August 2018

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.

PURPOSE OF REVIEW: Anterior visual pathway compression is a common feature of sellar region masses. We review the visual pathway neuroanatomy pertaining to sellar and parasellar lesions and describe recent advances in optical coherence tomography (OCT) imaging that have provided a novel quantitative perspective in the evaluation and management of such patients. RECENT FINDINGS: Ultrastructural measurements of optic nerve integrity using OCT, namely peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCIPL) thicknesses, have been shown to correlate with visual acuity and visual field deficits on perimetry in patients with compressive sellar region masses. In some cases, OCT can visualize early signs of anterior visual pathway involvement in the absence of clinically evident visual field loss or optic disc pallor. OCT is particularly useful when assessing patients who demonstrate less reliable visual field testing. Furthermore, there is growing awareness that pRNFL and GCIPL thinning preoperatively correlate with worse visual recovery following chiasmal decompression, highlighting the prognostic utility of OCT in this patient population. SUMMARY: OCT provides a complimentary, yet critical, role in quantitatively assessing ultrastructural retinal injury in patients with sellar and parasellar lesions compressing the anterior visual pathway and should be incorporated into routine evaluation.

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.

Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.

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.

AIMS: We set out to determine the optical coherence tomographic angiography (OCT-A) characteristics of arteritic anterior ischaemic optic neuropathy (AAION) in the context of giant cell arteritis (GCA). METHODS: This is an observational case series of four patients with AAION secondary to GCA, three with unilateral AAION and one with bilateral AAION. We reviewed the charts, fundus photography, visual fields, fluorescein angiography (FA) and OCT-A images for all patients to identify a unifying theme in a range of AAION clinical severity. Imaging of two healthy control eyes from two patients of similar age to the patients in our series were used for comparison. RESULTS: Superficial peripapillary capillary dilation was seen in eyes with acute AAION. It was also noted in the fellow eyes of two patients. Retinal capillary perfusion defects corresponded to visual field loss. Dense optic disc oedema and cotton-wool spots imparted blockage effects. OCT-A laminar analysis did not highlight the choroidal/choriocapillaris perfusion defects seen on FA in two patients. Follow-up OCT-A was obtained in two patients and revealed progression to superficial peripapillary capillary attenuation that corresponded with visual field loss. CONCLUSIONS: There are acute and chronic vascular changes in AAION that are detectable by OCT-A that correspond with visual function. Though the microvascular changes seen in GCA and AAION are not specific, the nearly ubiquitous findings among preclinical and clinically affected eyes in this series of patients with GCA support OCT-A as a potentially useful adjunctive diagnostic test in the work-up of ambiguous cases of suspected ischaemic optic neuropathy.

In the eye, goblet cells responsible for secreting mucins are found in the conjunctiva. When mucin production is not tightly regulated several ocular surface disorders may occur. In this study, the effect of the T helper (Th) 2-type cytokines IL4, IL5, and IL13 on conjunctival goblet cell function was explored. Goblet cells from rat conjunctiva were cultured and characterized. The presence of cytokine receptors was confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Changes in intracellular [Ca], high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with Th2 cytokines with or without the allergic mediator histamine. We found that IL4 and IL13 enhance cell proliferation and, along with histamine, stimulate goblet cell secretion. We conclude that the high levels of IL4, IL5, and IL13 that characterize allergic conjunctivitis could be the reason for higher numbers of goblet cells and mucin overproduction found in this condition.

The retina shares embryological derivation with the brain and may provide a new measurement of overall growth status, especially useful in resource-limited settings. Optical coherence tomography (OCT) provides detailed quantification of retinal structures. We enrolled community-dwelling children ages 3-11 years old in Siaya, Kenya and Thimphu, Bhutan in 2016. We measured head circumference (age < 5 years only), height, and weight, and standardized these by age and gender. Research staff performed OCT (; Optovue, Inc., Fremont, CA), measuring the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) thicknesses. A neuro-ophthalmologist performed quality control for centration, motion artifact, and algorithm-derived quality scores. Generalized estimating equations were used to determine the relationship between anthropometric and retinal measurements. Two hundred and fifty-eight children (139 females, average age 6.4 years) successfully completed at least one retinal scan, totaling 1,048 scans. Nine hundred and twenty-two scans (88.0%) were deemed usable. Fifty-three of the 258 children (20.5%) were able to complete all six scans. Kenyan children had a thinner average GCC ( < 0.001) than Bhutanese children after adjustment for age and gender, but not RNFL ( = 0.70). In models adjusting for age, gender, and study location, none of standardized height, weight, and body mass index (BMI) were statistically significantly associated with RNFL or GCC. We determined that OCT is feasible in some children in resource-limited settings, particularly those > 4 years old, using the device. We found no evidence for GCC or RNFL as a proxy for height-, weight-, or BMI-for-age. The variation in mean GCC thickness in Asian versus African children warrants further investigation.

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.

We generated a knockout mouse for the neuronal-specific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3 mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total β-tubulin levels in Tubb3 and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins.

Glycoconjugate mucin secretion from conjunctival goblet cells is tightly regulated by nerves and specialized pro-resolving mediators (SPMs) to maintain ocular surface health. Here we investigated the actions of the SPM resolvin E1 (RvE1) on cultured rat conjunctival goblet cell glycoconjugate secretion and intracellular [Ca] ([Ca]) and the signaling pathways used by RvE1. Goblet cells were cultured from rat conjunctiva in RPMI medium. The amount of RvE1-stimulated glycoconjugate mucin secretion was determined using an enzyme-linked lectin assay with Ulex Europaeus Agglutinin 1 lectin. Cultured goblet cells were also incubated with the Ca indicator dye fura 2/AM and [Ca] was measured. Cultured goblet cells were incubated with inhibitors to phospholipase (PL-) C, D, and A2 signaling pathways. RvE1 stimulated glycoconjugate secretion in a concentration dependent manner and was inhibited with the Ca chelator BAPTA. The Ca response was also increased in a concentration manner when stimulated by RvE1. Inhibition of PLC, PLD, and PLA2, but not Ca/calmodulin-dependent kinase blocked RvE1-stimulated increase in [Ca] and glycoconjugate secretion. We conclude that under normal, physiological conditions RvE1 stimulates multiple pathways to increase glycoconjugate secretion and [Ca]. RvE1 could be an important regulator of goblet cell glycoconjugate mucin secretion to maintain ocular surface health.

Currently available treatment options for non-infectious scleritis, including non-steroidal anti-inflammatory drugs, systemic corticosteroids and immunosuppressive therapies, have both efficacy and side effect limitations. Iontophoretic delivery of corticosteroids has been demonstrated to be effective for anterior uveitis and represents a potential new approach to scleritis therapy. We hypothesised that iontophoretic delivery would provide effective and precise medication delivery to the sclera, while limiting systemic exposure and side effects. This first-in-human randomised, double-masked, dose-escalating study of iontophoretic administration of dexamethasone phosphate for scleritis suggests the treatment to be well tolerated and safe (within the limitations of the 18 patients sample size). There was a suggestion of efficacy in the lowest (1.2 mA/min at 0.4 mA) dose group (corresponding to the superficial location of scleritis compared with anterior uveitis), with 5/7 eyes meeting the primary efficacy outcome within 28 days. Our results suggest iontophoretic delivery of corticosteroids is a promising potential treatment for scleritis, with favourable safety and preliminary efficacy results in this phase 1 trial. TRIAL REGISTRATION NUMBER: NCT01059955.

Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1. Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.

PURPOSE: To review the published literature on outcomes of keratolimbal allograft (KLAL) for the surgical treatment of limbal stem cell deficiency (LSCD) and corneal blindness after severe corneal chemical injury. METHODS: Literature searches were conducted in the following electronic databases: MEDLINE, EMBASE, Science Citation Index, CINAHL, LILACS and the Cochrane Library. Standard systematic review methodology was applied. The main outcome measure was the proportion of eyes with best-corrected visual acuity (BCVA) ≥20/200 at last follow-up. Other measures of allograft success were also collected. RESULTS: We identified six reports in which KLAL outcomes in the eyes after chemical injury could be distinguished. There were no randomised controlled studies. The outcomes of KLAL in 36 eyes of 33 patients were analysed. One study with seven eyes did not specify KLAL follow-up specific to chemical injury. Median postoperative follow-up for the other 29 eyes in 26 patients was 42 months (range 6.2-114 months). In the same 29 eyes, 69% (20/29) had BCVA ≥20/200 at the last follow-up examination. Eighty-nine per cent of all eyes (32/36) underwent penetrating keratoplasty simultaneous or subsequent to KLAL. CONCLUSIONS: The number of studies where outcomes of KLAL in eyes with severe corneal chemical injury could be discerned was limited, and variability was observed in outcome reporting. The quality of evidence to support the use of KLAL in LSCD in severe chemical corneal burns was low. Standardisation and longer follow-up are needed to better define evidence-based best practice when contemplating surgical intervention for blindness after corneal chemical injury. PROSPERO REGISTRATION NUMBER: CRD42017054733.

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.

PURPOSE: To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma. DESIGN: Double-masked, randomized, and vehicle-controlled study. METHODS: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once-daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multisite trial that evaluated intraocular pressure (IOP)-lowering efficacy of the MTD administered nightly for 1 week in 50 patients with minimum IOP of 24 mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at day 8 compared to baseline (ClinicalTrials.govNCT02743780). RESULTS: There was no difference in favor of MGV354 for IOP lowering; change from baseline to day 8 in mean diurnal IOP was -0.6 mm Hg for MGV354-treated patients and -1.1 mm Hg for vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia. CONCLUSIONS: Overall, MGV354 0.1% demonstrated no statistically significant effect compared to vehicle in lowering IOP based on the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology.

BACKGROUND/AIMS: To describe the design and baseline characteristics of patients enrolled in the multicenter, prospective natural history study of Stargardt disease type 4. METHODS: Fifteen eligible patients aged 6 years and older at baseline, harboring disease-causing variants in the PROM1 gene, and with specified ocular lesions were enrolled. They were examined at baseline using a standard protocol, with 6 monthly follow-up visits for a 2-year period including best-corrected ETDRS visual acuity, spectral-domain optical coherence tomography, fundus autofluorescence (FAF), mesopic and scotopic microperimetry (MP). Areas of definitely decreased FAF (DDAF) and questionably decreased FAF were outlined and quantified on FAF images. RESULTS: Amongst the 15 patients (29 eyes) that were enrolled at 5 centers in the USA and Europe, 10 eyes (34.5%) had areas of DDAF with an average lesion area of 3.2 ± 3.5 mm2 (range 0.36-10.39 mm2) at baseline. The mean retinal sensitivity of the posterior pole derived from mesopic MP was 8.8 ± 5.8 dB. CONCLUSIONS: Data on disease progression in PROM1-related retinopathy from this study will contribute to the characterization of the natural history of disease and the exploration of the utility of several modalities to track progression and therefore to potentially be used in future interventional clinical trials.

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.