Dietary supplements in retinal diseases, glaucoma, and other ocular conditions.

Environmental pollution, inadequate eating habits and unhealthy lifestyles have led to a tremendous increase in ocular diseases worldwide. Given the costly treatments that are currently available for the most common and threatening eye diseases (such as cataract, dry eye disorder, or diabetic retinopathy), curing these diseases or preventing refractive errors by taking nutraceuticals and natural compounds that are present in our daily diet is a very valuable intervention. The eyes are the most important part of our visual system and require micronutrients such as vitamins, carotenoids, trace metals, and omega-3 fatty acids in order to function properly and to protect themselves against light-induced and age-mediated degenerative disorders. The Mediterranean Diet (MedDiet) has been in the limelight since the 1980s because of the several health benefits it provides, including eye health. MedDiet is characterized by the consumption of small amounts of red meat, while emphasizing the intake of fish, eggs, nuts, legumes, citrus fruits, green vegetables, olives and their derivatives, especially olive oil, and dairy products in a proportionate manner, in order to achieve the maximum health benefits. The antioxidant, anti-inflammatory, and neuroprotective properties of these foods - both when used as an ingredient in the dietary regime or as a source of nutritional supplements - have shown promising results in the management of chronic degenerative ocular diseases, both in animal models and in human subjects. In this chapter, we will focus on the importance of MedDiet and natural compounds for the visual system and its role in slowing down age-related ocular degeneration.

Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy.

Retinal oxidative damage, associated with an ATP-binding cassette, sub-family A, member 4, also known as ABCA4 gene mutation, has been implicated as a major underlying mechanism for Stargardt disease/fundus flavimaculatus (STG/FF). Recent findings indicate that saffron carotenoid constituents crocins and crocetin may counteract retinal oxidative damage, inflammation and protect retinal cells from apoptosis. This pilot study aimed to evaluate central retinal function following saffron supplementation in STG/FF patients carrying ABCA4 mutations. METHODS: in a randomized, double-blind, placebo-controlled study (clinicaltrials.gov: NCT01278277), 31 patients with ABCA4-related STG/FF and a visual acuity >0.25 were randomly assigned to assume oral saffron (20 mg) or placebo over a six month period and then reverted to P or S for a further six month period. Full ophthalmic examinations, as well as central 18° focal electroretinogram (fERG) recordings, were performed at baseline and after six months of either saffron or placebo. The fERG fundamental harmonic component was isolated by Fourier analysis. Main outcome measures were fERG amplitude (in µV) and phase (in degrees). The secondary outcome measure was visual acuity. RESULTS: supplement was well tolerated by all patients throughout follow-up. After saffron, fERG amplitude was unchanged; after placebo, amplitude tended to decrease from baseline (mean change: -0.18 log µV, p < 0.05). Reverting the treatments, amplitude did not change significantly. fERG phase and visual acuity were unchanged throughout follow-up. CONCLUSIONS: short-term saffron supplementation was well tolerated and had no detrimental effects on the electroretinographic responses of the central retina and visual acuity. The current findings warrant further long-term clinical trials to assess the efficacy of saffron supplementation in slowing down the progression of central retinal dysfunction in ABCA4-related STG/FF.

Doyne honeycomb retinal dystrophy - functional improvement following subthreshold nanopulse laser treatment: a case report.

BACKGROUND: Based on phenotypic similarities between age-related macular degeneration and the autosomal disorder Doyne honeycomb retinal dystrophy, we report on a single nanolaser treatment of a patient with genotype Doyne honeycomb retinal dystrophy confirmation and evidence of disease progression over 12 months. The case study is the first report of short-term results of subthreshold nanolaser treatment in a patient with Doyne honeycomb retinal dystrophy. CASE PRESENTATION: A 43-year-old Caucasian man with moderate loss of visual acuity in his left eye (20/40) and normal visual acuity in his right eye (20/20), with clinical Doyne honeycomb retinal dystrophy diagnosis and genetic confirmation of the common heterozygous mutation (EFEMP1) by genetic testing, underwent nanopulse subthreshold laser treatment in his left eye. A safety examination, carried out 7 days after treatment, and clinical follow-up, conducted 60 days following laser treatment, showed improvement of visual acuity from baseline by two letters and a subjective improvement of blurring. While no apparent morphological changes were found on fundoscopy, increased autofluorescence in the treated eye was observed on imaging. In addition, 2 months after nanopulse subthreshold laser treatment, rod-mediated and cone-mediated full-field electroretinography b-wave amplitudes showed an increase from baseline in both the treated eye (300%) and untreated eye (50%). At 2 months after nanopulse subthreshold laser treatment, multifocal electroretinograms showed improvement. Acuity and full-field electroretinography improvement persisted at 6-month follow-up. CONCLUSIONS: Sustained improvements in retinal function on electroretinography persisted in both eyes 6 months after treatment, suggesting an enhancement of phototransduction and retinoid recycling induced by nanopulse subthreshold laser treatment. The functional improvement observed in the untreated eye is hypothesized to arise from an increased expression and release of metalloproteinases that circulate systemically.

Neurotrophin family members as neuroprotectants in retinal degenerations.

BACKGROUND AND OBJECTIVES: Inherited retinal degenerations (IRDs) are an untreatable cause of blindness due to photoreceptor apoptosis. Blocking apoptosis by exogenous neurotrophic factor administration is a promising therapeutic strategy in IRDs. The neurotrophin (NT) family are a group of peptide growth factors homologous to nerve growth factor that regulate the development, differentiation, survival, and function of neuronal cells. This mini-review summarizes the preclinical evidence for neuroprotection of photoreceptors by NTs and explores the molecular pathways responsible for this protective effect. METHODS: Studies published in the literature over the past 20 years that report on the effect of NTs on apoptotic photoreceptor death in IRDs and light-induced retinal degeneration, and the cellular pathways involved, are reviewed. RESULTS: Preclinical evidence suggests that exogenous NT administration may be protective against photoreceptor apoptosis. Each NT exerts a neuroprotective effect on photoreceptors that is specific depending upon the model of retinal degeneration and the delivery system. Signaling pathways and retinal cells mediating this effect are still uncertain. Alternatively, different NTs may protect or damage photoreceptors depending on the expression pattern of high- and low-affinity NT receptors on the retinal cells. CONCLUSIONS: Although there is evidence that NTs may exert a protective effect, most likely indirectly on photoreceptor cell apoptotic degeneration in IRDs, the precise cellular and molecular mechanisms underlying this effect are still largely unknown. Better understanding of these mechanisms may greatly improve the rationale and efficacy of NT strategy for treatment of IRDs.

Saffron and retina: neuroprotection and pharmacokinetics.

Age-related macular degeneration (AMD) is a retinal neurodegenerative disease whose development and progression are the results of a complex interaction between genetic and environmental risk factors. Both oxidative stress and chronic inflammation play a significant role in the pathogenesis of AMD. Experimental studies in rats with light-induced photoreceptors degeneration demonstrated that saffron may protect photoreceptor from retinal stress, preserving both morphology and function and probably acting as a regulator of programmed cell death, in addition to its antioxidant and anti-inflammatory properties. Recently, a randomized clinical trial showed that in patients with early AMD, dietary supplementation with saffron was able to improve significantly the retinal flicker sensitivity suggesting neuroprotective effect of the compound. Here, we examine the progress of saffron dietary supplementation both in animal model and AMD patients, and discuss the potential and safety for using dietary saffron to treat retinal degeneration.

Functional effect of Saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report.

BACKGROUND: To determine whether the functional effects of oral supplementation with Saffron, a natural compound that proved to be neuroprotective in early age-related macular degeneration, are influenced by complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk genotypes. METHODS: Thirty-three early AMD patients, screened for CFH (rs1061170) and ARMS2 (rs10490924) polymorphisms and receiving Saffron oral supplementation (20 mg/day) over an average period of treatment of 11 months (range, 6-12), were longitudinally evaluated by clinical examination and focal electroretinogram (fERG)-derived macular (18°) flicker sensitivity estimate. fERG amplitude and macular sensitivity, the reciprocal value of the estimated fERG amplitude threshold, were the main outcome measures. RESULTS: After three months of supplementation, mean fERG amplitude and fERG sensitivity improved significantly when compared to baseline values (p < 0.01). These changes were stable throughout the follow-up period. No significant differences in clinical and fERG improvements were observed across different CFH or ARMS2 genotypes. CONCLUSIONS: The present results indicate that the functional effect of Saffron supplementation in individual AMD patients is not related to the major risk genotypes of disease.

Occipital porencephaly in a child with gyrate atrophy of the choroid and retina.

A 4-year-old girl was hospitalized for psychomotor delay, low vision, and horizontal nystagmus. She was found to have bilateral chorioretinal atrophic scars and 2 large occipital porencephalic cavities. High plasma ornithine levels led to the presumed diagnosis of gyrate atrophy of the choroid and retina. After 6 months of arginine-restricted diet and high-dose pyridoxine (300 mg/d), there was no change of plasma ornithine level or ocular findings. To our knowledge, this is the first report showing an association of porencephaly with gyrate atrophy of the choroid and retina.

Influence of saffron supplementation on retinal flicker sensitivity in early age-related macular degeneration.

PURPOSE: To evaluate the functional effect of short-term supplementation of saffron, a spice containing the antioxidant carotenoids crocin and crocetin, in early age-related macular degeneration (AMD). METHODS: Twenty-five patients with AMD were randomly assigned to oral saffron 20 mg/d or placebo supplementation over a 3-month period and then reverted to placebo or saffron for a further 3 months. Focal electroretinograms (fERGs) and clinical findings were recorded at baseline and after 3 months of saffron or placebo supplementation. fERGs were recorded in response to a sinusoidally modulated (41 Hz), uniform field presented to the macular region (18°) at different modulations between 16.5% and 93.5%. Main outcome measures were fERG amplitude (in microvolts), phase (in degrees), and modulation thresholds. RESULTS: After saffron, patients' fERGs were increased in amplitude, compared with either baseline or values found after placebo supplementation (mean change after saffron, 0.25 log µV; mean change after placebo, -0.003 log µV; P < 0.01). fERG thresholds were decreased after saffron supplementation but not placebo, compared with baseline (mean change after saffron, -0.26 log units; mean change after placebo, 0.0003 log units). CONCLUSIONS: The results indicate that short-term saffron supplementation improves retinal flicker sensitivity in early AMD. Although the results must be further replicated and the clinical significance is yet to be evaluated, they provide important clues that nutritional carotenoids may affect AMD in novel and unexpected ways, possibly beyond their antioxidant properties. (ClinicalTrials.gov number, NCT00951288.).

Effect of epigallocatechin-gallate on inner retinal function in ocular hypertension and glaucoma: a short-term study by pattern electroretinogram.

BACKGROUND: Epigallocatechin-gallate (EGCG) is a powerful antioxidant with suggested neuroprotective action. The aim of this study was to evaluate the effect of short-term supplementation of EGCG on inner retinal function in ocular hypertension (OHT) and open-angle glaucoma (OAG). METHODS: Eighteen OHT and 18 OAG patients (perimetric mean deviation: >-10 dB) were randomly assigned to assume oral placebo or EGCG over a 3-month period in a randomized, placebo-controlled, double-blind, cross-over design clinical trial (clinicaltrials.gov identifier: NCT00476138). Pattern-evoked electroretinograms (PERGs) to 1.6 cycles/degree square-wave gratings, counterphased at 16 reversals/second, and standard automated perimetry (Humphrey 30-2) were assessed at the study entry (baseline), and after 3 months of placebo or EGCG. RESULTS: After EGCG, PERGs of OAG, but not OHT patients were increased in amplitude, compared either to baseline values (mean amplitude change: 0.06 log microV, p < 0.05) or to PERG amplitude values found in the same patients after placebo administration (mean change: -0.02 log microV, p not significant; difference between EGCG and placebo: 0.08 log microV, p < 0.05). In both OHT and OAG patients, standard automated perimetry did not show significant changes after either EGCG or placebo. In individual OAG patients, the magnitude of PERG amplitude increment after EGCG was inversely related (r = -0.8, p < 0.01) to corresponding baseline amplitudes. CONCLUSIONS: Although this study cannot provide evidence for long-term benefit of EGCG supplementation in OAG, and the observed effect is small, the results suggest that EGCG might favourably influence inner retinal function in eyes with early to moderately advanced glaucomatous damage.

Retinal function following transpupillary thermotherapy for occult choroidal neovascularization in age-related macular degeneration: a short-term study by focal electroretinography.

PURPOSE: To assess short-term changes in macular function after transpupillary thermotherapy (TTT) in patients with occult subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), using focal electroretinography (FERG). METHODS: Twenty-five patients with occult subfoveal CNV due to AMD were treated with TTT delivered using an infrared (810 nm) diode laser (spot size 3.0 mm, laser power 400-600 mW, duration 60 seconds). All patients were clinically evaluated before, 1 and 6 weeks after treatment. Snellen visual acuity (VA) was measured at each visit. Fluorescein angiography (FA) was performed at baseline and 6 weeks after TTT. Focal ERGs were recorded in all patients immediately before and 1 week after TTT in response to an 18-degree diameter, 41 Hz flickering spot (630 nm) centred on the fovea, presented on a steady background in Maxwellian view. A subgroup of 12 patients was also re-tested by FERG at 6-weeks post-TTT. RESULTS: No significant changes in mean FERG amplitude and phase were observed across the different recording sessions before and after TTT. One week after TTT, four patients had significant (> 2 SD from baseline variability) increases in FERG amplitude and/or phase advances, one had a decrease in amplitude and four had phase delays, compared to baseline. The remaining 15 patients had stable FERGs. Six weeks after TTT, four patients had significant increases in FERG amplitude and/or phase advances, four had decreases in amplitude and/or phase delays, and four had stable FERGs, compared to baseline. Improvement in FERG parameters after TTT was always associated with an improvement in VA and a decrease in exudation. Patients with post-TTT FERG deterioration had stable or deteriorated clinical pictures. At either 1 or 6 weeks post-TTT, the FERG amplitude increase was inversely correlated (p < 0.05) with the baseline FERG amplitude and VA. CONCLUSIONS: Three major conclusions can be drawn: in a short-term follow-up, TTT was not found to be associated with significant changes in macular function; FERG improvement was associated with VA improvement, and the increase in FERG amplitude was greatest in patients with the worst baseline acuity.

Monitoring retinal function during transpupillary thermotherapy for occult choroidal neovascularization in age-related macular degeneration.

PURPOSE: To use focal electroretinography to evaluate changes in retinal function during transpupillary thermotherapy (TTT) for neovascular age-related macular degeneration (ARMD). METHODS: Sixteen eyes of 16 patients with ARMD with occult choroidal neovascularization (CNV) were studied. A 630-nm photocoagulator aiming beam was modified for use as a 41-Hz square-wave focal electroretinogram (fERG) stimulus. The stimulus was presented on a light-adapting background by a Goldmann-type lens (visual angle, 18 degrees; mean luminance, 50 cd/m(2)). fERGs were continuously monitored before, during, and after TTT for occult CNV. The amplitude and phase of the fERG's fundamental harmonic were measured. RESULTS: No suprathreshold or adverse clinical events occurred during the course of the study. fERG amplitude decreased transiently during TTT (23% +/- 9% [SE]; P < 0.05). The decrease in amplitude was greatest 16 to 20 seconds and 32 to 40 seconds after the onset of TTT. It was followed by a recovery to baseline amplitude during TTT (48 to 60 seconds after TTT was begun). Within 60 seconds after TTT was completed, fERG amplitude was within the range of baseline. TTT did not alter the fERG phase. Mean fERG amplitudes and phases recorded 1 week and 1 month after TTT were comparable to mean pretreatment levels. CONCLUSIONS: fERG amplitude decreases transiently during TTT, despite the absence of ophthalmoscopically apparent lesions. Intraoperative amplitude depression may result from an adaptation effect to laser light energy and/or hyperthermia, resulting in desensitization of cone photoreceptors and bipolar cells. Treatment sites are electrophysiologically functional 1 month after TTT. Detailed parametric study of a larger patient group is needed to determine whether fERG testing is potentially useful for monitoring and perhaps for controlling and optimizing TTT for choroidal neovascularization.

Influence of short-term antioxidant supplementation on macular function in age-related maculopathy: a pilot study including electrophysiologic assessment.

PURPOSE: To evaluate the influence of short-term antioxidant supplementation on retinal function in age-related maculopathy (ARM) patients by recording focal electroretinograms (FERGs). DESIGN: Nonrandomized, comparative clinical trial. PARTICIPANTS: Thirty patients with early ARM and visual acuity >/=20/30, divided into two groups, similar for age and disease severity: antioxidant group (ARM-A, n = 17) and no treatment group (ARM-NT, n = 13). Eight age-matched normal subjects divided into antioxidant (N-A, n = 4) or no treatment (N-NT, n = 4) groups. METHODS: ARM-A patients and N-A patients had oral supplementation of lutein, 15 mg; vitamin E, 20 mg; and nicotinamide, 18 mg, daily for 180 days, whereas ARM-NT patients and N-NT patients had no dietary supplementation during the same period. Eight of the 17 ARM-A patients took supplementation for an additional 180-day period. In all patients and normal subjects, FERG assessment was performed at the study entry (baseline) and after 180 days. Further testing was performed at 360 days for the eight ARM-A patients taking supplements and for one ARM-A patient who had discontinued supplementation after 180 days. FERGs were recorded in response to a 41-Hz sinusoidally modulated uniform field (93.5% modulation depth) presented to the macular region (18 degrees ) on a light-adapting background. In a subgroup of patients (11 ARM-A and 5 ARM-NT), whose responses had suitable signal-to-noise ratios, FERGs were also recorded at different stimulus modulation depths between 8.25% and 93.5%. MAIN OUTCOME AND MEASURES: Amplitude (in micro V) and phase (in degrees) of the FERG fundamental harmonic component. FERG modulation thresholds, estimated from the value of log modulation depth yielding a criterion response. RESULTS: At 180 days, FERGs of ARM-A patients and N-A patients were increased in amplitude (mean change, 0.11 and 0.15 log micro V, respectively, P