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Glass LDGR, Freitag SK. Management of orbital IgG4-related disease. Curr Opin Ophthalmol 2015;Abstract

PURPOSE OF REVIEW: IgG4-related disease (IgG4-RD) is a systemic process that can cause significant orbital disease. It can affect both sexes and all ages, with irreversible consequences if left untreated. Diagnosis is currently based upon a combination of clinical and imaging evidence of tissue swelling or mass, serum evidence of elevated IgG4 levels and histopathologic evidence of inappropriate IgG4 presence. The cause of IgG4-RD is as of yet unclear; this lack of understanding and the dearth of prospective studies have limited our ability to manage patients effectively. In this review, we discuss the most recent published evidence regarding best-practice management of IgG4-related orbital disease. RECENT FINDINGS: Recent literature remains retrospective, and has focused on the use of corticosteroid therapy as a first-line treatment. Rituximab infusions have also received significant attention, among other second-line agents. Radiation therapy has been reported to be effective. Long-term monitoring for relapse, involvement of other organ systems and potential neoplastic transformation is required. SUMMARY: The management of orbital IgG4-RD will gain from more targeted therapy in the future as the underlying cause is better understood. In the meantime, randomized, controlled trials of varying treatment regimens would be of benefit.

Liu Y, Magro C, Loewenstein JI, Makar RS, Stowell CP, Dzik WH, Hochberg EP, Oaklander AL, Sobrin L. A Man with Paraneoplastic Retinopathy plus Small Fiber Polyneuropathy Associated with Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma): Insights into Mechanisms. Ocul Immunol Inflamm 2015;23(5):405-9.Abstract
PURPOSE: To report a well-characterized Waldenström's macroglobulinemia (WM) case that provides insight into the mechanisms of two paraneoplastic complications -- cancer-associated retinopathy (CAR) and small fiber polyneuropathy (SFPN). METHODS: Retrospective medical chart review. RESULTS: A 58-year old man with WM developed vision loss and bilateral lower extremity pain. CAR was diagnosed by history, a depressed electroretinogram (ERG) and positive anti-retinal antibodies. SFPN diagnosis was based on abnormal autonomic nerve function testing and a distal-leg skin biopsy that demonstrated absent epidermal small-fiber innervation, IgM and complement deposition and microvasculopathy. Plasma exchange (PLEX) led to dramatic pain relief and subjective improvement in eye symptoms along with improvement of some ERG parameters. Repeat skin biopsy after treatment showed less microvascular abnormalities and decreased complement deposition. CONCLUSIONS: The concurrence of CAR and SFPN in this patient suggest that both were complications of WM and their common response to PLEX suggests co-mediation by humoral factors that accessed target antigens through IgM-triggered, complement-mediated vascular damage.
Hu K, Harris DL, Yamaguchi T, von Andrian UH, Hamrah P. A Dual Role for Corneal Dendritic Cells in Herpes Simplex Keratitis: Local Suppression of Corneal Damage and Promotion of Systemic Viral Dissemination. PLoS One 2015;10(9):e0137123.Abstract

The cornea is the shield to the foreign world and thus, a primary site for peripheral infections. However, transparency and vision are incompatible with inflammation and scarring that may result from infections. Thus, the cornea is required to perform a delicate balance between fighting infections and preserving vision. To date, little is known about the specific role of antigen-presenting cells in viral keratitis. In this study, utilizing an established murine model of primary acute herpes simplex virus (HSV)-1 keratitis, we demonstrate that primary HSV keratitis results in increased conventional dendritic cells (cDCs) and macrophages within 24 hours after infection. Local depletion of cDCs in CD11c-DTR mice by subconjuntival diphtheria toxin injections, led to increased viral proliferation, and influx of inflammatory cells, resulting in increased scarring and clinical keratitis. In addition, while HSV infection resulted in significant corneal nerve destruction, local depletion of cDCs resulted in a much more severe loss of corneal nerves. Further, local cDC depletion resulted in decreased corneal nerve infection, and subsequently decreased and delayed systemic viral transmission in the trigeminal ganglion and draining lymph node, resulting in decreased mortality of mice. In contrast, sham depletion or depletion of macrophages through local injection of clodronate liposomes had neither a significant impact on the cornea, nor an effect on systemic viral transmission. In conclusion, we demonstrate that corneal cDCs may play a primary role in local corneal defense during viral keratitis and preserve vision, at the cost of inducing systemic viral dissemination, leading to increased mortality.

Pal-Ghosh S, Pajoohesh-Ganji A, Tadvalkar G, Kyne BM, Guo X, Zieske JD, Stepp MA. Topical Mitomycin-C enhances subbasal nerve regeneration and reduces erosion frequency in the debridement wounded mouse cornea. Exp Eye Res 2015;Abstract

Corneal epithelial basement membrane dystrophies and superficial injuries caused by scratches can lead to recurrent corneal erosion syndrome (RCES). Patients and animals with reduced corneal sensory nerve innervation can also develop recurrent erosions. Multiple wild-type mouse strains will spontaneously develop recurrent corneal erosions after single 1.5 mm debridement wounds. Here we show that this wound is accompanied by an increase in corneal epithelial cell proliferation after wound closure but without a commensurate increase in corneal epithelial thickness. We investigated whether excess corneal epithelial cell proliferation contributes to erosion formation. We found that topical application of Mitomycin C (MMC), a drug used clinically to improve healing after glaucoma and refractive surgery, reduces erosion frequency, enhances subbasal axon density to levels seen in unwounded corneas, and prevents excess epithelial cell proliferation after debridement wounding. These results suggest that topically applied MMC, which successfully reduces corneal haze and scarring after PRK, may also function to enhance subbasal nerve regeneration and epithelial adhesion when used to treat RCES.

Silva PS, Dela Cruz AJ, Ledesma MG, van Hemert J, Radwan A, Cavallerano JD, Aiello LM, Sun JK, Aiello LP. Diabetic Retinopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography. Ophthalmology 2015;122(12):2465-72.Abstract

PURPOSE: To assess whether the presence of peripheral nonperfusion on ultrawide field (UWF) fluorescein angiography (FA) is associated with diabetic retinopathy (DR) severity and the presence of predominantly peripheral lesions (PPLs). DESIGN: Single-site, cross-sectional, retrospective study. PARTICIPANTS: Sixty-eight eyes of 37 diabetic subjects with or without DR and no history of prior panretinal laser photocoagulation. METHODS: Both 200° UWF images and UWF FA images were acquired at the same visit. Early Treatment Diabetic Retinopathy Study (ETDRS) templates were overlaid digitally based on disc and macula location onto stereographically projected UWF images. Images were evaluated for the presence of PPLs, defined as more than 50% of the graded lesion located outside the ETDRS field in each of the 5 extended fields. The UWF-FA images were evaluated by 2 masked, independent graders for extent of retinal nonperfusion area (NPA) and nonperfusion index (NPI; nonperfused/total gradable area). MAIN OUTCOME MEASURES: Association of NPA and NPI with DR severity and presence of PPLs. RESULTS: Distribution of DR severity was as follows: no DR, 8.8% eyes; mild nonproliferative DR (NPDR), 17.6%; moderate NPDR, 32.4%; severe NPDR, 17.6%; proliferative DR (PDR), 19.1%; and high-risk PDR, 4.4%; with PPL present in 61.8%. There was strong intragrader (r = 0.95) and intergrader (r = 0.86) agreement for NPA. Presence of PPLs was associated with increased NPA (191.8 mm(2) vs. 306.1 mm(2); P = 0.0019) and NPI (0.25 vs. 0.43; P = 0.0003). These relationships remained significant after adjusting for DR severity and diabetes duration. In eyes without PDR (n = 52), increasing NPA and NPI was associated with worsening DR (NPA, P = 0.001; NPI, P = 0.0003). NPA and NPI were not associated with clinically significant macular edema (NPA, P = 0.99; NPI, P = 0.67), nor correlated with visual acuity (NPA, r = 0.14, P = 0.23; NPI, r = 0.24, P = 0.05). CONCLUSIONS: Following a standardized protocol, the evaluation of UWF FA for NPA and NPI is reproducible. Both parameters are correlated highly with the presence of PPLs and DR severity. Given that the presence and extent of PPLs have been associated with increased risks of DR progression, the clinical identification of PPLs may reflect closely the extent of nonperfusion and ischemia, thus accounting for the increased risk of progression.

Veldman PB, Dye PK, Holiman JD, Mayko ZM, Sáles CS, Straiko MD, Stoeger CG, Terry MA. Stamping an S on DMEK Donor Tissue to Prevent Upside-Down Grafts: Laboratory Validation and Detailed Preparation Technique Description. Cornea 2015;34(9):1175-8.Abstract

PURPOSE: To report endothelial cell loss (ECL) caused by a novel S-stamp preparation technique for Descemet membrane endothelial keratoplasty (DMEK). METHODS: Six cadaveric human corneas were prepared for DMEK transplantation using a single standardized technique, including the application of a dry ink gentian violet S-stamp to the stromal side of Descemet membrane. Endothelial cell death was evaluated and quantified using computerized analysis of vital dye staining. RESULTS: ECL caused by the S-stamp was 0.6% (range 0.1%-1.0%), which comprised less than one-tenth of the total ECL caused by our preparation of the DMEK graft from the start to finish, including recovery, prestripping, S-stamping, and trephination (13.7% total ECL, range 9.9%-17.6%). CONCLUSIONS: Our novel S-stamp donor tissue preparation technique is intuitive to learn and holds the promise of preventing iatrogenic primary graft failure due to upside-down grafts without causing unacceptable increases in ECL.

MacIntosh PW, Jakobiec FA, Stagner AM, Gilani S, Fay A. High grade neuroendocrine neoplasm of the antrum and orbit. Surv Ophthalmol 2015;60(5):486-94.Abstract

Neuroendocrine malignancies-tumors characterized by the production of dense-core secretory granules-are most often encountered in the lungs and can also be found in extrapulmonary sites. Our patient had a primary neuroendocrine tumor of the antrum with an elusive cell of origin that secondarily invaded the inferior orbit. In the sinuses, neuroendocrine tumors may be confused with infectious sinusitis or squamous cell carcinoma. There are no known pathognomonic clinical or radiographic signs to distinguish these tumors from other conditions. Diagnosis depends on a biopsy with histopathologic and immunohistochemical analysis to identify biomarkers such as synaptophysin, chromogranin, CD56 and neuron specific enolase. Our patient's tumor defied precise immunohistochemical characterization because of its primitive character and erratic biomarker expression. The diagnosis oscillated between a neuroendocrine carcinoma and an ectopic esthesioneuroblastoma grade IV-hence the use of the more generic nosologic category of neuroendocrine neoplasm without specifying a neuronal or epithelial origin. Data to guide management are limited, particularly in the ophthalmic literature, and derive from experience with tumors of the sinonasal compartments. In the present case of a sino-orbital high grade neuroendocrine neoplasm, regional lymph node metastases developed shortly after presentation. The tumor has responded well to chemotherapy and radiation, but recurrence is often encountered within 2 years in this class of neoplasms.

Dib B, Lin H, Maidana DE, Tian B, Miller JB, Bouzika P, Miller JW, Vavvas DG. Mitochondrial DNA has a pro-inflammatory role in AMD. Biochim Biophys Acta 2015;1853(11 Pt A):2897-906.Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly of industrialized nations, and there is increasing evidence to support a role for chronic inflammation in its pathogenesis. Mitochondrial DNA (mtDNA) has been recently reported to be pro-inflammatory in various diseases such as Alzheimer's and heart failure. Here, we report that intracellular mtDNA induces ARPE-19 cells to secrete inflammatory cytokines IL-6 and IL-8, which have been consistently associated with AMD onset and progression. The induction was dependent on the size of mtDNA, but not on specific sequence. Oxidative stress plays a major role in the development of AMD, and our findings indicate that mtDNA induces IL-6 and IL-8 more potently when oxidized. Cytokine induction was mediated by STING (Stimulator of Interferon Genes) and NF-κB as evidenced by abrogation of the cytokine response with the use of specific inhibitors (siRNA and BAY 11-7082, respectively). Finally, mtDNA primed the NLRP3 inflammasome. This study contributes to our understanding of the potential pro-inflammatory role of mtDNA in the pathogenesis of AMD.

Hellgren G, Löfqvist C, Hård A-L, Hansen-Pupp I, Gram M, Ley D, Smith LE, Hellström A. Serum concentrations of vascular endothelial growth factor in relation to retinopathy of prematurity. Pediatr Res 2015;Abstract

BACKGROUND: The role of VEGF in the pathogenesis of retinopathy of prematurity (ROP) has been clearly established. However, little is known about temporal changes in circulating VEGF concentrations in the preterm infant. The objective was to determine the longitudinal serum concentrations of VEGF in relation to ROP. METHODS: This study included 52 infants born at <31 weeks gestational age (non-ROP n=33, non-proliferative ROP n=10, treated for ROP n=9). VEGF concentrations were analyzed in blood samples collected at birth, at 3 days postnatal age, and then weekly until at least a gestational age of 35 weeks. RESULTS: VEGF concentrations at birth did not differ between groups, independent of later ROP status. In contrast, VEGF serum concentrations were significantly higher at first detection of ROP in infants who were later treated for ROP compared to infants without ROP. At the time of laser therapy, serum VEGF concentrations did not differ between groups. CONCLUSION: Circulatory concentrations of VEGF, in infants who later developed severe ROP, were elevated at the time when ROP first was detected but not at the time when current treatment most often occurred. This supports the need for further studies of circulating VEGF in relation to the timing of ROP treatment.Pediatric Research (2015); doi:10.1038/pr.2015.181.

Doherty AL, Peli E, Luo G. Hazard detection with a monocular bioptic telescope. Ophthalmic Physiol Opt 2015;35(5):530-9.Abstract

PURPOSE: The safety of bioptic telescopes for driving remains controversial. The ring scotoma, an area to the telescope eye due to the telescope magnification, has been the main cause of concern. This study evaluates whether bioptic users can use the fellow eye to detect in hazards driving videos that fall in the ring scotoma area. METHODS: Twelve visually impaired bioptic users watched a series of driving hazard perception training videos and responded as soon as they detected a hazard while reading aloud letters presented on the screen. The letters were placed such that when reading them through the telescope the hazard fell in the ring scotoma area. Four conditions were tested: no bioptic and no reading, reading without bioptic, reading with a bioptic that did not occlude the fellow eye (non-occluding bioptic), and reading with a bioptic that partially-occluded the fellow eye. Eight normally sighted subjects performed the same task with the partially occluding bioptic detecting lateral hazards (blocked by the device scotoma) and vertical hazards (outside the scotoma) to further determine the cause-and-effect relationship between hazard detection and the fellow eye. RESULTS: There were significant differences in performance between conditions: 83% of hazards were detected with no reading task, dropping to 67% in the reading task with no bioptic, to 50% while reading with the non-occluding bioptic, and 34% while reading with the partially occluding bioptic. For normally sighted, detection of vertical hazards (53%) was significantly higher than lateral hazards (38%) with the partially occluding bioptic. CONCLUSIONS: Detection of driving hazards is impaired by the addition of a secondary reading like task. Detection is further impaired when reading through a monocular telescope. The effect of the partially-occluding bioptic supports the role of the non-occluded fellow eye in compensating for the ring scotoma.

Campbell AA, Cunnane ME, Dunn GP, Gray ST, Lefebvre DR. Spontaneous Resorption of a Penetrating Orbital Bone Fracture Fragment. Ophthal Plast Reconstr Surg 2015;31(5):e123-5.Abstract

The authors describe a 20-year-old man who sustained multiple facial fractures in a high-speed motor vehicle crash, including a bone fragment from a skull base fracture that penetrated the orbital soft tissues superomedially. Serial CT scans documented spontaneous resorption over a 6-month period. While it is known that autologous bone grafts used in craniofacial reconstruction exhibit variable amounts of bone resorption, the complete resorption of an intraorbital fracture fragment has not been documented in the literature. His clinical care and the report of his case were undertaken in a fashion in accordance with the principles of the Health Insurance Portability and Accountability Act regulations.

Mayer C, Jaglin XH, Cobbs LV, Bandler RC, Streicher C, Cepko CL, Hippenmeyer S, Fishell G. Clonally Related Forebrain Interneurons Disperse Broadly across Both Functional Areas and Structural Boundaries. Neuron 2015;87(5):989-98.Abstract

The medial ganglionic eminence (MGE) gives rise to the majority of mouse forebrain interneurons. Here, we examine the lineage relationship among MGE-derived interneurons using a replication-defective retroviral library containing a highly diverse set of DNA barcodes. Recovering the barcodes from the mature progeny of infected progenitor cells enabled us to unambiguously determine their respective lineal relationship. We found that clonal dispersion occurs across large areas of the brain and is not restricted by anatomical divisions. As such, sibling interneurons can populate the cortex, hippocampus striatum, and globus pallidus. The majority of interneurons appeared to be generated from asymmetric divisions of MGE progenitor cells, followed by symmetric divisions within the subventricular zone. Altogether, our findings uncover that lineage relationships do not appear to determine interneuron allocation to particular regions. As such, it is likely that clonally related interneurons have considerable flexibility as to the particular forebrain circuits to which they can contribute.

Drokhlyansky E, Soh TK, Cepko CL. Preferential Budding of Vesicular Stomatitis Virus from the Basolateral Surface of Polarized Epithelial Cells Is Not Solely Directed by Matrix Protein or Glycoprotein. J Virol 2015;89(22):11718-22.Abstract

Vesicular stomatitis virus has been shown to bud basolaterally, and the matrix protein, but not glycoprotein, was proposed to mediate this asymmetry. Using polarized T84 monolayers, we demonstrate that no single viral protein is sufficient for polarized budding. Particles are released from the apical and basolateral surfaces and are indistinguishable, indicating that there is no apical assembly defect. We propose that aspects of host cell polarity create a more efficient budding process at the basolateral surface.

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