The retina continuously receives light to enable vision, and the related processes require a marked amount of energy. During active metabolism, reactive oxygen species (ROS) are generated in ...exchange. Although physiologically generated ROS may be removed by endogenous antioxidant systems, and the effects of oxidative stress may be recovered by repair systems to retain homeostasis and health, when ROS and oxidative stress exceed the capacity of the antioxidant and repair systems, the condition becomes pathological. Multiple mechanisms of oxidative stress and the effects of antioxidant and repair systems in the retina have long been analyzed using light-induced retinal degeneration models. Among the mechanisms, a positive feedback loop of oxidative stress and related inflammation may be involved in the pathogenesis of a blinding aging disease, age-related macular degeneration. Treatments for suppressing ROS and oxidative stress by administrating antioxidant products may support the tissue-protective function of antioxidant systems. Moreover, recent studies have proposed a new concept for maintaining homeostasis by supplying sufficient energy to activate the repair systems. The current review will help elucidate the influence of oxidative stress and guide future analyses to explore new therapeutic approaches for oxidative stress-mediated diseases.
•Vision formation requires marked amounts of energy and produces ROS.•Balanced oxidative stress and antioxidant/repair systems determine cellular health.•ROS-modified molecules affect multiple pathways to cause cell death and disorders.•A positive feedback loop of oxidative stress/related inflammation may lead to AMD.•Homeostasis can be retained by supplying enough energy to activate repair systems.
PurposeThe purpose of this study was to identify early changes in choriocapillaris flow in patients with age-related macular degeneration (AMD) with no history of macular neovascularization (MNV). ...MethodsClinical records of fellow eyes of patients with unilateral neovascular AMD without fundus findings and control eyes of otherwise healthy individuals, except for mild cataract, diagnosed at St. Luke's International Hospital from April 2020 to March 2021, were retrospectively analyzed. Optical coherence tomography (OCT) angiography images of the choriocapillaris slab were binarized using the Phansalkar local thresholding methods to evaluate the choriocapillaris flow area (CCFA) and its coefficient of variation (CV). ResultsThe data of 24 AMD fellow eyes (17 for men, 71.7 ± 1.9 years old) and 21 control eyes (11 for men, 69.1 ± 2.0 years old) were analyzed. The mean CCFA ratio was lower in the AMD fellow eyes (58.6 ± 1.2%) than in the control eyes (62.4 ± 1.3%, P = 0.032), and the mean CV of CCFA ratio was greater in the AMD fellow eyes (0.174 ± 0.007) than in the control eyes (0.154 ± 0.007, P = 0.032). Eyes with CCFA ratio <60% and CV of CCFA ratio ≥0.154 had a 4.371-fold higher risk of being AMD fellow eyes (95% confidence interval = 1.029-18.56, P = 0.046). Differences in CV of CCFA ratio between AMD fellow eyes and control eyes were particularly clear in eyes with thick choroids (mean CV of CCFA in control versus AMD fellow eyes with central choroidal thickness ≥220 µm: 0.144 ± 0.005 vs. 0.173 ± 0.007, P = 0.009**). ConclusionsNeovascular AMD fellow eyes without MNV had reduced, heterogeneous, and imbalanced choriocapillaris flow, which may constitute early changes in neovascular AMD, although further studies are required.
Patient systemic and ocular data based on optical coherence tomography (OCT) and OCT angiography images were analyzed (n = 45; control and diabetic eyes with or without diabetic retinopathy DR; mean ...age, 49.6 ± 8.1 years). All participants had best-corrected visual acuity < 0.05 in logMAR. The choriocapillaris flow area (CCFA) ratio was lower and the coefficient of variation (CV) of CCFA ratio was higher in diabetic eyes with or without DR than in control eyes. CCFA ratio of DR eyes was lower than that of diabetic eyes without DR. Superficial retinal vessel length density (VLD) was reduced only in DR eyes. CCFA ratio correlated with retinal VLD, photoreceptor outer segment (PROS) length, and retinal pigment epithelium (RPE) volume in the study population; mean PROS decreased in diabetic eyes with or without DR, and RPE volume increased in DR eyes. CCFA ratio < 65.9% and CV of CCFA ratio ≥ 0.140 were more frequently found in diabetic eyes (odds ratio OR, 13.333; P = 0.001), and related to HbA1c ≥ 7.0% (OR, 4.992; 95% confidence interval CI 1.164-21.412; P = 0.030) or systolic blood pressure ≥ 135 mmHg (OR, 5.572; 95% CI 1.156-26.863; P = 0.032). These findings could help understand diabetic pathogenesis in the choriocapillaris and outer retina, and remind clinicians to manage both diabetes and hypertension.
The visual function of diabetic eyes was assessed to evaluate spatial-sweep steady-state pattern electroretinography (swpPERG) as a potential high-sensitivity analysis method. Data from 24 control ...eyes, 28 diabetic eyes without diabetic retinopathy (DR), and 30 diabetic eyes with DR (all with best-corrected visual acuity BCVA better than logMAR 0.05; median age, 51) in response to spatial-patterned and contrast-reversed stimuli of sizes 1 (thickest) to 6 were converted into the frequency domain using a Fourier transform and expressed as signal-to-noise ratios (SNRs). SNRs of diabetic eyes, both with and without DR, were lower than those of controls (P < 0.05), and those of DR eyes were lower than those of diabetic eyes without DR (P < 0.05). The SNRs were correlated with ganglion cell layer volume measured using optical coherence tomography (OCT) and foveal vascular length density at the superficial retinal layer measured using OCT angiography (P < 0.05 or < 0.01, according to stimulus size). Therefore, swpPERG SNRs could detect fine reductions in visual function in diabetic eyes and were particularly low in DR eyes. Moreover, SNRs were correlated with inner retinal morphological changes in diabetic eyes, both with and without DR. swpPERG may therefore be useful for detecting fine fluctuations in visual function in diabetic eyes.
To explore the factors associated with best-corrected visual acuity (BCVA) after anti-vascular endothelial growth factor (anti-VEGF) treatment for macular edema secondary to central retinal vein ...occlusion (CRVO). We retrospectively reviewed the medical charts of 22 eyes of 22 treatment-naïve patients with CRVO diagnosed between September 2014 and December 2020. They received anti-VEGF treatment and follow-up for > 12 months. Mean patient age was 64.3 years; 13 (59.1%) were men. Eyes with baseline arm-to-retina (AR) time ≥ 16 s had better BCVA at 12 months (adjusted for baseline BCVA and age; B, - 0.658; 95% confidence interval - 1.058 to - 0.257; P = 0.003), greater mean BCVA change (P = 0.006), lower frequency of residual macular edema at 12 months (P = 0.026) and recurrent and/or unresolved macular edema during 12 months (P = 0.046), and higher frequency of reduction in central retinal thickness ≥ 150 μm at 1 and 12 months (both P = 0.046). Delayed AR time was associated with a better visual outcome and macular edema improvement in CRVO after anti-VEGF treatment regardless of initial BCVA and age. Our results may help understand the pathogenesis and predict the visual prognosis of patients before anti-VEGF therapy initiation.
To evaluate dynamic circulatory flow in the retinal or choroidal circulatory disease, we retrospectively reviewed medical charts of 128 eyes of 128 patients who underwent video recorded fluorescein ...angiography (FA), at Department of Ophthalmology, St Luke's International Hospital, between April and September 2020. Mean age was 64.2 ± 14.0 (range 37-93) years, and 87 (67.9%) patients were men. Mean arm-to-retina (AR) time was 16.2 ± 4.1 s, and mean retinal circulation (RC) time was 10.9 ± 3.3 s. Mean RC time/AR time (RC/AR) ratio was 0.69 ± 0.22. AR time was correlated with age, whereas RC time was not. RC time was positively correlated with AR time (R = 0.360, P = 0.017). Moreover, mean RC time was significantly longer, and RC/AR ratio was greater, in the retinal-disease group after adjusting for age and sex. Patients who had an RC/AR ratio ≥ 0.8 more frequently presented with retinal diseases. RC time and RC/AR ratio were negatively correlated with systolic blood pressure only in the retinal-disease group. Given that AR time reflects systemic hemodynamics, RC time, which reflects local circulatory fluency, was influenced by the systemic circulatory condition. Moreover, RC/AR ratio revealed that circulatory changes peculiar to the retina may also be involved in retinal-disease pathogenesis. This study may help elucidate the mechanisms of retinal diseases and assist in diagnosis, although further studies are required.
To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD).
Retrospective case series.
Forty-two patients who were diagnosed with STGD in ...childhood at a single institution between January 2001 and January 2012.
A detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next-generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients.
Clinical, imaging, electrophysiologic, and molecular genetic findings.
The median ages of onset and the median age at baseline examination were 8.5 (range, 3–16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD.
Childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease.
Lutein slows the progression of age-related macular degeneration (AMD), a leading cause of blindness in ageing societies. However, the underlying mechanisms remain elusive. Here, we evaluated ...lutein's effects on light-induced AMD-related pathological events. Balb/c mice exposed to light (2000 lux, 3 h) showed tight junction disruption in the retinal pigment epithelium (RPE) at 12 h, as detected by zona occludens-1 immunostaining. Substantial disruption remained 48 h after light exposure in the vehicle-treated group; however, this was ameliorated in the mice treated with intraperitoneal lutein at 12 h, suggesting that lutein promoted tight junction repair. In the photo-stressed RPE and the neighbouring choroid tissue, lutein suppressed reactive oxygen species and increased superoxide dismutase (SOD) activity at 24 h, and produced sustained increases in sod1 and sod2 mRNA levels at 48 h. SOD activity was induced by lutein in an RPE cell line, ARPE19. We also found that lutein suppressed upregulation of macrophage-related markers, f4/80 and mcp-1, in the RPE-choroid tissue at 18 h. In ARPE19, lutein reduced mcp-1 mRNA levels. These findings indicated that lutein promoted tight junction repair and suppressed inflammation in photo-stressed mice, reducing local oxidative stress by direct scavenging and most likely by induction of endogenous antioxidant enzymes.
TAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca including pleural effusion and ascites, fever, renal insufficiency, and organomegaly including ...hepatosplenomegaly and lymphadenopathy. Its onset may be acute or sub-acute, but its etiology is undetermined. Although several clinical and pathological characteristics of TAFRO syndrome resemble those of multicentric Castleman disease (MCD), other specific features can differentiate between them. Some TAFRO syndrome patients have been successfully treated with glucocorticoids and/or immunosuppressants, including cyclosporin A, tocilizumab and rituximab, whereas others are refractory to treatment, and eventually succumb to the disease. Early and reliable diagnoses and early treatments with appropriate agents are essential to enhancing patient survival. The present article reports the 2015 updated diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, as formulated by Japanese research teams. These criteria and classification have been applied and retrospectively validated on clinicopathologic data of 28 patients with this and similar conditions (e.g. MCD with serositis and thrombocytopenia).
Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the ...influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. At 3 weeks of age, visual function impairment, specifically photoreceptor dysfunction, as recorded by electroretinography (ERG), was evident in homozygous, but not heterozygous, Adipor1 KO mice. However, although photoreceptor loss was evident at 3 weeks of age and progressed until 10 weeks, the level of visual dysfunction was already substantial by 3 weeks, after which it was retained until 10 weeks of age. The rhodopsin mRNA levels had already decreased at 3 weeks, suggesting that reduced rhodopsin may have contributed to early visual loss. Moreover, inflammation and oxidative stress were induced in homozygous KO retinas. Prior to observation of photoreceptor loss via optical microscopy, electron microscopy revealed that POSs were present; however, they were misaligned and their lipid composition, including docosahexaenoic acid (DHA), which is critical in forming POSs, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids expressed in the PIS, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in homozygous KO mice. The causal relationship between ADIPOR1 deficiency and Elovl2 repression, together with upregulation of lipogenic genes, was confirmed in vitro. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required to supply sufficient DHA for appropriate photoreceptor function and survival.
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