REGIONAL SCLERAL THICKNESS AS A RISK FACTOR FOR CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To evaluate regional sclera thicknesses as possible risk factors for central serous chorioretinopathy (CSC). METHODS: Patients with CSC and controls were evaluated with contact B-scan ultrasonography using a 20 Mhz concentric phased array ultrasound unit and enhanced depth imaging optical coherence tomography to measure the scleral thickness at the equator and posterior pole. The resultant data were evaluated using univariate analysis and generalized estimating equations. RESULTS: There were 40 patients with CSC with a mean age of 58 years and 23 controls with a mean age of 60.7 years (P = 0.31). The mean subfoveal scleral thicknesses were 1.3 mm in the CSC group and 0.86 mm in the control group (P < 0.001). The mean equatorial scleral thickness was 0.61 mm in the CSC group and 0.42 mm in the control group (P < 0.001). Using generalized estimating equations, the equatorial scleral thickness (P = 0.001), posterior scleral thickness (P < 0.001), and subfoveal choroidal thickness (P = 0.032) were independent predictors of CSC. Once these variables were entered into the equation, neither sex nor age were significant predictors. Generalized estimating equation analysis showed that equatorial, but not posterior, scleral thickness was a significant predictor of subfoveal choroidal thickness. CONCLUSION: Scleral thicknesses of the posterior and equatorial portions of the eye were found to be significant predictors of CSC, consistent with what was proposed in the theory of venous overload choroidopathy. Direct measurement by high resolution ultrasonography provides independent information about specific regions of the sclera and also avoids making speculative assumptions derived from anterior segment measurements.

SAUSAGING AND BULBOSITIES OF THE CHOROIDAL VEINS IN CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To evaluate the caliber of the choroidal veins in central serous chorioretinopathy, a disease proposed to be associated with overloading of choroidal venous outflow. METHODS: Widefield indocyanine green angiograms of eyes with central serous chorioretinopathy were graded for sausaging defined as three or more contiguous fusiform dilations that vary by at least 50% from the narrowest to largest diameters. A bulbosity was defined as a focal 2X dilation of a blood vessel as compared with the diameter of the surrounding host vessel. The data underwent statistical analysis including the use of generalized estimating equations. RESULTS: There were 73 eyes of 41 patients with a mean age of 53.5 years. Sausaging of vessels was seen in a mean and median of three quadrants per eye. Using generalized estimating equations, the only significant risk factor for sausaging was the use of corticosteroids. The two significant predictors of subfoveal choroidal thickness using generalized estimating equations were age ( P = 0.021) and proportion of quadrants involved by sausaging ( P < 0.001). The decrease in choroidal thickness per year of age was estimated to be 3.7 µ m, while the increase with four quadrant involvement with sausaging was estimated to be 236 µ m. There were a total of 39 bulbosities in 26 eyes (35.6%), preferentially involving intervortex venous anastomoses. CONCLUSION: Variations in the venous caliber are very common in eyes with central serous chorioretinopathy and seems to be associated with pathophysiologic alterations related to increased pressure within and remodeling of the larger choroidal veins. This may lead to overloading of the choriocapillaris with leakage as one manifestation.

SUBFOVEAL CHOROIDAL THICKNESS AND VASCULAR ARCHITECTURE IN FELLOW EYES OF PATIENTS WITH CIRCUMSCRIBED CHOROIDAL HEMANGIOMA.

PURPOSE: To evaluate the subfoveal choroidal thickness (SFCT) and vascular architecture in the fellow eyes of patients with circumscribed choroidal hemangioma (CCH). METHODS: In this retrospective observational study, patients were selected from outpatient ophthalmology clinics at the Memorial Sloan Kettering Cancer Center and Vitreous Retina Macula Consultants of New York. Subfoveal choroidal thickness was measured using enhanced depth imaging spectral domain optical coherence tomography from the outer portion of Bruch membrane to the choroidal-scleral interface. Choroidal vascular architecture was qualitatively examined. The main outcome measure was SFCT in fellow eyes of patients with CCH, which was compared with an age- and gender-matched control group. RESULTS: Thirty-one fellow eyes (15 right eyes and 16 left eyes) of patients with CCH (23 males and 8 females) were examined. The fellow eye had a mean SFCT of 361.2 ± 99.9 µm compared with 252.0 ± 77.6 µm in the control group (P < 0.0001). Vascular architecture was disorganized in 13 (42%) fellow eyes and 1 (3%) control eye (P < 0.0001), with no apparent gradient of vessel sizes or discrete choroidal layers. The normal association between older age and a thinner choroid existed in control eyes but not in fellow eyes. Hemangioma thickness measured by ultrasound and the presence of subfoveal fluid in the CCH eye did not correlate with the fellow-eye SFCT. CONCLUSION: In patients with CCH, fellow eyes had thicker SFCT when compared with age- and gender-matched control eyes. Choroidal architecture was often irregular, without segmented vascular layers. These findings suggest that inherent choroidal changes may exist in patients with CCH.

Idiopathic Acute Exudative Polymorphous Vitelliform Maculopathy: Clinical Spectrum and Multimodal Imaging Characteristics.

PURPOSE: To describe clinical findings in patients with acute exudative polymorphous vitelliform maculopathy (AEPVM). DESIGN: Retrospective, observational, multicenter case series review. PARTICIPANTS: Consecutive patients diagnosed with idiopathic AEPVM. METHODS: Review of clinical charts, multimodal imaging, electrophysiologic findings, and genetic findings in previously unpublished patients and review of the literature. MAIN OUTCOME MEASURES: Clinical features of idiopathic AEPVM and differential diagnosis. RESULTS: Eighteen patients (age range, 21-74 years) with typical features of AEPVM, including initial localized, serous detachments followed by the development of characteristic yellow-white deposits in the vitelliform space. Over time, this hyperautofluorescent material gravitated within the larger lesions, resulting in typical curvilinear deposits characteristic of later stages. Symptoms and clinical findings lasted from weeks to several years. Some patients showed previously undescribed features such as fluorescein-negative intraretinal cystic changes, choroidal neovascularization, serous retinal elevations mimicking retinal folds, increased choroidal thickness, lack of rapid visual recovery, and recurrence years after complete resolution of initial manifestations. CONCLUSIONS: Acute exudative polymorphous vitelliform maculopathy can present with a more variable natural course than previously described. Paraneoplastic retinopathy and autosomal recessive bestrophinopathy closely resemble AEPVM, necessitating medical and hereditary evaluation to exclude these clinical possibilities. This series of patients with AEPVM expands the clinical spectrum of the disorder, including demographics, clinical manifestations, imaging features, natural course, and visual prognosis.

Bullous Variant of Central Serous Chorioretinopathy: Expansion of Phenotypic Features Using Multimethod Imaging.

PURPOSE: To define the phenotypic characteristics of the bullous variant of central serous chorioretinopathy (CSC) using multimethod imaging. DESIGN: Retrospective, observational case series. PARTICIPANTS: Twenty-one eyes of 14 patients with bullous retinal detachment resulting from CSC (bullous CSC group) and 122 eyes of 84 patients with chronic CSC without bullous retinal detachment (nonbullous CSC group). METHODS: We performed a retrospective review of clinical and multimethod imaging data of patients who sought treatment from the authors with bullous retinal detachment resulting from CSC between January 2010 and November 2015. Multimethod imaging comprised color photography, fluorescein angiography, fundus autofluorescence, and high-resolution optical coherence tomography. Consecutive cases of chronic CSC without bullous retinal detachment, seen during the same period, comprised a comparative group. MAIN OUTCOME MEASURES: Qualitative and quantitative characteristics of the choroid, retinal pigment epithelium, and retina were compared between the 2 groups. RESULTS: Mean age of the bullous CSC group was 53.8 years. There was no difference in age, visual acuity, corticosteroid use, or the proportion of white patients and men between the 2 groups (all P > 0.132). Peripheral nonperfusion occurred only in eyes with bullous retinal detachment (38% of cases). Retinal pigment epithelial tears were seen in 95% of eyes in the bullous group and none of the eyes in the nonbullous CSC group. The bullous CSC group demonstrated a greater number of pigment epithelial detachments (PEDs) and more eyes demonstrated PEDs with internal hyperreflectivity (both P < 0.016). Mean subfoveal choroidal thickness in the bullous CSC group (463.1±83.1 µm) was not different compared with that of the nonbullous CSC group (400.6±100.6 µm; P = 0.993). More eyes in the bullous CSC group demonstrated hyperreflectivity around large choroidal vessels and at the level of the choriocapillaris on OCT (P < 0.001). Retinal folds and subretinal fibrin were identified in a greater proportion of eyes in the bullous CSC group (both P < 0.001). CONCLUSIONS: Bullous retinal detachment is a rare manifestation of chronic CSC and is characterized by a unique constellation of phenotypic and multimethod imaging features.

Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy.

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 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four 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; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [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 predetermined 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.

Reduced effect of anti-vascular endothelial growth factor agents on diabetics with vitreomacular interface abnormalities.

This study investigated whether the presence of vitreomacular interface abnormalities (VMIAs) affects the improvement in visual acuity and edema of patients with diabetic macular edema (DME) who received three anti-vascular endothelial growth factor (VEGF) injections. Fifteen eyes of 11 patients with clinically significant macular edema were retrospectively divided into either the control group (only DME) or the experimental group (DME and VMIA) based on optical coherence tomography images. We defined VMIA patterns as epiretinal membrane and/or anomalous vitreomacular adhesion. Changes in central macular thickness (CMT), total macular volume (TMV), and best-corrected visual acuity (BCVA) from the baseline to post third injection were compared between the two groups. After the third injection, the decreases in CMT and TMV were not statistically different between the two groups. The improvement in BCVA was larger in the control group (0.1742 ± 0.0508 logMAR) than in the experimental group (0.0766 ± 0.0562 logMAR; p < 0.01). Our study showed that after the third anti-VEGF injection, the BCVA of patients with both DME and VMIAs improved significantly less than that of patients with only DME. Our results suggest that VMIAs may play a crucial role in reducing the therapeutic effects of anti-VEGF agents.

Intravitreal cellular infiltrate imaged as punctate spots by spectral-domain optical coherence tomography in eyes with posterior segment inflammatory disease.

PURPOSE: To investigate the posterior segment in cases of clinically evident intraocular inflammation for punctate reflections consistent with that expected to arise from inflammatory cells. METHODS: Patients with ocular inflammatory diseases imaged with spectral-domain optical coherence tomography (SD-OCT) were retrospectively reviewed. RESULTS: There were 7 patients with mean age of 66.7 years, and the diagnosis was toxoplasmosis in 5 eyes, multiple evanescent white dot syndrome in 1 eye, and posttraumatic outer retinitis in 1 eye. At baseline, the SD-OCT showed vitreous cells as numerous punctate spots in the vitreous in all seven eyes. The SD-OCT also showed similar-sized hyperreflective dots in the retina in all seven eyes. During follow-up, reduced vitreous cellular infiltration was correlated with a decrease in the number of the punctate spots visible by SD-OCT. CONCLUSION: Eyes with intraocular inflammation had SD-OCT images of the vitreous containing punctate spots of a size consistent with that expected from inflammatory cells. Similarly sized punctate spots were seen within the retina in regions of retinitis. Additional characterization of the optical section should permit stereological estimations of actual cell counts per unit volume.

ATYPICAL CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM COMPLICATED BY PRESUMED RETINAL PIGMENT EPITHELIAL ADENOMA AND EXUDATIVE MACULOPATHY.

PURPOSE: To report a retinal pigment epithelium (RPE) tumor with exudative maculopathy, originating from an atypical RPE lesion presumed to represent congenital hypertrophy of the RPE or RPE hyperplasia. METHODS: Multimodal imaging including fundus autofluorescence, optical coherence tomography, fluorescein angiography, and optical coherence tomography angiography. RESULTS: A 76-year-old West African man noted visual acuity reduction to count fingers in the right eye and 20/400 in the left eye. Features of chronic glaucoma were noted. In addition, there was a fairly well-circumscribed darkly pigmented RPE lesion in the paramacular region in the right eye, measuring 4 mm in diameter and flat and consistent with atypical congenital hypertrophy of the RPE or RPE hyperplasia. On the posterior margin of this mass was an RPE tumor, presumed to represent RPE adenoma, producing exudative maculopathy and cystoid macular edema. Multimodal imaging was used to distinguish the RPE tumor from macular neovascularization. A similar atypical congenital hypertrophy of the RPE without retinopathy measuring 3.5mm in diameter was noted in the temporal macular region in the left eye. After six monthly doses of intravitreal bevacizumab (1.25 mg/0.05 mL) in the right eye, the maculopathy resolved and the RPE mass showed partial involution with visual acuity return to baseline 20/200. CONCLUSION: Congenital hypertrophy of the RPE and RPE hyperplasia can produce RPE adenoma with related exudative maculopathy. In this case, the maculopathy responded to bevacizumab.

Dosing regimen and the frequency of macular hemorrhages in neovascular age-related macular degeneration treated with ranibizumab.

PURPOSE: The purpose of this study was to investigate if monthly intravitreal ranibizumab decreases risk of macular hemorrhages in patients with choroidal neovascularization secondary to age-related macular degeneration. METHODS: Incidences of macular hemorrhages in the control and ranibizumab groups from three, multicenter, randomized, clinical trials (MARINA, ANCHOR, and PIER) were compared. Two time intervals (Months 0-3 and 5-17) were evaluated to account for transition from monthly to quarterly injections in PIER. Time interval after Month 17 was excluded because of crossover from control to active treatment in all trials. RESULTS: Months 0-3: All trials showed higher incidence rates of hemorrhages in control compared with ranibizumab groups (ANCHOR: photodynamic therapy [27.3%], 0.3 mg [8.0%], 0.5 mg [8.6%]; MARINA: sham [18.6%], 0.3 mg [8.8%], 0.5 mg [8.8%]; and PIER: sham [16.1%], 0.3 mg [3.4%], 0.5 mg [3.3%]). In ANCHOR and MARINA, data of Months 5-17 showed higher incidence rates in control compared with monthly ranibizumab groups (ANCHOR: photodynamic therapy [47.8%], 0.3 mg [12.5%], 0.5 mg [12.3%]; and MARINA: sham [38.0%], 0.3 mg [13.2%], 0.5 mg [13.0%]), but this was not seen for quarterly ranibizumab groups in PIER (sham [22.4%], 0.3 mg [23.7%], 0.5 mg [28.3%]). CONCLUSION: Treatment with monthly intravitreal ranibizumab was associated with reduced risk of new macular hemorrhages when compared with photodynamic therapy (ANCHOR) or sham (MARINA and PIER). There was no difference between PIER quarterly ranibizumab-treated and sham patients.

LONG-TERM MULTIMODAL IMAGING OF OCULAR FINDINGS ASSOCIATED WITH THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA.

PURPOSE: To report on 5-year multimodal imaging of ocular findings in a patient with thiamine-responsive megaloblastic anemia. METHODS: Observational case report. RESULTS: A 20-year-old-man with a history of thiamine-responsive megaloblastic anemia demonstrated a symmetric bull's eye maculopathy. Spectral domain optical coherence tomography revealed disruption of the parafoveal ellipsoid zone, fundus autofluorescence demonstrated foveal hypoautofluorescence, and full-field electroretinogram testing revealed a decreased photopic and scotopic response consistent with cone-rod dystrophy. His best-corrected visual acuity remained stable over 5 years at 20/50 in the right eye and 20/40 in the left eye, and visual field testing remained stable over time. CONCLUSION: Ocular manifestations in thiamine-responsive megaloblastic anemia are uncommon and variable. In this case, multimodal imaging and electroretinogram findings are consistent with cone-rod degeneration. The patient is taking daily thiamine supplementation, and visual acuity, funduscopic examination, spectral domain optical coherence tomography, and autofluorescence remained stable over a 5-year period.

MULTIMODAL IMAGING OF ANGIOID STREAKS ASSOCIATED WITH TURNER SYNDROME.

PURPOSE: To report multimodal imaging in a novel case of angioid streaks in a patient with Turner syndrome with 10-year follow-up. METHODS: Case report of a patient with Turner syndrome and angioid streaks followed at Bellevue Hospital Eye Clinic from 2007 to 2017. Fundus photography, fluorescein angiography, and optical coherence tomography angiography were obtained. RESULTS: Angioid streaks with choroidal neovascularization were noted in this patient with Turner syndrome without other systemic conditions previously correlated with angioid streaks. CONCLUSION: We report a case of angioid streaks with choroidal neovascularization in a patient with Turner syndrome. We demonstrate that angioid streaks, previously associated with pseudoxanthoma elasticum, Ehlers-Danlos syndrome, Paget disease of bone, and hemoglobinopathies, may also be associated with Turner syndrome, and may continue to develop choroidal neovascularization, suggesting the need for careful ophthalmic examination in these patients.

Ocular Involvement in Patients with Fungemia in an Urban Tertiary Care Center.

PURPOSE: To illustrate the rate of endogenous endophthalmitis associated with fungemia and evaluate the importance of screening in a public city hospital. METHODS: A retrospective review was performed on all inpatient ophthalmology consults for fungemia from 2010 to 2015. Clinical histories, ocular examinations, and microbial cultures were reviewed. RESULTS: Of 95 patients (mean age 51.6 years, 75% male) with fungemia, 9/95 (9.5%) demonstrated intraocular involvement. Of these nine patients, two were unable to participate in the ophthalmic exam due to intubation, while the remaining seven reported no changes in their vision. Two patients had their antifungal medications adjusted to optimize intraocular penetration and one patient progressed to develop vitreous involvement but died before further escalation of care occurred. CONCLUSION: All involved individuals in this study were either non-communicative or without visual complaints. This suggests that routine screening should still be recommended, especially in a public hospital setting.

Comprehensive analysis of the candidate genes CCL2, CCR2, and TLR4 in age-related macular degeneration.

PURPOSE: To determine whether variants in the candidate genes TLR4, CCL2, and CCR2 are associated with age-related macular degeneration (AMD). METHODS: This study was performed in two independent Caucasian populations that included 357 cases and 173 controls from the Netherlands and 368 cases and 368 controls from the United States. Exon 4 of the TLR4 gene and the promoter, all exons, and flanking intronic regions of the CCL2 and CCR2 genes were analyzed in the Dutch study and common variants were validated in the U.S. study. Quantitative (q)PCR reactions were performed to evaluate expression of these genes in laser-dissected retinal pigment epithelium from 13 donor AMD and 13 control eyes. RESULTS: Analysis of single nucleotide polymorphisms (SNPs) in the TLR4 gene did not show a significant association between D299G or T399I and AMD, nor did haplotypes containing these variants. Univariate analyses of the SNPs in CCL2 and CCR2 did not demonstrate an association with AMD. For CCR2, haplotype frequencies were not significantly different between cases and controls. For CCL2, one haplotype containing the minor allele of C35C was significantly associated with AMD (P = 0.03), but this did not sustain after adjustment for multiple testing (q = 0.30). Expression analysis did not demonstrate altered RNA expression of CCL2 and CCR2 in the retinal pigment epithelium from AMD eyes (for CCL2 P = 0.62; for CCR2 P = 0.97). CONCLUSIONS: No evidence was found of an association between TLR4, CCR2, and CCL2 and AMD, which implies that the common genetic variation in these genes does not play a significant role in the etiology of AMD.

Unilateral Ocular Manifestations of Vogt-Koyanagi-Harada Disease.

PURPOSE: To describe a case of unilateral Vogt-Koyanagi-Harada (VKH) disease and associated multimodal imaging. METHODS: Retrospective case report. RESULTS: A 50-year-old Hispanic male presented with three days of painless decreased vision in his left eye, headache, and decreased hearing. His visual acuity was 20/20 in the right eye and counting fingers in the left eye. Examination of his right eye was unremarkable. Funduscopic examination of his left eye revealed multiple serous retinal detachments. Fluorescein angiography demonstrated late multifocal pinpoint hyperfluorescence in his left eye and a diagnosis of VKH disease was made. He was treated with oral prednisone. Serial re-examination demonstrated resolution of the serous retinal detachments and a taper of his oral prednisone was initiated with improvement of his visual acuity to 20/25. CONCLUSIONS: Our patient had imaging and a clinical course that was consistent with VKH disease. This unilateral presentation may represent a clinical variant of VKH disease.

Pseudo-vitelliform macular detachment and cuticular drusen: exclusion of 6 candidate genes.

PURPOSE: The etiology and genetic cause of pseudo-vitelliform macular detachment with cuticular drusen (PVMD/CD) are unknown; nor is it clear if this phenotype represents a separate disease entity, or is a sub-phenotype of disorders with overlapping clinical presentation. To answer this question, we screened a cohort of patients affected with PVMD/CD for variation in six plausible candidate genes (ABCA4, VMD2, TIMP-3, peripherin/RDS, fibulin 5 (FIBL5) and complement factor H (CFH)) associated with diseases of overlapping phenotypes. METHODS: Twenty-eight patients, diagnosed with pseudo-vitelliform macular detachment and cuticular drusen, were evaluated by clinical examination, fundus photography, fluorescein angiography and autofluorescence imaging. DNA from all study subjects were screened for variants in the ABCA4, VMD2, TIMP-3, peripherin/RDS, FIBL5 and CFH genes by a combination of DHPLC, array screening and direct sequencing. RESULTS: All patients presented with cuticular drusen; pseudo-vitelliform detachment was seen in 21 cases, while atrophic changes following regression of the detachment were seen in the remaining 7 subjects. Visual acuity ranged from 20/20 to CF. The screening revealed an I32V mutation in peripherin/RDS in one patient and 2ABCA4 variants, T897I and G1961E, in 2 more patients. No amino acid-altering variants were detected in VMD2, TIMP-3, and FIBL5 genes. The frequency of the CFH Y402H variant in this cohort corresponded to that detected in the general population. CONCLUSIONS: Screening of 6 candidate genes detected possibly disease-associated mutations in only 3/28 (10.7%) of patients presenting with PVMD/CD, eliminating these genes as causal for this phenotype.

Ocular photodynamic therapy--standard applications and new indications. Part 2. Review of the literature and personal experience.

Photodynamic therapy (PDT) has become a well-established treatment for vascular forms of age-related macular degeneration (AMD). The implementation of evidence-based medicine principles into the treatment regimen of AMD seems to be immensly important, since AMD continues to be the most frequent cause of blindness among patients older than 65 years in industrialized countries. Numerous randomized prospective studies demonstrated high levels of evidence for the efficacy of various treatment approaches such as laser photocoagulation, PDT, subretinal surgery or novel anti-angiogenic drugs [Arch Ophthalmol 2006;124:597-599]. The high evidence shown by these studies supported the rationale to use PDT also in additional, less frequent, vasoproliferative diseases. Although these 'case series' and 'individual case control studies' have a low level of evidence, they give us important information for treatment decisions in these rare conditions. The goal of this survey is to review the current literature regarding PDT in vasoproliferative and exudative ocular diseases outside AMD. Many studies modified the treatment parameters of PDT to address the specific pathology of the underlying disease. Table 1 summarizes the diseases and treatment parameters that are described in this part 2, the entire table of this review is included in part 1 (www.karger.com/doi/10.1159/ 000101922).