Mrinali P. Gupta

Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations

IMPORTANCE Somatic mutations in BAP1 (BRCA1-associated protein 1 gene) are frequently identified in uveal melanoma. To date, the role of germline BAP1 mutations in uveal melanoma has not been characterized. OBJECTIVE To characterize the clinical phenotype of uveal melanoma in patients with germline BAP1 mutations. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at an academic ophthalmology referral center among 507 patients with uveal melanoma who consented for collection of blood samples. The study dates were June 22, 1992, to December 14, 2010. MAIN OUTCOMES AND MEASURES Clinical characteristics of uveal melanoma and the development of metastases. BAP1 gene sequencing from blood samples of patients with uveal melanoma was correlated with clinical characteristics. RESULTS Of 507 blood samples analyzed, 25 patients (4.9%) exhibited 18 BAP1 polymorphisms, of which 9 were novel. Computational analyses predicted that 8 BAP1 mutations in 8 patients (1.6%) were likely to result in damaged BAP1 protein. Five of these 8 mutations were novel. These 8 patients were compared with 482 patients in whom no BAP1 polymorphisms were identified. In univariate analyses, patients with germline BAP1 mutations exhibited larger tumor diameters (mean, 15.9 vs 12.3 mm; P = .004) and higher rates of ciliary body involvement (75.0% vs 21.6%, P = .002) and metastases (71.4% vs 18.0%, P = .003) compared with control subjects. Patients with germline BAP1 mutations exhibited increased frequency of family history of cancer (100% vs 65.9%, P = .06), particularly cutaneous melanoma (62.5% vs 9.9%, P < .001) and ocular melanoma (25.0% vs 1.9%, P = .01). No differences were identified in age at diagnosis, sex, history of other malignant neoplasm, presenting visual acuity, distance of the tumor from the optic nerve or fovea, iris involvement, extrascleral extension, or tumor pigmentation. Germline BAP1 mutations increased risk of metastasis independent of ciliary body involvement (P = .02). Germline BAP1 mutation approached significance as an independent risk factor for metastasis (P = .09). CONCLUSIONS AND RELEVANCE These data suggest that germline BAP1 mutations occur infrequently in uveal melanoma and are associated with larger tumors and higher rates of ciliary body involvement, 2 known risk factors for metastasis.

Influence of Fluorescein Angiography on the Diagnosis and Management of Retinopathy of Prematurity

PURPOSE To examine the influence of fluorescein angiography (FA) on the diagnosis and management of retinopathy of prematurity (ROP). DESIGN Prospective cohort study. PARTICIPANTS Nine recognized ROP experts (3 pediatric ophthalmologists and 6 retina specialists) interpreted 32 sets (16 color fundus photographs and 16 color fundus photographs paired with the corresponding FA images) of wide-angle retinal images from infants with ROP. METHODS All experts independently reviewed the 32 image sets on a secure website and provided a diagnosis and management plan for the case presented, first based on color fundus photographs alone, and then based on color fundus photographs and corresponding FA images. MAIN OUTCOME MEASURES Sensitivity and specificity of the ROP diagnosis (zone, stage, plus disease, and category, i.e., no ROP, mild ROP, type 2 ROP, and ROP requiring treatment) were calculated using a consensus reference standard diagnosis, determined from the diagnosis of the color fundus photographs by 3 experienced readers in combination with the clinical diagnosis based on ophthalmoscopic examination. The κ statistic was used to analyze the average intergrader agreement among experts for the diagnosis of zone, stage, plus disease, and category. RESULTS Addition of FA to color fundus photography resulted in a significant improvement in sensitivity for diagnosis of stage 3 or worse disease (39.8% vs. 74.1%; P = 0.008), type 2 or worse ROP (69.4% vs. 86.8%; P = 0.013), and pre-plus or worse disease (50.5 vs. 62.6%; P = 0.031). There was a nonsignificant trend toward improved sensitivity for diagnosis of ROP requiring treatment (22.2% vs. 40.3%; P = 0.063). Using the κ statistic, addition of FA to color fundus photography significantly improved intergrader agreement for diagnosis of ROP requiring treatment. Addition of FA to color fundus photography did not affect intergrader agreement significantly for the diagnosis of stage, zone, or plus disease. CONCLUSIONS Compared with color fundus photography alone, FA may improve the sensitivity of diagnosis of ROP by experts, particularly for stage 3 disease. In addition, intergrader agreement for diagnosis of ROP requiring treatment may improve with FA interpretation.

Retinal reperfusion in diabetic retinopathy following treatment with anti-VEGF intravitreal injections

Purpose The aim of this study is to report peripheral reperfusion of ischemic areas of the retina on ultra-widefield fluorescein angiography (UWFA) following anti-vascular endothelial growth factor (VEGF) intravitreal injections in patients treated for diabetic retinopathy. Methods This study is a retrospective review of 16 eyes of 15 patients with diabetic retinopathy, who received anti-VEGF intravitreal injections and underwent pre- and postinjection UWFA. The main outcome measured was the presence of reperfusion in postinjection UWFA images in areas of the retina that demonstrated nonperfusion in preinjection images. Images were analyzed for reperfusion qualitatively and quantitatively by two graders. Results Twelve of 16 eyes (75%) or 11 of 15 patients (73.3%) demonstrated reperfusion following anti-VEGF injection. On UWFA, reperfusion was detected both within the field of 7-standard field (7SF) fluorescein angiography and in the periphery outside the 7SF. Four of 16 eyes or 4 of 15 patients did not demonstrate reperfusion, one of which had extensive scarring from prior panretinal photocoagulation. Conclusion In patients with diabetic retinopathy, treatment with anti-VEGF agents can be associated with reperfusion of areas of nonperfusion, as demonstrated by UWFA.

Practice Patterns in Retinopathy of Prematurity Treatment for Disease Milder Than Recommended by Guidelines

PURPOSE To characterize the frequency of and clinical indications for which experts treat retinopathy of prematurity (ROP) milder than type 1 disease, the recommended threshold for treatment from established consensus guidelines. DESIGN Descriptive analysis. METHODS setting: Multicenter. STUDY POPULATION A database of 1444 eyes generated prospectively from all babies screened for ROP at 1 of 6 major ROP centers whose parents provided informed consent. INTERVENTION Retrospective review of the database and charts to identify all patients treated for ROP milder than type 1. MAIN OUTCOME MEASURE Indication(s) for treatment. RESULTS A total of 137 eyes of 70 infants were treated for ROP. Of these 137 eyes, 13 (9.5%) were treated despite a clinical diagnosis milder than type 1 ROP. Indications for treatment included active ROP with the fellow eye being treated for type 1 ROP (2 eyes, 15.4%); concerning structural changes (9 eyes, 69.2%), including tangential traction with temporal vessel straightening concerning for macular dragging (8 eyes, 61.5%) and thick stage 3 membranes with anteroposterior traction concerning for progression to stage 4 ROP (3 eyes, 23.1%); persistent ROP at an advanced postmenstrual age (4 eyes, 30.8%); and/or vitreous hemorrhage (3 eyes, 23.1%). CONCLUSIONS Experts in this study occasionally recommended treatment in eyes with disease less than type 1 ROP. This study has important clinical implications and highlights the role of individual clinical judgment in situations not covered by evidence-based treatment guidelines.

Treatment of cytomegalovirus retinitis with cytomegalovirus-specific T-lymphocyte infusion.

Cytomegalovirus (CMV) retinitis is a potentially blinding infection that affects immunocompromised patients who are unable to generate a T-cell response against the organism. Infusion of CMV-specific leukocytes has been shown to be effective in patients with systemic CMV infection, especially those resistant to standard therapies. The authors report a case of a patient with CMV viremia with progressive retinitis in whom infusion of third-party donor-derived CMV pp65-specific T cells alone prompted resolution of CMV retinitis. This case suggests a potential role for CMV-specific leukocyte infusion in the treatment of CMV retinitis, especially in cases resistant or refractory to antiviral therapies.

Progressive outer retinal necrosis in a multiple sclerosis patient on natalizumab

A 54-year-old woman with multiple sclerosis, on natalizumab, reported 2 weeks of left eye redness and blurry vision, previously diagnosed as conjunctivitis. Visual acuity was 20/125. Funduscopy revealed progressive outer retinal necrosis (figure 1), a viral retinitis of immunocompromised patients that frequently causes vision loss.1 Sequential bilateral involvement is common. Etiologies include varicella zoster, herpes simplex, and rarely cytomegalovirus; aqueous PCR revealed varicella. Natalizumab was held. IV and intravitreal antivirals were administered. After repair of retinitis-induced retinal detachment and resolution of retinitis, visual acuity was 20/125 (figure 2). In immunocompromised patients with ocular symptoms, clinicians should consider infectious retinitis and obtain prompt funduscopic evaluation.

Retinal vascular nonperfusion in siblings with Dandy-Walker variant

We report the case of a 2-month-old girl with Dandy-Walker variant who presented with strabismus, pathologic myopia measuring -16.00 D in each eye, diffuse chorioretinal atrophy and pigment mottling in the macula of both eyes, and areas of retinal capillary nonperfusion in both eyes. The patients brother also has Dandy-Walker variant and was found to have bilateral severe myopia, myopic fundi, tilted optic disks with peripapillary atrophy, extensive areas of white without pressure, areas of lattice degeneration, and several chronic-appearing atrophic retinal holes surrounded by pigmentation. We hypothesize that children with Dandy-Walker variant may present with refractive errors such as pathologic myopia and with diverse retinal findings, including retinal ischemia. A lower threshold for ophthalmologic examination may be considered in this population.

Retinal findings and a novel TINF2 mutation in Revesz syndrome: Clinical and molecular correlations with pediatric retinal vasculopathies

ABSTRACT Background: Revesz syndrome is a telomere disorder in the dyskeratosis congenita (DKC) spectrum characterized by exudative retinopathy, bone marrow failure, neuroradiographic abnormalities, and integumentary findings. Materials/methods: We report the ophthalmologic findings, documented by examinations under anesthesia with clinical photography and fluorescein angiography, as well as the systemic manifestations and genetic and molecular testing, in identical twins with Revesz syndrome, and compare and contrast these features to those of other pediatric retinal vasculopathies. Results: Both twins exhibited widespread avascularity and anomalous vasculature of the retinal periphery, retinal telangiectasias, and exudation. One twin developed a combination exudative/tractional/rhegmatogenous retinal detachment, while the other exhibited a focal collection of buds of retinal neovascularization. Both twins developed bone marrow failure and were found to have cerebellar hypoplasia and widespread cerebral calcifications. Telomere testing in lymphocytes and granulocytes revealed telomere length less than the 1st percentile for age, and gene sequencing revealed a novel mutation in the TINF2 gene, resulting in the T284P TIN2 protein variant. Conclusions: We report ophthalmic findings in twins with Revesz syndrome due to a previously unreported mutation in TINF2 and propose that phenotypic and molecular overlaps between DKC spectrum disorders and pediatric retinal vasculopathies may reflect a shared pathophysiologic basis.

Ocular Decompression Retinopathy After Uncomplicated Cataract Surgery in a Patient With a History of Narrow-Angle Glaucoma.

Purpose:To describe a case of ocular decompression retinopathy following uncomplicated cataract surgery in a patient with phacomorphic narrow-angle glaucoma. Methods:Case report with wide-field fundus imaging. Results:A 57-year-old woman with a history of phacomorphic narrow-angle glaucoma presented 1 day after uncomplicated cataract extraction with intraocular lens insertion of the left eye with hand motion vision. She was found to have decompression retinopathy with large prefoveal subhyaloid hemorrhage. The hemorrhages gradually improved over time with observation. Conclusions:We report a case of decompression retinopathy after uncomplicated cataract extraction in a patient with phacomorphic narrow-angle glaucoma. This report expands upon the procedures after which decompression retinopathy has been diagnosed and suggests a need for careful perioperative management in patients with glaucoma.

Pachychoroid neovasculopathy in extramacular choroidal neovascularization

Purpose To review a series of extramacular choroidal neovascular membranes (CNVMs) in the context of their choroidal features, as determined by optical coherence tomography (OCT). Methods Patients with extramacular CNVMs were identified from a tertiary care center through a review of records. The charts and cases were reviewed using multimodal imaging including fundus photography, OCT, fluorescein angiography (FA), and indocyanine angio-graphy (ICG). Results Of six patients with extramacular CNVMs evaluated in this series, four patients (66.7%) exhibited pachychoroidopathy on OCT imaging under or adjacent to the extramacular CNVM. All four of these patients also exhibited pachychoroidopathy in the macular OCT distant from the CNVM. Conclusion Pachychoroidopathy is implicated in some cases of extramacular CNVMs. This represents the first report, to our knowledge, of pachychoroidopathy in extramacular CNVM.