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PURPOSE OF REVIEW: The pathophysiology of thyroid eye disease (TED) is still not fully understood. However, recently described risk factors and molecular findings have brought new insights into the mechanisms of TED and could lead to the emerging use of more targeted therapies. This article aims to review the clinical findings of TED, and the most recent advances in our understanding of the risk factors and therapeutic options for TED. RECENT FINDINGS: Smoking has been recently shown to have an impact on specific gene expression involved in several disease-related pathways, which seems to be reversible with smoking cessation. This finding further emphasizes the importance of smoking cessation in the prevention and treatment of TED. Selenium deficiency and high-serum cholesterol have been described to be potential independent risk factors for TED and their management could decrease the incidence and severity of TED. In terms of therapeutic options, immunomodulatory medications have shown some promising results for disease control in TED over the past years, but further randomized prospective studies with larger sample sizes are still needed to prove their efficacy. A new technique of P brachytherapy was shown to have quick therapeutic effects on TED without significant side effects and could be a promising therapy for selected cases of TED. SUMMARY: TED is one of the most common autoimmune inflammatory disorders of the orbit. Although its pathophysiology remains unclear, newly described genetic findings and risk factors could help in explaining its occurrence and guide future therapies. Immunosuppressant medications are increasingly used in the management of TED, but further studies are needed to confirm their effectiveness.

Purpose: If you cannot follow the story when watching a video, then the viewing experience is degraded. We measured the difficulty of following the story, defined as the ability to acquire visual information, which is experienced by people with homonymous hemianopia (HH). Further, we proposed and tested a novel rehabilitation aid. Methods: Participants watched 30-second directed video clips. Following each video clip, subjects described the visual content of the clip. An objective score of information acquisition (IA) was derived by comparing each new response to a control database of descriptions of the same clip using natural language processing. Study 1 compared 60 participants with normal vision (NV) to 24 participants with HH to test the hypothesis that participants with HH would score lower than NV participants, consistent with reports from people with HH that describe difficulties in video watching. In the second study, 21 participants with HH viewed clips with or without a superimposed dynamic cue that we called a content guide. We hypothesized that IA scores would increase using this content guide. Results: The HH group had a significantly lower IA score, with an average of 2.8, compared with 4.3 shared words of the NV group (mixed-effects regression, < 0.001). Presence of the content guide significantly increased the IA score by 0.5 shared words ( = 0.03). Conclusions: Participants with HH had more difficulty acquiring information from a video, which was objectively demonstrated (reduced IA score). The content guide improved information acquisition, but not to the level of people with NV. Translational Relevance: The value as a possible rehabilitation aid of the content guide warrants further study that involves an extended period of content-guide use and a randomized controlled trial.

Corneal transplantation is the most prevalent form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain graft transparency. CEnC density decreases significantly after corneal transplantation even in the absence of graft rejection. To date, different strategies have been used to enhance CEnC survival. The neuropeptide vasoactive intestinal peptide (VIP) improves CEnC integrity during donor cornea tissue storage and protects CEnCs against oxidative stress-induced apoptosis. However, little is known about the effect of exogenous administration of VIP on corneal transplant outcomes. We found that VIP significantly accelerates endothelial wound closure and suppresses interferon-γ- and tumor necrosis factor-α-induced CEnC apoptosis in vitro in a dose-dependent manner. In addition, we found that intracameral administration of VIP to mice undergoing syngeneic corneal transplantation with endothelial injury increases CEnC density and decreases graft opacity scores. Finally, using a mouse model of allogeneic corneal transplantation, we found for the first time that treatment with VIP significantly suppresses posttransplantation CEnC loss and improves corneal allograft survival.

PURPOSE: Prior research in animal models has shown that macrophages and microglia play an important role in pathogenesis of glaucoma, but the phenotype and distribution of macrophages in human glaucomatous tissue have not been sufficiently characterized. METHODS: We analyzed H&E, CD68-, and CD163-immunostained slides from 25 formaldehyde-fixed, paraffin-embedded autopsy eyes: 12 control eyes and 13 eyes with glaucoma. The diagnosis of glaucoma was made based on a history of glaucoma as reported in the medical record and histological changes characteristic of glaucoma. Glaucoma cases and controls were matched in terms of age, sex, and race. RESULTS: Qualitative analysis of the conventional outflow pathway and the optic nerve revealed that all eyes contained CD163+ cells but a negligible number of CD68+ cells. CD163+ macrophages infiltrated the trabecular meshwork and surrounded Schlemm's canal of normal eyes and eyes with glaucoma, but the pattern was variable and qualitatively similar between groups. In optic nerves of control eyes, CD163+ macrophages were present at low levels and restricted to septa between axon bundles. In glaucomatous optic nerves, the number of CD163+ cells was increased both qualitatively and quantitatively (glaucoma 5.1 ± 0.6 CD163+ cells/mm, control 2.5 ± 0.3 CD163+ cells/mm, p < 0.001), with CD163+ cells infiltrating axon bundles in cases of both mild and severe diseases. CONCLUSIONS: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.

SIGNIFICANCE: Full-field prisms that fill the entire spectacle eye wire have been considered as field expansion devices for homonymous hemianopia (HH) and acquired monocular vision (AMV). Although the full-field prism is used for addressing binocular dysfunction and for prism adaptation training after brain injury as treatment for spatial hemineglect, we show that the full-field prism for field expansion does not effectively expand the visual field in either HH or AMV. PURPOSE: Full-field prisms may shift a portion of the blind side to the residual seeing side. However, foveal fixation on an object of interest through a full-field prism requires head and/or eye rotation away from the blind side, thus negating the shift of the field toward the blind side. METHODS: We fit meniscus and flat full-field 7Δ and 12Δ yoked prisms and conducted Goldmann perimetry in HH and AMV. We compared the perimetry results with ray tracing calculations. RESULTS: The rated prism power was in effect at the primary position of gaze for all prisms, and the meniscus prisms maintained almost constant power at all eccentricities. To fixate on the perimetry target, the subjects needed to turn their head and/or eyes away from the blind side, which negated the field shift into the blind side. In HH, there was no difference in the perimetry results on the blind side with any of the prisms. In AMV, the lower nasal field of view was slightly shifted into the blind side with the flat prisms, but not with the meniscus prisms. CONCLUSIONS: Full-field prisms are not an effective field expansion device owing to the inevitable fixation shift. There is potential for a small field shift with the flat full-field prism in AMV, but such lenses cannot incorporate refractive correction. Furthermore, in considering the apical scotoma, the shift provides a mere field substitution at best.

The purpose of this study was to evaluate absorbable polyethylene glycol (PEG)-based synthetic hydrogel as a sealant for retinal breaks in rhegmatogenous retinal detachment (RD). A three-port, 25-gauge vitrectomy was performed on nine Dutch pigmented rabbit eyes. Subsequently, RD was induced by creating a retinal break. The retina was then reattached by fluid-air exchange. In six of nine eyes (RD-PEG group), PEG sealant was applied to completely cover the retinal breaks, and then photopolymerized with light; thereafter, intravitreous air was replaced with balanced salt solution (BSS). In the remaining three eyes (RD group), PEG sealant was not applied, but the intravitreous air was replaced with BSS. Ophthalmological examinations and intraocular pressure measurements were conducted preoperatively, and at 1 and 7 days, and 1, 3, and 6 months postoperatively. Histological examinations of the eyes were performed after 6 postoperative months. At surgery, retinal reattachment with PEG sealant was achieved in all eyes in the RD-PEG group. Fundoscopic and optical coherence tomographic examinations revealed that the retina remained attached in all the eyes of the RD-PEG group throughout the 6-month observation period. Histological examination revealed no signs of damage in the retinal layers at the edges of the retinal breaks that were in contact with the sealant. In the RD group, the retinas detached in all eyes within 7 days postoperatively. The PEG sealant closed the retinal breaks and maintained retinal reattachment. Intraocular tamponade was not necessary.

AIMS: To compare functional and anatomical outcomes of continued anti-vascular endothelial growth factor (VEGF) therapy versus dexamethasone (DEX) implant in eyes with refractory diabetic macular edema (DME) after three initial anti-VEGF injections in a real-world setting. METHODS: To be included in this retrospective multicenter, case-control study, eyes were required: (1) to present with early refractory DME, as defined by visual acuity (VA) gain ≤ 5 letters or reduction in central subfield thickness (CST) ≤ 20%, after a loading phase of anti-VEGF therapy (three monthly injections) and (2) to treat further with (a) anti-VEGF therapy or (b) DEX implant. Main outcome measures were change in visual acuity (VA) and central subfield thickness (CST) at 12 months. Due to imbalanced baseline characteristics, a matched anti-VEGF group was formed by only keeping eyes with similar baseline characteristics as those in the DEX group. RESULTS: A total of 110 eyes from 105 patients were included (anti-VEGF group: 72 eyes, DEX group: 38 eyes). Mean change in VA at 12 months was - 0.4 ± 10.8 letters (anti-VEGF group), and + 6.1 ± 10.6 letters (DEX group) (P = 0.004). Over the same period, mean change in CST was + 18.3 ± 145.9 µm (anti-VEGF group) and - 92.8 ± 173.6 µm (DEX group) (P < 0.001). Eyes in the DEX group were more likely to gain ≥ 10 letters (OR 3.71, 95% CI 1.19-11.61, P = 0.024) at month 12. CONCLUSIONS: In a real-world setting, eyes with DME considered refractory to anti-VEGF therapy after three monthly injections which were switched to DEX implant and had better visual and anatomical outcomes at 12 months than those that continued treatment with anti-VEGF therapy.

PURPOSE: We conducted a secondary analysis of a randomized, placebo-controlled trial to test if hormone therapy (HT) altered the risk of open-angle glaucoma (OAG), and if the risk reduction varied by race. DESIGN: Secondary analysis of randomized controlled trial data. METHODS: We linked Medicare claims data to 25 535 women in the Women's Health Initiative. Women without a uterus were randomized to receive either oral conjugated equine estrogens (CEE 0.625 mg/day) or placebo, and women with a uterus received oral CEE and medroxyprogesterone acetate (CEE 0.625 mg/day + MPA 2.5 mg/day) or placebo. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence interval. RESULTS: After exclusion of women with prevalent glaucoma or without claims for eye care provider visits, the final analysis included 8102 women (mean age = 68.5 ± 4.8 years). The OAG incidence was 7.6% (mean follow-up = 11.5 ± 5.2 years; mean HT duration = 4.4 ± 2.3 years). Increased age (P trend = .01) and African-American race (HR = 2.69, 95% CI = 2.13-3.42; white as a reference) were significant risk factors for incident OAG. We found no overall benefit of HT in reducing incident OAG (HR = 1.01, 95% CI = 0.79-1.29 in the CEE trial, and HR = 1.05, 95% CI = 0.85-1.29 in the CEE + MPA trial). However, race modified the relationship between CEE use and OAG risk (P interaction = .01), and risk was reduced in African-American women treated with CEE (HR = 0.49, 95% CI = 0.27-0.88), compared to placebo. Race did not modify the relation between CEE + MPA use and OAG risk (P interaction = .68). CONCLUSIONS: Analysis suggests that HT containing estrogen, but not a combination of estrogen and progesterone, reduces the risk of incident OAG among African-American women. Further investigation is needed.

Purpose: To evaluate the collective user experience with an image-guided femtosecond laser (FSL) for cataract surgery in a high-volume, multi-surgeon, ambulatory surgical center. Subjects and methods: A detailed online survey was distributed to all surgeons in a single ambulatory surgical center who had performed cataract surgery using a FSL since its acquisition in December 2012. Information collected included the number of cases performed, typical surgical techniques and parameters, satisfaction with individual features of the laser (rated on a scale from 1=completely unsatisfied to 10=extremely satisfied) and commentary on ease of use and suggested improvements. Results: Seventeen of 30 surgeons (56.7%) completed the survey, representing a case volume of 1,967 eyes. Fourteen surgeons (82.4%) felt they required ≤10 cases with the FSL to operate with the same safety and control as in standard phacoemulsification surgery. Satisfaction was highest for capsulotomies, lens fragmentation, lens softening, arcuate incisions and the graphic user interface (mean scores 9.4, 8.7, 8.7, 7.2 and 8.9, respectively). Preferred capsulotomy diameter was 4.8-5.2 mm (64.7% of respondents). About half (52.9%) of respondents centered the capsulotomy on the pupil and the other 47.1% centered the capsulotomy using optical coherence tomography. Most respondents (81.3%) preferred transepithelial arcuate incisions compared to intrastromal incisions. Satisfaction was lowest with FSL-created, main, clear corneal incisions and paracenteses (mean scores 4.4 and 4.2, respectively). Conclusion: Laser-assisted cataract surgery has a short learning curve and a high rate of user satisfaction. Further software and hardware development is warranted to improve user satisfaction with peripheral and clear corneal incisions.

Adeno-associated viral vectors (AAVs) have demonstrated potential in applications for neurologic disorders, and the discovery that some AAVs can cross the blood-brain barrier (BBB) after intravenous injection has further expanded these opportunities for non-invasive brain delivery. Anc80L65, a novel AAV capsid designed from reconstruction of the viral evolutionary lineage, has previously demonstrated robust transduction capabilities after local delivery in various tissues such as liver, retina, or cochlea, compared with conventional AAVs. Here, we compared the transduction efficacy of Anc80L65 with conventional AAV9 in the CNS after intravenous, intracerebroventricular (i.c.v.), or intraparenchymal injections. Anc80L65 was more potent at targeting the brain and spinal cord after intravenous injection than AAV9, and mostly transduced astrocytes and a wide range of neuronal subpopulations. Although the efficacy of Anc80L65 and AAV9 is similar after direct intraparenchymal injection in the striatum, Anc80L65's diffusion throughout the CNS was more extensive than AAV9 after i.c.v. infusion, leading to widespread expression in the cerebellum. These findings demonstrate that Anc80L65 is a highly efficient gene transfer vector for the murine CNS. Systemic injection of Anc80L65 leads to notable expression in the CNS that does not rely on a self-complementary genome. These data warrant further testing in larger animal models.

Purpose: Radiation therapy results in severe chronic keratopathy and dry eye disease. We developed a novel mouse model for radiation keratopathy to allow future mechanistic studies. Methods: Six to 8-week-old BALB/c mice underwent sublethal irradiation to the head only from a Cesium-137 irradiator, 2 × 550 rad, 3-hours apart. Irradiated mice were clinically evaluated by corneal fluorescein staining (CFS) at 1, 2, and 3 months, after which corneas were excised and immunofluorescence histochemistry performed with anti-CD45, anti-MHC class II, and anti-β-tubulin antibodies. Results: The survival rate after irradiation was 100%. Mice demonstrated significant CFS and hair loss around the eyes. Corneal nerve density decreased in the central and peripheral corneas (P < 0.01) at 2 and 3 months, respectively. CD45+ immune cell densities increased in the central and peripheral corneas (P < 0.005, P < 0.001) at 2 and 3 months, respectively. MHC class II, a sign of antigen presenting cell activation, significantly increased after irradiation in the central and peripheral corneas at 2 and 3 months (P = 0.02). A strong inverse correlation was noted between decreased corneal nerves and increase in CD45+ cells in the central cornea at 2 (P = 0.04, r = -0.89) and 3 months (P = 0.03, r = -0.91) after irradiation. Conclusions: We present a model of radiation keratopathy and demonstrate significant nerve loss and increase in immune cell influx and activation within months. This model will enable future investigations to understand the effects of radiation therapy on the eye, and to study mechanisms of neuro-immune crosstalk in the cornea.

Purpose: To study age- and intraocular pressure-induced changes in the glial lamina of the murine optic nerve on the ultrastructural level. Methods: Naïve C57bl/6 mice at various ages spanning the time between early adulthood (3 months) and senescence (30 months) were used in this study. In addition, the intraocular pressure (IOP) was increased in a group of young mice by injection of microbeads into the anterior chamber. The unmyelinated segments of the optic nerve containing the glial lamina were prepared for transmission electron microscopy and imaged at high resolution. Results: Axon packing density decreased slightly with age. Aging nerves contained higher numbers of enlarged and degenerating axons. Mean axonal diameter and in particular the variance of axonal diameter correlated well with age. Axonal mitochondria also showed age-dependent signs of pathology. The mean diameter of axonal mitochondria increased, and aged axons often contained profiles of mitochondria with very few or no cristae. Astrocytic mitochondria remained normal even in very old nerves. Changes to axons and axonal mitochondria in young glaucomatous nerves were comparable with those of 18- to 30-month-old naïve mice. In addition to axons and mitochondria, aged and glaucomatous nerves showed thickening of the blood vessel basement membranes and increased deposition of basement membrane collagen. Conclusions: On the ultrastructural level, the effects of age and elevated IOP are quite similar. One month of elevated IOP seems to have as strongly detrimental effects on the nerve as at least 18 months of normal aging.

PURPOSE: To contribute a global description of the spectrum of choroidal involvement in tubercular uveitis (TBU). METHODS: Retrospective cohort study of TBU patients with choroidal involvement from 25 centers between January 2004 and December 2014. Medical records of patients with a minimum follow-up of 1 year were reviewed. RESULTS: 245 patients were included. The phenotypic variations included serpiginous-like choroiditis (SLC) (46%), tuberculoma (13.5%), multifocal choroiditis (MFC) (9.4%), ampiginous choroiditis (9%), among others. 219 patients were treated with anti-tubercular therapy (ATT) (n = 219/245, 89.38%), 229 patients with steroids (n = 229/245, 93.47%) and 28 patients with immunosuppressive agents (n = 28/245, 11.42%). Treatment failure was noted in 38 patients (n = 38/245, 15.5%). Patients with SLC and ampiginous choroiditis appeared to have superior outcomes on survival analysis (p = 0.06). CONCLUSION: This study provides a comprehensive description of choroidal involvement in TBU. Patients with SLC and ampiginous choroiditis may have better clinical outcomes.