New associations of classic acute macular neuroretinopathy

PURPOSE: To describe novel underlying associations of classic acute macular neuroretinopathy (AMN). METHODS: Multimodal imaging case series evaluating patients with classic AMN lesions and previously unreported underlying aetiologies. RESULTS: Six patients were included (five women, one man, mean age 30±7 years). Mean distance best corrected visual acuity at initial presentation was 0.21±0.3 logMAR (mean Snellen acuity: 20/30, range 20/15-20/100) and at last follow-up visit 0.09±0.17 logMAR (Snellen acuity: 20/20, range 20/15-20/60). All cases but one had bilateral lesions and showed typical parafoveal hyporeflective lesions on infrared imaging, which corresponded to the hyper-reflectivity in the Henle's layer with attenuation of the external limiting membrane, the ellipsoid zone and interdigitation zone. Underlying diseases included thrombocytopenia and anaemia associated with dengue fever, acute lymphoblastic leukaemia, chronic kidney disease and ulcerative colitis, while Valsalva-like manoeuvre was found to be a potential trigger. Other novel associations included the use of lisdexamphetamine. CONCLUSIONS: Classic AMN may be associated with leukaemia, dengue fever, ulcerative colitis and chronic kidney disease, probably as a result of chorioretinal hypoxia in the setting of thrombocytopenia and anaemia. Adrenergic agonists such as lisdexamphetamine may also contribute to the manifestation of AMN.

Expanded Clinical Spectrum of Multiple Evanescent White Dot Syndrome with Multimodal Imaging

PURPOSE: To evaluate and characterize multiple evanescent white dot syndrome abnormalities with modern multimodal imaging modalities. METHODS: This retrospective cohort study evaluated fundus photography, fluorescein angiography, indocyanine green angiography, optical coherence tomography, enhanced depth imaging optical coherence tomography, short-wavelength autofluorescence, and near-infrared autofluorescence. RESULTS: Thirty-four multiple evanescent white dot syndrome patients with mean age of 28.7 years were studied (range, 14-49 years). Twenty-six patients were women, and eight were men. Initial mean visual acuity was 0.41 logMAR. Final mean visual acuity was 0.03 logMAR. Fluorescein angiography shows a variable number of mid retinal early fluorescent dots distributed in a wreathlike pattern, which correlate to fundus photography, fundus autofluorescence, and indocyanine green angiography. Indocyanine green angiography imaging shows the dots and also hypofluorescent, deeper, and larger spots, which are occasionally confluent, demonstrating a large plaque of deep retinal hypofluorescence. Optical coherence tomography imaging shows multifocal debris centered at and around the ellipsoid layer, corresponding to the location of spots seen with photography, indocyanine green angiography, and fluorescein angiography. Protrusions of the hyperreflectant material from the ellipsoid layer toward the outer nuclear layer correspond to the location of dots seen with photography, indocyanine green angiography, and fluorescein angiography. CONCLUSION: Multimodal imaging analysis of the retina in patients with multiple evanescent white dot syndrome shows additional features that may help in the diagnosis of the disease and in further understanding its etiology. Multiple evanescent white dot syndrome is predominantly a disease of the outer retina, centered at the ellipsoid zone, but also involving the interdigitation zone and the outer nuclear layer.

Ranibizumab for subfoveal choroidal neovascularisation associated with Stargardt disease.

INTRODUCTION: To describe the clinical outcomes of intravitreal ranibizumab treatment for subfoveal choroidal neovascularisation (CNV) associated with Stargardt disease. METHODS: Prospective, interventional, case series. All patients underwent intravitreal ranibizumab injections following a pro re nata regimen with monthly examination, over a 24-month follow-up. RESULTS: Three eyes were included in the study. Best corrected visual acuity changed from 0.47±0.06 (mean±SD) at baseline to 0.90±0.17 LogMAR at the end of the 24-month follow-up. Overall, a mean number of 11 ranibizumab injections were administered in 24 months. Significant atrophic growth was detected in all cases, with the mean atrophy area increasing from 2.34±2.60 mm(2) (mean±SD) at baseline to 4.23±3.31 mm(2) at the end of the follow-up. CONCLUSIONS: Ranibizumab treatment can stop the CNV progression, but cannot ensure a significant visual improvement. Macular atrophy tends to significantly enlarge under ranibizumab treatment over the follow-up. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Natural History of Geographic Atrophy Progression Secondary to Age-Related Macular Degeneration (Geographic Atrophy Progression Study).

PURPOSE The Geographic Atrophy Progression (GAP) study was designed to assess the rate of geographic atrophy (GA) progression and to identify prognostic factors by measuring the enlargement of the atrophic lesions using fundus autofluorescence (FAF) and color fundus photography (CFP). DESIGN Prospective, multicenter, noninterventional natural history study. PARTICIPANTS A total of 603 participants were enrolled in the study; 413 of those had gradable lesion data from FAF or CFP, and 321 had gradable lesion data from both FAF and CFP. METHODS Atrophic lesion areas were measured by FAF and CFP to assess lesion progression over time. Lesion size assessments and best-corrected visual acuity (BCVA) were conducted at screening/baseline (day 0) and at 3 follow-up visits: month 6, month 12, and month 18 (or early exit). MAIN OUTCOME MEASURES The GA lesion progression rate in disease subgroups and mean change from baseline visual acuity. RESULTS Mean (standard error) lesion size changes from baseline, determined by FAF and CFP, respectively, were 0.88 (0.1) and 0.78 (0.1) mm(2) at 6 months, 1.85 (0.1) and 1.57 (0.1) mm(2) at 12 months, and 3.14 (0.4) and 3.17 (0.5) mm(2) at 18 months. The mean change in lesion size from baseline to month 12 was significantly greater in participants who had eyes with multifocal atrophic spots compared with those with unifocal spots (P < 0.001) and those with extrafoveal lesions compared with those with foveal lesions (P = 0.001). The mean (standard deviation) decrease in visual acuity was 6.2 ± 15.6 letters for patients with image data available. Atrophic lesions with a diffuse (mean 0.95 mm(2)) or banded (mean 1.01 mm(2)) FAF pattern grew more rapidly by month 6 compared with those with the "none" (mean, 0.13 mm(2)) and focal (mean, 0.36 mm(2)) FAF patterns. CONCLUSIONS Although differences were observed in mean lesion size measurements using FAF imaging compared with CFP, the measurements were highly correlated with one another. Significant differences were found in lesion progression rates in participants stratified by hyperfluorescence pattern subtype. This large GA natural history study provides a strong foundation for future clinical trials.

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol.

INTRODUCTION Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER NCT01962571.

RETINAL LAYER RESPONSE TO RANIBIZUMAB DURING TREATMENT OF DIABETIC MACULAR EDEMA: Thinner is Not Always Better.

PURPOSE To identify individual retinal layer thickness changes associated with visual acuity gain in diabetic macular edema treated with ranibizumab using layer segmentation on high-resolution optical coherence tomography scans. METHODS Retrospective observational case series. Thirty-three treatment-naive eyes with diabetic macular edema were imaged by spectral domain optical coherence tomography at monthly visits while receiving intravitreal ranibizumab treatment as needed, guided by visual acuity. Thickness changes of individual layers after 1 year were quantitatively analyzed and correlated with visual acuity gain. RESULTS The mean best-corrected visual acuity improvement at 1 year was 6.2 (SEM ± 1.5) Early Treatment Diabetic Retinopathy Study letters, and central retinal thickness decreased by 66 ± 18 μm. In the central subfield, there was a significant decrease of thickness for all layers (P < 0.05) except the outer nuclear layer. Multiple linear regression analysis revealed that thickness decrease of the inner retina was associated with better visual acuity, whereas for the outer retina the opposite was true. The best estimate of final visual acuity (R = 0.817, P < 0.001) was obtained, by including baseline visual acuity and thickness change of the inner and outer plexiform layers in the model. CONCLUSION Whereas thickness decrease of the inner retina was positively associated with visual acuity gain, the opposite was found for the outer retina. This might be indirect evidence for recovery of the outer retina during ranibizumab treatment.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Multiple retinal detachment surgery: A functional outcome study. The Houston Vision Assessment Test-Retina (HVAT-Retina)

Retinal detachment is a common ophthalmologic procedure, and outcome is typically measured by a single factor-improvement in visual acuity. Health related functional outcome testing, which quantifies patient's self-reported perception of impairment, can be integrated with objective clinical findings. Based on the patient's self-assessed lifestyle impairment, the physician and patient together can make an informed decision on the treatment that is most likely to benefit the patient. ^ A functional outcome test (the Houston Vision Assessment Test-Retina; HVAT-Retina) was developed and validated in patients with multiple retinal detachments in the same eye. The HVAT-Retina divides an estimated total impairment into subcomponents: contribution of visual disability (potentially correctable by retinal detachment surgery) and nonvisual physical disabilities (co-morbidities not affected by retinal detachment surgery. ^ Seventy-six patients participated in this prospective multicenter study. Seven patients were excluded from the analysis because they were not certain of their answers. Cronbach's alpha coefficient was 0.91 for presurgery HVAT-Retina and 0.94 post-surgery. The item-to-total correlation ranged from 0.50 to 0.88. Visual impairment score improved by 9 points from pre-surgery (p = 0.0003). Physical impairment score also improved from pre-surgery (p = 0.0002). ^ In conclusion, the results of this study demonstrate that the instrument is reliable and valid in patients presenting with recurrent retinal detachments. The HVAT-Retina is a simple instrument and does not burden the patient or the health professional in terms of time or cost. It may be self-administrated, not requiring an interviewer. Because the HVAT-Retina was designed to demonstrate outcomes perceivable by the patient, it has the potential to guide the decision making process between patient and physician. ^

Evaluation of risk factors for long term changes in refractive error among adult patients at a Dallas Texas private setting A retrospective chart-review study

Background. Over 39.9% of the adult population forty or older in the United States has refractive error, little is known about the etiology of this condition and associated risk factors and their entailed mechanism due to the paucity of data regarding the changes of refractive error for the adult population over time.^ Aim. To evaluate risk factors over a long term, 5-year period, in refractive error changes among persons 43 or older by testing the hypothesis that age, gender, systemic diseases, nuclear sclerosis and baseline refractive errors are all significantly associated with refractive errors changes in patients at a Dallas, Texas private optometric office.^ Methods. A retrospective chart review of subjective refraction, eye health, and self-report health history was done on patients at a private optometric office who were 43 or older in 2000 who had eye examinations both in 2000 and 2005. Aphakic and pseudophakic eyes were excluded as well as eyes with best corrected Snellen visual acuity of 20/40 and worse. After exclusions, refraction was obtained on 114 right eyes and 114 left eyes. Spherical equivalent (sum of sphere + ½ cylinder) was used as the measure of refractive error.^ Results. Similar changes in refractive error were observed for the two eyes. The 5-year change in spherical power was in a hyperopic direction for younger age groups and in a myopic direction for older subjects, P<0.0001. The gender-adjusted mean change in refractive error in right eyes of persons aged 43 to 54, 55 to 64, 65 to 74, and 75 or older at baseline was +0.43D, +0.46 D, -0.09 D, and -0.23D, respectively. Refractive change was strongly related to baseline nuclear cataract severity; grades 4 to 5 were associated with a myopic shift (-0.38 D, P< 0.0001). The mean age-adjusted change in refraction was +0.27 D for hyperopic eyes, +0.56 D for emmetropic eyes, and +0.26 D for myopic eyes.^ Conclusions. This report has documented refractive error changes in an older population and confirmed reported trends of a hyperopic shift before age 65 and a myopic shift thereafter associated with the development of nuclear cataract.^

Identification and evaluation of candidate genes for inherited retinal -degenerative diseases

Although more than 100 genes associated with inherited retinal disease have been mapped to chromosomal locations, less than half of these genes have been cloned. This text includes identification and evaluation of candidate genes for three autosomal dominant forms of inherited retinal degeneration: atypical vitelliform macular dystrophy (VMD1), cone-rod dystrophy (CORD), and retinitis pigmentosa (RP). ^ VMD1 is a disorder characterized by complete penetrance but extremely variable expressivity, and includes macular or peripheral retinal lesions and peripappilary abnormalitites. In 1984, linkage was reported between VMD1 and soluble glutamate-pyruvate transaminase GPT); however, placement of GPT to 8q24 on linkage maps had been debated, and VMD1 did not show linkage to microsatellite markers in that region. This study excluded linkage between the loci by cloning GPT, identifying the nucleotide substitution associated with the GPT sozymes, and by assaying VMD1 family samples with an RFLP designed to detect the substitution. In addition, linkage of VMD1 to the known dominant macular degeneration loci was excluded. ^ CORD is characterized by early onset of color-vision deficiency, and decreased visual acuity, However, this retinal degeneration progresses to no light perception, severe macular lesion, and “bone-spicule” accumulations in the peripheral retina. In this study, the disorder in a large Texan family was mapped to the CORD2 locus of 19q13, and a mutation in the retina/pineal-specific cone-rod homeobox gene (CRX) was identified as the disease cause. In addition, mutations in CRX were associated with significantly different retinal disease phenotypes, including retinitis pigmentosa and Leber congenital amaurosis. ^ Many of the mutations leading to inherited retinal disorders have been identified in genes like CRX, which are expressed predominantly in the retina and pineal gland. Therefore, a combination of database analysis and laboratory investigation was used to identify 26 novel retina/pineal-specific expressed sequence tag (EST) clusters as candidate genes for inherited retinal disorders. Eight of these genes were mapped into the candidate regions of inherited retinal degeneration loci. ^ Two of the eight clusters mapped into the retinitis pigmentosa RP13 candidate region of 17p13, and were both determined to represent a single gene that is highly expressed in photoreceptors. This gene, the Ah receptor-interacting like protein-1 (AIPL1), was cloned, characterized, and screened for mutations in RP13 patient DNA samples. ^

Influence of the vitreomacular interface on the efficacy of intravitreal therapy for uveitis-associated cystoid macular oedema.

PURPOSE To evaluate the effect of the vitreomacular interface (VMI) on treatment efficacy of intravitreal therapy in uveitic cystoid macular oedema (CME). METHODS Retrospective analysis of CME resolution, CME recurrence rate and monthly course of central retinal thickness (CRT), retinal volume (RV) and best corrected visual acuity (BCVA) after intravitreal injection with respect to the VMI configuration on spectral-domain OCT using chi-squared test and repeated measures anova adjusted for confounding covariates epiretinal membrane, administered drug and subretinal fluid. RESULTS Fifty-nine eyes of 53 patients (mean age: 47.4 ± 16.9 years) were included. VMI status had no effect on complete CME resolution rate (p = 0.16, corrected p-value: 0.32), time until resolution (p = 0.09, corrected p-value: 0.27) or CME relapse rate (p = 0.29, corrected p-value: 0.29). Change over time did not differ among the VMI configuration groups for BVCA (p = 0.82) and RV (p = 0.18), but CRT decrease was greater and faster in the posterior vitreous detachment (PVD) group compared to the posterior vitreous attachment (PVA) and vitreous macular adhesion (VMA) groups (p = 0.04). Also, the percentage of patients experiencing a ≥ 20% CRT thickness decrease after intravitreal injection was greater in the PVD group (83%) compared to the VMA (64%) and the PVA (16%) group (p = 0.027), however, not after correction for multiple testing (corrected p-value: 0.11). CONCLUSION The VMI configuration seems to be a factor contributing to treatment efficacy in uveitic CME in terms of CRT decrease, although BCVA outcome did not differ according to VMI status.

Enhanced depth imaging optical coherence tomography of congenital cavitary optic disc anomaly (CODA).

AIM To report the finding of extension of the 4th hyper-reflective band and retinal tissue into the optic disc in patients with cavitary optic disc anomalies (CODAs). METHODS In this observational study, 10 patients (18 eyes) with sporadic or autosomal dominant CODA were evaluated with enhanced depth imaging optical coherence tomography (EDI-OCT) and colour fundus images for the presence of 4th hyper-reflective band extension into the optic disc. RESULTS Of 10 CODA patients (18 eyes), five patients (8 eyes) showed a definite 4th hyper-reflective band (presumed retinal pigment epithelium (RPE)) extension into the optic disc. In these five patients (seven eyes), the inner retinal layers also extended with the 4th hyper-reflective band into the optic disc. Best corrected visual acuity ranged from 20/20 to 20/200. In three patients (four eyes), retinal splitting/schisis was present and in two patients (two eyes), the macula was involved. In all cases, the 4th hyper-reflective band extended far beyond the termination of the choroid into the optic disc. The RPE extension was found either temporally or nasally in areas of optic nerve head excavation, most often adjacent to peripapillary pigment. Compared with eyes without RPE extension, eyes with RPE extension were more myopic (mean dioptres -0.9±2.6 vs -8.8±5, p=0.043). CONCLUSIONS The RPE usually stops near the optic nerve border separated by a border tissue. With CODA, extension of this hyper-reflective band and retinal tissue into the disc is possible and best evaluable using EDI-OCT or analogous image modalities. Whether this is a finding specific for CODA, linked to specific gene loci or is also seen in patients with other optic disc abnormalities needs further evaluation.

The ocular albinism type 1 gene product is a membrane glycoprotein localized to melanosomes.

Ocular albinism type 1 (OA1) is an inherited disorder characterized by severe reduction of visual acuity, photophobia, and retinal hypopigmentation. Ultrastructural examination of skin melanocytes and of the retinal pigment epithelium reveals the presence of macromelanosomes, suggesting a defect in melanosome biogenesis. The gene responsible for OA1 is exclusively expressed in pigment cells and encodes a predicted protein of 404 aa displaying several putative transmembrane domains and sharing no similarities with previously identified molecules. Using polyclonal antibodies we have identified the endogenous OA1 protein in retinal pigment epithelial cells, in normal human melanocytes and in various melanoma cell lines. Two forms of the OA1 protein were identified by Western analysis, a 60-kDa glycoprotein and a doublet of 48 and 45 kDa probably corresponding to unglycosylated precursor polypeptides. Upon subcellular fractionation and phase separation with the nonionic detergent Triton X-114, the OA1 protein segregated into the melanosome-rich fraction and behaved as an authentic integral membrane protein. Immunofluorescence and immunogold analyses on normal human melanocytes confirmed the melanosomal membrane localization of the endogenous OA1 protein, consistent with its possible involvement in melanosome biogenesis. The identification of a novel melanosomal membrane protein involved in a human disease will provide insights into the mechanisms that control the cell-specific pathways of subcellular morphogenesis.

Neuronal abnormalities in microtubule-associated protein 1B mutant mice.

Microtubules play an important role in establishing cellular architecture. Neuronal microtubules are considered to have a role in dendrite and axon formation. Different portions of the developing and adult brain microtubules are associated with different microtubule-associated proteins (MAPs). The roles of each of the different MAPs are not well understood. One of these proteins, MAP1B, is expressed in different portions of the brain and has been postulated to have a role in neuronal plasticity and brain development. To ascertain the role of MAP1B, we generated mice which carry an insertion in the gene by gene-targeting methods. Mice which are homozygous for the modification die during embryogenesis. The heterozygotes exhibit a spectrum of phenotypes including slower growth rates, lack of visual acuity in one or both eyes, and motor system abnormalities. Histochemical analysis of the severely affected mice revealed that their Purkinje cell dendritic processes are abnormal, do not react with MAP1B antibodies, and show reduced staining with MAP1A antibodies. Similar histological and immunochemical changes were observed in the olfactory bulb, hippocampus, and retina, providing a basis for the observed phenotypes.

Comparison between clinical results of two diffractive multifocal lenses with the same platform but different additions

PURPOSE: To evaluate visual results with two multifocal diffractive lenses designed with the same platform but with different additions. SETTING: Grupo Innova Ocular clinics. METHODS: A total of 50 eyes from 50 patients were included. Group 1 (n = 25) was implanted with the TECNIS® 1 ZLB +3.25 and group 2 (n = 25) with the TECNIS® 1 ZKB +2.75. Patients were assessed at 24 hours, 1 week and 1 month postoperatively. At surgical discharge, corrected (CDVA) and uncorrected distance visual acuity (UCDVA), near visual acuity (VA) at 25, 40 and 80 cm, visual quality and the defocus curve were measured. RESULTS: Changes in sphere and spherical equivalent were statistically significant (p<0.01) in both groups at 1 week and 1 month compared to preoperative values. In group 1, UCDVA logMAR at 1 month was 0.06 ± 0.02. In group 2, UCDVA at 1 month was 0.03 ± 0.03. In near vision, the TECNIS® 1 ZLB group obtained a VA logMAR of 0.35 ± 0.02 at 25 cm, 0.13 ± 0.02 at 40 cm and 0.27 ± 0.02 at 80 cm, while in the TECNIS® 1 ZKB group, the values were 0.38  ± 0.03, 0.14 ± 0.03 and 0.23 ± 0.06, respectively. No statistically significant differences were found either when results for visual quality were compared. CONCLUSION: Both the TECNIS® 1 ZLB and TECNIS® 1 ZKB are excellent options for obtaining good distance and near vision, in addition to providing good intermediate vision, especially at distances such as those required for working with computers.

Cystoid Macular Edema: Causes, Diagnosis and Treatment

The purpose of this paper is to conduct a review of studies on cystoid macular edema published in the last seven years. Cystoid macular edema is a major cause of loss of visual acuity. It is the final common pathway of many diseases and can be caused by numerous processes including inflammatory, vascular, adverse drug reactions, retinal dystrophy or intraocular tumors. These processes disrupt the blood-retinal barrier, with fluid extravasation to the macular parenchyma. Imaging tests are essential for both detection and monitoring of this pathology. Fluorescein angiography and autofluorescence show the leakage of liquid from perifoveal vessels into the tissue where it forms cystic spaces. Optical coherence tomography is currently the gold standard technique for diagnosis and monitoring. This allows objective measurement of retinal thickness, which correlates with visual acuity and provides more complete morphological information. Based on the underlying etiology, the therapeutic approach can be either surgical or medical with anti-inflammatory drugs. We found that disruption of the blood-retinal barrier for various reasons is the key point in the pathogenesis of cystoid macular edema, therefore we believe that studies on its treatment should proceed on this path.