Melkersson-Rosenthal syndrome with isolated unilateral eyelid edema: an immunopathologic study.

Lymphedema is caused by defective drainage of the lymphatic system. In Melkersson-Rosenthal syndrome, involvement is predominantly of the lumens with blockage of lymphatic channels by histiocytic-epithelioid cell clusters accompanied by dermal granulomas and lymphocytes. It is a localized, painless, nonitching, and nonpitting form of lymphedema. Besides the eyelids, the disease can cause lip edema, facial palsy, and/or fissured tongue. It is rare and has received little attention in the ophthalmic literature, either in its complete triadic form, or more frequently, in its monosymptomatic forms. Pathogenesis is not well understood, and there is no effective therapy. The authors describe a case of Melkesson-Rosenthal syndrome in a 45-year-old Hispanic man with isolated unilateral upper eyelid edema. Histopathological and immunohistochemical evaluations of an eyelid biopsy specimen revealed intravascular and extravascular clusters of histiocytic-epithelioid cells that were CD68/163-positive. Variable numbers of mostly T-lymphocytes were found in the epidermis, dermis, and orbicularis muscle and by virtue of the associated granulomas established the diagnosis of Melkersson-Rosenthal syndrome. CD4 helper and CD8 suppressor T-lymphocytes were equally represented. CD20 B-lymphocytes were exceedingly sparse. Conspicuous CD1a-positive Langerhans' cells were present in the epidermis, sometimes formed subepithelial loose aggregates and were also incorporated in the granulomas. The differential diagnosis includes the far more common condition of acne rosacea. Management of Melkersson-Rosenthal syndrome, and of angioedema in general, is reviewed.

Systemic diseases associated with retinal dystrophies.

Inherited retinal degeneration (IRD) may occur in isolation or as part of a multi-systemic condition. Ocular manifestations may be the presenting symptom of a syndromic disease and can include retinitis pigmentosa, cone-rod dystrophy, or maculopathy. Alternatively, patients affected with syndromic disease may already have other systemic manifestations at the time retinal disease is diagnosed. Some of these systemic diseases can cause significant morbidity. Here, we review several of these syndromic IRDs and their underlying genetic causes. Early recognition and referral for systemic evaluation and surveillance may lead to early intervention and an improved outcome. Obtaining a molecular diagnosis can be beneficial in securing a definitive diagnosis, especially in cases with atypical presentations. A genetic diagnosis may also be informative with regard to prognosis and potential therapies. Effective management and rehabilitation for patients with syndromic retinal dystrophy requires a comprehensive genetic-based team approach involving patients, family members, ophthalmologists, primary care physicians, and geneticists.

A clinical, radiologic, and immunopathologic study of five periorbital intraosseous cavernous vascular malformations.

PURPOSE: To correlate the clinical, radiographic, histopathologic, and immunohistochemical features of 5 primary periorbital intraosseous cavernous vascular malformations. DESIGN: Retrospective interventional case series. METHODS: Clinical and operative records and radiographic images were reviewed. Histopathologic slides were evaluated with hematoxylin-eosin, trichrome, and elastin stains. Immunohistochemical studies were performed with a spectrum of monoclonal antibodies directed at antigens of vascular cells. RESULTS: Three men and 2 women ranged in age from 36 to 64 years. Vision was unaffected and there was no proptosis or globe displacement. The slow-growing lesions measured 13-25 mm in greatest diameter (mean 16.4 mm). Computed tomographic studies revealed that 2 lesions were situated in the maxillary bone, 2 in the frontal, and 1 in the zygoma, all anteriorly and with circumscribed, lucent, honeycombed, or sunburst characteristics. Histopathologically the lesions were composed of cavernous or telangiectatic channels; 1 showed advanced fibrotic vascular involution. Immunohistochemistry demonstrated CD31/34 positivity for vascular endothelium and D2-40 negativity for lymphatic endothelium. A typically thin mural myofibroblastic cuff was smooth muscle actin positive, weakly calponin positive, and desmin negative. Glucose transporter-1 and Ki-67 were negative in the endothelium. CONCLUSIONS: Intraosseous vascular lesions resemble orbital cavernous venous malformations (not true hemangiomas), except that their vascular walls are thinner owing to the constraints imposed by neighboring bone spicules, which limit the amount of interstitium from which mural myofibroblasts can be recruited. The bony trabeculae conferred the honeycomb or sunburst appearances observed radiographically. En bloc excision of these lesions was successful and avoided complications (mean follow-up, 46 months).

An analysis of conjunctival and periocular venous malformations: clinicopathologic and immunohistochemical features with a comparison of racemose and cirsoid lesions.

Vascular tumors (in contrast to dilations or ectasias) of the conjunctiva and other adnexal tissues are rare, with no previous convincing example of a congenital, purely venous conjunctival malformation having been described. A 33-year-old man with a previously well-tolerated racemose conjunctival lesion present from birth developed bothersome symptoms when it underwent multifocal thrombosis with papillary endothelial cell hyperplasia as part of the process of thrombotic organization. Conservative subtotal excision with placement of an amniotic graft led to an acceptable cosmetic appearance, abatement of symptoms, and retention of full ocular function. Histopathologically, the lesion was composed of patulous vascular channels with thin walls displaying a negligible and irregular muscularis, diffuse supportive mural fibrosis, and the absence of an elastic lamina. Immunohistochemically the endothelial cells were CD31- and CD34-positive (vascular origin) but D2-40-negative (lymphatic origin). An associated neovascular capillary bed was not detected. Venous (racemose or grape-like) malformations should be distinguished from: arteriovenous (cirsoid or twisted) malformations in which the vessels possess thicker and more uniform muscular walls, some of which are endowed with an elastica; varices (hemorrhoidal dilations typically of a pre-existent vein); and venous angiomas (noncongenital lesions acquired in middle life) composed of regularly structured muscular channels devoid of an elastic lamina. Other conditions not to be confused with congenital venous malformations include hemorrhagic lymphangiectasia (of Leber), hemorrhagic lymphangiomas, and complex lymphaticovenous malformations.

A review of advanced genetic testing for clinical prognostication in uveal melanoma.

Uveal melanoma (UM) has a strong propensity to metastasize and the prognosis for metastatic disease is very poor. It has been suggested that occult micrometastases are already present, but undetectable, in many patients at the time when the primary ocular tumor is diagnosed and treated. To identify high-risk patients for close monitoring and early intervention with prophylactic adjuvant systemic therapy, an accurate predictive system is necessary for stratifying those patients at risk of developing metastatic disease. To date, many clinical and histopathological features, molecular pathway characteristics, and genetic fingerprints of UM have been suggested for disease prognostication. Among the newest of them, tumor genetics has received the most attention in demonstrating promise as a prognostic tool. Because of the plethora of recent developments, we summarize and compare in this review the important standard and more advanced cytogenetic prognostic markers. We further describe the variety of genetic tests available for prognostication of UM, and provide a critical assessment of the respective advantages and disadvantages of these tools.

Magnetic resonance volumetric assessments of brains in fetuses with ventriculomegaly correlated to outcomes.

OBJECTIVES: The purpose of this study was to correlate 2-dimensional magnetic resonance (MR) measurements of lateral ventricular width and 3-dimensional measurements of lateral ventricular and supratentorial parenchymal volumes to postnatal outcomes in fetuses with ventriculomegaly. METHODS: A total of 307 fetuses (mean gestational age, 26.0 weeks; range, 15.7-39.4 weeks) had MR volumetry after referral for ventriculomegaly. Fetuses were grouped into those with (n = 114) and without (n = 193) other central nervous system (CNS) anomalies. Pregnancy and postnatal neurodevelopmental outcomes up to 3 years of age were obtained. A subgroup analysis was performed excluding fetuses with other CNS anomalies. Logistic regression analysis was performed to assess which measurement was most predictive of outcomes. RESULTS: There were 50 terminations, 2 stillbirths, and 255 live births. Seventy-five cases were lost to follow-up. Among 180 live-born neonates with follow-up, 140 had abnormal and 40 had normal outcomes. Atrial diameter (P < .0001), frontal horn diameter (P < .0001), and ventricular volume (P = .04) were predictive of live birth, with 92% specificity at 60% sensitivity. Among fetuses without other CNS anomalies, 180 of 193 pregnancies (93%) resulted in live deliveries, with atrial diameter (P < .0001), frontal horn diameter (P = .003), and ventricular volume (P = .008) associated with live birth and atrial diameter having the highest specificity (>99% at 60% sensitivity). Parenchymal volume was not associated with normal or abnormal outcomes (either live birth versus death or normal versus abnormal neurodevelopmental outcome). Among live-born neonates, no age-adjusted threshold for any of the measurements reliably distinguished between normal and abnormal neurodevelopmental outcomes. CONCLUSIONS: Ventricular volume and diameter, but not parenchymal volume, correlate with live birth in fetuses with ventriculomegaly. However, once live born, neither 2- nor 3-dimensional measurements can distinguish a fetus that will have a normal outcome.

Specific involvement of SRC family kinase activation in the pathogenesis of retinal neovascularization.

PURPOSE: Src family kinases (SFKs) are membrane-attached nonreceptor protein tyrosine kinases that link a variety of extracellular cues to intracellular signal pathways. The purpose of this study was to characterize the roles of SFKs in vascular endothelial growth factor (VEGF)-mediated retinal angiogenesis. METHODS: Primary rat retinal glial Müller cells and bovine and human retinal microvascular endothelial cells (RMECs) were used in the in vitro studies. A rat model of retinopathy of prematurity (ROP) was used in the in vivo studies. RESULTS: In vitro, SFKs were essential for hypoxia-induced VEGF expression in Müller cells and for VEGF signaling in RMECs. However, neither process required significant further phosphorylation of the SFK activation loop Tyr416. In vivo, in a rat model of ROP, a pronounced increase of retinal SFK Tyr416 phosphorylation was observed that was specifically associated with pathologic angiogenesis. These retinas also expressed significantly higher levels of VEGF than did those in healthy controls. Immunohistochemical analysis indicated that Müller cells were the major source of the elevated level of phospho-SFK Tyr416. Intravitreous injection of a selective SFK inhibitor, PP2, significantly reduced retinal VEGF and retinopathy in the ROP model, indicating that SFKs acted as important regulators in abnormal retinal angiogenesis. CONCLUSIONS: Together, these data suggest that SFK activation through a Tyr416-dependent mechanism may be an important factor in the pathogenesis of retinal neovascularization.

Angiostatic effect of penetrating ocular injury: role of pigment epithelium-derived factor.

PURPOSE: To characterize the angiostatic effect of penetrating ocular injury and to begin to explore its mechanism, with an emphasis on the role of pigment epithelium-derived factor (PEDF). METHODS: Using the rat model of oxygen-induced retinopathy (OIR), single or multiple dry needle injuries were made, penetrating the globe of one eye; the opposite eye served as a control. Eyes were harvested from rats killed 1, 3, and 6 days after injury, and retinas were dissected and processed for assessment of neovascularization and microglial activation or were processed for genetic and proteomic analysis. Temporal and spatial expression patterns of PEDF were analyzed by in situ hybridization. RESULTS: Penetrating ocular injury resulted in a 30% decrease in neovascular area in the retinas of OIR rats. At day 1 after injury, needle insertion caused a 4.1-fold increase in retinal PEDF mRNA and a 1.5-fold increase in retinal PEDF protein. Vitreous PEDF protein increased 3.4-fold in injured eyes compared with noninjured eyes. In situ hybridization showed an increase in PEDF mRNA in areas surrounding the puncture site. Concentrated vitreous protein from injured eyes caused a 60% decrease in retinal neovascularization when injected into the vitreous cavity of OIR rats. Preincubation of vitreous samples with anti-PEDF partially abolished this efficacy. CONCLUSIONS: The pattern of angiostasis resulting from penetrating ocular injury is consistent with the release of an endogenous antiangiogenic factor from the wound site. Preliminary studies show a possible role for PEDF in this effect. Further characterization of this role and the identification of other factors may lead to new therapeutic strategies for angiogenic eye conditions.

Src, Fyn and Yes play differential roles in VEGF-mediated endothelial cell events.

Widely coexpressed Src family kinase (SFK) members Src, Fyn and Yes are involved in various cellular events, often acting downstream of receptor tyrosine kinases, such as vascular endothelial growth factor (VEGF) receptors. They are well known for their functional redundancy; any unique features remain largely undefined. Utilizing RNA interference, we have selectively knocked down Src, Fyn and Yes in human retinal microvascular endothelial cells (HRMECs). Cells with single SFK knockdown showed that all three kinases were required for VEGF mitogenic signaling. VEGF-induced cell migration was significantly increased in Fyn-deficient cells and decreased in Yes-deficient cells. Selective interference of Fyn, but not Src or Yes, impaired VEGF-induced tube formation in HRMECs. Cells in which all three SFKs were targeted showed significant inhibition of all three cellular events. In addition, interference of Src, Fyn and Yes did not affect the anti-apoptotic effect of VEGF in HRMECs, as determined by DNA fragmentation analysis. These results provide direct evidence that Src, Fyn and Yes maintain distinct properties in the regulation of VEGF-mediated endothelial cell events.

Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy.

Retinal capillary quiescence is regulated by a delicate balance between proangiogenic and anti-angiogenic factors. Pathological angiogenesis is the result of a shift in this balance towards proangiogenic influences. Pathological angiogenesis is produced in a rat model of oxygen-induced retinopathy (OIR) by exposing newborn rat pups to alternating periods of hyperoxia and hypoxia. Based upon previous work, two similar exposure paradigms were investigated and compared, exposure of rat pups to alternating periods of 45 and 12.5% oxygen, and to alternating periods of 40 and 15% oxygen. The resulting retinal pathology was assessed by measurement of retinal clock hours with pathological blood vessel growth and the percentage of the retina that is avascular. The 45 and 12.5% exposure produced significantly greater incidence and severity of pathology than the 40 and 15% protocol. To explain the difference in pathology between these two very similar exposure protocols, retinal levels of proangiogenic vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) and anti-angiogenic pigment epithelium-derived factor (PEDF) were measured by ELISA and western blot analysis at 0, 2, and 6 days post-exposure. In whole retinal lysates, there were no significant differences in VEGFR2 and PEDF levels. However, VEGF levels were approximately 48 and 78% higher on post-oxygen exposure day 0 and 2, respectively, in the group treated with alternating periods of 45 and 12.5% oxygen compared to the group treated with alternating periods of 40 and 15% oxygen. There was no significant difference in VEGF levels between these two groups on day 6 post-exposure. Therefore, the difference in pathology observed between these two experimental paradigms is associated with differences in whole retinal VEGF levels, but not changes in whole retinal VEGFR2 or PEDF levels. The results of this study suggest the existence of a threshold in the rat model of OIR, such that a small change in blood oxygen profile triggers a disproportionate increase in subsequent neovascularization, which is accompanied by more dramatic changes of retinal VEGF level than VEGFR2 or PEDF level. If a similar threshold exists for humans, it could explain why some oxygen-treated premature infants develop retinopathy and others do not, despite similar gestational ages, birth weights and clinical courses.