Macular dystrophy associated with the mitochondrial DNA A3243G mutation: pericentral pigment deposits or atrophy? Report of two cases and review of the literature.

BACKGROUND: The A3243G point mutation in mitochondrial DNA (mtDNA) is associated with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and MIDD syndromes (maternally inherited diabetes and deafness). Both MELAS and MIDD patients can present with visual symptoms due to a retinopathy, sometimes before the genetic diagnosis is made. CASE PRESENTATION: Patient 1: 46 year-old woman with diabetes mellitus and hearing loss was referred for an unspecified maculopathy detected during screening evaluation for diabetic retinopathy. Visual acuity was 20/20 in both eyes. Fundus examination showed bilateral macular and peripapillary hyperpigmented/depigmented areas.Patient 2: 45 year-old woman was referred for recent vision loss in her left eye. History was remarkable for chronic fatigue, migraine and diffuse muscular pain. Visual acuity was 20/20 in her right eye and 20/30 in her left eye. Fundus exhibited several nummular perifoveal islands of retinal pigment epithelium atrophy and adjacent pale deposits in both eyes.Retinal anatomy was investigated with autofluorescence, retinal angiography and optical coherence tomography. Retinal function was assessed with automated static perimetry, full-field and multifocal electroretinography and electro-oculography. Genetic testing of mtDNA identified a point mutation at the locus 3243. CONCLUSION: Observation of RPE abnormalities in the context of suggestive systemic findings should prompt mtDNA testing

Radiation Maculopathy After Proton Beam Therapy for Uveal Melanoma: Optical Coherence Tomography Angiography Alterations Influencing Visual Acuity.

To analyze microvascular and structural changes in radiation maculopathy and their influence on visual acuity (VA), using optical coherence tomography (OCT) and OCT angiography (OCTA). This was a retrospective analysis of consecutive patients with radiation maculopathy, 12 months or more after proton-beam irradiation for uveal melanoma, imaged with fluorescein angiography, OCT, and OCTA. Clinical parameters potentially affecting VA were recorded, including OCTA-derived metrics: foveal avascular zone (FAZ) area, vascular density, and local fractal dimension of the superficial (SCP) and deep capillary plexuses (DCP). Nonirradiated fellow eyes served as controls. Ninety-three patients were included. FAZ was larger, while SCP/DCP capillary density and local fractal dimension were lower in the 35 irradiated than in the 35 fellow eyes (P < 0.0001). Microvascular alterations graded on fluorescein angiography (minimally damaged/disrupted/disorganized) were correlated to FAZ area and SCP/DCP density on OCTA (P < 0.01). By univariate analysis, worse VA was associated to macular detachment at presentation (P = 0.024), total macular irradiation (P = 0.0008), higher central macular thickness (CMT) (P = 0.019), higher absolute CMT variation (P < 0.0001), cystoid edema (P = 0.030), ellipsoid zone disruption (P = 0.002), larger FAZ (P < 0.0001), lower SCP (P = 0.001) and DCP capillary density (P < 0.0001), and lower SCP (P = 0.009) and DCP local fractal dimension (P < 0.0001). Two multivariate models with either capillary density or fractal dimension as covariate showed that younger age (P = 0.014/0.017), ellipsoid zone disruption (P = 0.034/0.019), larger FAZ (P = 0.0006/0.002), and lower DCP density (P = 0.008) or DCP fractal dimension (P = 0.012), respectively, were associated with worse VA. VA of eyes with radiation maculopathy is influenced by structural and microvascular factors identified with OCTA, including FAZ area and DCP integrity

Sustained-release steroids for the treatment of diabetic macular edema.

Glucocorticoids have been used for decades in the treatment of ocular disorders via topical, periocular, and more recently intravitreal routes. However, their exact mechanisms of action on ocular tissues remain imperfectly understood. Fortunately, two recently approved intravitreal sustained-release drug delivery systems have opened new perspectives for these very potent drugs. To date, among other retinal conditions, their label includes diabetic macular edema, for which a long-lasting therapeutic effect has been demonstrated both morphologically and functionally in several randomized clinical trials. The rate of ocular complications of intravitreal sustained-release steroids, mainly cataract formation and intraocular pressure elevation, is higher than with anti-vascular endothelial growth factor agents. Yet, a better understanding of the mechanisms underlying these adverse effects and the search for the minimal efficient dose should help optimize their therapeutic window

The Eye on Mitochondrial Disorders.

Ophthalmologic manifestations of mitochondrial disorders are frequently neglected or overlooked because they are often not regarded as part of the phenotype. This review aims at summarizing and discussing the etiology, pathogenesis, diagnosis, and treatment of ophthalmologic manifestations of mitochondrial disorders. Review of publications about ophthalmologic involvement in mitochondrial disorders by search of Medline applying appropriate search terms. The eye is frequently affected by syndromic as well as nonsyndromic mitochondrial disorders. Primary and secondary ophthalmologic manifestations can be differentiated. The most frequent ophthalmologic manifestations of mitochondrial disorders include ptosis, progressive external ophthalmoplegia, optic atrophy, retinopathy, and cataract. More rarely occurring are nystagmus and abnormalities of the cornea, ciliary body, intraocular pressure, the choroidea, or the brain secondarily affecting the eyes. It is important to recognize and diagnose ophthalmologic manifestations of mitochondrial disorders as early as possible because most are accessible to symptomatic treatment with partial or complete short-term or long-term beneficial effect. Ophthalmologic manifestations of mitochondrial disorders need to be appropriately diagnosed to initiate the most effective management and guarantee optimal outcome

Systemic adalimumab induces peripheral corneal infiltrates: a case report.

BACKGROUND: Tumor necrosis factor-alpha inhibitors are widely used agents in the treatment of immune disorders such as rheumatoid arthritis and inflammatory bowel disease. Despite their anti-inflammatory action, paradoxical drug-induced inflammatory events have been occasionally associated with the use of infliximab, etanercept, and in a lesser extent adalimumab. However, eye involvement is uncommon and anterior uveitis is the only reported ocular adverse manifestation. It can be induced by etanercept, but has also been described during adalimumab therapy. We present here the first report of recurrent peripheral corneal infiltrates following subcutaneous injections of adalimumab. CASE PRESENTATION: A 34 year-old Caucasian woman with Crohn's disease presented to the emergency department with bilateral red eyes and discomfort 36 hours after she received her bimonthly dose of subcutaneous adalimumab. Examination revealed bilateral peripheral corneal infiltrates with characteristic features of immune infiltrates. Symptoms and infiltrates regressed after topical corticosteroid therapy, but recurred after each adalimumab injection over the following weeks. CONCLUSION: Paradoxical immune reactions associated with tumor necrosis factor-alpha inhibitors may result either from hypersensitivity mechanisms, or from immune-complex deposition via anti-adalimumab antibodies. Both mechanisms could explain this newly described manifestation. Care should be taken to search for corneal infiltrates in the event of red eye symptoms during adalimumab therapy since they respond to topical corticosteroids and do not necessarily prompt the discontinuation of the immunosuppressive therapy

SUBFOVEAL NODULE IN COATS' DISEASE: Toward an Updated Classification Predicting Visual Prognosis.

To determine the prevalence, clinical characteristics and nature of subfoveal nodules in Coats' disease and the associated impact on the long-term visual outcome. Consecutive cases of Coats' disease with foveal exudation were retrospectively reviewed. The presence of a subfoveal nodule or macular fibrosis was recorded. Clinical characteristics, retinal imaging, and outcome were analyzed by comparative analysis. The histopathological description of an enucleated eye with subfoveal nodule was performed. Among 40 patients presenting unilateral Stage 2B or 3A1 Coats' disease, a subfoveal nodule was detected in 21 patients (52.5%). The median follow-up was 4.7 years. Nineteen patients (47.5%) did not present a subfoveal nodule. Three patients (15.8%) without subfoveal nodule and 21 patients (100%) with subfoveal nodule progressed to a macular fibrotic scar (P < 0.0001), and the mean time of macular fibrosis onset was 11.0 ± 2.6 months. Final visual acuity was significantly worse in patients who presented a subfoveal nodule at diagnosis (P = 0.01). Of 18 cases with subfoveal nodule who underwent fluorescein angiography, retinal-retinal anastomosis and neovascularization were detected in 13 (72.2%) and 2 eyes (11.1%), respectively. Histopathological analysis of a subfoveal nodule revealed an aggregate of proteinaceous material including fibrin, spindle cells, macrophages, and pigmented cells. The presence of a subfoveal nodule at presentation is a predictive factor for macular fibrosis development and worse visual outcome in patients with Coats' disease. These observations suggest an updated classification introducing two subcategories within Stage 2B: without subfoveal nodule (Stage 2B1) and with subfoveal nodule (Stage 2B2)

Oral Mineralocorticoid-Receptor Antagonists: Real-Life Experience in Clinical Subtypes of Nonresolving Central Serous Chorioretinopathy With Chronic Epitheliopathy.

PURPOSE: To evaluate the efficacy and safety of oral mineralocorticoid-receptor antagonist (MRa) therapy in three clinical presentations of nonresolving central serous chorioretinopathy (CSCR) with chronic epitheliopathy. METHODS: Retrospective case series of consecutive patients with nonresolving CSCR treated with oral eplerenone or spironolactone. Treatment criteria were: persistent CSCR with subretinal fluid (SRF) lasting longer than 4 months; recurrent CSCR with SRF lasting longer than 2 months; persistent CSCR (SRF ≥ 4 months) with fundus autofluorescence gravitational tracks. Outcomes at 1, 3, and 6 months were: foveal SRF height, central macular thickness (CMT), subfoveal choroidal thickness (SFCT), best-corrected visual acuity (BCVA), and occurrence of side effects. RESULTS: Among 54 eyes from 42 patients (mean age: 53 years), mean foveal SRF, CMT, and SFCT decreased significantly at 1, 3, and 6 months after treatment initiation. Mean BCVA improved significantly at 6 months. In the subgroup analysis, mean foveal SRF, CMT, and SFCT decreased significantly at 3 and 6 months in the persistent and recurrent groups. In persistent cases with tracks, a significant diminution of mean CMT and SFCT was achieved at 6 months. Treatment-related side effects were observed in 6 patients, prompting treatment discontinuation in one case. CONCLUSION: Response to treatment was observed in the three subgroups. In persistent CSCR with tracks the response was delayed compared with persistent and recurrent cases, suggesting that longer treatment durations would be beneficial in patients with gravitational tracks of RPE alteration. TRANSLATIONAL RELEVANCE: The clinical response to oral MRa is consistent with the involvement of the mineralocorticoid pathway in CSCR pathogenesis

ACUTE CENTRAL SEROUS CHORIORETINOPATHY: Factors Influencing Episode Duration.

To evaluate the influence of clinical and multimodal imaging parameters on the duration of acute central serous chorioretinopathy (CSCR) episodes. Consecutive patients with first, treatment-naïve central serous chorioretinopathy episodes presenting within 20 days of symptoms onset were prospectively included. They were reevaluated 15 days to 20 days later, followed by monthly evaluation for 6 months. Subfoveal choroidal thickness (SFCT), fluorescein leakage intensity on fluorescein angiography, elevation of retinal pigment epithelium (RPE) lesions at leakage sites, focal/multifocal pattern of indocyanine green angiography (ICGA) at baseline, time-dependent pattern of subretinal fluid (SRF) resorption on OCT using volume segmentation, history of corticosteroid intake and mean blood pressure were evaluated using univariate (Log rank test) and multivariate (Cox proportional hazard regression) survival analysis. Thirty-one patients were included (26 men, 5 women, mean age: 40.0 ± 8.9 years, range: 24-58), of which 26 (84%) had episode resolution by 6 months. Using univariate analysis, episode duration was longer in cases with subfoveal choroidal thickness ≥500 μm (P = 0.0002), retinal pigment epithelium elevation at leakage sites ≥50 μm (P = 0.033), and a peak in subretinal fluid observed during follow-up (P = 0.013), and there was a near-significant association of intense fluorescein leakage (P = 0.074) with longer episodes. Using multivariate analysis, subfoveal choroidal thickness ≥500 μm (P = 0.017), retinal pigment epithelium elevation at leakage sites ≥50 μm (P = 0.010) and patient age ≥40 years (P = 0.010) were significantly and independently associated to longer episodes. Indocyanine green angiography pattern, corticosteroid intake, and blood pressure did not influence episode duration. Older age, higher subfoveal choroidal thickness, and higher degree of retinal pigment epithelium alteration at leakage sites are independent factors of longer acute central serous chorioretinopathy episodes

Levels of the oxidative stress biomarker malondialdehyde in tears of patients with central serous chorioretinopathy relate to disease activity.

Central serous chorioretinopathy (CSCR) has been associated with oxidative stress-related risk factors. The objective of this study was to optimize an analytical method for evaluating the oxidative stress biomarker malondialdehyde (MDA) in human tears and determine its level in the tears of patients with CSCR. In this pilot study, tear samples were obtained from 34 healthy donors and 31 treatment-naïve CSCR male patients (eight with acute CSCR and 23 with chronic CSCR). Two analytical methods based on high-performance liquid chromatography followed by fluorescence detection were evaluated, with either 2-thiobarbituric derivative (TBA) or 2-aminoacridone (2-AA). Activity of CSCR was defined by the serous retinal detachment (SRD) height, which was measured by two independent observers on spectral-domain optical coherence tomography. The 2-AA method showed higher sensitivity and precision compared to the TBA method. When the 2-AA method was applied to tears from healthy donors, the levels of MDA were statistically significantly higher in men compared to women (mean ± standard deviation, SD: 9,914 nM ± 6,126 versus 4,635 nM ± 1,173, p = 0.006). No difference was found in tear MDA levels between male patients with CSCR and age-matched control men (p = 0.17). However, MDA levels were statistically significantly higher in acute compared to chronic CSCR cases (mean ± SD: 12,295 nM ± 8,495 versus 6,790 ± 3,969 nM, p = 0.03). Additionally, there was a correlation between MDA levels and RPE leakage, quantified by the height of the serous retinal detachment (p = 0.02, r = 0.40). Levels of MDA in tears, measured with an optimized analytical method, correlate with RPE leakage in CSCR

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.

Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress