Connie J. Chen

Emerging Treatments for Choroidal Metastases

It has been over a century since Perls described the first case of choroidal metastasis. For the next six decades only 230 cases were described in the literature. Today, however, ocular metastasis is recognized as the most common intraocular malignancy. Thanks to recent advances in treatment options for metastatic disease, patients are living longer, and choroidal metastases will become an increasingly important issue for oncologists and ophthalmologists alike. We summarize the current knowledge of choroidal metastases and examine their emerging systemic and local therapies. Targeted therapies for metastatic lung, breast, and colon cancer--the most common causes of choroidal metastases--are reviewed in detail with the goal of identifying the most effective treatment strategies.

Pro-Permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; the Ozurdex for Retinal Vein Occlusion (ORVO) Study

PURPOSE To correlate aqueous vasoactive protein changes with macular edema after dexamethasone implant in retinal vein occlusion (RVO). DESIGN Prospective, interventional case series. METHODS Twenty-three central RVO (CRVO) and 17 branch RVO (BRVO) subjects with edema despite prior anti-vascular endothelial growth factor (VEGF) treatment had aqueous taps at baseline and 4 and 16 weeks after dexamethasone implant. Best-corrected visual acuity (BCVA) and center subfield thickness were measured every 4 weeks. Aqueous vasoactive protein levels were measured by protein array or enzyme-linked immunosorbent assay. RESULTS Thirty-two vasoactive proteins were detected in aqueous in untreated eyes with macular edema due to RVO. Reduction in excess foveal thickness after dexamethasone implant correlated with reduction in persephin and pentraxin 3 (Pearson correlation coefficients = 0.682 and 0.638, P = .014 and P = .003). Other protein changes differed among RVO patients as edema decreased, but ≥50% of patients showed reductions in hepatocyte growth factor, endocrine gland VEGF, insulin-like growth factor binding proteins, or endostatin by ≥30%. Enzyme-linked immunosorbent assay in 18 eyes (12 CRVO, 6 BRVO) showed baseline levels of hepatocyte growth factor and VEGF of 168.2 ± 20.1 pg/mL and 78.7 ± 10.0 pg/mL, and each was reduced in 12 eyes after dexamethasone implant. CONCLUSIONS Dexamethasone implants reduce several pro-permeability proteins providing a multitargeted approach in RVO. No single protein in addition to VEGF can be implicated as a contributor in all patients. Candidates for contribution to chronic edema in subgroups of patients that deserve further study include persephin, hepatocyte growth factor, and endocrine gland VEGF.

Characterizing the Phenotype and Genotype of a Family With Occult Macular Dystrophy

OBJECTIVE To characterize the phenotype of a white patient with occult macular dystrophy (OMD) and her clinically unaffected family members and to determine whether similar mutations were present in the RP1L1 gene in this family. Occult macular dystrophy is a rare macular dystrophy with central cone dysfunction hidden behind a normal fundus appearance that has been attributed to a mutation in the retinitis pigmentosa 1-like 1 (RP1L1) gene in 4 Japanese families. METHODS In this observational cross-sectional study of 1 white family with OMD, patients meeting the clinical criteria for OMD and their family members were evaluated by use of multifocal electroretinography, the Farnsworth D-15 color vision test, automated perimetry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and fundus photography. Fluorescein angiography was performed only on the proband. Members of this family were screened for genetic mutations in the RP1L1 gene. RESULTS In the family studied, the clinically affected proband was noted to have loss of the foveal outer segments and absence of bowing of the inner segment/outer segment junction on SD-OCT scans. In addition, 1 clinically unaffected family member also demonstrated loss of the foveal photoreceptor outer segments and, therefore, decreased bowing of the inner segment/outer segment junction on SD-OCT scans. The fundus autofluorescence images of the eyes of the proband and her family members were normal. Although mutations in the RP1L1 gene have been identified in sporadic and autosomal dominant OMD pedigrees, no mutations in the RP1L1 gene were found in any of the participants. CONCLUSIONS Loss of the outer segments of foveal photoreceptors can be detected and quantified by use of SD-OCT in patients with OMD. Similar findings are present in some clinically unaffected family members and may represent subclinical manifestations of the disease. Although mutations in the RP1L1 gene have been described in several Japanese families with OMD, there were no such mutations in this white family of European descent, which suggests that inherited OMD is a genetically heterogeneous disorder.

Progressive Cone Dysfunction and Geographic Atrophy of the Macula in Late Stage Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC)

Abstract Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare inherited ocular disease associated with distinct mutations in the BEST1 gene. Typically, patients have only mild visual impairment, and rarely do patients have moderate or severe visual impairment, often as a result of vitreous hemorrhage. We now describe progressive central macular atrophy and cone dysfunction leading to visual loss in an elderly ADVIRC patient 33 years after initial presentation.

Long-Term Macular Changes in the First Proband of Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Due to a Newly Identified Mutation in BEST1.

Abstract Background: Mutations in BEST1 account for autosomal dominant vitreoretinochoroidopathy (ADVIRC), a rare inherited retinal dystrophy with presenile cataracts and incomplete anterior segment development. The long-term clinical findings and visual prognosis of these patients continues to evolve over time. Materials and Methods: The retina was assessed by fundus photography, fluorescein angiography, and spectral domain optical coherence tomography. Sanger dideoxy chain-termination sequencing identified mutations in BEST1. Bioinformatic tools were used to predict changes in splicing. An in vitro splicing assay was applied to evaluate for altered pre-mRNA splicing. Results: Long-term follow up of the first ever reported ADVIRC proband revealed progressive foveal atrophy in both eyes 3 decades after his initial presentation. Progressive retinal ischemia, bilateral iris atrophy, and pseudophakodnesis were observed on follow up. The patient was heterozygous for a c.248G > A missense mutation in exon 4 of BEST1, affecting a highly conserved transmembrane domain. Although computational prediction models suggest a change in the binding probability of splicing-associated SR proteins, in vitro splicing assays failed to demonstrate an effect of the c.248G > A mutation on splicing of BEST1 exon 3 or exon 4. Conclusions: Progressive posterior chorioretinal changes occurred over time in the initial ADVIRC proband, leading to visual loss. The causative mutation in this patient falls in the transmembrane domain of the BEST1 protein, with unclear functional consequences. Although previous studies showed alteration in pre-mRNA splicing, in vitro splicing assays failed to demonstrate this in our patient.

VARIABLE EXPRESSION OF RETINOPATHY IN A PEDIGREE OF PATIENTS WITH INCONTINENTIA PIGMENTI.

Purpose: To characterize the varied ocular manifestations of incontinentia pigmenti (IP) in a large pedigree. Methods: All available members of the kindred who were affected with IP were examined with ophthalmoscopy, wide-field color photos, and fluorescein angiography. Results: Individual family members demonstrated variable expression of retinopathy characteristic of IP. There was severe retinopathy in two eyes: one associated with concurrent persistent fetal vasculature and another with rhegmatogenous retinal detachment. Another individual with biopsy-confirmed IP demonstrated no retinopathy in either eye. When present, retinopathy manifested asymmetrically between eyes of the same individual. Conclusion: Cutaneous manifestations of IP are irregular and nonuniform due to lyonization of the X chromosome. In this report, we identify asymmetric retinal disease between eyes in the same individual and variable retinal findings within the kindred. These differences may be explained by random inactivation of the X chromosome or other epigenetic modifications.

Extended Follow-up of Treated and Untreated Retinopathy in Incontinentia Pigmenti: Analysis of Peripheral Vascular Changes and Incidence of Retinal Detachment.

IMPORTANCE Extended follow-up of treated and untreated retinopathy in incontinentia pigmenti (IP) has not previously been documented, to our knowledge. OBJECTIVE To determine which eyes with IP are at risk for retinal detachment. DESIGN, SETTING, AND PARTICIPANTS Observational cohort study of patients with IP who were retrospectively identified at a tertiary care academic center between 1976 and 2013. Fifty eyes of 25 female participants meeting clinical criteria for IP were followed up for at least 6 months. The last year of follow-up was between 1987 and 2014. MAIN OUTCOMES AND MEASURES Progression of retinopathy or the development of retinal detachment was assessed with fluorescein angiography, clinical examination, or both. RESULTS The median duration of follow-up was 9.3 years (range, 0.5-22.8 years). Over this period, 11 eyes (22%; 95% CI, 11%-33%) developed retinal detachment. The odds of retinal detachment were increased if there was retinal neovascularization (odds ratio, 11.61; 95% CI, 1.34-100.56; P = .03) or ischemic optic neuropathy (odds ratio, 5.27; 95% CI, 1.61-17.23; P = .006) on initial examination. A bimodal distribution of retinal detachments was observed, with most tractional detachments (7 eyes) occurring by age 2.5 years (median, 1.5 years; range, 14 days-7.0 years) and most rhegmatogenous detachments (4 eyes) occurring in adults (median age, 31.5 years; range, 14.0-47.0 years). Three eyes of young patients (≤2.5 years) developed tractional detachment, despite prophylactic ablation in 4 eyes; only one eye of older patients (≥14.0 years) developed retinal detachment following prophylactic ablation in 6 eyes. Persistent fetal vasculature appears to occur more commonly in IP (14%; 95% CI, 4%-25%) than in the general population. CONCLUSIONS AND RELEVANCE All eyes with retinopathy due to IP should be monitored throughout adulthood for the development of retinal complications. During infancy and early childhood, ophthalmoscopic examination should be performed frequently so that prompt treatment can be initiated if there is progressive disease. Because of the nonrandomized nature of this study, the indications for prophylactic ablation and its success rate remain uncertain. Patients with less than 6 months of follow-up were excluded from the analysis, which could have biased this study cohort toward patients with more severe or less severe disease.

Multimodal Retinal Imaging in Incontinentia Pigmenti Including Optical Coherence Tomography Angiography: Findings From an Older Cohort With Mild Phenotype

Importance Incontinentia pigmenti (IP) is a rare, X-linked dominant disease with potentially severe ocular complications that predominantly affect the peripheral retina. However, little is known about its effects on the macula. Objective To describe the structural and vascular abnormalities observed in the maculas of patients with IP and to correlate these findings with peripheral pathologies. Design, Setting, and Participants Prospective, cross-sectional study at Wilmer Eye Institute, Johns Hopkins University. Five participants with a clinical diagnosis of IP were included and underwent multimodal imaging with ultra–wide-field fluorescein angiography (FA), spectral-domain optical coherence tomography (OCT), and OCT angiography. Main Outcomes and Measures The structural and vascular abnormalities observed on spectral-domain OCT and OCT angiography and their correlation with peripheral pathologies seen on ultra–wide-field FA. Results A total of 9 eyes from 5 patients (median age, 20.5 years; range, 8.4-54.2 years) were included. Median Snellen visual acuity was 20/32 (range, 20/16 to 20/63). ultra–wide-field FA-identified retinal vascular abnormalities in all 7 eyes in which FA was obtained. These abnormalities included microaneurysms, areas of nonperfusion, and vascular anastomoses, most of which were peripheral to the standard view of 30° FA with peripheral sweeps. Structural abnormalities were observed in 6 eyes on spectral-domain OCT, including inner retinal thinning and irregularities in the outer plexiform layer. Optical coherence tomography angiography abnormalities were noted in all 9 eyes, including decreased vascular density, abnormal vascular loops, and flow loss in the superficial and deep plexuses, which corresponded to areas of retinal thinning on spectral-domain OCT. Conclusions and Relevance Although our study is limited by the small sample size, the findings suggest that multimodal imaging is useful for detecting structural and vascular abnormalities that may not be apparent on ophthalmoscopy in patients with IP. Macular pathologies, especially a decrease in vascular density on OCT angiography, are common. Further studies are needed to characterize further the association between macular and peripheral abnormalities in patients with IP.

Macular caldera in North Carolina macular dystrophy: Only an illusion of posterior pole staphyloma

Macular Caldera in North Carolina Macular Dystrophy: Only an Illusion of Posterior Pole Staphyloma To the Editor We read with interest the article by Schoenberger and Agarwal titled “Intrachoroidal Cavitation in North Carolina Macular Dystrophy.”1 They describe 2 patients who had bilateral macular “staphylomas.” We disagree with the nomenclature (staphyloma) used to describe these advanced macular lesions and favor the term macular caldera, as previously explained by Khurana et al.2 Staphyloma refers to a definite outpouching of the sclera that is lined with uveal tissue. Although Schoenberger and Agarwal demonstrate with optical coherence tomography (OCT) the posterior bowing of the central macula, the entire sclerochoroidal interface is not well visualized on their conventional spectral-domain OCT. We have previously examined several patients with advanced North Carolina macular dystrophy (NCMD)2 in whom there was an illusion of a staphylomatous appearance on binocular ophthalmoscopic examination. Now, with enhanceddepth imaging OCT (EDI-OCT) in both eyes of a patient not previously described, we are able to demonstrate lack of combined scleral and uveal outpouching (Figure 1). Although there is a microscopic outward convexity of underlying Bruch membrane and choroid, it is not proportional to the markedly excavated appearance on ophthalmoscopy, ie, there is a major inconsistency between the EDI-OCT findings and the ophthalmoscopic findings. B-scan ultrasonography in our present case (Figure 2) and in our previously published account2 do not show any sclerochoroidal bowing or outpouching, confirming the EDI-OCT interpretation. In addition, A-scan ultrasonography showed no increased anteroposterior length in the axis of the advanced macular lesions. Interestingly, EDI-OCT shows that the choroid appears unusually thick (Figure 1), which also is inconsistent with the normally stretched and attenuated uveal tissue seen in true staphylomas. Because ophthalmoscopic appraisal by itself falsely suggests a very deep crater, whereas EDI-OCT and ultrasonography show virtually no significant sclerochoroidal outpouching, we continue to avoid using the misnomer staphyloma. It is possible, of course, that further study of additional cases will