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radiation protection (oral mucositis), den- tal, sports medicine and skeletal muscle disorders (trauma and pain). Low-level laser therapy exerts its beneficial effects through increased blood flow and stimu- lation of cellular functions, a process called photobiomodulation (PBM). Photobiomodulation (PBM) involves the use of visible to near-infrared (NIR) light (500–1000 nm) produced by a laser or non-coherent light sources such as light emitting diodes (LEDs) applied to the body to produce beneficial cellu- lar effects. Light in this range penetrates tissue depending on the wavelength and stimulates cellular function via activa- tion of photoacceptors (Rojas et al. 2008; Tata & Waynant 2010; Rojas & Gonzalaz-Lima 2011). Published studies demonstrate that mitochondrial cytochrome C oxidase (CCO) is a key photoacceptor of light at these wavelengths and improves blood flow and ATP formation, enhances O2 binding and reduces oxidative stress and inflammation (Karu et al. 1995; Karu & Kolyakov 2005; Wong-Riley et al. 2005). Although early studies identified mitochondrial CCO as an endogenous photoacceptor for PBM, the cellular and molecular mechanisms underlying PBM are better understood. Recent findings provide important new insight. First, nitric oxide has been implicated. Second, CCO, an enzyme known to reduce oxygen to water at the end of the mitochondrial respiratory chain, has been shown to have a new enzymatic activity – the reduction of nitrite to nitric oxide. This nitrite reductase activ- ity is elevated under hypoxic conditions but also occurs under normoxia. And third, low-intensity light regulates nitric oxide synthesis by CCO without alter- ing its ability to reduce oxygen. From these findings, Poyton and Ball have proposed that CCO functions in PBM by regulating nitric oxide, a signalling molecule which can then function in both intra- and extracellular signalling pathways. They also propose that the effectiveness of PBM is under the con- trol of tissue oxygen and nitrite levels (Poyton & Ball 2011). Previous reports have suggested that phagocytosis is reduced by age- related increased oxidative stress in AMD. Investigations on PBM in the human retinal pigment epithelial (ARPE-19) cell lines demonstrate PBM- improved phagocytosis, which is reduced under oxidative stress (Fuma et al. 2015). Multiple preclinical animal models of ocular disease or disorders show PBM to be beneficial. These effects include reductions in damage observed in methanol toxicity, laser burn, com- plement factor H knockout inflamma- tory, bright light damage, retinitis pigmentosa and diabetic retinopathy animal models (Eells et al. 2003; Albar- racin et al. 2011; Tang et al. 2013; Gkotsi et al. 2014). Photobiomodula- tion (PBM) can increase mitochondrial ATP, replication, density and activity and increase RNA and protein synthe- sis (Passarella & Karu 2014). McDaniels has reported the effect of PBM using 590/870-nm light on the expression of VEGF in 0- and 4-week cultured human RPE cells where up to a sevenfold decrease in VEGF expression was seen. McDaniels also reported the response of PBM using 670-nm light on the revitalization of RPE cells after an acute high-dose blue light injury. Fol- lowing blue light insult at 30 J/cm2, it was observed that 90% of RPE cells died. This is in contrast to the 5% of cells that died with blue light insult followed by red light therapy (LED photomodulation ‘reverses’ acute retinal injury, ASLMS Conference, 2006). Ivandic and Ivandic show clinically that PBM with a laser diode aimed at the macular area significantly improves visual acuity in a case series of both dry and wet AMD subjects. Visual acuity (VA) in the control group remains unchanged. No adverse effects were observed in patients undergoing PBM therapy (Ivandic & Ivandic 2008). Merry et al. have previously pre- sented results of a PBM pilot study in a small cohort of dry AMD patients, The Toronto and Oak Ridge Photobiomod- ulation Study for Dry Age-Related Macular Degeneration (TORPA) that demonstrated statistically significant improvements in early treatment dia- betic retinopathy study (ETDRS) best- corrected visual acuity (BCVA) and contrast sensitivity (CS) (PBM as a new treatment for dry AMD, ARVO, 2012). Further, PBM has recently been shown to reduce non-central diabetic macular oedema in a case series (Tang et al. 2014). Therefore, a growing body of evidence suggests that PBM treatment could have a beneficial role in dry AMD, a condition Acta Ophthalmologica 2017 characterized by mitochondrial dysfunc- tion, oxidative stress and inflammation within the RPE cell layer, choriocapil- laris and neuroretina. We report the findings from 42 eyes in an interventional, longitudinal case ser- ies. This study evaluated functional and pathological end-points including retinal and drusen morphology using Spectral domain-Optical coherence tomography (SD- OCT). We demonstrate that PBM has the potential to significantly improve both functional clinical and morpholog- ical outcomes in dry AMD. Materials and Methods Patient selection and setting Subjects ≥50 years of age with dry AMD were eligible for study participa- tion and were enrolled at the practices of Drs. Merry and Devenyi within a time period of 2011–2015. Subjects were treated off-label with available LED instruments approved for other indications by the FDA and Health Canada. Subjects who met the inclusion criteria and gave written informed consent underwent PBM with three treatment sessions per week for 3 weeks. Optical coherence tomography retinal images and fundus autofluorescence (FAF) were obtained at baseline (BL), immediately following the initial 3-week treatment course at visit 1 and at a subsequent visit at 3 months (visit 2). Formal data collection with indepen- dent OCT and FAF analysis was con- ducted to evaluate both clinical and anatomical benefits of PBM. The study analysis protocol was approved by the Chesapeake Investigational Review Board and performed in adherence to the guidelines of the Declaration of Helsinki. Inclusion criteria were dry AMD, AREDS grades (according to the American Academy of Ophthalmol- ogy) 2, 3 and 4 [geographic atrophy (GA), no choroidal neovascularization (CNV)] and a BCVA of letter score 50 (logMAR 1.0, Snellen 20/200) or bet- ter. A wide range of dry AMD cate- gories were included as the study goal was to explore the potential benefit of PBM in varying stages and severity of AMD. Subjects with previous/active wet AMD, a history of epilepsy, other retinal diseases, significant media opac- ity and cataracts worse than grade 2 (LOCS III) were excluded. e271PDF Image | Photobiomodulation reduces drusen in macular degeneration
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