Light therapy in retinal vascular disease

Light is a novel, simple approach that may be used to alter retinal hypoxia [5,6], which is a major component in retinal vascular diseases such as diabetes and age-related macular degeneration (AMD). Evidences show that inner segment hypoxia is sufficient to trigger microvascular changes [7], which may be further enhanced by choroidal vasculopathy, an early feature of systemic vascular diseases, such as diabetes [8].


Introduction
The outer retina is an avascular layer that is predominantly composed by photoreceptors. Its vascular supply depends on simple diffusion, relying in the integrity of choroidal circulation [1].
Rods are highly metabolic active [2,3] , consuming the most oxygen delivered to the retina. In bright light, oxygen consumption decreases due to a drop in the energy required by these cells [4]. In contrast, cones seem to consume the same amount of O 2 as it would in dark environments, and energy requirement is minimally affect by differences is luminosity.
Light is a novel, simple approach that may be used to alter retinal hypoxia [5,6], which is a major component in retinal vascular diseases such as diabetes and age-related macular degeneration (AMD). Evidences show that inner segment hypoxia is sufficient to trigger microvascular changes [7], which may be further enhanced by choroidal vasculopathy, an early feature of systemic vascular diseases, such as diabetes [8].
In this review, the authors will present the latest evidence on how light can affect vascular integrity and disease progression based on recent experimental and clinical trials.

Methods
A retrospective, descriptive review of current models using light devices to prevent nocturnal retinal hypoxia was conducted, based on recent clinical trials available in literature. Four national and international databases were consulted (PubMed, Scielo, Medline, and Cochrane). An initial screen yielded a total of twenty three articles, each meeting at least one of the following criteria: (1) retinal changes in diabetes mellitus and age-related macular degeneration, (2) light-masks for the treatment of retinal hypoxia, and (3) rod metabolism.
After secondary analysis, only 5 clinical trials were considered to meet two or three of the above criteria. These were included in this review.

Results and discussion
The idea to prevent retinal hypoxia using light therapy during sleep has been promising, although there is little evidence to support it. In 2008, Okawa, et al. [4] showed that mice retinal oxygen consumption is decreased approximately by half in the presence of bright light. On the contrary, using diabetic mice in a 12-week period, Kur, et al. [9] showed that a 12:12 hour light-adapted photocycle (30 lux during day, and 3 lux during night) did not prevent the progression of neuronal and glial abnormalities when compared to control group (30 lux during day, and 0 lux during night). However, the authors postulate that a 12 week period may have been insufficient to detect positive effects with this intervention, although some studies described below report positive results during the same period of intervention.
Sahni, et al. [10] evaluated the use of a light-mask (504 nm wavelength, 80 cd/m², for 8 hours nightly) in two different age-groups with healthy participants compared to a third group, composed by patients with diabetic macular edema. Several parameters were evaluated after a three month period, including psychological assessment. Intolerance to light and sleep disturbance were reported, which caused a withdrawal of 6 patients. However, in those with macular edema, there was a reduction of optical coherence tomography mean central subfield thickness (OCT CST; p=0.001) and mean thickness of OCT subfield with maximal pathology (OCT maxST; p=0.05) at months 3 and 4, as well as cyst resolution/reduction in 67% of patients.
Even though sleep and psychological wellbeing were compromised, the authors reported no major safety precaution. Further, the rise in PO 2 with this approach does not seem to harm the rods, even in prolonged periods of illumination [11].
Noctura 400 ® (PolyPhotonix Medical Ltd, Sedgefield, UK) is a lightmask recently developed for the treatment of diabetic retinopathy and diabetic macular edema, and is currently being (or have been) used in large clinical trials, with promising results. It consists in a lightemitting diode placed inside a fabric mask, originally intended for a 12 week period during night-time sleep [12]. Although there is a focus on diabetes, a recent protocol [13] has been developed for patients with early AMD, and is currently in progress. Vascular compromise in patients with AMD may correlate to the thickness of Bruch's membrane, which further impair oxygen diffusion to the outer segment [14]. A newer version, Noctura 500, has been designed for wet AMD. Currently, however, no evidence is available for its use in this disease.
The adoption of a light-mask may also have an impact on health care cost. Patients with proliferative diabetic retinopathy typically require costly treatments, such as laser photocoagulation or repeated sessions of intra-ocular anti-vascular endothelial growth factor (anti-VEGF). Light therapy may potentially replace these options in the future (Table 1) [10,13,[15][16][17].

Conclusion
Latest clinical trials seem to favor effect of low-level night-time light therapy in patients with diabetic maculopathy, non-central diabetic maculopathy and early AMD. To our knowledge, this was the first review on this subject, concerning the newest experimental protocols of light therapy. The approach of this review is to organize the information needed for future research. Copyright: ©2017 Ricci LH. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.