ENDOGENOUS ENDOPHTHALMITIS CAUSED BY GROUP B STREPTOCOCCUS IN A HEALTHY, TERM NEONATE.

PURPOSE: The purpose of this study was to describe an unusual case of unilateral, endogenous endophthalmitis in an otherwise healthy, term neonate. METHODS: A 3-week-old otherwise healthy, term male infant was referred to St. Louis Children's Hospital for a second opinion of presumed panuveitis of the right eye. RESULTS: Diffusion-weighted magnetic resonance imaging demonstrating purulent intraocular contents facilitated the diagnosis of endophthalmitis. Examination of surgical vitreous samples by staining and cytology demonstrated gram-positive bacterial cocci in short chains, thereby confirming endophthalmitis. Polymerase chain reaction testing of vitreous fluid identified Streptococcus agalactiae , despite an unremarkable systemic workup and a negative prepartum maternal Group B streptococcal screen. CONCLUSION: Endogenous endophthalmitis is a rare but devastating cause of vision loss in otherwise healthy, term neonates. Prompt diagnosis may be facilitated by magnetic resonance imaging and diagnostic vitreous biopsy.

SUBHYALOID HEMORRHAGE IN EVANS SYNDROME.

PURPOSE: Evans syndrome is a rare disorder characterized by autoimmune hemolytic anemia and immune thrombocytopenia. We report the first case of ophthalmic involvement in a pediatric patient with Evans syndrome, in which painless vision loss was the presenting symptom. METHOD: A 15-year-old girl presented with acute painless loss of vision in her right eye and was found to have bilateral subhyaloid hemorrhages. RESULTS: She was treated with intravenous steroids and transitioned to hydroxychloroquine. Her retinal hemorrhages resolved and her vision improved. CONCLUSION: Nontraumatic subhyaloid hemorrhage is a rare cause of vision loss in children. Evans syndrome should be considered in the differential diagnosis of such patients when hematologic abnormalities are present.

Longitudinal Changes in Vision and Retinal Morphology in Wolfram Syndrome.

PURPOSE: To report long-term ophthalmic findings in Wolfram syndrome, including rates of visual decline, macular thinning, retinal nerve fiber layer (RNFL) thinning, and outer plexiform layer (OPL) lamination. DESIGN: Single-center, cohort study. METHODS: A total of 38 participants were studied, who underwent a complete ophthalmic examination as well as optical coherence tomography imaging of the macula and nerve on an annual basis. Linear mixed-effects models for longitudinal data were used to examine both fixed and random effects related to visual acuity and optic nerve quadrants of RNFL and macula thickness. RESULTS: Participants completed a mean of 6.44 years of follow-up (range 2-10 years). Visual acuity declined over time in all participants, with a mean slope of 0.059 logMAR/y (95% CI = 0.07-0.05 logMAR/y), although nearly 25% of participants experienced more rapid visual decline. RNFL thickness decreased in superior, inferior, and nasal quadrants (ß = -0.5 µm/y, -0.98 µm/y, -0.28 µm/y, respectively). OPL lamination was noted in 3 study participants, 2 of whom had autosomal dominant mutations. CONCLUSIONS: Our study describes the longest and largest natural history study of visual acuity decline and retinal morphometry in Wolfram syndrome to date. Results suggest that there are slower and faster progressing subgroups and that OPL lamination is present in some individuals with this disease.

BILATERAL CHOROIDAL DETACHMENTS SECONDARY TO IPILIMUMAB AND PEMBROLIZUMAB USE.

PURPOSE: To report the occurrence of bilateral choroidal detachments due to the use of ipilimumab and pembrolizumab immunochemotherapeutics to treat widely metastatic cutaneous melanoma and to raise awareness about this potentially vision-threatening adverse drug event. METHODS: A 77 year-old man presented with acute onset, painless, and bilateral blurry vision. He had started ipilimumab and pembrolizumab 2 weeks prior for Stage IV metastatic cutaneous melanoma. RESULTS: Clinical examination revealed bilateral choroidal detachments. After discussion with the patient's medical oncologist, the patient discontinued both medications and began oral prednisone to expedite visual recovery. The choroidal detachments subsequently resolved, and visual acuity improved 2 weeks later. CONCLUSION: Ipilimumab and pembrolizumab have been reported both in monotherapy and in combination to cause a wide variety of ophthalmic adverse events. This is the first report of choroidal detachments as a complication.

Identification of Retinal Vascular Lesions Using Ultra-Widefield Angiography in Hereditary Hemorrhagic Telangiectasia Patients.

PURPOSE: To determine the presence and to characterize location of retinal vascular lesions in patients with hereditary hemorrhagic telangiectasia (HHT). DESIGN: Prospective cross-sectional pilot descriptive study. PARTICIPANTS: Eighteen patients (age range, 22-65 years) with a clinical diagnosis of HHT. METHODS: Patients completed the 25-item National Eye Institute Visual Function Questionnaire and underwent a single study visit with dilated ophthalmic examination, OCT angiography (OCTA), and fluorescein angiography (FA) with widefield imaging. MAIN OUTCOME MEASURES: Presence of retinal vascular abnormalities in 1 or more quadrants identified on widefield FA, Visual Function Questionnaire scores, retinal vessel architecture on FA and OCTA, and dilated ophthalmic examination findings. RESULTS: Of the 18 patients recruited, fine telangiectatic vessels with capillary dilation and tortuosity were identified in 78% by FA imaging. CONCLUSIONS: In the first FA and OCTA analysis of the retina of unrelated HHT patients, we found a high rate of temporal and nasal telangiectasias. These telangiectasias were more apparent in older patients, suggesting that they may appear in later stages of HHT development. No abnormalities of the macular vasculature and architecture were identified, explaining the generally well-preserved visual acuity. Temporal and nasal telangiectasias may have clinical significance in a patient's risk for retinal hemorrhage and likely warrant periodic surveillance by annual FA imaging.

Successful treatment of an exudative choroidal hemangioma with oral propranolol in a 10-year-old boy.

A 10-year-old boy was referred for a circumscribed choroidal hemangioma with underlying exudative detachment of the left eye. To avoid general anesthetics required for laser-based therapy in a child, we began a trial of oral propranolol. The patient's exudative detachment resolved, with resulting improvement in visual acuity, and remained quiescent for 3 years.

Association of Preclinical Alzheimer Disease With Optical Coherence Tomographic Angiography Findings.

Importance: Biomarker testing for asymptomatic, preclinical Alzheimer disease (AD) is invasive and expensive. Optical coherence tomographic angiography (OCTA) is a noninvasive technique that allows analysis of retinal and microvascular anatomy, which is altered in early-stage AD. Objective: To determine whether OCTA can detect early retinal alterations in cognitively normal study participants with preclinical AD diagnosed by criterion standard biomarker testing. Design, Setting, and Participants: This case-control study included 32 participants recruited from the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St Louis, St Louis, Missouri. Results of extensive neuropsychometric testing determined that all participants were cognitively normal. Participants underwent positron emission tomography and/or cerebral spinal fluid testing to determine biomarker status. Individuals with prior ophthalmic disease, media opacity, diabetes, or uncontrolled hypertension were excluded. Data were collected from July 1, 2016, through September 30, 2017, and analyzed from July 30, 2016, through December 31, 2017. Main Outcomes and Measures: Automated measurements of retinal nerve fiber layer thickness, ganglion cell layer thickness, inner and outer foveal thickness, vascular density, macular volume, and foveal avascular zone were collected using an OCTA system from both eyes of all participants. Separate model III analyses of covariance were used to analyze individual data outcome. Results: Fifty-eight eyes from 30 participants (53% female; mean [SD] age, 74.5 [5.6] years; age range, 62-92 years) were included in the analysis. One participant was African American and 29 were white. Fourteen participants had biomarkers positive for AD and thus a diagnosis of preclinical AD (mean [SD] age, 73.5 [4.7] years); 16 without biomarkers served as a control group (mean [SD] age, 75.4 [6.6] years). The foveal avascular zone was increased in the biomarker-positive group compared with controls (mean [SD], 0.364 [0.095] vs 0.275 [0.060] mm2; P = .002). Mean (SD) inner foveal thickness was decreased in the biomarker-positive group (66.0 [9.9] vs 75.4 [10.6] µm; P = .03). Conclusions and Relevance: This study suggests that cognitively healthy individuals with preclinical AD have retinal microvascular abnormalities in addition to architectural alterations and that these changes occur at earlier stages of AD than has previously been demonstrated. Longitudinal studies in larger cohorts are needed to determine whether this finding has value in identifying preclinical AD.

Cytokine profiles in clinical subtypes of ophthalmic Graves' disease.

PURPOSE: To examine the association of cytokines in the two clinical subtypes of ophthalmic Graves' disease by comparing cytokine expression in the fat and ethmoid tissue of type I and type II patients. METHODS: Patients needing orbital decompression or eyelid surgery were identified and enrolled into a prospective study. Patients were assigned to the type I or type II subclassification, based on the presence of diplopia. Orbital fat, sinus tissue or muscle removed during surgery was evaluated. The mRNA expression profiles of Th1 cytokines (TNF-alpha/beta, IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-5, IL-6, IL-10) were analyzed using real time PCR. RESULTS: 30 patients were enrolled in the study: 5 type I (80% female), 14 type II (71% female) and 11 controls (73% female). There were 14 decompressions (3 type I and 11 type II), 17 lid procedures (2 type I, 4 type II and 11 controls) and 10 ethmoidectomies (3 type I and 7 type II). The average ages were 45, 56 and 66 in the type I, type II and control groups, respectively. There was more TNF-alpha (p value 0.009) and IL-6 (p value 0.04) in ethmoid sinus cells of type II patients compared to ethmoid sinus cells of type I patients and a trend of higher expression of all cytokines in type II patients. CONCLUSIONS: There is a trend towards greater mRNA expression of both Th1 and Th2 cytokines in both orbital fat and ethmoidal sinus tissue of type II patients compared to type I patients.

Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model.

Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.

The genetic control of avascular area in mouse oxygen-induced retinopathy.

PURPOSE: The C57BL/6ByJ and BALB/cByJ inbred strains of mice are, respectively, susceptible and resistant to oxygen-induced retinopathy (OIR). The purpose of this work was to investigate the genetic control of the retinal avascular area in mouse OIR using a mapping cross. METHODS: The central retinal avascular area was measured on postnatal day 16 (P16) in C57BL/6ByJ, BALB/cByJ, 101 (C57BL/6ByJ x BALB/cByJ)F2, and 116 (BALB/cByJ x C57BL/6ByJ)F2 mice that had been subjected to the OIR protocol. A genome-wide scan was performed of selected albino and non-albino mice to determine quantitative trait loci associated with weight and avascular area. RESULTS: C57BL/6ByJ mice had significantly larger avascular areas than BALB/cByJ ones. Albino mice of the F2 generation had smaller avascular areas than the non-albino mice. Genotyping was performed at 856 informative single nucleotide polymorphisms approximately evenly distributed across the genome from each of 85 selected F2 mice. Weight, sex, and the paternal grandmother were found to act as additive covariates associated with the avascular area on P16; mapping analyses that used a model incorporating these covariates found a quantitative trait locus on chromosome 7 related to avascular area. Mapping analyses that used a model that did not incorporate covariates found a quantitative trait locus on chromosome 9 related to avascular area. A quantitative trait locus for bodyweight on P16 was mapped to chromosome 5. CONCLUSIONS: The retinal avascular area in the mouse OIR model is under genetic control. Revascularization in OIR is related to the weight, strain of paternal grandmother, sex, and albinism. Our data support the existence of a quantitative trait locus on chromosome 5 that influences weight after exposure to hyperoxia, as well as quantitative trait loci on chromosomes 7 and 9 that modify susceptibility to OIR.

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.