Faculty Bibliography

The authors describe fundus autofluorescence (AF) and spectral-domain optical coherence tomography (SD-OCT) findings in three patients with enhanced S-cone syndrome and their correlation around the hyperautofluorescent ring border. Patients had AF imaging in combination with SD-OCT line-scans through the fovea, at the posterior pole, and at a temporal locus centered on the ring border. All eyes demonstrated a macular ring of high-intensity AF. The inner segment ellipsoid band showed thinning and disorganization toward the ring border, where it was lost. [Ophthalmic Surg Lasers Imaging Retina. 2014;45:592-595.].

BACKGROUND AND OBJECTIVE: To assess the cone photoreceptor mosaic in acute macular neuroretinopathy (AMN) using adaptive optics (AO) imaging. PATIENTS AND METHODS: Four patients with AMN were evaluated retrospectively by near-infrared reflectance (IR) confocal scanning laser ophthalmoscopy (SLO), spectral-domain optical coherence tomography (SD-OCT), and a flood-illuminated retinal AO camera. Microperimetry was performed in one patient. RESULTS: The cone photoreceptor density was decreased at the level of the AMN lesions. The cone mosaic disruption appeared heterogeneous and more widespread than the lesion detected in the IR-SLO and SD-OCT images. The areas of cone loss correlated with SD-OCT and microperimetry. After resolution of the AMN lesion on IR-SLO, there was incomplete recovery of the cone photoreceptor mosaic. CONCLUSION: Cone photoreceptor damage and reconstitution were documented in vivo at the cellular level in AMN using AO imaging. AO imaging appeared more sensitive than combined IR-SLO and SD-OCT to detect and follow photoreceptor damage in patients with AMN. [Ophthalmic Surg Lasers Imaging Retina. 2014;45:562-569.].

Autosomal recessive Stargardt disease (STGD1) is caused by hundreds of mutations in the ABCA4 gene, which are often specific to racial and ethnic groups. Here, we investigated the ABCA4 variation and their phenotypic expression in a cohort of 44 patients of African American descent, a previously under-characterized racial group. Patients were screened for mutations in ABCA4 by next-generation sequencing (NGS) and array-comparative genome hybridization (aCGH), followed by analyses for pathogenicity by in silico programs. Thorough ophthalmic examination was performed on all patients. At least two (expected) disease-causing alleles in the ABCA4 gene were identified in 27 (61.4%) patients, one allele in 11 (25%) patients, and no ABCA4 mutations were found in 6 (13.6%) patients. Altogether, 39 different disease-causing ABCA4 variants, including 7 new, were identified on 65 (74%) chromosomes, most of which were unique for this racial group. The most frequent ABCA4 mutation in this cohort was c.6320G>A (p.(R2107H)), representing 19.3% of all disease-associated alleles. No large copy number variants were identified in any patient. Most patients reported later onset of symptoms. In summary, the ABCA4 mutation spectrum in patients of West African descent differs significantly from that in patients of European descent, resulting in a later onset and 'milder' disease

Abstract Purpose: To demonstrate the utility and characteristics of fundus autofluorescence in late-onset retinitis pigmentosa. Methods: Observational case series. Patients diagnosed with late-onset retinitis pigmentosa were identified retrospectively in an institutional setting. Twelve eyes of six patients were identified and medical records were reviewed. Results: All patients presented with slowly progressive peripheral field loss and initial clinical examination revealed only subtle retinal changes. There was a notable lack of intraretinal pigment migration in all patients. Five out of six patients underwent magnetic resonance imaging of the brain to rule out intracranial processes and all were referred from another ophthalmologist for further evaluation. Fundus autofluorescence was ultimately employed in all patients and revealed more extensive retinal pathology than initially appreciated on clinical examination. Fundus autofluorescence directed the workup toward a retinal etiology in all cases and led to the eventual diagnosis of late-onset retinitis pigmentosa through electroretinogram testing. Conclusion: Fundus autofluorescence may be a more sensitive marker for retinal pathology than stereo fundus biomicroscopy alone in late-onset retinitis pigmentosa. Early use of fundus autofluorescence imaging in the evaluation of patients with subtle retinal lesions and complaints of peripheral field loss may be an effective strategy for timely and cost-efficient diagnosis.

Importance: We describe the multimodal imaging in a group of patients showing a distinct clinical entity that best represents acute zonal occult outer retinopathy (AZOOR). Objective: To propose a classification of AZOOR based on clinical fundus and multimodal imaging. Design, Setting and Participants: A retrospective review of patients diagnosed as having AZOOR at 2 centers. After reviewing more than 400 cases diagnosed or referred to us as AZOOR or AZOOR complex, we assembled 30 cases that fit our current definition; (48 eyes) with a median age at diagnosis of 47 years (age range, 17-86 years) and a mean follow-up period of 39 months. Twenty patients were female. Eighteen patients had initially been seen with bilateral lesions, mostly asymmetric (4 cases were symmetric). Most patients had no remarkable medical or ocular history. The median visual acuity at the time of presentation was 20/25 (range, 20/20 to 20/400). Main Outcomes and Measures: Multimodal imaging, including fundus photography, fluorescein and indocyanine green angiography, fundus autofluorescence imaging, and corresponding eye-tracked spectral-domain coherence tomography imaging. Results: Each patient was initially seen with visual symptoms of photopsia and scotoma, and most had a detectable lesion in the fundus evident clinically or detected on multimodal imaging. The clinical appearance of the AZOOR lesions varied depending on their duration and location, but some features were characteristic, including a demarcating line of the progression at the level of the outer retina and a trizonal pattern of sequential involvement of the outer retina, retinal pigment epithelium, and choroid, as well as frequent zonal progression. Advanced cases of AZOOR demonstrated disruption of the inner and outer retina and severe damage or loss of the retinal pigment epithelium and the choroid. Conclusions and Relevance: A specific definition of AZOOR based on multimodal imaging is proposed to help physicians distinguish it from other diseases of the posterior fundus, including white spot syndromes and autoimmune, hereditary, paraneoplastic, toxic, and other inflammatory retinopathies.

Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patient-specific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naive human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrprd6/Mfrprd6 mice-an established preclinical model of RP-and long-term improvement in visual function was observed in AAV-Mfrp treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines and the Mfrprd6/Mfrprd6 preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.Molecular Therapy (2014); doi:10.1038/mt.2014.100.

PURPOSE:: To report thirteen cases of idiopathic multifocal choroiditis with discrete chorioretinal lesions who were found to have zonal, multizonal, or diffuse outer retinal or chorioretinal atrophy. METHODS:: A retrospective observational case series using multimodal imaging including high-definition optical coherence tomography, fundus autofluorescence imaging, and fluorescein and indocyanine green angiography. RESULTS:: Twenty-one eyes in 13 patients with idiopathic multifocal choroiditis were found to have zonal, multizonal, or diffuse outer retinal or chorioretinal atrophy visualized using multimodal imaging. Thirteen eyes presented with diffuse disease, six eyes with multizonal, and two with zonal atrophy. Patterns of atrophy included zones surrounding the optic nerve, multiple geographic zones in the mid and far periphery, and a diffuse peripheral pattern with relative sparing of the central macula until later in the course of disease. Eleven of the 13 patients were treated with topical, periocular, or systemic corticosteroids, and 1 patient was also treated with systemic immunomodulatory treatment. The atrophic changes progressed over an average of 8 years of follow-up in 10 eyes despite therapy. CONCLUSION:: Idiopathic multifocal choroiditis can present with an uncommon pattern of zonal, multizonal, or diffuse outer retinal or chorioretinal atrophy as part of its clinical spectrum. The severity, extent, and progression of these atrophic changes are best appreciated using multimodal diagnostic imaging.

PURPOSE: To describe a new classification of stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR). DESIGN: Retrospective case series and literature review. PARTICIPANTS: A total of 17 patients from 5 institutions. METHODS: Detailed case history, multimodal imaging, and genetic testing were reviewed for patients with macular schisis without a known predisposing condition. Patients with a stellate appearance centered on the fovea with correlating confirmed expansion of the outer plexiform layer (OPL) by optical coherence tomography (OCT) were included. Exclusion criteria included a family history of macular retinoschisis, a known genetic abnormality associated with retinoschisis, myopic traction maculopathy, epiretinal membrane, vitreoretinal traction, optic or scleral pit, or advanced glaucomatous optic nerve changes. MAIN OUTCOME MEASURES: Clinical features, anatomic characteristics, and visual acuity. RESULTS: A total of 22 eyes from 16 female patients and 1 male patient with foveomacular schisis were reviewed from 5 institutions. Initial visual acuity was >/=20/50 in all eyes (mean, 20/27), but visual acuity in a single eye decreased from 20/20 to 20/200 after the development of subfoveal fluid. The refractive status was myopic in 16 eyes, plano in 3 eyes, and hyperopic in 2 eyes. Three eyes had a preexisting vitreous separation, and 19 eyes had an attached posterior hyaloid. Follow-up ranged from 6 months to >5 years. CONCLUSIONS: In this largest known series of patients with SNIFR, all patients demonstrated splitting of the OPL in the macula with relatively preserved visual acuity (>/=20/40) except in a single patient in whom subretinal fluid developed under the fovea.

Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was down-regulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of 4 common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; p=0.00012; OR=1.5; 95%C.I. [1.2;1.8], and p=0.0014; OR=0.70; 95%C.I. [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (p=0.0002; OR=0.61, 95%CI [0.47-0.79]). We propose that genetically pre-determined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population