Emerging Insights and Interventions for Diabetic Retinopathy.

PURPOSE OF REVIEW: To introduce recent advances in the understanding of diabetic retinopathy and to summarize current and emerging strategies to treat this common and complex cause of vision loss. RECENT FINDINGS: Advances in retinal imaging and functional analysis indicate that retinal vascular and neural pathologies exist long before the development of clinically visible retinopathy. Such diagnostics could facilitate risk stratification and selective early intervention in high-risk patients. Antagonists of the vascular endothelial growth factor pathway effectively reduce vision loss in diabetes and promote regression of disease severity. Promising new strategies to treat diabetic retinopathy involve novel systemic diabetes therapy and ocular therapies that antagonize angiogenic growth factor signaling, improve blood-retina barrier function and neurovascular coupling, modulate neuroretinal metabolism, or provide neuroprotection. Long considered a pure microvasculopathy, diabetic retinopathy in fact affects the neural and vascular retina as well as neurovascular communication. Emerging therapies include those that target neuroretinal dysfunction in addition to those modulating vascular biology.

Identification of Herpes Zoster-Associated Temporal Arteritis Among Cases of Giant Cell Arteritis.

PURPOSE: To examine whether herpes zoster antigen (also called varicella-zoster virus antigen) was detectable in temporal artery biopsies taken from individuals with giant cell arteritis (GCA). DESIGN: Retrospective comparative case series. METHODS: Sections of formalin-fixed paraffin-embedded temporal arteries were examined first by hematoxylin-eosin (H&E) staining to establish the diagnosis of GCA. Adjacent sections of the same biopsy were then examined by immunohistochemistry, using 2 different monoclonal antibodies against a major antigen of varicella-zoster virus called gE. Pathologic specimens were obtained from patients cared for at the University of Iowa and Washington University in St. Louis ophthalmology clinics. RESULTS: The study included biopsies from 25 patients with symptoms of GCA as well as positive H&E pathology and 25 patients with symptoms compatible with GCA but negative H&E pathology. Among the GCA-positive group, 3 patients had positive staining for herpes zoster antigen. Among the GCA-negative group, herpes zoster antigen was not detected in any biopsy. In both groups of patients, false-positive staining for herpes zoster antigen was detected in the presence of calcifications in the arteries. False-positive staining was also detected on some extra-arterial skeletal muscle and erythrocytes. CONCLUSION: Herpes zoster antigen was detected in 3 of 25 temporal arteries from patients with biopsy-proven GCA. One of the 3 positive cases was noteworthy because the patient had had herpes zoster ophthalmicus diagnosed 3 weeks before the onset of GCA symptoms. False-positive staining for herpes zoster antigen was detected on several temporal artery biopsies.

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE: This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN: Prospective, multicenter study. PARTICIPANTS: A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING: Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES: Patients were managed for their primary tumor and monitored for metastasis. RESULTS: The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS: The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Histologic and immunohistochemical features of an epiretinal membrane overlying a combined hamartoma of the retina and retinal pigment epithelium.

PURPOSE: To present the histologic and immunohistochemical findings of an epiretinal membrane overlying a combined hamartoma of the retina and retinal pigment epithelium. METHODS: An interventional case report. RESULTS: A 17-year-old healthy girl with a history of congenital cataract presented with a combined hamartoma of the retina and retinal pigment epithelium with prominent epiretinal membrane portion. Pars plana vitrectomy and membranectomy were performed, and the excised epiretinal membrane was submitted for routine histology and immunohistochemistry. Hematoxylin and eosin stain showed a monolayer of cells with an underlying basement membrane. Some of the nuclei were more epithelioid, consistent with retinal pigment epithelium (but without pigment in the cytoplasm), and other nuclei were more spindle-shaped, consistent with fibroglial elements. The initial immunostains suggested an admixture of retinal pigment epithelium and retinal elements. CONCLUSION: To the authors' knowledge, this is the first study to use immunohistochemistry to elucidate the composition of these membranes. Future studies investigating the immunohistochemical profile of combined hamartomas are necessary.

Histopathology of deep anterior lamellar keratoplasty with pneumatic dissection: the "big-bubble" technique.

PURPOSE: To describe characteristic histopathologic markers in deep anterior lamellar keratoplasty (DALK) using pneumatic dissection: Anwar "big-bubble" technique. METHODS: Case reports. Deep stromal buttons from 2 patients with keratoconus who had undergone DALK surgery using the "big-bubble" technique were examined by light microscopy. RESULTS: The histopathology of excised corneal buttons demonstrated multiple intrastromal spaces consistent with air bubbles. Apical stromal thinning seen clinically was not as readily appreciated on histopathology. CONCLUSIONS: Pneumatic dissection in DALK produces diffuse intrastromal air bubbles that may mask the corneal thinning that usually characterizes keratoconus histopathologically. This is a characteristic finding of which ocular pathologists and corneal surgeons should be aware.

The castroviejo square graft: wound healing after 51 years.

PURPOSE: To describe the histopathologic characteristics of a 51-year-old Castroviejo square graft that remained functional for more than 50 years and to describe the wound-healing characteristics over this period of time. METHODS: An 80-year-old woman with a history of keratoconus underwent penetrating keratoplasty with square grafts in 1956 and 1957 in the right and left eyes, respectively. The graft from the right eye was replaced in 2007, and the corneal specimen was submitted for histopathologic analysis. RESULTS: Light microscopy demonstrated a smooth transition between host and donor stroma. Descemet's membrane was markedly thickened (>40 m) and laminated, and a very thin retrocorneal membrane was visible at high magnification. CONCLUSIONS: This case provides an opportunity to observe the histopathology of corneal wound healing over a period of more than half a century.

Histologic and immunohistochemical features of a vitreous cyst.

PURPOSE: To report the histologic and immunohistochemical features of a congenital vitreous cyst. METHODS: Interventional case report with immunohistochemical correlation. A 58-year-old woman with known vitreous cyst since childhood had an enlarging visual floater. The vitreous cyst was removed by pars plana vitrectomy and central vision was restored. RESULTS: Pathology confirmed a vitreous cyst derived from neural and glial tissue and consistent with retinal origin. CONCLUSIONS: Congenital vitreous cysts, derived from neural and glial tissue, can be safely removed using pars plana vitrectomy.

Correlation study of benign cytomorphology and final clinical diagnosis.

OBJECTIVE: To assess significance of cytologically benign vitreous samples and identify cellular patterns that may correspond to specific clinical entities. STUDY DESIGN: Vitreous fluids with "negative for malignancy" cytologic diagnosis were identified from pathology department records, cytologic slides reviewed and clinical and follow-up information obtained. RESULTS: Fifty-four cytologically benign samples were identified (1994-2004). The main indication for vitrectomy was confirmation of intraocular inflammatory process. Malignant process was included in the differential diagnoses of most samples. Macrophages or lymphocytes were the predominant cell types in 76% of cases. Most cases with macrophage or lymphocyte predominance were diagnosed as chronic uveitis or vitritis of unknown etiology. Infectious agents were identified in 7 cases with macrophage or lymphocyte predominance, 2 with abundant neutrophils and 1 with eosinophils. One had a diagnosis of malignant lymphoma, based on vitreous fluid from the opposite eye at another hospital. Three cases had blood only and 1 had lens fragments, both consistent with the diagnosis. CONCLUSION: Most cytologic features of benign vitreous fluids did not correspond to specific clinical entities. Abundant eosinophils suggested parasitic infection; the almost exclusive presence of blood indicated hemorrhage. Based on our study, negative predictive value of a benign vitreous sample is 98%.

Diagnosis of limited ophthalmic Wegener granulomatosis: distinctive pathologic features with ANCA test confirmation.

PURPOSE: To describe the clinical and histopathologic finding of very limited ophthalmic Wegener granulomatosis (WG). METHODS: Thirteen patients with scleritis, orbitopathy, episcleritis, and panuveitis were studied. They presented without evidence of lung or kidney disease, though eight had sinus involvement. We reviewed the biopsies for histopathologic findings consistent with WG, and tested for antineutrophil cytoplasmic antibodies antineutrophil cytoplasmic antibody (ANCA). RESULTS: WG was suggested by granulomatous foci, collagen necrosis, neutrophils/nuclear dust, plasma cells and infiltrating eosinophils. Granular degeneration of the interstitial collagen; mummification of the collagen with disappearance of fibroblastic nuclei; and a polymorphous infiltrate exhibiting plasma cells, lymphocytes, neutrophils, and eosinophils within the epithelioid granulomas should suggest the diagnosis. ANCA test results supported the diagnosis of WG in all cases. CONCLUSION: The described histologic characteristics are highly suggestive of WG. These findings along with clinical or laboratory findings, allow the diagnosis of very limited ophthalmic WG in the absence of systemic involvement.

Mucormycosis endophthalmitis after cataract surgery.

PURPOSE: To describe a rare case of Mucor endophthalmitis that occurred in well-controlled diabetes after cataract surgery. DESIGN: Interventional case report. METHODS: Description of case and review of literature. RESULTS/CONCLUSION: Mucor endophthalmitis may occur after cataract surgery and should be considered in the differential for patients with unresolving postoperative uveitis.

Partidos político-religiosos que conformaron el Antiguo Testamento

Contiene: La identidad de Israel; Orígenes y conformación; La adoración israelita de otros dioses; Factores que conforman la historia del culto en Israel; El patronazgo real; La piedad popular; El partido "sólo- Yahvé"; La evidencia del partido sólo.Yahvé en el Antiguo Testamento; Las afirmaciones generales en Reyes y Crónicas; Las afirmaciones específicas en Reyes y Crónicas; El material en los libros proféticos; El material de los códigos legales pre-exílicos.

Cannulation of the suprachoroidal space: a novel drug delivery methodology to the posterior segment.

PURPOSE: To describe, test, and evaluate the pharmacokinetics of a novel posterior drug delivery system (PDS) by means of microcannulation of the suprachoroidal space in both the primate and pig animal model. DESIGN: Animal study. METHODS: A rhesus macaque (Macaca mulatta) (n = 1) and pig model (n = 93) were used to evaluate the PDS, a microcannula that combines a drug delivery channel with a fiber-optic illumination and optimal transition properties. The surgical technique, safety profile, histopathology, retinal and choroidal blood flow, injection of tracer dyes, and triamcinolone pharmacokinetics were studied. Pre- and postsurgical high-speed video confocal scanning laser ophthalmoscopy (cSLO) that used fluorescein and indocyanine green (ICG) imaging and wide-field fundus imaging studies were performed. Globes were enucleated for either histopathology or pharmacokinetics. RESULTS: Cannulation was performed in 93 of 94 animals. Complications included: endophthalmitis (1/94), choroidal tear (1/94), choroidal blood flow irregularities (4/94), postoperative inflammation (6/94), scleral ectasia (4/94), wound abscess (1/94), and others. Histopathology demonstrated normal anatomy in uncomplicated cases. Triamcinolone remains in the local ocular tissue for at least 120 days, and measurable at very low levels in the systemic circulation. CONCLUSIONS: Accessing the suprachoroidal space by the microcannulation system can be performed in a safe and reproducible manner by using careful surgical technique. Forceful PDS tip impact into connective tissues in the macular and optic nerve regions should be avoided. Triamcinolone pharmacokinetics are unique and suggest long-term local tissue levels with low systemic levels. PDS access to the suprachoroidal space represents a novel drug delivery method, applicable to a wide variety of pharmacotherapies to the macula, optic nerve, and posterior pole.

Triamcinolone-assisted internal limiting membrane peeling.

PURPOSE: To review our experience with triamcinolone-assisted pars plana vitrectomy for internal limiting membrane (ILM) peeling for various retinal diseases. METHODS: Twenty-one patients underwent surgery in which intraoperative triamcinolone acetonide (TA) was used. Indications for surgery included epiretinal membrane (3 patients), branch retinal vein occlusion associated with macular edema (2), traction retinal detachment (3), diabetic macular edema (4), vitreous hemorrhage with diabetic macular edema (4), macular hole (4), and cystoid macular edema (1). RESULTS: TA was useful in the removal of the ILM in all cases. There were no intraoperative complications or toxicity. The mean follow-up was 22 weeks (range, 9-30 weeks). Eleven patients improved by >or=2 Snellen lines, 1 lost >or=2 Snellen lines, and 9 were within 2 Snellen lines of preoperative vision at the last follow-up. CONCLUSIONS: The intraoperative use of TA improves visualization of ILMs associated with a variety of conditions. No intraoperative or postoperative complications were observed. TA-assisted removal of the ILM appears to be safe and cost effective. TA-assisted ILM peeling should be considered as an alternative to the use of intraoperative dyes.

Fine needle aspiration biopsy with adjunct immunohistochemistry in intraocular tumor management.

OBJECTIVE: To assess the effectiveness of fine needle aspiration biopsy (FNAB), with and without immunohistochemistry (IHC), in the management of solid intraocular tumors. STUDY DESIGN: Thirty-three consecutive adults undergoing FNAB of suspected intraocular tumors were studied. Clinical, cytologic and histologic diagnoses were correlated. The positive predictive value, sensitivity and specificity of FNAB for detecting malignancy, the effect of lHC on the final cytologic diagnosis and the number of patients in whom clinical management was altered as a result of cytologic evaluation were determined. RESULTS: The positive predictive value was 96% with and 93% without adjunct IHC. The sensitivity and specificity of FNAB for detecting malignancy were 96% and 83%, respectively, with IHC. Without IHC, the sensitivity was unaltered, but the specificity was 67%. IHC confirmed the morphologic diagnosis in 75% of cases, made a diagnosis in 12.5% and changed a malignant diagnosis from carcinoma to melanoma in 6% of cases. The planned management was changed by the FNAB findings in 24% of patients. In 3 patients (9%), IHC was essential for diagnosis and management. No patients exhibited local tumor dissemination or recurrence associated with the biopsy. CONCLUSION: FNAB is a safe, sensitive and specific method of establishing a tissue diagnosis in a subset of patients with solid intraocular tumors. The routine use of immunohistochemical stain ing increases the diagnostic utility of the technique and may change clinical management.

Internal limiting membrane peeling using triamcinolone acetonide: histopathologic confirmation.

PURPOSE: To report histopathologic confirmation of the internal limiting membrane (ILM) using triamcinolone acetonide (TA). DESIGN: Interventional case report. METHODS: One eye of one patient who underwent macular hole repair using TA suspension to help visualize the internal limiting membrane (ILM). The specimen was sent to pathology. RESULTS: Triamcinolone acetonide greatly improved the visualization of the ILM; the peeled area was seen as an area lacking white specks. The macular hole closed with an improvement in vision. No adverse effects were observed during the follow-up period. The specimen was identified as ILM by histopathologic examination. CONCLUSION: Peeling of the ILM is facilitated by the use of TA. Microscopic confirmation of ILM was made.