SPOTLIGHT: AMD s PHOTOBIOMODULATION AS A TREATMENT IN DRY AMD Doctors and patients have found this new mode of beneficial.

BY HAKAN KAYMAK, MD; AND HARTMUT SCHWAHN, PHD

he development of innova- offered PBM treatment with Valeda to These changes in cellular outcomes tive treatments for debilitating patients as an alternative or supportive lead to therapeutic benefits at the diseases such as age-related treatment option for dry AMD. clinical level. The treatment param- macular degeneration (AMD) is eters of PBM are crucial, as PBM dis- crucial to advance patient care INTRO TO PHOTOBIOMODULATION plays a biphasic dose-response output. andT to reduce burdens on patients, PBM is a light-based technology that Selection of wavelengths and the dose, caregivers, and . The dry, or stimulates bioenergetic output in target- timing, and delivery of PBM treatment nonexudative, form of AMD affects ed tissues. Selected wavelengths of light must be appropriate to elicit these approximately 85% to 90% of individu- in the far red to near infrared spectrum beneficial cellular effects. als with AMD, and, until now, there (500–1,000 nm) modulate biologic func- Preclinical evidence supports the have been no approved treatments for tion through direct and indirect cellular use of PBM as an effective treatment this condition aside from nutritional effects on mitochondrial respiratory in retinal cell injury and multiple supplementation. chain components. The is one of animal models of ocular disease and The Valeda Light Delivery System the most energy-demanding tissues in disorders.6-8 Small pilot studies have (LumiThera) was designed as a safe, the body. PBM activation of photoac- shown promising effects for PBM in multiwavelength platform for pho- ceptors in the mitochondria improves dry AMD and other ocular indica- tobiomodulation (PBM). The device generation of adenosine triphosphate tions.1-3,9-11 In recently published received the CE Mark in the European (ATP), modulates the production of results, a double-masked, randomized, Union, where its indicated uses include intracellular signaling molecules such sham-controlled study in patients treatment of ocular damage and dis- as reactive-oxygen species (ROS) and with dry AMD (LIGHTSITE I) dem- ease using PBM, including inhibition nitric oxide (NO), and triggers secondary onstrated improvements in clinical of inflammatory mediators, edema, effects that produce sustained changes in measures (visual acuity and contrast or drusen deposition; improvement cell function and viability. sensitivity) and reduction in anatomic of wound healing following ocular trauma or ; and increase in visual acuity and contrast sensitivity AT A GLANCE

in patients with degenerative diseases s such as dry AMD. The Valeda Light Delivery System is a light-based approach to treatment The underlying mitochondrial with a CE Mark in the European Union for multiple ocular indications, mechanisms of PBM therapy and including dry AMD. recent clinical studies demonstrating

1-5 s positive improvements in patients Photobiomodulation (PBM), as performed with the Valeda, acts at the have increased interest in PBM as a treatment approach in dry AMD. mitochondrial level by improving cellular output and reestablishing In our specialty for vitre- metabolic function.

ous, retina, and macula therapy, we s see 20 to 40 patients with macular Patients with dry AMD treated with PBM have shown improvements in degeneration, particularly AMD, each clinical, anatomic, and quality-of-life assessments. day. For about a year now, we have

MAY/JUNE 2020 | RETINA TODAY 23 - - C C Both received the same recommended series of PBMof series recommended same the received eyes Both pigmentretinal the treatment, of end the after month One A 77-year-old white woman with intermediate stage drystage intermediate with woman white 77-year-old A eyes were hyperopic and had undergone surgery. cataract undergone had and hyperopic were eyes objectiveby assessed was VA above. described treatments darkperipheral and acquired, were images OCT refraction, andbefore assessed was MacuLogix) (AdaptDX, adaptation treatments. PBM the after decreasedstatus, drusen of measure a as detachment, epithelial thein change not did but 2) (Figure right the in significantly eyes 7 months after initial treatment, from a baseline ofbaseline a from treatment, initial after months 7 eyes deficiency).(mild “suspect” to deficiency) (severe “abnormal” improvedthreshold average Concomitantly, inremained and “normal” to “suspect” from eye right the in Fixation treatment. after eye left the in range “normal” the andeye right the in 96% to 85% from improved stability sub reported patient The eye. left the in 96% to 87% from describ particular in quality, vision in improvements jective andcolor, deeper contrast, better images, brighter ing speed. reading increased CASE REPORT NO. 2 awith presented years several for 3) category (AREDS AMD eye.each in equivalent Snellen 20/28 of acuity visual baseline detachmentbody vitreous a and drusen large eyes, both In Theidentified. be could atrophy retinal No identified. be could - - - B B 3 A A | MAY/JUNE 2020 | MAY/JUNE

VA remained at 20/20 after treatment. After both sets ofsets both After treatment. after 20/20 at remained VA Both eyes received a series of PBM treatments (ie, the rec the (ie, treatments PBM of series a received eyes Both A 73-year-old white woman with intermediate stage drystage intermediate with woman white 73-year-old A These findings support further study of the use of PBM as PBM of use the of study further support findings These before the beginning of PBM treatment (A), at the as a measure of drusen status in OCT of the right eye at 6 months before the beginning of PBM treatment (A), at the Figure 2. Color-coded analysis of RPE detachment from choroid (C). beginning of PBM (B), and 2 months after beginning of treatment of the right eye at 12 months before the beginning before the beginning as a measure of drusen status in OCT of the right eye at 12 months of retinal pigment epithelium (RPE) detachment from choroid Figure 1. Color-coded analysis beginning of PBM (B), and 7 months after treatment (C). of PBM treatment (A), at the VA by objective refraction, OCT imaging, and automatedand imaging, OCT refraction, objective by VA CenterVue). (Maia, microperimetry eyeright the in notably decreased had drusen treatment, microperimetry,On eye. left the in slightly and 1) (Figure bothin improved index integrity macular functional the of 12 months before the patient underwent PBM treatment. PBM underwent patient the before months 12 of weeka times three Valeda with treatments nine ommended patientthe later, months Seven weeks). consecutive three for weeka twice delivered treatments additional four received includedmeasures Outcome weeks. consecutive two over CASE REPORT NO. 1 CASE REPORT NO. 1 3)category [AREDS] Study Disease Eye Related (Age AMD Snellen20/20 of VA baseline with presented years several for dru medium-sized showed eyes Both eye. each in equivalent sur cataract after pseudophakic and hyperopic were and sen periodobservation an over unchanged was status Drusen gery. improvement in quality-of-life endpoints. quality-of-life in improvement clinicown our In patients. AMD dry for option treatment a astreatment, PBM of effects beneficial the observed have we reports. case following the by anecdotally illustrated measures (drusen volume and thickness), along with along thickness), and volume (drusen measures RETINA TODAY

24 s SPOTLIGHT: AMD SPOTLIGHT: AMD s

the treatment of dry age-related macular degeneration [published online A B ahead of print August 9, 2019]. Retina. 4. Chung H, Dai T, Sharma SK, et al. The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng. 2012;40(2):516-533. 5. de Freitas LF, Hamblin MR. Proposed mechanisms of photobiomodulation or low-level light therapy. IEEE J Sel Top Quantum Electron. 2016;22(3). pii: 7000417. 6. Eells JT, Wong-Riley MT, VerHoeve J, et al. Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy. Mitochondrion. 2004;4(5-6):559-567. 7. Albarracin R, Eells J, Valter K. Photobiomodulation protects the retina from light-induced photoreceptor degeneration. Invest Ophthalmol Vis Sci. 20111;52(6):3582-3592. 8. Eells JT, Henry MM, Summerfelt P, et al. Therapeutic photobiomodulation for methanol-induced retinal toxicity. Proc Natl Acad Sci USA. 2003;100(6):3439- 4344. 9. Tang J, Herda AA, Kern TS. Photobiomodulation in the treatment of patients with non-center-involving diabetic macular oedema. Br J Ophthal- mol. 2014;98(8):1013-1015. 10. Ivandic BT, Ivandic T. Low-level laser therapy improves vision in a patient Figure 3. Color-coded results of microperimetry (response thresholds [in decibels]: green = good; yellow with retinitis pigmentosa. Photomed Laser Surg. 2014;32(3):181-184. and orange = abnormal) and fixation position overlaid on the fundus image of the right eye, at baseline (A) 11. Ivandic BT, Ivandic T. Low-level laser therapy improves visual acuity in adolescent and adult patients with amblyopia. Photomed La- and 4 months after PBM treatment (B). ser Surg. 2012;30(3):167-171. 12. Study of Photobiomodulation to Treat Dry Age-Related Macular Degenera- tion (LIGHTSITE II). ClinTrials.gov. ClinicalTrials.gov Identifier: NCT03878420. left eye. Functional dark adaptation at an “stable” 92% in the right eye (Figure 3). Accessed May 13, 2020. 13. Study of Photobiomodulation to Treat Dry Age-Related Macular Degenera- eccentricity of 5° did not improve, but Similar but less prominent results were tion (LIGHTSITE III). ClinTrials.gov. ClinicalTrials.gov Identifier: NCT04065490. the fixation error rate during the dark seen in the left eye. Contrast sensitivity Accessed May 13, 2020. adaptation sessions improved slightly at increased by about 15% after treatment. 1 month after treatment. Although VA remained at 20/28 (0.7 logMAR), the WHAT’S NEXT? HAKAN KAYMAK, MD patient reported subjective improve- The benefits of PBM have been n Breyer Kaymak and Klabe Eye Surgery, Macula- ment in vision toward better contrast documented in one randomized Retina Department, Duesseldorf, Germany and better color after treatment. clinical trial. Now, the multicenter n [email protected] LIGHTSITE II12 and LIGHTSITE III13 n Financial disclosure: None CASE REPORT NO. 3 clinical trials in dry AMD patients are An 83-year-old white man with under way in the European Union and HARTMUT SCHWAHN, PHD intermediate stage dry AMD (AREDS the United States, respectively. (Valeda n Breyer Kaymak and Klabe Eye Surgery, Macula- category 3) for several years presented is investigational and not approved for Retina Department, Duesseldorf, Germany with baseline visual acuity of 20/25 use in the United States.) Additional n [email protected] (0.8 logMAR) in both eyes with large studies are also planned or in progress n Financial disclosure: None drusen and no retinal atrophy. to investigate the use of PBM in other The same regimen of PBM treat- ocular indications such as trauma, dia- ments with Valeda described above betic retinopathy and diabetic macular was administered. VA was assessed by edema, and . objective refraction, OCT images were As these additional diseases and obtained, and automated micrope- conditions are studied, we may be able rimetry and contrast sensitivity testing to customize light profiles and dura- (automated randomized stimuli at tion required for relevant treatments. 6 cycles per degree) were performed Future studies will also aid in optimiz- before and after the PBM treatments. ing PBM treatment parameters and Four months after the end of treat- may expand our understanding of the ment, VA had improved from 20/25 mechanisms and benefit of PBM in to 20/20 in the right eye and had ocular disease. n improved slightly in the left. On micro- 1. Ivandic BT, Ivandic T.Low-level laser therapy improves vi- perimetry, the functional macular integ- sion in patients with age-related maculardegeneration. Photomed La- rity index improved from a baseline ser Surg. 2008;26(3):241-245. 2. Merry GF, Munk MR, Dotson RS, Walker MG, Devenyi RG. Photobiomodu- of “severely abnormal” to “normal,” lation reduces drusen volume and improves visual acuity and contrast- average threshold improved from “sus- sensitivity in dry age-related macular degeneration. Acta Ophthal- mol. 2017;95(4):e270-e277. pect” to “normal,” and fixation stability 3. Markowitz SN, Devenyi RG, Munk MR, et al. A double-masked, random- improved from an “unstable” 53% to ized, sham-controlled, single-center studywith photobiomodulation for

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