LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the Lumithera Valeda Light Delivery System.

PURPOSE: The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) age-related macular degeneration (AMD) using the LumiThera Valeda Light Delivery System. METHODS: LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were given multiwavelength PBM (590, 660, and 850 nm) or Sham treatment delivered in a series of nine sessions over 3 to 5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS: A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy best-corrected visual acuity endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 to -0.1, P = 0.02) (PBM alone: 5.4 letters (SE 0.96), CI: 3.5 to 7.3, P < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7-5.2, P < 0.0001). The PBM group showed a significant decrease in new onset geographic atrophy ( P = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSION: LIGHTSITE III provides a prospective, randomized, controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM therapy.

Short-Term Results of Photobiomodulation Using Light-Emitting Diode Light of 670 nm in Eyes with Age-Related Macular Degeneration.

Objective: To evaluate the short-term result of retinal functional behavior in patients with dry age-related macular degeneration (AMD) corrected by photobiomodulation (PBM) with 670 nm light-emitting diode (LED) light. Materials and methods: Ten patients with dry AMD underwent a treatment consisting of nine PBM sessions with LED light of 670 nm with two cycles of 50 mW/cm2, producing 4 J/cm2 per dose in 88 sec. The studied eye was compared with the baseline (before therapy), and after nine PBM sessions, the following aspects were evaluated: best-corrected visual acuity (VA), retinal sensitivity, and characteristics of the correction area by the fundus automated perimetry using the Compass system. A functional and structural assessment of the retina was also performed using the multifocal electroretinography (ERG), optical coherence tomography (OCT), fluorescence retinography (FR), and autofluorescence (AF). All examinations were performed 1, 4, and 16 weeks after the therapy. The Chi-square and Student's t-tests were used for comparisons. The analyses followed the 95% confidence level (p-value ≤0.05). Results: The BCVA significantly improved, from an average of 1.1 to 0.98 LogMAR (p = 0.01). The visual field examination, according to the parameters of mean deviation, standard deviation, and index of deviation of background perimeter, showed a significant improvement of -12.6% to -10.6%, 10.54% to 9.89%, and 56% to 60%, respectively (p = 0.02, 0.03, and 0.02, respectively). No participant had an adverse effect during the follow-up period; neither did any participant experience abnormalities in OCT, ERG, FR, and AF findings. Conclusions: In this short-term study, the PBM technique in patients with dry AMD showed the potential to improve VA and macular perimetry without causing significant adverse events. A larger number of patients and a longer follow-up will be necessary to further assess the success of this technique in these patients.

Photobiomodulation for non-exudative age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of blindness in high-income countries. The majority of cases of AMD are of the non-exudative type. Experts have proposed photobiomodulation (PBM) therapy as a non-invasive procedure to restore mitochondrial function, upregulate cytoprotective factors and prevent apoptotic cell death in retinal tissue affected by AMD. OBJECTIVES: To assess the effectiveness and safety of PBM compared to standard care, no treatment or sham treatment for people with non-exudative AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 5, 2020), Ovid MEDLINE, Embase, ISRCTN, ClinicalTrials.gov and the WHO ICTRP to 11 May 2020 with no language restrictions. SELECTION CRITERIA: The review included randomised controlled trials (RCTs) on participants receiving any type of PBM therapy for non-exudative AMD compared to standard care, sham treatment or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We considered the following outcome measures at 12 months: best-corrected visual acuity (BCVA) ; contrast sensitivity; near vision; low luminance density score; reading speed; vision-related quality of life score; and adverse events such as progression of AMD and conversion to exudative AMD. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We included two published RCTs from single centres in the UK and Canada, which recruited 60 participants (60 eyes) and 30 participants (46 eyes) respectively. Participants in these trials were people with non-exudative AMD with Age-Related Eye Disease Study (AREDS) categories 2 to 4. One study compared single wavelength PBM with no treatment. This study was at risk of performance bias because the study was not masked, and there was attrition bias. One study compared multi-wavelength PBM with sham treatment and conflicts of interest were reported by study investigators. We also identified three eligible ongoing RCTs from searching the clinical trials database. When comparing PBM with sham treatment or no treatment for non-exudative AMD, there was no evidence of any meaningful clinical difference in BCVA at 12 months (mean difference (MD) 0.02 logMAR, 95% confidence interval (CI) -0.02 to 0.05; 2 RCTs, 90 eyes; low-certainty evidence). One study comparing multi-wavelength PBM with sham treatment showed an improvement in contrast sensitivity at Level E (18 cycles/degree) at 12 months (MD 0.29 LogCS, 95% CI 0.23 to 0.35; 1 RCT, 46 eyes; low-certainty evidence). Visual function and health-related quality of life scores were comparable between single wavelength PBM and no treatment groups at 12 months (VFQ-48 score MD 0.43, 95% CI -0.17 to 1.03; P = 0.16; 1 RCT, 47 eyes; low-certainty evidence). When comparing PBM with sham treatment or no treatment for non-exudative AMD, there was no evidence of any meaningful clinical difference in conversion to exudative AMD (risk ratio (RR) 0.97, 95% CI 0.17 to 5.44; 2 RCTs, 96 eyes; very low-certainty evidence) at 12 months. There was inconclusive evidence that single wavelength PBM prevents the progression of AMD (RR 0.79, 95% CI 0.41 to 1.53; P = 0.48; 1 RCT, 50 eyes; low-certainty evidence). Disease progression was defined as the development of advanced AMD or significant increase in drusen volume. No included study reported near vision, low luminance vision or reading speed outcomes. AUTHORS' CONCLUSIONS: Currently there remains uncertainty whether PBM treatment is beneficial in slowing progression of non-exudative macular degeneration. There is a need for further well-designed controlled trials assessing dosimetry, powered for both effectiveness and safety outcomes. Consideration should be given to the adoption of agreed clinical outcome measures and patient-based outcome measures for AMD.

ANTECEDENTES: La degeneración macular senil (DMS) es una de las principales causas de ceguera en los países de ingresos altos. La mayoría de los casos de DMS son de tipo no exudativo. Los expertos han propuesto el tratamiento con fotobiomodulación (PBM por sus siglas en inglés) como procedimiento no invasivo para restaurar la función mitocondrial, aumentar los factores citoprotectores y prevenir la muerte celular apoptótica en el tejido retiniano afectado por la DMS. OBJETIVOS: Evaluar la eficacia y la seguridad de la PBM en comparación con la atención estándar, ningún tratamiento o el tratamiento simulado en personas con DMS no exudativa. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en CENTRAL (que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión [Cochrane Eyes and Vision]) (número 5, 2020), Ovid MEDLINE, Embase, ISRCTN, ClinicalTrials.gov y la ICTRP de la OMS hasta el 11 de mayo de 2020 sin restricciones de idioma. CRITERIOS DE SELECCIÓN: La revisión incluyó ensayos controlados aleatorizados (ECA) sobre participantes que recibían cualquier tipo de tratamiento con PBM para la DMS no exudativa en comparación con atención estándar, tratamiento simulado o ningún tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Se consideraron las siguientes medidas de desenlace a los 12 meses: agudeza visual mejor corregida (AVMC); sensibilidad al contraste; visión de cerca; puntuación de la densidad de baja luminancia; velocidad de lectura; puntuación de la calidad de vida relacionada con la visión; y eventos adversos como la progresión de la DMS y la conversión a DMS exudativa. La certeza de la evidencia se evaluó mediante el método GRADE. RESULTADOS PRINCIPALES: Se incluyeron dos ECA publicados de centros únicos en el Reino Unido y Canadá, que reclutaron 60 participantes (60 ojos) y 30 participantes (46 ojos) respectivamente. Los participantes en estos ensayos eran personas con DMS no exudativa con categorías 2 a 4 del Age­Related Eye Disease Study (AREDS). Un estudio comparó la PBM de longitud de onda única con ningún tratamiento. Este estudio tenía riesgo de sesgo de realización porque el estudio no estaba enmascarado y había sesgo de desgaste. Un estudio comparó la PBM de longitud de onda múltiple con tratamiento simulado y los investigadores del estudio informaron conflictos de intereses. A partir de la búsqueda en la base de datos de ensayos clínicos también se identificaron tres ECA elegibles en curso. Cuando se comparó la PBM con el tratamiento simulado o ningún tratamiento para la DMS no exudativa, no hubo evidencia de una diferencia clínica significativa en la AVMC a los 12 meses (diferencia de medias [DM] 0,02 logMAR; intervalo de confianza [IC] del 95%: ­0,02 a 0,05; dos ECA, 90 ojos; evidencia de certeza baja). Un estudio que comparó la PBM de longitud de onda múltiple con el tratamiento simulado mostró una mejoría en la sensibilidad al contraste en el nivel E (18 ciclos/grado) a los 12 meses (DM 0,29 LogCS; IC del 95%: 0,23 a 0,35; un ECA, 46 ojos; evidencia de certeza baja). Las puntuaciones de la función visual y de la calidad de vida relacionada con la salud fueron comparables entre los grupos de PBM de longitud de onda única y ningún tratamiento a los 12 meses (puntuación VFQ­48 DM 0,43; IC del 95%: ­0,17 a 1,03; p = 0,16; un ECA, 47 ojos; evidencia de certeza baja). Cuando se comparó la PBM con el tratamiento simulado o ningún tratamiento para la DMS no exudativa, no hubo evidencia de una diferencia clínica significativa en la conversión a DMS exudativa (razón de riesgos [RR] 0,97; IC del 95%: 0,17 a 5,44; dos ECA, 96 ojos; evidencia de certeza muy baja) a los 12 meses. No hubo evidencia concluyente de que la PBM de longitud de onda única prevenga la progresión de la DMS (RR 0,79; IC del 95%: 0,41 a 1,53; p = 0,48; un ECA, 50 ojos; evidencia de certeza baja). La progresión de la enfermedad se definió como el desarrollo de DMS avanzada o el aumento significativo del volumen de drusas. Ningún estudio incluido informó sobre los desenlaces de la visión de cerca, la visión de baja luminancia o la velocidad de lectura. CONCLUSIONES DE LOS AUTORES: En la actualidad no se sabe si el tratamiento con PBM es beneficioso para frenar la progresión de la degeneración macular no exudativa. Se necesitan más ensayos controlados y bien diseñados que evalúen la dosimetría y con poder estadístico para evaluar los desenlaces de eficacia y seguridad. Se debe considerar la adopción de medidas de desenlace clínicas acordadas y medidas de desenlace basadas en el paciente para la DMS.

Three-year clinical and optical coherence tomography follow-up after stereotactic radiotherapy for neovascular age-related macular degeneration.

PURPOSE: The long-term clinical outcome of adjuvant stereotactic radiotherapy (SRT) in neovascular age-related macular degeneration (nAMD) patients was evaluated. METHODS: This case-control study included patients with unilateral nAMD, who underwent SRT complementary to standard anti-VEGF treatment. Only patients with monthly follow-up over at least three years were considered. Number of intravitreal injections, visual acuity (VA), central retinal thickness (CRT), and subfoveal choroidal thickness (SFCT) were evaluated and compared to baseline as well as to an age- and gender-matched control group, who received anti-VEGF monotherapy. RESULTS: Twenty patients were irradiated and had complete follow-up. Cumulatively, SRT patients needed significantly less injections than non-irradiated ones over three years (14 vs. 18, p â€‹= â€‹0.014), while median VA did not show statistically significant changes (0.4 logMAR at baseline to 0.65 logMAR at final follow-up, p â€‹= â€‹0.061). CRT remained steady, but SFCT showed a continuous thinning of almost 50 â€‹µm (p â€‹= â€‹0.031) in irradiated patients over three years. Multiple linear regression analysis revealed that SFCT and VA at time of irradiation are significant prognostic factors of VA change in SRT patients over the following three years (F(2,17) â€‹= â€‹23.946, p<0.001, R2 of 0.738). CONCLUSIONS: SRT significantly reduced the cumulative anti-VEGF treatment burden over three years, however, this was mainly driven by the results of the first year after irradiation. A thinner SFCT at time of irradiation was associated with poorer visual outcome. While further research and investigation are warranted to elucidate the underlying pathogenesis, SFCT could be a potential biomarker when evaluating a patient's suitability for SRT.

Laser and anti-vascular endothelial growth factor treatment for drusenoid pigment epithelial detachment in age-related macular degeneration.

This study aims to report the 12 months results of efficacy and safety of laser photocoagulation and anti-vascular endothelial growth factor (VEGF) injections for drusenoid pigment epithelial detachment (dPED). In this prospective study, patients with treatment naïve bilateral intermediate age-related macular degeneration, featuring dPED, with visual acuity ≤ 83 letters were enrolled. The study group received PASCAL laser (532 nm) along the periphery of the dPED, and the fellow eye served as a control group. To prevent complications of choroidal neovascularization, intravitreal anti-VEGF injections to laser treated eye were performed on a 3-month interval up to 1 year. Primary outcomes-drusen area, PED height-and secondary outcomes-best-corrected visual acuity (BCVA), contrast sensitivity, degree of metamorphopsia, NEI-VFQ 25, and fundus autofluorescence-were analyzed. Among 21 patients, a total of 20 patients satisfied the 12 months follow-up. Drusen area and PED height decreased significantly in the laser group, while no significant change appeared in the control group (74.1% vs. - 3.5%, P < 0.001; 76.6% vs. 0.1%, P < 0.001). Mean BCVA improved 4.6 letters in the laser group (vs. 1.1 letters in the control group, P = 0.019). As for safety, one study eye developed retinal pigment epithelial tear, and one control eye developed retinal angiomatous proliferation. Low energy laser photocoagulation and anti-VEGF injection in eyes with dPED showed some improvement in visual acuity. dPED regressed without developing center involving GA in the study eye, but a longer term follow-up is necessary to reveal the efficacy and safety of these treatments. The 2-year results of this study will be followed to reveal long term efficacy and safety of the treatment for dPED.

Radiotherapy for neovascular age-related macular degeneration.

BACKGROUND: Radiotherapy has been proposed as a treatment for new vessel growth in people with neovascular age-related macular degeneration (AMD). OBJECTIVES: To examine the effects of radiotherapy on neovascular AMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS and three trials registers and checked references of included studies. We last searched the databases on 4 May 2020.  SELECTION CRITERIA: We included all randomised controlled trials in which radiotherapy was compared to another treatment, sham treatment, low dosage irradiation or no treatment in people with choroidal neovascularisation (CNV) secondary to AMD. DATA COLLECTION AND ANALYSIS: We used standard procedures expected by Cochrane. We graded the certainty of the evidence using GRADE. We considered the following outcomes at 12 months: best-corrected visual acuity (BCVA) (loss of 3 or more lines, change in visual acuity), contrast sensitivity, new vessel growth, quality of life and adverse effects at any time point.  MAIN RESULTS: We included 18 studies (n = 2430 people, 2432 eyes) of radiation therapy with dosages ranging from 7.5 to 24 Gy. These studies mainly took place in Europe and North America but two studies were from Japan and one multicentre study included sites in South America. Three of these studies investigated brachytherapy (plaque and epimacular), the rest were studies of external beam radiotherapy (EBM) including one trial of stereotactic radiotherapy. Four studies compared radiotherapy combined with anti-vascular endothelial growth factor (anti-VEGF) with anti-VEGF alone. Eleven studies gave no radiotherapy treatment to the control group; five studies used sham irradiation; and one study used very low-dose irradiation (1 Gy). One study used a mixture of sham irradiation and no treatment. Fifteen studies were judged to be at high risk of bias in one or more domains. Radiotherapy versus no radiotherapy There may be little or no difference in loss of 3 lines of vision at 12 months in eyes treated with radiotherapy compared with no radiotherapy (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.64 to 1.04, 811 eyes, 8 studies, I2 = 66%, low-certainty evidence). Low-certainty evidence suggests a small benefit in change in visual acuity (mean difference (MD) -0.10 logMAR, 95% CI -0.17 to -0.03; eyes = 883; studies = 10) and average contrast sensitivity at 12 months (MD 0.15 log units, 95% CI 0.05 to 0.25; eyes = 267; studies = 2). Growth of new vessels (largely change in CNV size) was variably reported and It was not possible to produce a summary estimate of this outcome. The studies were small with imprecise estimates and there was no consistent pattern to the study results (very low-certainty evidence). Quality of life was only reported in one study of 199 people; there was no clear difference between treatment and control groups (low-certainty evidence). Low-certainty evidence was available on adverse effects from eight of 14 studies. Seven studies reported on radiation retinopathy and/or neuropathy. Five of these studies reported no radiation-associated adverse effects. One study of 88 eyes reported one case of possible radiation retinopathy. One study of 74 eyes graded retinal abnormalities in some detail and found that 72% of participants who had radiation compared with 71% of participants in the control group had retinal abnormalities resembling radiation retinopathy or choroidopathy. Four studies reported cataract surgery or progression: events were generally few with no consistent evidence of any increased occurrence in the radiation group. One study noted transient disturbance of the precorneal tear film but there was no evidence from the other two studies that reported dry eye of any increased risk with radiation therapy. None of the participants received anti-VEGF injections. Radiotherapy combined with anti-VEGF versus anti-VEGF alone People receiving radiotherapy/anti-VEGF were probably more likely to lose 3 or more lines of BCVA at 12 months compared with anti-VEGF alone (RR 2.11, 95% CI 1.40 to 3.17, 1050 eyes, 3 studies, moderate-certainty). Most of the data for this outcome come from two studies of epimacular brachytherapy (114 events) compared with 20 events from the one trial of EBM. Data on change in BCVA were heterogenous (I2 = 82%). Individual study results ranged from a small difference of -0.03 logMAR in favour of radiotherapy/anti-VEGF to a difference of 0.13 logMAR in favour of anti-VEGF alone (low-certainty evidence). The effect differed depending on how the radiotherapy was delivered (test for interaction P = 0.0007). Epimacular brachytherapy was associated with worse visual outcomes (MD 0.10 logMAR, 95% CI 0.05 to 0.15, 820 eyes, 2 studies) compared with EBM (MD -0.03 logMAR, 95% CI -0.09 to 0.03, 252 eyes, 2 studies). None of the included studies reported contrast sensitivity or quality of life. Growth of new vessels (largely change in CNV size) was variably reported in three studies (803 eyes). It was not possible to produce a summary estimate and there was no consistent pattern to the study results (very low-certainty evidence). For adverse outcomes, variable results were reported in the four studies. In three studies reports of adverse events were low and no radiation-associated adverse events were reported. In one study of epimacular brachytherapy there was a higher proportion of ocular adverse events (54%) compared to the anti-VEGF alone (18%). The majority of these adverse events were cataract. Overall 5% of the treatment group had radiation device-related adverse events (17 cases); 10 of these cases were radiation retinopathy. There were differences in average number of injections given between the four studies (1072 eyes). In three of the four studies, the anti-VEGF alone group on average received more injections (moderate-certainty evidence). AUTHORS' CONCLUSIONS: The evidence is uncertain regarding the use of radiotherapy for neovascular AMD. Most studies took place before the routine use of anti-VEGF, and before the development of modern radiotherapy techniques such as stereotactic radiotherapy. Visual outcomes with epimacular brachytherapy are likely to be worse, with an increased risk of adverse events,  probably related to vitrectomy. The role of stereotactic radiotherapy combined with anti-VEGF is currently uncertain. Further research on radiotherapy for neovascular AMD may not be justified until current ongoing studies have reported their results.

Radiation Therapy for Benign Disease: Keloids, Macular Degeneration, Orbital Pseudotumor, Pterygium, Peyronie Disease, Trigeminal Neuralgia.

Although the use of ionizing radiation on malignant conditions has been well established, its application on benign conditions has not been fully accepted and has been inadequately recognized by health care providers outside of radiation therapy. Most frequently, radiation therapy in these benign conditions is used along with other treatment modalities, such as surgery, when the condition causes significant disability or could even lead to death. Radiation therapy can be helpful for inflammatory/proliferative disorders. This article discusses the present use of radiation therapy for some of the most common benign conditions.

Subfoveal Choroidal Thickness as a Potential Predictor of Clinical Response to Stereotactic Radiotherapy for Neovascular Age-Related Macular Degeneration.

BACKGROUND AND OBJECTIVE: Stereotactic radiotherapy (SRT) is a new adjuvant treatment modality that has been shown to reduce the need for repetitive intravitreal injections (IVIs) in patients with neovascular age-related macular degeneration (nAMD). The authors aimed to determine baseline predictors of clinical response to SRT. PATIENTS AND METHODS: This was a retrospective, observational case series of patients with nAMD who underwent SRT and subsequently had at least 12 months of complete follow-up. After SRT and one mandatory IVI, patients were examined every 4 weeks and received further treatment on a pro re nata basis. Examination included enhanced depth imaging spectral-domain optical coherence tomography (SD-OCT) to measure subfoveal choroidal thickness (SFCT) and central macular thickness (CMT). Patients' data were retrieved from medical records and included demographics, disease duration, lesion size, best-corrected visual acuity (BCVA), previous number of IVIs, and type of drug applied. RESULTS: A total of 35 eyes of 35 patients (76.23 years ± 7.05 years) were included, and 21 eyes (60%) responded well to SRT. The annual injection rate decreased from 6.86 before SRT to 3.46 afterward, whereas BCVA improved from 0.49 logMAR at baseline to 0.37 logMAR at final follow-up. From a morphologic point of view, CMT and SFCT decreased by 71 µm and 37 µm, respectively, at 12-month follow-up compared to baseline. Of all investigated parameters, only SFCT proved to be significant, as a higher baseline SFCT was found to be a strong negative predictor for the number of IVIs needed after SRT (regression coefficient: -0.678; P < .001). CONCLUSIONS: Baseline SFCT may help predict which patients with nAMD will respond more favorably to SRT. The authors found eyes with a thicker baseline SFCT needed fewer IVIs after SRT. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:320-328.].

Nanosecond Laser Treatment for Age-Related Macular Degeneration Does Not Induce Focal Vision Loss or New Vessel Growth in the Retina.

Purpose: Subthreshold, nanosecond pulsed laser treatment shows promise as a treatment for age-related macular degeneration (AMD); however, the safety profile needs to be robustly examined. The aim of this study was to investigate the effects of laser treatment in humans and mice. Methods: Patients with AMD were treated with nanosecond pulsed laser at subthreshold (no visible retinal effect) energy doses (0.15-0.45 mJ) and retinal sensitivity was assessed with microperimetry. Adult C57BL6J mice were treated at subthreshold (0.065 mJ) and suprathreshold (photoreceptor loss, 0.5 mJ) energy settings. The retinal and vascular responses were analyzed by fundus imaging, histologic assessment, and quantitative PCR. Results: Microperimetry analysis showed laser treatment had no effect on retinal sensitivity under treated areas in patients 6 months to 7 years after treatment. In mice, subthreshold laser treatment induced RPE loss at 5 hours, and by 7 days the RPE had retiled. Fundus imaging showed reduced RPE pigmentation but no change in retinal thickness up to 3 months. Electron microscopy revealed changes in melanosomes in the RPE, but Bruch's membrane was intact across the laser regions. Histologic analysis showed normal vasculature and no neovascularization. Suprathreshold laser treatment did not induce changes in angiogenic genes associated with neovascularization. Instead pigment epithelium-derived factor, an antiangiogenic factor, was upregulated. Conclusions: In humans, low-energy, nanosecond pulsed laser treatment is not damaging to local retinal sensitivity. In mice, treatment does not damage Bruch's membrane or induce neovascularization, highlighting a reduced side effect profile of this nanosecond laser when used in a subthreshold manner.

Aging retinal function is improved by near infrared light (670 nm) that is associated with corrected mitochondrial decline.

Aging is associated with cellular decline and reduced function, partly mediated by mitochondrial compromise. However, aged mitochondrial function is corrected with near infrared light (670 nm) that improves their membrane potentials and adenosine triphosphate production and also reduces age-related inflammation. We ask if 670 nm light can also improve declining retinal function. Electroretinograms were measured in 2-, 7-, and 12-month old C57BL/6 mice. Significant age-related declines were measured in the photoreceptor generated a-wave and the postreceptoral b-wave. Seven- and 12-month-old mice were exposed to 670 nm for 15 minutes daily over 1 month. These showed significant improved retinal function in both waves of approximately 25% but did not reach levels found in 2-month-old animals. Our data suggest, 670 nm light can significantly improve aged retinal function, perhaps by providing additional adenosine triphosphate production for photoreceptor ion pumps or reduced aged inflammation. This may have implications for the treatment of retinal aging and age-related retinal disease, such as macular degeneration.

Stereotactic radiotherapy in neovascular age-related macular degeneration: Real-life efficacy and morphological evaluation of the outer retina-choroid complex.

Stereotactic radiotherapy (SRT) is a new approach to treat neovascular age-related macular degeneration (nAMD). The INTREPID trial suggested that SRT could reduce the frequency of regular intravitreal injections (IVIs) with antivascular endothelial growth factor drugs, which are necessary to control disease activity. However, the efficacy of SRT in nAMD and resulting morphological changes have not been validated under real-life circumstances, an issue, which we would like to address in this retrospective analysis.Patients who met the INTREPID criteria for best responders were eligible for SRT. A total of 32 eyes of 32 patients were treated. Thereafter, patients were examined monthly for 12 months and received pro re nata IVI of aflibercept or ranibizumab. Outcome measures were: mean number of injections, best-corrected visual acuity, and morphological changes of the outer retina-choroid complex as well as patient safety.Mean number of IVI decreased by almost 50% during the 12 months after SRT compared to the year before, whereas visual acuity increased by one line (logMAR). Morphological evaluation showed that most changes affect outer retinal layers.Stereotactic radiotherapy significantly reduced IVI retreatment in nAMD patients under real-life circumstances. Therefore, SRT might be the first step to stop visual loss as a result of IVI undertreatment, which is a major risk.

Mitochondrial decline precedes phenotype development in the complement factor H mouse model of retinal degeneration but can be corrected by near infrared light.

Mitochondria produce adenosine triphosphate (ATP), critical for cellular metabolism. ATP declines with age, which is associated with inflammation. Here, we measure retinal and brain ATP in normal C57BL/6 and complement factor H knockout mice (Cfh(-/-)), which are proposed as a model of age-related macular degeneration. We show a significant premature 30% decline in retinal ATP in Cfh(-/-) mice and a subsequent shift in expression of a heat shock protein that is predominantly mitochondrial (Hsp60). Changes in Hsp60 are associated with stress and neuroprotection. We find no differences in brain ATP between C57BL/6 and Cfh(-/-) mice. Near infrared (NIR) increases ATP and reduces inflammation. ATP decline in Cfh(-/-) mice was corrected with NIR which also shifted Hsp60 labeling patterns. ATP decline in Cfh(-/-) mice occurs before inflammation becomes established and photoreceptor loss occurs and may relate to disease etiology. However, ATP levels were corrected with NIR. In summary, we provide evidence for a mitochondrial basis for this disease in mice and correct this with simple light exposure known to improve mitochondrial function.

Pre-exposure to low-power diode laser irradiation promotes cytoprotection in the rat retina.

The aim of this study was to investigate whether pre-exposure to low-power laser irradiation can provoke an effect on cellular protection in the rat retina. The right eyes of 40 rats were exposed to a 3-mm diode laser beam for 1 min in different light intensities and different experimental sets: group A low power of 60 mW (34.27 J/cm(2) on the retina in consideration of the energy losses along the optical pathway) prior to high power of 80 mW (44.88 J/cm(2) on the retina in consideration of the energy losses along the optical pathway), group B high power, group C low power, group D (the left eyes from the counterpart of group A) and group E (untreated rat eyes) as controls. Morphological retinal change retinas were assessed using light microscopy and/or transmission electron microscopy. Heat shock protein (Hsp) 70 and cleaved caspase 3 protein expression were analyzed by immunohistochemical staining and Western blot. Cellular injury was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Hsp 70 expression in the inner plexiform layer and the outer plexiform layer in group A were 73.09 ± 6.49 and 78.03 ± 3.05%, respectively, which was significantly higher (P < 0.05) than those observed in group B (59.07 ± 1.40 and 32.25 ± 4.26%, respectively). The Hsp70/ß-actin ratio was 0.49 ± 0.06 in group C, which was significantly higher (P < 0.05) than that of group B (0.27 ± 0.04). Cleaved caspase 3 expression in group C both was significantly lower than that observed in group B. TUNEL staining showed that positive cells in the outer nuclear layer and inner nuclear layer in group A were significantly lower than those of group B. Pre-exposure to a 60-mW (34.27 J/cm(2) on the retina) power laser irradiation stimulates a hyperexpression of Hsp70 together with a hypoexpression of cleaved caspase 3 in rat retina, which may suggest a cellular protective effect.

ITAR: A modified TAR method to determine depth dose distribution for an ophthalmic device that performs kilovoltage x-ray pencil-beam stereotaxy.

PURPOSE: New technology has been developed to treat age-related macular degeneration (AMD) using 100 kVp pencil-beams that enter the patient through the radio-resistant sclera with a depth of interest between 1.6 and 2.6 cm. Measurement of reference and relative dose in a kilovoltage x-ray beam with a 0.42 cm diameter field size and a 15 cm source to axis distance (SAD) is a challenge that is not fully addressed in current guidelines to medical physicists. AAPM's TG-61 gives dosimetry recommendations for low and medium energy x-rays, but not all of them are feasible to follow for this modality. METHODS: An investigation was conducted to select appropriate equipment for the application. PTW's Type 34013 Soft X-Ray Chamber (Freiburg, Germany) and CIRS's Plastic Water LR (Norfolk, VA) were found to be the best available options. Attenuation curves were measured with minimal scatter contribution and thus called Low Scatter Tissue Air Ratio (LSTAR). A scatter conversion coefficient (C(scat)) was derived through Monte Carlo radiation transport simulation using MCNPX (LANL, Los Alamos, NM) to quantify the difference between a traditional TAR curve and the LSTAR curve. A material conversion coefficient (C(mat)) was determined through experimentation to evaluate the difference in attenuation properties between water and Plastic Water LR. Validity of performing direct dosimetry measurements with a source to detector distance other than the treatment distance, and therefore a different field size due to a fixed collimator, was explored. A method--Integrated Tissue Air Ratio (ITAR)--has been developed that isolates each of the three main radiological effects (distance from source, attenuation, and scatter) during measurement, and integrates them to determine the dose rate to the macula during treatment. RESULTS: LSTAR curves were determined to be field size independent within the range explored, indicating that direct dosimetry measurements may be performed with a source to detector distance of 20 cm even though the SAD is 15 cm during treatment. C(scat) varied from 1.102 to 1.106 within the range of depths of interest. The experimental variance among repeated measurements of C(mat) was larger than depth dependence, so C(mat) was estimated as1.019 for all depths of interest. CONCLUSIONS: Equipment selection, measurement techniques, and formalism for the determination of dose rate to the macula during stereotaxy for AMD have been determined and are strongly recommended by the authors of this paper to be used by clinical medical physicists.

Nanosecond-laser application in intermediate AMD: 12-month results of fundus appearance and macular function.

BACKGROUND: A novel, ultra-low energy nanosecond laser (retinal rejuvenation therapy) has been developed with the aim to slow progression of early age-related macular degeneration (AMD). The safety, changes in fundus characteristics and macular function in a cohort of participants with bilateral intermediate AMD are reported. DESIGN: Prospective non-randomised, pilot intervention study. PARTICIPANTS OR SAMPLES: Subjects with bilateral intermediate AMD (n = 50, aged 50-75 years). METHODS: Ultra-low energy laser pulses applied in 12 spots around the macula of one eye (0.15-0.45 mJ), using 400 µm diameter spot, 3 nanosecond pulse length, 532 nm wavelength and energy titrated to each patient. MAIN OUTCOME MEASURES: Best corrected visual acuity, drusen area and macular sensitivity (flicker perimetry) at baseline and at 3, 6 and 12 months post-laser. RESULTS: Treatment was painless with no clinically visible lesions. No participant developed choroidal neovascularization, while two with thin central retinal thickness at baseline developed atrophy at 12-month follow up. Drusen area was reduced in 44% of treated eyes and 22% of untreated fellow eyes, with changes in drusen and function not being coincident. Improvement in flicker threshold within the central 3° was observed in both the treated and untreated fellow eyes at 3 months post-laser. Of the 11 eyes at greatest risk of progression (flicker defect >15 dB), seven improved sufficiently to be taken out of this high-risk category. CONCLUSIONS: A single unilateral application of nanosecond laser to the macula produced bilateral improvements in macula appearance and function. The nanosecond retinal rejuvenation therapy laser warrants ongoing evaluation as an early intervention for AMD.