review data from the extension study of the LIGHTSITE III trial, check out the story LumiThera Valeda system extension trial data expands dry AMD vision improvements!
Future and access
Future clinical studies are planned for other retinal diseases, including trials for retinal vein occlusions (NCT04847869), and hopefully other diseases. LIGHTSITE III is also being extended into a third year.
Equity and access are very important factors when considering this novel treatment (Table 1). While a CPT code exists for PBM, the LumiThera Valeda Light Delivery System treatment is not currently covered by Medicare or Medicaid, so most patients pay out of pocket.
The out-of-pocket cost for patients can be very high. For example, some ophthalmology practices report charging $2,500 for nine treatments. This is significant, especially given the intensive treatment schedule used in the LIGHTSITE III trial. Hopefully, this treatment will become more affordable with time.
Table 1: Information patients and practitioners should consider regarding PBM therapy.
| Question | Answer |
|---|---|
| CPT code? | Yes: 0936T, 1/1/25 |
| CMS payment? | No: Therefore, most pay out of pocket |
| Cost out of pocket? | $2,500 for nine treatments per eye |
| Who can administer? | Depends on state |
| Valeda cost? | Unclear: Negotiate with company |
Table 1: Courtesy of Grace Baldwin, MD.
Conclusion
In summary, PBM represents a novel non-invasive treatment being investigated for a variety of retinal conditions.
While current clinical evidence has major limitations of small sample sizes and study variability in devices and endpoints, the data generally points toward a positive clinical impact without significant risk, particularly in myopia and potentially in AMD.
Continued investigation with larger, rigorously designed clinical studies is warranted and important.
