Multifocal Evanescent White Dot Syndrome-like Phenotypes Associated with Inflammatory and Myopic Choroidal Neovascularization.

PURPOSE: To present the observation of multifocal evanescent white dot syndrome (MEWDS)-like phenotypes developing in association with the onset of choroidal neovascularization (CNV) in a series of patients. METHODS: Patients presenting to tertiary-care centers with MEWDS-like phenotypes and CNV were identified. RESULTS: Five patients presented for the management of CNV in the context of previous diagnoses of punctate inner choroidopathy (PIC) and/or myopia. In time-periods ranging from 0 days to 12 weeks from the diagnosis of active CNV, MEWDS-like changes were observed. Treatment with anti-VEGF agents were instituted in four cases, in an as-required protocol. 1 patient received systemic steroid. CONCLUSIONS: The development of MEWDS-like phenotypes in association with CNVM can occur in eyes with either inflammatory or non-inflammatory CNVM, and in those who were or were not treated with anti-VEGF therapy. The association suggests an inflammatory event, which causes RPE changes and probably induces the development of the CNV.

Longitudinal follow-up of dome-shaped macula.

BACKGROUND/OBJECTIVES: To determine if the presence of sub-retinal fluid (SRF) was associated with reduced vision in dome-shaped macula (DSM), and to assess its effect and response to treatment during follow-up. METHODS: Patients were identified retrospectively. Baseline and follow-up data were recorded. The diagnosis of DSM, and presence or absence of SRF and intra-retinal fluid (IRF) was confirmed using Spectral Domain-Optical Coherence Tomography (SD-OCT). Decisions to treat oedema were based on clinician preference. RESULTS: 193 eyes of 106 patients (71 female) were confirmed to have DSM. Overall mean duration of follow-up for this cohort was 3.5 years. Mean BRVA for all eyes at baseline was 0.38 (range: -0.20 to 'light perception'). A significant difference was noted in mean baseline BRVA between those eyes with SRF compared with those without SRF at baseline (0.48 vs. 0.31, p < 0.001). Intra-retinal fluid moderately correlated with poorer baseline BRVA (r = 0.31, p < 0.003). No significant change in BRVA was noted during follow-up. No significant effect of treatment on BRVA was observed. CONCLUSIONS: The presence of SRF at baseline was associated with poorer vision. Vision appears to remain stable irrespective of the presence or absence of SRF at baseline. The treatments administered in this cohort did not affect final vision or SRF.

Polypoidal Choroidal Vasculopathy Complicating Retinal Laser in Quiescent Uveitis.

A 58-year-old Afro-Caribbean gentleman with a diagnosis of quiescent systemic lupus erythematosus- (SLE-) related occlusive retinal vasculitis was previously treated with sector pan-retinal photocoagulation in his right eye to control temporal retinal neovascularization. At routine review he was found to have a focal area of subretinal fluid in the temporal macula sparing an ischaemic fovea. Fundus fluorescein angiography and indocyanine green angiography confirmed a branching vascular network (BVN) and terminal polys (i.e., polypoidal choroidal vasculopathy (PCV)). Interestingly, the BVN arose within an old laser scar. To our knowledge this is the first report of PCV in uveitis in an Afro-Caribbean patient and of the lesions arising within a laser scar.

Acute Macular Neuroretinopathy Phenotype in Behçet's Disease.

Acute macular neuroretinopathy (AMN) is a rare disease, the etiology of which remains unclear. An ischemic event at the level of the deep capillary plexus has been proposed. The authors present three cases of AMN in the context of active systemic Behçet's disease, with the support of multimodal imaging. All patients were known to have Behçet's disease before the diagnosis of AMN. AMN was confirmed in all three cases on spectral domain optical coherence tomography (SD-OCT), near infrared reflectance and OCT angiography. Behçet's disease is known to be a prothrombotic disease. The presentation of AMN in this context supports the presumed ischemic etiology of AMN. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:634-638.].

Multimodal analysis of the Preferred Retinal Location and the Transition Zone in patients with Stargardt Disease.

PURPOSE: The purpose of our study was to investigate morpho-functional features of the preferred retinal location (PRL) and the transition zone (TZ) in a series of patients with recessive Stargardt disease (STGD1). METHODS: Fifty-two STGD1 patients with at least one ABCA4 mutation, atrophy of the central macula (MA) and an eccentric PRL were recruited for the study. Microperimetry, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) were performed. The location and stability of the PRL along with the associated FAF pattern and visual sensitivities were determined and compared to the underlying retinal structure. RESULTS: The mean visual sensitivity of the PRLs for the 52 eyes was 10.76 +/- 3.70 dB. For the majority of eyes, PRLs were associated with intact ellipsoid zone (EZ) bands and qualitatively normal FAF patterns. In 17 eyes (32.7%) the eccentric PRL was located at the edge of the MA. In 35 eyes (67.3%) it was located at varying distances from the border of the MA with a TZ between the PRL and the MA. The TZ was associated with decreased sensitivity values (5.92 +/- 4.69 dB) compared to PRLs (p<0.05), with absence/disruption of the EZ band and abnormal FAF patterns (hyper or hypo-autofluorescence). CONCLUSIONS: In STGD1 eccentric PRLs are located away from the border of MA and associated with intact EZ bands and normal FAF. The TZ is characterized by structural and functional abnormalities. The results of multimodal imaging of the PRL and TZ suggest a possible sequence of retinal and functional changes with disease progression that may help in the planning of future therapies; RPE dysfunction appears to be the primary event leading to photoreceptor degeneration and then to RPE loss.

Sulcus-fixated intraocular lens implantation for the management of negative dysphotopsia.

PURPOSE: To determine whether intraocular lens (IOL) exchange with insertion of a sulcus-fixated IOL is an effective treatment for the management of pseudophakic negative dysphotopsia. SETTING: Department of Ophthalmology, Stoke Mandeville Hospital, Buckinghamshire, United Kingdom. DESIGN: Case series. METHODS: Participants in the study were recruited prospectively from the clinic at the time of diagnosis or retrospectively from the operating room logs by identifying all patients who had IOL exchanges over a 4-year period (2009 to 2012). RESULTS: Five eyes of 5 women with negative dysphotopsia were treated with IOL exchange and replacement with a 3-piece IOL (Acrysof MA60AC) inserted in the ciliary sulcus. All patients had a resolution of the negative dysphotopsia symptoms. One patient had primary insertion of a sulcus IOL in the fellow eye and did not develop negative dysphotopsia symptoms. CONCLUSION: Intraocular lens exchange with insertion of a 3-piece IOL in the ciliary sulcus appears to be a safe and effective treatment for the management of pseudophakic negative dysphotopsia. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.

Quantitative fundus autofluorescence in recessive Stargardt disease.

PURPOSE: To quantify fundus autofluorescence (qAF) in patients with recessive Stargardt disease (STGD1). METHODS: A total of 42 STGD1 patients (ages: 7-52 years) with at least one confirmed disease-associated ABCA4 mutation were studied. Fundus AF images (488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Texture factor (TF) was calculated to characterize inhomogeneities in the AF image and patients were assigned to the phenotypes of Fishman I through III. RESULTS: Quantified fundus autofluorescence in 36 of 42 patients and TF in 27 of 42 patients were above normal limits for age. Young patients exhibited the relatively highest qAF, with levels up to 8-fold higher than healthy eyes. Quantified fundus autofluorescence and TF were higher in Fishman II and III than Fishman I, who had higher qAF and TF than healthy eyes. Patients carrying the G1916E mutation had lower qAF and TF than most other patients, even in the presence of a second allele associated with severe disease. CONCLUSIONS: Quantified fundus autofluorescence is an indirect approach to measuring RPE lipofuscin in vivo. We report that ABCA4 mutations cause significantly elevated qAF, consistent with previous reports indicating that increased RPE lipofuscin is a hallmark of STGD1. Even when qualitative differences in fundus AF images are not evident, qAF can elucidate phenotypic variation. Quantified fundus autofluorescence will serve to establish genotype-phenotype correlations and as an outcome measure in clinical trials.

Cryptic uveitis in a patient with morning glory syndrome.

BACKGROUND: A 71-year-old female presented on 3 occasions with escalating pain in a congenitally blind eye. Examination revealed hypertensive uveitis with morning glory optic disc dysplasia and absence of a crystalline lens. There was no previous intraocular surgery or trauma. Intensive anti-hypertensive agents and topical steroids did not control intraocular pressure (IOP) or inflammation. RESULTS: Dilated fundus examination on the third clinical review revealed a luxated cataractous lens on the retina. Pars plana vitrectomy and fragmatome lensectomy controlled inflammation and IOP, with resolution of ocular pain. DISCUSSION: This is an exceptional case of phacogenic uveitis with secondary glaucoma occurring years after spontaneous crystalline lens luxation in a patient with morning glory syndrome. The embryological pathogenesis of morning glory syndrome and the significance of accelerated cataractogenesis and zonular weakness are discussed. Hypertensive uveitis with unexplained absence of a crystalline lens in a blind eye must prompt suspicion of delayed phacogenic uveitis following asymptomatic lens luxation.

Abnormality in the external limiting membrane in early Stargardt disease.

Stargardt disease (STGD1) is caused by mutations in the ABCA4 gene. It has previously been reported that abnormalities in STGD1 may be detectable in the photoreceptors using spectral domain-optical coherence tomography (SD-OCT) prior to the detection of retinal pigment epithelium abnormalities. We present a 5-year-old asymptomatic girl with normal appearing fundi who possessed pathogenic ABCA4 variants on both chromosomes and where thickening of the external limiting membrane was the only abnormality detected on SD-OCT.

Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene.

PURPOSE: We evaluated the pathogenicity of the G1961E mutation in the ABCA4 gene, and present the range of retinal phenotypes associated with this mutation in homozygosity in a patient cohort with ABCA4-associated phenotypes. METHODS: Patients were enrolled from the ABCA4 disease database at Columbia University or by inquiry from collaborating physicians. Only patients homozygous for the G1961E mutation were enrolled. The entire ABCA4 gene open reading frame, including all exons and flanking intronic sequences, was sequenced in all patients. Phenotype data were obtained from clinical history and examination, fundus photography, infrared imaging, fundus autofluorescence, fluorescein angiography, and spectral domain-optical coherence tomography. Additional functional data were obtained using the full-field electroretinogram, and static or kinetic perimetry. RESULTS: We evaluated 12 patients homozygous for the G1961E mutation. All patients had evidence of retinal pathology consistent with the range of phenotypes observed in ABCA4 disease. The latest age of onset was recorded at 64 years, in a patient diagnosed initially with age-related macular degeneration (AMD). Of 6 patients in whom severe structural (with/without functional) fundus changes were detected, 5 had additional, heterozygous or homozygous, variants detected in the ABCA4 gene. CONCLUSIONS: Homozygous G1961E mutation in ABCA4 results in a range of retinal pathology. The phenotype usually is at the milder end of the disease spectrum, with severe phenotypes linked to the presence of additional ABCA4 variants. Our report also highlights that milder, late-onset Stargardt disease may be confused with AMD.

Familial discordance in Stargardt disease.

PURPOSE: To report genetic and phenotypic discordance across two generations of a family with autosomal recessive Stargardt disease (STGD1) and to compare pathogenicities of the G1961E and A1038V alleles of the ATP-binding cassette transporter, subfamily A, member 4 (ABCA4) gene. METHODS: Five members of a family with STGD1 (patients 1-4, affected; patient 5, carrier) were included. Clinical assessment was performed together with fundus autofluorescence and spectral domain-optical coherence tomography. Patients were stratified based on the results of electroretinogram testing. Genotyping of the ABCA4 gene was performed with the ABCR500 microarray. RESULTS: STGD1 was diagnosed in the male proband and his female sibling (patients 1 and 2, respectively). Two children of patient 2 (patients 3 and 4) were also affected. Genotyping revealed the W663X stop mutation in all affected patients. Patients 3 and 4, who were compound heterozygous for the G1961E mutation, had earlier ages of onset than patients 1 and 2, who were compound heterozygous for the A1038V mutation. Patient 1 had an age of onset 28 years younger than patient 2, whose delayed onset can be explained by relative foveal sparing, while patient 4 had an age of onset 44 years younger than patient 2. CONCLUSIONS: The G1961E mutation, which has been considered "mild," yields a more severe phenotype in this family than the A1038V mutation, which has been considered "severe." Marked intrasibship discordance in clinical course is described, suggesting an additional role for modifying factors in ABCA4 pleiotropism.

Infrared imaging and optical coherence tomography reveal early-stage astrocytic hamartomas not detectable by fundoscopy.

PURPOSE: To describe and correlate the features of astrocytic hamartomas using multimodal imaging. DESIGN: Prospective, noncomparative, observational case series. METHODS: This was a single-center study of 4 patients (8 eyes) with tuberous sclerosis complex. A complete ophthalmologic examination, fundus photography, fundus autofluorescence (FAF), infrared imaging, and spectral-domain optical coherence tomography (SD-OCT) were performed for each patient. Images from each modality were analyzed and compared. RESULTS: In 2 patients, infrared imaging and SD-OCT detected occult retinal astrocytic hamartomas that were not observed on clinical examination or color fundus photography. FAF demonstrated the greatest contrast between lesions and surrounding retina but failed to identify 1 occult lesion that was detected with infrared imaging and SD-OCT. SD-OCT revealed lesions arising from the retinal nerve fiber layer with overlying vitreous adhesions, hyperreflective dots, and optically empty spaces at all depths of the tumor. Hamartomas were hyporeflective on infrared imaging and hypoautofluorescent on FAF. FAF of some lesions demonstrated hyperautofluorescent spots. CONCLUSIONS: Infrared imaging and SD-OCT aid in the detection of astrocytic hamartomas that are not visible on clinical examination or color fundus photography. SD-OCT enhances visualization of structural details. FAF is a useful adjunctive test to obtain greater contrast between lesions and surrounding retina. The ability to monitor structural changes over time in astrocytic hamartomas using SD-OCT may be beneficial for monitoring the success of systemic chemotherapy in the treatment of various tuberous sclerosis tumors.

Disruption in Bruch membrane in patients with Stargardt disease.

PURPOSE: To describe the spectral domain-optical coherence tomography (SD-OCT) findings of two patients with complete defects in the retinal pigment epithelium (RPE) with disruptions in Bruch membrane in Stargardt disease (STGD1). METHODS: Two patients with STGD1 were referred to our clinic for further evaluation. Fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT), electroretinography (ERG) and Microperimetry (MP-1) were performed to assess the retinal anatomy and function. Screening for mutations in the ABCA4 gene was carried out and detected mutations were confirmed by direct sequencing. RESULTS: Both patients had bilateral macular geographic atrophy (GA) and yellowish subretinal pisciform flecks and mutations were detected in the ABCA4 gene by chip screening. SD-OCT revealed marked atrophy of the retina in the central macula, with focal defects in the RPE with disruptions in Bruch membrane and herniation of the retina through the defect in three of four eyes. CONCLUSION: This case report highlights the necessity for a detailed ophthalmic examination including SD-OCT of patients with STGD1.

Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP).

PURPOSE: To describe the structural changes across the transition zone (TZ) in choroideremia (CHM) and Stargardt disease (STGD) and to compare these to the TZ in retinitis pigmentosa (RP). METHODS: Frequency-domain (Fd)OCT line scans were obtained from seven patients with CHM, 20 with STGD, and 12 with RP and compared with those of 30 previously studied controls. A computer-aided manual segmentation procedure was used to determine the thicknesses of the outer segment (OS) layer, the outer nuclear layer plus outer plexiform layer (ONL+), the retinal pigment epithelium plus Bruch's membrane (RPE+BM), and the outer retina (OR). RESULTS: The TZ, while consistent within patient groups, showed differences across disease groups. In particular, (1) OS loss occurred before ONL+ loss in CHM and RP, whereas ONL+ loss occurred before OS loss in STGD; (2) ONL+ was preserved over a wider region of the retina in CHM than in RP; (3) RPE+BM remained normal across the RP TZ, but was typically thinned in CHM. In some CHM patients, it was abnormally thin in regions with normal OS and ONL+ thickness. In STGD, RPE+BM was thinned by the end of the TZ; and (4) the disappearances of the IS/OS and OLM were more abrupt in CHM and STGD than in RP. CONCLUSIONS: On fdOCT scans, patients with RP, CHM, and STGD all have a TZ between relatively healthy and severely affected retina. The patterns of changes in the receptor layers are similar within a disease category, but different across categories. The findings suggest that the pattern of progression of each disease is distinct and may offer clues for strategies in the development of future therapies.

Quantification of peripapillary sparing and macular involvement in Stargardt disease (STGD1).

PURPOSE: To quantify and compare structure and function across the macula and peripapillary area in Stargardt disease (STGD1). METHODS: Twenty-seven patients (27 eyes) and 12 age-similar controls (12 eyes) were studied. Patients were classified on the basis of full-field electroretinogram (ERG) results: Fundus autofluorescence (FAF) and spectral domain-optical coherence tomography (SD-OCT) horizontal line scans were obtained through the fovea and peripapillary area. The thicknesses of the outer nuclear layer plus outer plexiform layer (ONL+), outer segment (OS), and retinal pigment epithelium (RPE) were measured through the fovea, and peripapillary areas from 1° to 4° temporal to the optic disc edge using a computer-aided, manual segmentation technique. Visual sensitivities in the central 10° were assessed using microperimetry and related to retinal layer thicknesses. RESULTS: Compared to the central macula, the differences between controls and patients in ONL+, OS, and RPE layer thicknesses were less in the nasal and temporal macula. Relative sparing of the ONL+ and/or OS layers was detected in the nasal (i.e., peripapillary) macula in 8 of 13 patients with extramacular disease on FAF; relative functional sparing was also detected in this subgroup. All 14 patients with disease confined to the central macula, as detected on FAF, showed ONL+ and OS layer thinning in regions of normal RPE thickness. CONCLUSIONS: Relative peripapillary sparing was detected in STGD1 patients with extramacular disease on FAF. Photoreceptor thinning may precede RPE degeneration in STGD1.

Allelic and phenotypic heterogeneity in ABCA4 mutations.

Since the discovery of the ABCA4 gene as the cause of autosomal recessive Stargardt disease/fundus flavimaculatus much has been written of the phenotypic variability in ABCA4 retinopathy. In this review the authors discuss the findings seen on examination and the disease features detected using various clinical tests. Important differential diagnoses are presented and unusual presentations of ABCA4 disease highlighted.

Loss of peripapillary sparing in non-group I Stargardt disease.

The aim of this study was to assess peripapillary sparing in patients with non-group I Stargardt disease. We suggest this as a useful clinical sign for formulating disease severity. Patients with a diagnosis of Stargardt disease were grouped by electroretinogram (ERG). Fundus autofluorescence was used to assess the peripapillary area for involvement in the Stargardt disease process. From a cohort of 32 patients (64 eyes), 17 patients (33 eyes) demonstrated loss of peripapillary sparing. One of 15 patients in Group I, six of 7 patients in group II and 9 of 10 patients in group III demonstrated peripapillary atrophy. One patient in group II had peripapillary flecks. All patients had at least one mutation detected in the ABCA4 gene. Both mutations were detected in 21 patients. Patients in groups II and III had the earliest ages of onset and the poorest visual acuities. Two novel disease causing mutation in the ABCA4 gene were detected. Our data supports the observation that peripapillary sparing is not universal finding for Stargardt disease and peripapillary atrophy is a useful clinical sign for identifying patients with Stargardt disease who fall into the more severe ERG groups, i.e. groups II and III. The presence of atrophy suggests a continuum of disease between groups II and III. Loss of peripapillary sparing is likely associated with the more deleterious mutations of the ABCA4 gene.