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A case of hypertrophic herpes simplex virus affecting the eyelid and cornea masquerading as IgG4-related disease

Dua, Prachi; Shinder, Roman; Laskar, Derek B; Lazzaro, Douglas R; Rizzuti, Allison E
Purpose/UNASSIGNED:To report a case of hypertrophic herpes simplex virus (HSV) of the eyelid and cornea masquerading as IgG4-related disease. Observations/UNASSIGNED:A 37-year old African American female with a past medical history of human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) and a recent history of treated genital herpes, presented with an ulcerative lesion of the left upper and lower eyelids, and severe ocular inflammation with symblepharon. Initially, eyelid biopsy revealed findings consistent with IgG4-related disease, and the patient was treated with high dose oral prednisone. After one week of therapy, there was no improvement in the patient's symptoms, and she subsequently developed a corneal epithelial defect which progressed to chronic ulceration. Repeat biopsy and corneal cultures revealed herpes simplex virus type 2. The patient was treated with high dose acyclovir, and the lid lesion improved. The conjunctival inflammation and corneal epithelial defect resolved but symblepharon restricting her eye movement remained. She also developed corneal vascularization and opacification causing severe vision loss. Conclusions and importance/UNASSIGNED:Chronic hypertrophic herpes simplex virus infection is a rare condition reported in patients with HIV. While there have been few reports of hypertrophic HSV affecting the eyelid, this is the first reported case of hypertrophic HSV affecting the eye, resulting in severe vision loss.
PMID: 29468223
ISSN: 2451-9936
CID: 2991042

Ruptured globe from badminton racquet injury while wearing spectacles [Letter]

Tsui, Edmund; Lo, Christopher C; Lazzaro, Douglas R
PMID: 29217034
ISSN: 1715-3360
CID: 2837982

Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy

Lee, Sangmi; Elaskandrany, Menna; Lau, Lester F; Lazzaro, Douglas; Grant, Maria B; Chaqour, Brahim
CYR61-CTGF-NOV (CCN)1 is a dynamically expressed extracellular matrix (ECM) protein with critical functions in cardiovascular development and tissue repair. Angiogenic endothelial cells (ECs) are a major cellular source of CCN1 which, once secreted, associates with the ECM and the cell surface and tightly controls the bidirectional flow of information between cells and the surrounding matrix. Endothelium-specific CCN1 deletion in mice using a cre/lox strategy induces EC hyperplasia and causes blood vessels to coalesce into large flat hyperplastic sinuses with no distinctive hierarchical organization. This is consistent with the role of CCN1 as a negative feedback regulator of vascular endothelial growth factor (VEGF) receptor activation. In the mouse model of oxygen-induced retinopathy (OIR), pericytes become the predominant CCN1 producing cells. Pericyte-specific deletion of CCN1 significantly decreases pathological retinal neovascularization following OIR. CCN1 induces the expression of the non-canonical Wnt5a in pericyte but not in EC cultures. In turn, exogenous Wnt5a inhibits CCN1 gene expression, induces EC proliferation and increases hypersprouting. Concordantly, treatment of mice with TNP470, a non-canonical Wnt5a inhibitor, reestablishes endothelial expression of CCN1 and significantly decreases pathological neovascular growth in OIR. Our data highlight the significance of CCN1-EC and CCN1-pericyte communication signals in driving physiological and pathological angiogenesis.
PMID: 28469167
ISSN: 2045-2322
CID: 2604852

Neonatal Intermittent Hypoxia, Reactive Oxygen Species, and Oxygen-Induced Retinopathy

Beharry, Kay D; Cai, Charles L; Valencia, Gloria B; Valencia, Arwin M; Lazzaro, Douglas R; Bany-Mohammed, Fayez; Aranda, Jacob V
Most of the major morbidities in the preterm newborn are caused by or are associated with oxygen-induced injuries and are aptly called "oxygen radical diseases in neonatology or ORDIN". These include bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, intraventricular hemorrhage, necrotizing enterocolitis and others. Relative hyperoxia immediately after birth, immature antioxidant systems, biomolecular events favoring oxidative stress such as iron availability and the role of hydrogen peroxide as a key molecular mediator of these events are reviewed. Potential therapeutic strategies such as caffeine, antioxidants, non-steroidal anti-inflammatory drugs, and others targeted to these critical sites may help prevent oxidative radical diseases in the newborn resulting in improved neonatal outcomes.
PMID: 29951586
ISSN: 2380-2367
CID: 3234932

Ocular Adverse Effects of Intravitreal Bevacizumab Are Potentiated by Intermittent Hypoxia in a Rat Model of Oxygen-Induced Retinopathy

Tan, Jeffrey J; Cai, Charles L; Shrier, Eric M; McNally, Lois; Lazzaro, Douglas R; Aranda, Jacob V; Beharry, Kay D
Intravitreal bevacizumab (Avastin) use in preterm infants with retinopathy of prematurity is associated with severe neurological disabilities, suggesting vascular leakage. We examined the hypothesis that intermittent hypoxia (IH) potentiates intravitreal Avastin leakage. Neonatal rats at birth were exposed to IH from birth (P0)-P14. At P14, the time of eye opening in rats, a single dose of Avastin (0.125 mg) was injected intravitreally into the left eye. Animals were placed in room air (RA) until P23 or P45 for recovery (IHR). Hyperoxia-exposed and RA littermates served as oxygen controls, and equivalent volume saline served as the placebo controls. At P23 and P45 ocular angiogenesis, retinal pathology and ocular and systemic biomarkers of angiogenesis were examined. Retinal flatmounts showed poor peripheral vascularization in Avastin-treated and fellow eyes at P23, with numerous punctate hemorrhages and dilated, tortuous vessels with anastomoses at P45 in the rats exposed to IH. These adverse effects were associated with robust increases in systemic VEGF and in both treated and untreated fellow eyes. Histological analysis showed severe damage in the inner plexiform and inner nuclear layers. Exposure of IH/IHR-induced injured retinal microvasculature to anti-VEGF substances can result in vascular leakage and adverse effects in the developing neonate.
PMID: 28770109
ISSN: 2090-004x
CID: 3072442

Pharmacologic synergism of ocular ketorolac and systemic caffeine citrate in rat oxygen-induced retinopathy

Aranda, Jacob V; Cai, Charles L; Ahmad, Taimur; Bronshtein, Vadim; Sadeh, Jonathan; Valencia, Gloria B; Lazzaro, Douglas R; Beharry, Kay D
BACKGROUND: Caffeine or ketorolac decrease the risk of retinopathy of prematurity and may act synergistically to improve beneficial effect. Combination of caffeine (Caff) and ketorolac (Keto) to prevent oxygen-induced retinopathy was studied. METHODS: Newborn rats exposed to room air (RA) or intermittent hypoxia (IH) consisting of 12% O2 during hyperoxia (50% O2) from birth (P0) had single daily IP injections of Caff from P0-P13 or saline; and/or ocular Keto (Acuvail, 0.45% ophthalmic solution) administered subcutaneously over the eyes from P5-P7. Pups were studied at P14 or placed in RA for recovery from IH (IHR) until P21. Eyes were examined for neovascularization, histopathology, growth factors, and VEGF-signaling genes. RESULTS: Severe retinal damage noted during IHR in the untreated groups evidenced by hemorrhage, neovascularization, and oxygen-induced retinopathy (OIR) pathologies were prevented with Keto/Caff treatment. Keto and/or Caff treatment in IH also promoted retinal neural development evidenced by eye opening (92%, P < 0.001 vs. 31% in the placebo-treated IH group). No corneal pathologies were noted with Keto. CONCLUSION: Caff or Keto given individually reduced retinal neovascularization, but the two drugs given together prevented severe OIR.
PMID: 27438224
ISSN: 1530-0447
CID: 2604872

Seasonal Variation in the Presentation of Infectious Keratitis

Gorski, Matthew; Genis, Alina; Yushvayev, Sharon; Awwad, Ahmed; Lazzaro, Douglas R
INTRODUCTION: Infectious keratitis is a common ophthalmic disease with the potential for severe ocular morbidity. Multiple studies have described various risk factors for the development of infectious keratitis. The purpose of this study was to analyze the seasonal variation in the presentation of infectious keratitis, and also seasonal changes in its etiologies and risk factors. METHODS: A retrospective chart review was performed on consecutive patients presenting to the emergency department at our tertiary care urban hospital center who were diagnosed with infectious keratitis from 2008 to 2013. A chi-square analysis was performed to determine whether a significant seasonal variation existed between the month, season, frequency of presentation of ulcers, and other risk factors. RESULTS: A total of 155 patients-53 men and 102 women-with a mean age of 40 (range, 3-97; median, 36) diagnosed with infectious keratitis were included in the analysis. Sixty-nine (44.5%) ulcers presented in the summer, 19 (12.3%) in the fall, 34 (21.9%) in the winter, and 33 (21.3%) in the spring (P<0.0001). Seventeen (11%) patients experienced diabetes mellitus, 60 (39%) were contact lens wearers, 12 (8%) ulcers occurred in the setting of trauma, and 19 (12%) patients underwent previous ocular surgery. A total of 92 ulcers were cultured, of which 53.8% were positive in the summer, 42.9% in the fall, 55.0% in the winter, and 42.1% in the spring. A significant seasonal variation in the frequency of 1 organism, Pseudomonas aeruginosa, was identified (P=<0.0001); up to 47.6% of culture-positive ulcers in the summer were P. aeruginosa positive, whereas cultures in the remaining seasons were 0, 9.1% and 12.5% positive for this organism. DISCUSSION: The summer months have a higher frequency of infectious keratitis and P. aeruginosa positivity in this study. Possible factors leading to this increased summer presentation include warmer temperatures, higher humidity, and greater ocular exposure to water. Clinicians should increase their vigilance and education to high-risk patients during these periods and potentially modify empiric treatment regimens.
PMID: 26618904
ISSN: 1542-233x
CID: 1891492

Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity

Beharry, Kay D; Valencia, Gloria B; Lazzaro, Douglas R; Aranda, Jacob V
Retinopathy of prematurity (ROP), a significant morbidity in prematurely born infants, is the most common cause of visual impairment and blindness in children and persists till adulthood. Strict control of oxygen therapy and prevention of intermittent hypoxia are the keys in the prevention of ROP, but pharmacologic interventions have decreased risk of ROP. Various drug classes such as methylxanthines (caffeine), VEGF inhibitors, antioxidants, and others have decreased ROP occurrence. The timing of pharmacologic intervention remains unsettled, but early prevention rather than controlling disease progression may be preferred. These drugs act through different mechanisms, and synergistic approaches should be considered to maximize efficacy and safety.
PMID: 26831641
ISSN: 1558-075x
CID: 2044252

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia

Yan, Lulu; Lee, Sangmi; Lazzaro, Douglas R; Aranda, Jacob; Grant, Maria B; Chaqour, Brahim
The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR-155 binds to the 3'-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair.
PMID: 26242736
ISSN: 1083-351x
CID: 1891502

Exogenous Superoxide Dismutase Mimetic Without Scavenging H2O2 Causes Photoreceptor Damage in a Rat Model for Oxygen-Induced Retinopathy

Jivabhai Patel, Shamin; Bany-Mohammed, Fayez; McNally, Lois; Valencia, Gloria B; Lazzaro, Douglas R; Aranda, Jacob V; Beharry, Kay D
PURPOSE: Frequent, brief intermittent episodes of hypoxia (IH) during hyperoxia increase reactive oxygen species in the immature retina with compromised antioxidant systems, thus leading to oxygen-induced retinopathy (OIR). We examined the hypothesis that early exposure to a mimetic of superoxide dismutase (SOD), the first line of defense against oxidative stress, will decrease IH-induced reactive oxygen species (ROS) and prevent severe OIR in our rat model. METHODS: To test this hypothesis, newborn rats (P0) were exposed to IH consisting of alternating cycles of 50% O(2) with brief hypoxia (12% O(2)) until P14 during which they were treated with a single daily intraperitoneal (IP) dose of MnTBAP (a SOD mimetic) at 1.0, 5.0, or 10.0 mg/kg on P0, P1, and P2. A saline-treated group served as vehicle controls. Groups were analyzed following IH at P14 or allowed to recover in room air (RA) until P21. Control littermates were raised in RA with all conditions identical except for inspired O(2). Ocular assessment of OIR severity, oxidative stress, angiogenesis, antioxidant activity, and oxidative phosphorylation (OXPHOS) were conducted at P14 and P21. RESULTS: Collectively, the data show increased oxidative stress and angiogenesis with MnTBAP, which was associated with photoreceptor damage, retinal characteristics consistent with severe OIR, and changes in genes regulating OXPHOS. CONCLUSIONS: In the setting of IH, the use of exogenous SOD mimetics must be combined with H(2)O(2) scavengers in order to prevent photoreceptor damage and severe OIR.
PMID: 25670494
ISSN: 0146-0404
CID: 1891522