Long-Term Outcome of Photobiomodulation for Diabetic Macular Edema: A Case Report.

Background: Macular edema is the major cause of decreased vision in patients with diabetes. Antioxidative and anti-inflammatory effects of photobiomodulation (PBM) have been reported with near-infrared irradiation. Objective: In this study, the efficacy and safety of PBM with near-infrared radiation in a patient with diabetic macular edema were assessed. Methods: We present the case of a 60-year-old man with diabetic macular edema responding to 670 nm light PBM alone. Results: After PBM, his vision improved and macular edema resolved on optical coherence tomography (OCT) findings without adverse events. In 16 months follow-up, visual acuity remained stable and OCT showed no evidence of recurrence of edema. Conclusions: Six hundred seventy nanometers light PBM can be potentially considered as a therapeutic method in diabetic patients with macular edema. Also, it provides a noninvasive and nonexpensive treatment in home.

Preclinical and clinical studies of photobiomodulation therapy for macular oedema.

AIMS/HYPOTHESIS: Diabetic macular oedema (DME) is the leading cause of visual impairment in people with diabetes. Intravitreal injections of vascular endothelial growth factor inhibitors or corticosteroids prevent loss of vision by reducing DME, but the injections must be given frequently and usually for years. Here we report laboratory and clinical studies on the safety and efficacy of 670 nm photobiomodulation (PBM) for treatment of centre-involving DME. METHODS: The therapeutic effect of PBM delivered via a light-emitting diode (LED) device was tested in transgenic mice in which induced Müller cell disruption led to photoreceptor degeneration and retinal vascular leakage. We also developed a purpose-built 670 nm retinal laser for PBM to treat DME in humans. The effect of laser-delivered PBM on improving mitochondrial function and protecting against oxidative stress was studied in cultured rat Müller cells and its safety was studied in pigmented and non-pigmented rat eyes. We then used the retinal laser to perform PBM in an open-label, dose-escalation Phase IIa clinical trial involving 21 patients with centre-involving DME. Patients received 12 sessions of PBM over 5 weeks for 90 s per treatment at a setting of 25, 100 or 200 mW/cm2 for the three sequential cohorts of 6-8 patients each. Patients were recruited from the Sydney Eye Hospital, over the age of 18 and had centre-involving DME with central macular thickness (CMT) of >300 µm with visual acuity of 75-35 Log minimum angle of resolution (logMAR) letters (Snellen visual acuity equivalent of 20/30-20/200). The objective of this trial was to assess the safety and efficacy of laser-delivered PBM at 2 and 6 months. The primary efficacy outcome was change in CMT at 2 and 6 months. RESULTS: LED-delivered PBM enhanced photoreceptor mitochondrial membrane potential, protected Müller cells and photoreceptors from damage and reduced retinal vascular leakage resulting from induced Müller cell disruption in transgenic mice. PBM delivered via the retinal laser enhanced mitochondrial function and protected against oxidative stress in cultured Müller cells. Laser-delivered PBM did not damage the retina in pigmented rat eyes at 100 mW/cm2. The completed clinical trial found a significant reduction in CMT at 2 months by 59 ± 46 µm (p = 0.03 at 200 mW/cm2) and significant reduction at all three settings at 6 months (25 mW/cm2: 53 ± 24 µm, p = 0.04; 100 mW/cm2: 129 ± 51 µm, p < 0.01; 200 mW/cm2: 114 ± 60 µm, p < 0.01). Laser-delivered PBM was well tolerated in humans at settings up to 200 mW/cm2 with no significant side effects. CONCLUSIONS/INTERPRETATION: PBM results in anatomical improvement of DME over 6 months and may represent a safe and non-invasive treatment. Further testing is warranted in randomised clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02181400 Graphical abstract.

Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice.

OBJECTIVE: Daily application of far-red light from the onset of diabetes mitigated diabetes-induced abnormalities in retinas of albino rats. Here, we test the hypothesis that photobiomodulation (PBM) is effective in diabetic, pigmented mice, even when delayed until weeks after onset of diabetes. Direct and indirect effects of PBM on the retina also were studied. METHODS: Diabetes was induced in C57Bl/6J mice using streptozotocin. Some diabetics were exposed to PBM therapy (4 min/day; 670 nm) daily. In one study, mice were diabetic for 4 weeks before initiation of PBM for an additional 10 weeks. Retinal oxidative stress, inflammation, and retinal function were measured. In some mice, heads were covered with a lead shield during PBM to prevent direct illumination of the eye, or animals were treated with an inhibitor of heme oxygenase-1. In a second study, PBM was initiated immediately after onset of diabetes, and administered daily for 2 months. These mice were examined using manganese-enhanced MRI to assess effects of PBM on transretinal calcium channel function in vivo. RESULTS: PBM intervention improved diabetes-induced changes in superoxide generation, leukostasis, expression of ICAM-1, and visual performance. PBM acted in part remotely from the retina because the beneficial effects were achieved even with the head shielded from the light therapy, and because leukocyte-mediated cytotoxicity of retinal endothelial cells was less in diabetics treated with PBM. SnPP+PBM significantly reduced iNOS expression compared to PBM alone, but significantly exacerbated leukostasis. In study 2, PBM largely mitigated diabetes-induced retinal calcium channel dysfunction in all retinal layers. CONCLUSIONS: PBM induces retinal protection against abnormalities induced by diabetes in pigmented animals, and even as an intervention. Beneficial effects on the retina likely are mediated by both direct and indirect mechanisms. PBM is a novel non-pharmacologic treatment strategy to inhibit early changes of diabetic retinopathy.

Safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in eyes with good visual acuity.

PURPOSE: To determine the safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema. METHODS: The records of all patients treated with transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in two retina clinics were reviewed. The eligibility included fovea-involving diabetic macular edema by spectral domain optical coherence tomography and pretreatment visual acuity of 20/40 or better. RESULTS: Thirty-nine eyes of 27 patients aged 50 years to 87 years (mean, 69 years) were included. Postoperative follow-up ranged from 3 months to 36 months (mean, 11 months). Fourteen patients were insulin dependent, and 19 had nonproliferative retinopathy. The preoperative visual acuity was 20/20 (10 eyes), 20/25 (10 eyes), 20/30 (8 eyes), and 20/40 (11 eyes). No eye had evidence of laser-induced macular damage by any imaging means postoperatively. There were no adverse treatment effects. Logarithm of the minimum angle of resolution visual acuity was improved on average of 0.03 units at 4 months to 7 months of follow-up (P = 0.0449, paired t-test) and otherwise stable. The central foveal thickness was improved at 4 months to 7 months (P = 0.05, paired t-test) and 8 months to 12 months, postoperatively (P = 0.04, mixed model accounting). Maximum macular thickness was improved at 4 months to 7 months postoperatively (P = 0.01, paired t-test and mixed model accounting). CONCLUSION: In a small retrospective series, transfoveal subthreshold diode micropulse laser was safe and effective for the treatment of fovea-involving diabetic macular edema in eyes with good preoperative visual acuity that were not the candidates for conventional photocoagulation or intravitreal injection. Further study is warranted.

Low-intensity far-red light inhibits early lesions that contribute to diabetic retinopathy: in vivo and in vitro.

PURPOSE: Treatment with light in the far-red to near-infrared region of the spectrum (photobiomodulation [PBM]) has beneficial effects in tissue injury. We investigated the therapeutic efficacy of 670-nm PBM in rodent and cultured cell models of diabetic retinopathy. METHODS: Studies were conducted in streptozotocin-induced diabetic rats and in cultured retinal cells. Diabetes-induced retinal abnormalities were assessed functionally, biochemically, and histologically in vivo and in vitro. RESULTS: We observed beneficial effects of PBM on the neural and vascular elements of retina. Daily 670-nm PBM treatment (6 J/cm(2)) resulted in significant inhibition in the diabetes-induced death of retinal ganglion cells, as well as a 50% improvement of the ERG amplitude (photopic b wave responses) (both P < 0.01). To explore the mechanism for these beneficial effects, we examined physiologic and molecular changes related to cell survival, oxidative stress, and inflammation. PBM did not alter cytochrome oxidase activity in the retina or in cultured retinal cells. PBM inhibited diabetes-induced superoxide production and preserved MnSOD expression in vivo. Diabetes significantly increased both leukostasis and expression of ICAM-1, and PBM essentially prevented both of these abnormalities. In cultured retinal cells, 30-mM glucose exposure increased superoxide production, inflammatory biomarker expression, and cell death. PBM inhibited all of these abnormalities. CONCLUSIONS: PBM ameliorated lesions of diabetic retinopathy in vivo and reduced oxidative stress and cell death in vitro. PBM has been documented to have minimal risk. PBM is noninvasive, inexpensive, and easy to administer. We conclude that PBM is a simple adjunct therapy to attenuate the development of diabetic retinopathy.

Subthreshold micropulse diode laser and double frequency neodymium: YAG laser in treatment of diabetic macular edema: a prospective, randomized study using multifocal electroretinography.

OBJECTIVE: The purpose of this study was to compare the efficacy of subthreshold micropulse diode (SDM) laser with double-frequency neodymium YAG (Nd:YAG) laser in treatment of clinically significant diabetic macular edema. METHODS: Forty-six eyes of 33 patients with clinically significant macular edema (CSME) caused by diabetic retinopathy were randomized to either SDM (810?nm) laser or the conventional double-frequency Nd:YAG (532?nm) laser. Primary outcome measures were: change in the central macular thickness as measured by optical coherence tomography (OCT) and change in macular retinal sensitivity measured using multifocal electroretinography (MfERG). Secondary outcomes were: change in best corrected visual acuity (BCVA) and contrast sensitivity. RESULTS: The group was divided in half, with 23 eyes assigned to SDM laser and 23 eyes assigned to double-frequency Nd:YAG laser. Mean follow-up period was 6 months. No statistically significant difference was noted in either the primary or the secondary outcome measures between the two groups. Macular thickness decreased from the baseline measures of 298.5?49.3 and 312.9?45.8??m to 274.9?62.9 and 286.7?32.8??m in the SDM laser and Nd:YAG laser groups, respectively. On MfERG, P1 implicit wave time delay at baseline changed from 46.27?4.9 to 45.27?3.4?ms in the SDM group and from 46.55?4.9 to 45.27?4.1?ms in the Nd:YAG group. MfERG recordings of 18 of the 23 eyes treated with double-frequency Nd:YAG laser showed areas of signal void as compared to 4 eyes treated with the SDM laser. CONCLUSIONS: SDM laser photocoagulation showed an equally good effect on visual acuity, contrast sensitivity, and reduction of diabetic macular edema (DME) as compared to conventional Nd:YAG laser photocoagulation. MfERG recordings, however, suggest that SDM laser results in better preservation of electrophysiological indices.

Attenuation of diabetes-induced renal dysfunction by multiple exposures to low-dose radiation is associated with the suppression of systemic and renal inflammation.

Renal protection against diabetes-induced pathogenic injuries by multiple exposures to low-dose radiation (LDR) was investigated to develop a novel approach to the prevention of renal disease for diabetic subjects. C57BL/6J mice were given multiple low-dose streptozotocin (STZ; 6 x 60 [corrected] mg/kg) to produce a type 1 diabetes. Two weeks after diabetes onset, some of diabetic mice and age-matched nondiabetic mice were exposed whole body to 25 mGy X-rays every other day for 2, 4, 8, 12, and 16 wk. Diabetes caused a significant renal dysfunction, shown by time-dependent increase in urinary microalbumin (Malb) and decrease in urinary creatinine (Cre), and pathological changes, shown by significant increases in renal structural changes and PAS-positive staining. However, diabetes-induced renal dysfunction and pathological changes were significantly, albeit partially, attenuated by multiple exposures to LDR. Furthermore, LDR protection against diabetes-induced renal dysfunction and pathological changes was associated with a significant suppression of diabetes-increased systemic and renal inflammation, shown by significant increases in serum and renal TNFalpha, ICAM-1, IL-18, MCP-1, and PAI-1 contents. To further explore the mechanism by which LDR prevents diabetes-induced renal pathological changes, renal oxidative damage was examined by Western blotting and immunohistochemical staining for 3-nitrotyrosine and 4-hydroxynonenal. Significant increase in oxidative damage was observed in diabetic mice, but not diabetic mice, with LDR. Renal fibrosis, examined by Western blotting of connective tissue growth factor and Masson's trichrome staining, was also evident in the kidneys of diabetic mice but not diabetic mice with LDR. These results suggest that multiple exposures to LDR significantly suppress diabetes-induced systemic and renal inflammatory response and renal oxidative damage, resulting in a prevention of the renal dysfunction and fibrosis.

Computer-aided diagnosis: the emerging of three CAD systems induced by Japanese health care needs.

The aim of this paper is to describe three emerging computer-aided diagnosis (CAD) systems induced by Japanese health care needs. CAD has been developing fast in the last two decades. The idea of using a computer to help in medical image diagnosis is not new. Some pioneer studies are dated back to the 1960s. In 1998, the first U.S. FDA (Food and Drug Administration) approved commercial CAD system, a film-digitized mammography system, was launched by R2 Technologies, Inc. The success was quickly repeated by a number of companies. The approval of Medicare CAD reimbursement in the U.S. in 2001 further boosted the industry. Today, CAD has its significance in the economy of the medical industry. FDA approved CAD products in the field of breast imaging (mammography, ultrasonography and breast MRI) and chest imaging (radiography and CT) can be seen. In Japan, as part of the "Knowledge Cluster Initiative" of the government, three computer-aided diagnosis (CAD) projects are hosted at the Gifu University since 2004. These projects are regarding the development of CAD systems for the early detection of (1) cerebrovascular diseases using brain MRI and MRA images by detecting lacunar infarcts, unruptured aneurysms, and arterial occlusions; (2) ocular diseases such as glaucoma, diabetic retinopathy, and hypertensive retinopathy using retinal fundus images; and (3) breast cancers using ultrasound 3-D volumetric whole breast data by detecting the breast masses. The projects are entering their final development stage. Preliminary results are presented in this paper. Clinical examinations will be started soon, and commercialized CAD systems for the above subjects will appear by the completion of this project.

The effect of aspirin on hemorheological parameters of patients with diabetic retinopathy.

Hemorheological factors play an important role in the pathogenesis of severe complications of diabetes. The diabetic retinopathy is the leading cause of blindness in patients aged 20-65 years. In our study we investigated the effect of aspirin on the hemorheological parameters in patients with different diabetic retinopathies. Hemorheological parameters (hematocrit, fibrinogen, plasma and whole blood viscosity, red blood cell aggregation) of diabetic patients with non-proliferative (n=14, mean age: 66 years) and proliferative retinopathy (n=8, mean age: 48 years) were measured. The results between the two groups were compared: twelve patients were taking aspirin (group A), while ten patients were not (group B).Hematocrit, fibrinogen, plasma and whole blood viscosity were significantly higher (p < 0.05-0.001) in patients with diabetic retinopathy who did not take aspirin than in those who took. No significant difference was observed in red blood cell aggregation parameters between the two groups. We could not find any significant difference in the measured parameters between patients with non-proliferative and proliferative diabetic retinopathy. According to our results, all the measured hemorheological parameters were in the pathological range, although aspirin treatment could decrease these factors and thus may help to prevent the progression of severe diabetic retinopathy and perhaps blindness.

Large-spot subthreshold infrared laser to treat diabetic macular edema.

PURPOSE: To evaluate the efficacy of a large-spot subthreshold infrared laser protocol to treat diabetic maculopathy. METHODS: In a prospective, fellow eye, controlled case series, all patients had clinically significant diabetic macular edema (DME) treated with a single application of subthreshold infrared (810 nm) laser. If bilateral disease was present, the fellow eye was treated with conventional macular laser. The study was to include 20 patients. Visual acuity and central macular thickness (CMT) measured by optical coherence tomography (OCT) were assessed in the study and fellow eyes at baseline and 6 months, and any changes were compared. RESULTS: The 11th patient developed a choroidal infarct with subsequent profound loss of vision immediately after treatment. The study was terminated prematurely at this point. For the remaining 10 patients, there was a trend toward improvement in visual acuity in the study eye compared with the fellow eye at the 6-month follow-up (median change: +1.5 letters for study eye vs -6.5 letters for fellow eye; P = 0.08). There was also significant improvement in OCT-measured CMT in the study eye (mean decrease, 117 microm) compared with deterioration in OCT-measured CMT in the fellow eye (mean increase, 24 microm; P = 0.02). CONCLUSION: This subthreshold infrared laser protocol led to improvement in OCT-measured CMT and stabilization of vision in most subjects. The current protocol is however unpredictable and should not be used in the treatment of DME without further modification.

Effects of endogenous cyclotronic ionic resonance (ICR) on macular diabetic edema: preliminary results.

The intent in this research was to verify the effects of the application of low frequency magnetic fields to cases of macular diabetic edema. We treated six patients afflicted by non-proliferating diabetic retinopathy with macular oedema. Quantitative clinical appraisals of the retinal thickness were obtained for the Optical Coherence Tomography (OCT I). None of the cases affected by non-cystoid macular oedema (non-CMO), or with a relevant ischemic component, evidenced by retinal fluorangiography, had further worsening in their clinical course during the treatment. Only one of the patients, who underwent a long treatment period with ICR demonstrated a significant reduction of the macular edema, with no need of other invasive therapeutic procedures (intravitreous injection of triamcinolone and/or laser therapy).

An evaluation of the change in activity and workload arising from diabetic ophthalmology referrals following the introduction of a community based digital retinal photographic screening programme.

AIMS: To determine how the workload of an ophthalmology department changed following the introduction of an organised retinal screening programme. METHODS: Information was collected from the hospital medical record of people with diabetes attending eye clinics over 4 years. The first year was before screening, the next 2 years the first round, and the fourth year the second round. RESULTS: The total number of people with diabetes referred each year over the 4 year period was 853, 954, 974, 1051 consecutively. The number of people with diabetes in the county rose by 1400 per annum. The total number of referrals for an opinion about diabetic retinopathy was 227, 333, 363, 368, for cataract was 64, 57, 77, 93, and for glaucoma was 57, 62, 61, 68. The total number of patients referred for laser treatment over the 4 years was 77, 124, 111, and 63 CONCLUSION: This study suggests that the workload in the eye clinic increases in the first round of screening but in subsequent rounds it does not fall below the pre-screening level, except for laser treatment. This may be partly because of increasing numbers of people with diabetes. With the introduction of a national screening programme, this has significant workload implications for the National Health Service.

The challenge of preventing vision loss from diabetic retinopathy.

Diabetes is present in 7% of Missourians. Another 52% are at risk. Periodic eye examinations are key to averting vision loss from diabetic retinopathy. Signs of diabetic retinopathy are evident long before vision loss and include microaneurysms, retinal hemorrhage, microvascular and venous caliber abnormalities and neovascularization. Loss of vascular integrity can lead to retinal edema and neovascular growth. Laser ablation of the peripheral retina can curb neovascular growth. It can also help stabilize macular edema.

[Clinical-immunological and ecological research in diabetic retinopathy]. / Kliniko-immunologicheskie i ékologicheskie issledovaniia pri diabeticheskoi retinopatii.

Two hundred and ninety-six patients with diabetic retinopathy (DR) were examined: conservative therapy and laser coagulation of the retina were applied in 120 and 176 of them, respectively. The ecological situation in the residence region and its impact on the morbidity and immune status of DR patients were analyzed. The comfort degree of the environment and the level of anthropogenic contamination affect the morbidity and immunogram results. Immune-correctors, i.e. T-activin, sodium nucleinate and laser blood irradiation (LBI), were used within treatment schemes in DR. Laser coagulation of the retina is advisable to assign in combination with sodium nucleinate and LBI in the aftercare of patients concurrently with complex therapy; T-activin is used, within conservative therapy, to correct the unfavorable ecological impact exerted on patient's body.

[Proton therapy: clinico-methodological aspects, treatment results]. / Protonnaia terapiia: kliniko-metodicheskie aspekty, rezul'taty lecheniia.

In the period of 1975-1986, 457 patients (81 with breast and prostatic cancer, 24 with endocrine ophthalmopathy, 20 with diabetic angioretinopathy, 206 with pituitary adenomas, 115 with arteriovenous and 6 with arterial brain malformations, and 6 with epilepsy) were given proton beam therapy at the Central Research Roentgenoradiology Institute using the 1000 MeV synchrocyclotron of the Leningrad Institute for Nuclear Physics. A prolonged remission was noted in 75-90% of the patients with pituitary adenomas. Angiography showed complete exclusion of aneurysm from the blood flow 2 yrs. after irradiation almost in 50% of the patients with arteriovenous malformations. A high efficacy and safety of the method was shown.

Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema.

One hundred sixty eyes of 92 patients with diffuse diabetic maculopathy with or without cystoid macular edema were enrolled in a prospective randomized clinical trial to determine the efficacy of "modified grid" argon (blue-green) laser photocoagulation. At the 12- and 24-month follow-ups, visual acuity significantly improved in treated eyes (P = 0.00007 and P = 0.00031, respectively) compared to the observation group. In addition, at the 12- and 24-month follow-ups, visual acuity significantly worsened in observation eyes (P = 0.00007 and P = 0.0007, respectively) compared to the treatment group. The following factors did not statistically alter the visual prognosis: a history of systemic hypertension (P = 0.2921); systemic vascular disease (P = 0.5324); cystoid macular edema (P = 0.1010); and initial poor visual acuity (P = 0.3032).