Transactions of the American Ophthalmological Society最新文献

Purpose: The role of T regulatory (Treg) cells in blunting immune response to cancer appears to be significant, but the presence of Treg cells in uveal melanoma has not been extensively examined. We therefore evaluated the presence of tumor-infiltrating Treg cells in uveal melanomas.

Methods: A retrospective search of Mayo Clinic records from 2000 to 2005 was performed to identify cases of eyes enucleated as a consequence of uveal melanoma. Histologic examination included location of the tumor, presence of emissary canal invasion, direct sclera extension, extraocular extension, cell type and predominant cell type, mitotic figures per 40 high-power fields, lymphocytic tumor invasion, necrosis, microvascular pattern, and presence of CD3, CD4, CD25, and Foxp3cells. Factors obtained by chart review were also evaluated, including clinical size and ultrasound thickness of tumor before enucleation, patient age at time of enucleation, systemic evaluation for metastatic disease both before and after enucleation, monosomy 3, and systemic status at last patient visit.

Results: Of 42 enucleated eyes, 17 (40.5 %) were found to have lymphocytic infiltrate and 5 (11.9%) were considered positive for the presence of Treg cells (CD3+CD4+CD25+Foxp3+ or CD3+CD4+CD25-Foxp3+). Thus 29.4% (5 of 17) of those with lymphocytic infiltates had Treg cells, and 4 of the 5 with Treg cells had a large lymphocytic infiltrate (>1400 CD3 cells). When using "death due to disease" as the hazard ratio (HR) end point, the HR for presence of CD3 was 5.5 (P = .03) and for clinical size, 1.2 (P = .03). Furthermore, when using "presence of metastasis" as the end point, the HR for presence of CD3 was 3.6 (P = .05) and for clinical size, 1.3 (P = .003).

Conclusion: Though T lymphocyte infiltration is a bad prognostic indicator, Treg cells are rarely seen in enucleated choroidal melanoma, so their local effect may be limited in contradistinction to other cancers.

Purpose: To describe spectral-domain optical coherence tomography (SD-OCT) and adaptive optics (AO) imaging in hydroxychloroquine retinal toxicity.

Methods: Two patients with long-term hydroxychloroquine use, subtle perifoveal ophthalmoscopic pigmentary changes, and bilateral perifoveal defects on automated Humphrey visual field (HVF) 10-2 perimetry were imaged using SD-OCT and AO.

Results: SD-OCT images demonstrated loss of photoreceptor inner segment/outer segment (IS/OS) junction and a downward "sink-hole" displacement of inner retinal structures in areas of hydroxychloroquine toxicity corresponding to HVF 10-2 defects and ophthalmoscopic clinical examination findings. SD-OCT irregularities in the IS/OS junction were also seen in areas not detected on HVF 10-2. AO images showed disruption of the cone photoreceptor mosaic in areas corresponding to HVF 10-2 defects and SD-OCT IS/OS junction abnormalities. Additionally, irregularities in the cone photoreceptor density and mosaic were seen in areas with normal HVF 10-2 and SD-OCT findings.

Conclusions: SD-OCT and AO detected abnormalities that correlate topographically with visual field loss from hydroxychloroquine toxicity as demonstrated by HVF 10-2 and may be useful in the detection of subclinical abnormalities that precede symptoms or objective visual field loss.

Purpose: The effect of vitreopapillary adhesion (VPA) in macular diseases is not understood. Spectral-domain optical coherence tomography/scanning laser ophthalmoscopy (SD-OCT/SLO) was used to identify VPA in macular holes, lamellar holes, macular pucker, and dry age-related macular degeneration (AMD).

Methods: Ultrasonography and SD-OCT/SLO were performed in 99 subjects: 17 with macular holes, 11 with lamellar holes, 28 with macular pucker, 15 with dry AMD, and 28 age-matched controls. Outcome measures were the presence of total posterior vitreous detachment (PVD) by ultrasound and the presence or absence of VPA and intraretinal cystoid spaces by SD-OCT/SLO.

Results: PVD was detected by ultrasound in 26 (92.9%) of 28 eyes with macular pucker, 6 (54.5%) of 11 eyes with lamellar holes (P = .01), and 4 (23.5%) of 17 eyes with macular holes (P = .000003). SD-OCT/SLO detected VPA in 15 (88.2%) of 17 eyes with macular holes, 11 (39.3%) of 28 age-matched controls (P = .002), 4 (36.4%) of 11 eyes with lamellar holes (P = .01), 4 (26.7%) of 15 eyes with dry AMD (P = .0008), and 5 (17.9%) of 28 eyes with macular pucker (P = .000005). Intraretinal cystoid spaces were present in 15 (100%) of 15 eyes with macular holes with VPA. In eyes with macular pucker, 4 (80%) of 5 with VPA had intraretinal cystoid spaces, but only 1 (4.3%) of 23 without VPA had intraretinal cystoid spaces (P = .001).

Conclusions: VPA was significantly more common in eyes with macular holes than in controls or eyes with dry AMD, lamellar holes, or macular pucker. Intraretinal cystoid spaces were found in all eyes with macular holes with VPA. When present in macular pucker, VPA was frequently associated with intraretinal cystoid spaces. Although these investigations do not study causation directly, VPA may have an important influence on the vectors of force at the vitreoretinal interface inducing cystoid spaces and holes.

Purpose: To determine if the patterns uncovered with variational Bayesian-independent component analysis-mixture model (VIM) applied to a large set of normal and glaucomatous fields obtained with the Swedish Interactive Thresholding Algorithm (SITA) are distinct, recognizable, and useful for modeling the severity of the field loss.

Methods: SITA fields were obtained with the Humphrey Visual Field Analyzer (Carl Zeiss Meditec, Inc, Dublin, California) on 1,146 normal eyes and 939 glaucoma eyes from subjects followed by the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. VIM modifies independent component analysis (ICA) to develop separate sets of ICA axes in the cluster of normal fields and the 2 clusters of abnormal fields. Of 360 models, the model with the best separation of normal and glaucomatous fields was chosen for creating the maximally independent axes. Grayscale displays of fields generated by VIM on each axis were compared. SITA fields most closely associated with each axis and displayed in grayscale were evaluated for consistency of pattern at all severities.

Results: The best VIM model had 3 clusters. Cluster 1 (1,193) was mostly normal (1,089, 95% specificity) and had 2 axes. Cluster 2 (596) contained mildly abnormal fields (513) and 2 axes; cluster 3 (323) held mostly moderately to severely abnormal fields (322) and 5 axes. Sensitivity for clusters 2 and 3 combined was 88.9%. The VIM-generated field patterns differed from each other and resembled glaucomatous defects (eg, nasal step, arcuate, temporal wedge). SITA fields assigned to an axis resembled each other and the VIM-generated patterns for that axis. Pattern severity increased in the positive direction of each axis by expansion or deepening of the axis pattern.

Conclusions: VIM worked well on SITA fields, separating them into distinctly different yet recognizable patterns of glaucomatous field defects. The axis and pattern properties make VIM a good candidate as a preliminary process for detecting progression.

Purpose: The primary indication for laser treatment in retinopathy of prematurity (ROP) is plus disease, or abnormal dilation and tortuosity of arterioles and venules. ROPtool is a computer program that traces retinal blood vessels and measures their width and tortuosity. Our purpose was to gain insight into the evolution of plus disease by applying ROPtool to RetCam images from eyes of infants who had serial photographs taken during their ROP screening period.

Methods: Serial images were collected from eyes of 62 infants screened for ROP as part of another study. Fifty-nine images of one eye of 7 infants who developed plus disease were selected and analyzed by ROPtool. The average tortuosity of the most tortuous blood vessel and the average width of the most dilated vessel in each quadrant were calculated for each image.

Results: Tortuosity increased from an average of 7.72 units at the first examination to 24.44 units at the examination with maximum tortuosity, or an increase of 217% over a mean time period of 6.2 weeks. Two eyes had an increase in tortuosity of more than 500% from the first examination. Vessel width increased from an average of 8.60 units at the first examination to 11.03 units at the examination with maximum blood vessel width, or an increase of 28% over a mean time period of 5.1 weeks.

Conclusions: ROPtool can measure changes in retinal vascular dilation and tortuosity in individual eyes over time. As plus disease develops, changes in tortuosity are sometimes very large, whereas changes in vessel width tend to be more subtle. Quantification of plus disease over time may help to improve our understanding of its mechanism and to monitor disease progression or response to treatment.

Purpose: We report the results of injection of bupivacaine (BUP) and botulinum toxin (BT) into agonist and antagonist muscles, respectively, to treat horizontal strabismus.

Methods: We treated both horizontal muscles of 7 patients with comitant horizontal strabismus, 2 patients with partial lateral rectus (LR) paralysis, and one elderly myopic patient with acquired esotropia, injecting the agonist muscle with BUP in concentrations of 0.75% to 3.0% and volumes of 3.0 to 5.0 mL, and the antagonist with BT in about half the usual therapeutic dose to prevent it from stretching the BUP-treated muscle during its regeneration following BUP myotoxicity. We reinjected BT in one patient who had an inadequate response from the initial BT dose.

Results: The 7 comitant patients were corrected (on average) 19.7 prism diopters (Delta), from 28.3Delta to 8.6Delta, at 193 days after injection. Muscle volume increase after BUP injection was 5.8% at 158 days. One LR palsy patient without LR atrophy was changed 55Delta; the other, with LR atrophy, was corrected 4Delta. Two patients had transient vertical deviations from the BT injection. The myopic patient with esotropia was unchanged.

Conclusions: Injections of BUP and BT corrected 7 patients with comitant horizontal strabismus an average of 19.7Delta, about double the correction reported from BUP injection alone. BUP-injected muscles increased size by 5.8%. Of 2 patients with LR weakness, one without LR atrophy was changed by 55Delta, but another with LR atrophy was corrected only 4Delta.

Purpose: To determine the effects of the advanced glycation end product (AGE) cross-link breaker alagebrium on intraocular pressure (IOP), accommodation (ACC), outflow facility (OF), anterior segment morphology, and ocular AGE and receptors for AGE (RAGE) in older rhesus monkeys.

Methods: Six rhesus monkeys (aged 19 to 20 years) received 3 or 4 intracameral and intravitreal (final concentration, 1 mM) injections of alagebrium to one eye over 2.5 to 3 weeks and vehicle to the opposite eye. ACC and OF responses to intramuscular or intravenous pilocarpine were measured at baseline and at 1 to 2 weeks and 2, 4, and 6 months postinjection. IOP was measured prior to all injections, ACC, and OF measurements. Monkeys were euthanized 3 to 6 months after the last injection, the eyes were enucleated, and anterior and posterior segments were examined by electron microscopy or immunohistochemistry.

Results: No significant differences were found in ACC or IOP at any time point after alagebrium treatment. Baseline OF was higher (37.0 +/- 6.0%; P < or = .005) in alagebrium-treated vs control eyes at 6 months postinjection. In 3 monkeys, alagebrium-treated eyes, compared to control eyes, showed greater focal plaque formation, similar to that seen in primary open-angle glaucoma, in the juxtacanalicular meshwork/inner wall of Schlemm's canal. No changes in anterior segment AGE or RAGE were detectable. However, some areas of the retina and optic nerve head exhibited decreased AGE and increased RAGE immunostaining.

Conclusions: Intraocular injection of AGE cross-link breakers is an unlikely approach for glaucoma therapy. However, it may generate a model for further study of glaucomatous-like plaque formation. Immunohistochemical changes in the posterior segment in response to alagebrium warrant further functional studies.

Purpose: Oxidative damage is implicated in retinal ganglion cell (RGC) death after optic nerve transection (ONT) and in glaucoma. We analyzed the expression and protective effects of thioredoxins (TRXs), regulators of the cellular reduction-oxidative (redox) state, in RGCs damaged by pharmacologically induced oxidative stress, ONT, and elevated intraocular pressure (IOP).

Methods: ONT and glaucoma models in the rat were used. The glaucoma model was generated in albino rats by intracameral injection of india ink followed by ab externo laser applications to the pigmented trabecular band. Retrograde labeling of RGCs was performed with dextran tetramethylrhodamine. RGC isolation from rat retinas was performed with magnetic beads coated with Thy-1 monoclonal antibody. Immunoblot analysis, RGC-5 culture and transfection, and cell viability assays were used. Gene delivery was performed with in vivo electroporation.

Results: Endogenous levels of thioredoxin-2 (TRX2) in RGCs after axotomy and in RGC-5 cells after glutamate/buthionine sulfoximine (BSO) treatment were up-regulated. An increased level of TRX-interacting protein (TXNIP) in the retina was observed 2 and 5 weeks after IOP elevation. TRX1 levels were decreased at 2 weeks and more prominently at 5 weeks after IOP elevation. No change in TRX2 levels in response to IOP elevation was detected. Overexpression of TRX1 and TRX2 in RGC-5 treated with glutamate/BSO increased the cell survival by twofold and threefold 24 and 48 hours after treatment, respectively. Overexpression of these proteins in the retina in vivo increased the survival of RGCs by 35% and 135% at 7 and 14 days after ONT, respectively. In hypertensive eyes, RGC loss was approximately 27% after 5 weeks of IOP elevation compared to controls. TRX1 and TRX2 overexpression preserved approximately 45% and 37% of RGCs, respectively, in the glaucoma model compared to controls.

Conclusion: Thioredoxin overexpression protects RGCs from death after optic nerve axotomy, in pharmacologically induced oxidative stress in vitro and in an animal model of glaucoma.

Purpose: To determine whether selective laser trabeculoplasty (SLT) and prostaglandin analogues (PGAs) have a common mechanism of action that involves increasing conductivity across Schlemm's canal endothelial cells (SCEs) and inducing a similar decrease in intraocular pressure (IOP) in a given patient.

Methods: The intercellular junctions in SCEs were made visible by transfection of a plasmid containing a GFP-tagged gene for ZO-1 protein. Transfected SCEs were treated with media conditioned by lasered trabecular meshwork endothelial cells (TMEs), or with latanoprost, bimatoprost, or travoprost. Non-transfected SCEs were exposed to brimonidine, timolol, or brinzolamide. Confocal microscopy and conductivity measurements documented the in vitro treatment effects. Clinically, the IOP in the first SLT-treated eye of 24 patients was measured (1) while on PGA therapy, (2) at "baseline" several weeks after discontinuing PGA therapy, and (3) approximately 90 days after SLT treatment.

Results: Both the in vitro addition of any of the 3 PGAs and of media conditioned by lasered TMEs induced similar SCE effects involving junction disassembly, paracellular pathway widening, and increased conductivity. Clinically, PGAs decreased IOP by a mean of 5.58 mmHg and SLT decreased IOP by 6.60 mmHg from a baseline of 21.52 mmHg.

Conclusions: Exposure to media conditioned by lasered TMEs, or the addition of PGAs, induces the disassembly of intercellular junctions opening up the SCE barrier. Clinically, a positive PGA response predicts both a successful SLT outcome and the magnitude of the decrease in IOP after SLT. We hypothesize that SLT and PGA therapies may share a common mechanism of action.

Purpose: The mini-tenotomy is a novel minimally invasive surgical technique that weakens rectus muscles to treat small-angle strabismus. The mini-tenotomy is an alternative to the standard rectus muscle recession that requires hooking the muscle, suturing the muscle, removing the muscle from sclera, and reattaching the muscle to sclera.

Methods: This is a retrospective chart review of outcomes of the mini-tenotomy procedure on 15 consecutive adult patients. A central tenotomy of 3 mm was performed cutting through intact conjunctiva using a blunt Westcott scissors.

Results: Preoperatively 6 patients were esotropic, measuring between 2 and 16Delta (mean, 8Delta), and 9 patients had vertical deviations that measured between 2 and 6Delta (mean, 3.5Delta). Final postoperative esodeviations ranged from 1 to 8Delta (mean, 5.8Delta), and hyperdeviations ranged from 0 to 4Delta (mean, 1.3Delta). Final improvement of the deviation was larger for hypertropia, with a mean of 2.3Delta, vs esotropia, with a mean of 1.3Delta.

Conclusion: The mini-tenotomy is a safe and effective treatment for diplopia caused by a small-angle hypertropia or esotropia. It is a minimally invasive surgery that can be done in office with topical anesthesia. As with any strabismus procedure, more than one surgery may be necessary.