March 2018

Muscular dystrophy-dystroglycanopathy type A (MDDGA3), one of a group of diseases collectively known as congenital muscular dystrophies, is an alpha-dystroglycanopathy with characteristic brain and ocular abnormalities. We report the case of a 9-month-old boy with developmental delay whose family sought evaluation for esotropia. Subsequent examination, imaging, and testing revealed significant motor and cognitive delay, marked weakness with appendicular spasticity, and a diffuse brain malformation. In addition, the patient had poor visual acuity, nystagmus, optic nerve hypoplasia, bilateral retinal dysplasia and retinal dragging with a large vertical angle kappa, and an avascular peripheral retina. Genetic testing revealed two known heterozygous mutations in the POMGnT1 gene confirming MDDGA3. He was treated with botulinum toxin injections for his strabismus and continues to be followed, with planned laser ablation of the peripheral avascular retina.

We report a unique case of optic nerve lymphoma after completion of chemotherapy for non-Hodgkin's lymphoma. The uncommon nature of presentation, our therapeutic dilemma and the further course of treatment are reported. In cases with extremely poor prognosis, unnecessary treatment puts additional strain both financially and psychologically on the patients and their family. Therapeutic focus should be on hospice care and family counselling. The decision to not treat is a crucial component of cancer management; however, the ethics of this decision are yet to be suitably addressed by the literature.

PURPOSE: To develop a visual field (VF) feature model to predict the reversal of glaucoma hemifield test (GHT) results to within normal limits (WNL) after 2 consecutive outside normal limits (ONL) results. DESIGN: Retrospective cohort study. PARTICIPANTS: Visual fields of 44 503 eyes from 26 130 participants. METHODS: Eyes with 3 or more consecutive reliable VFs measured with the Humphrey Field Analyzer (Swedish interactive threshold algorithm standard 24-2) were included. Eyes with ONL GHT results for the 2 baseline VFs were selected. We extracted 3 categories of VF features from the baseline tests: (1) VF global indices (mean deviation [MD] and pattern standard deviation), (2) mismatch between baseline VFs, and (3) VF loss patterns (archetypes). Logistic regression was applied to predict the GHT results reversal. Cross-validation was applied to evaluate the model on testing data by the area under the receiver operating characteristic curve (AUC). We ascertained clinical glaucoma status on a patient subset (n = 97) to determine the usefulness of our model. MAIN OUTCOME MEASURES: Predictive models for GHT results reversal using VF features. RESULTS: For the 16 604 eyes with 2 initial ONL results, the prevalence of a subsequent WNL result increased from 0.1% for MD < -12 dB to 13.8% for MD ≥-3 dB. Compared with models with VF global indices, the AUC of predictive models increased from 0.669 (MD ≥-3 dB) and 0.697 (-6 dB ≤ MD < -3 dB) to 0.770 and 0.820, respectively, by adding VF mismatch features and computationally derived VF archetypes (P < 0.001 for both). The GHT results reversal was associated with a large mismatch between baseline VFs. Moreover, the GHT results reversal was associated more with VF archetypes of nonglaucomatous loss, severe widespread loss, and lens rim artifacts. For a subset of 97 eyes, using our model to predict absence of glaucoma based on clinical evidence after 2 ONL results yielded significantly better prediction accuracy (87.7%; P < 0.001) than predicting GHT results reversal (68.8%) with a prescribed specificity 67.7%. CONCLUSIONS: Using VF features may predict the GHT results reversal to WNL after 2 consecutive ONL results.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Oncoming headlight glare (HLG) reduces the visibility of objects on the road and may affect the safety of nighttime driving. With cataracts, the impact of oncoming HLG is expected to be more severe. We used our custom HLG simulator in a driving simulator to measure the impact of HLG on pedestrian detection by normal vision subjects with simulated mild cataracts and by patients with real cataracts.Five normal vision subjects drove nighttime scenarios under two HLG conditions (with and without HLG: HLGY and HLGN, respectively), and three vision conditions (with plano lens, simulated mild cataract, and optically blurred clip-on). Mild cataract was simulated by applying a 0.8 Bangerter diffusion foil to clip-on plano lenses. The visual acuity with the optically blurred lenses was individually chosen to match the visual acuity with the simulated cataract clip-ons under HLGN. Each nighttime driving scenario contains 24 pedestrian encounters, encompassing four pedestrian types; walking along the left side of the road, walking along the right side of the road, crossing the road from left to right, and crossing the road from right to left. Pedestrian detection performances of five patients with mild real cataracts were measured using the same setup. The cataract patients were tested only in HLGY and HLGN conditions. Participants' visual acuity and contrast sensitivity were also measured in the simulator with and without stationary HLG.For normal vision subjects, both the presence of oncoming HLG and wearing the simulated cataract clip-on reduced pedestrian detection performance. The subjects performed worst in events where the pedestrian crossed from the left, followed by events where the pedestrian crossed from the right. Significant interactions between HLG condition and other factors were also found: (1) the impact of oncoming HLG with the simulated cataract clip-on was larger than with the plano lens clip-on, (2) the impact of oncoming HLG was larger with the optically blurred clip-on than with the plano lens clip-on, but smaller than with the simulated cataract clip-on, and (3) the impact was larger for the pedestrians that crossed from the left than those that crossed from the right, and for the pedestrians walking along the left side of the road than walking along the right side of the road, suggesting that the pedestrian proximity to the glare source contributed to the performance reduction. Under HLGN, almost no pedestrians were missed with the plano lens or the simulated cataract clip-on (0 and 0.5%, respectively), but under HLGY, the rate of pedestrian misses increased to 0.5 and 6%, respectively. With the optically blurred clip-on, the percent of missed pedestrians under HLGN and HLGY did not change much (5% and 6%, respectively). Untimely response rate increased under HLGY with the plano lens and simulated cataract clip-ons, but the increase with the simulated cataract clip-on was significantly larger than with the plano lens clip-on. The contrast sensitivity with the simulated cataract clip-on was significantly degraded under HLGY. The visual acuity with the plano lens clip-on was significantly improved under HLGY, possibly due to pupil myosis. The impact of HLG measured for real cataract patients was similar to the impact on performance of normal vision subjects with simulated cataract clip-ons.Even with mild (simulated or real) cataracts, a substantial negative effect of oncoming HLG was measurable in the detection of crossing and walking-along pedestrians. The lowered pedestrian detection rates and longer response times with HLGY demonstrate a possible risk that oncoming HLG poses to patients driving with cataracts.

The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788 ± 16% (SD), which dropped to 49,545 ± 20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p < 0.05) on Chromosome 18 between 53.6 and 57 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.

We report a case of myeloid sarcoma with multifocal skeletal involvement, including the greater wing of the sphenoid bone. A 23-month-old boy presented with left-sided proptosis and fevers, and was found to have an infiltrative mass involving the left sphenoid bone on orbital imaging. Full body imaging further demonstrated multiple bony lesions in the pelvis, thoracic and lumbar vertebrae, bilateral femura, and left humerus, and biopsies of the humerus were consistent with myeloid sarcoma. The patient was started on a standard chemotherapy regimen and is responding well. Myeloid sarcoma presenting with proptosis due to sphenoid bone involvement with simultaneous multifocal skeletal involvement is very uncommon and highlights the importance of biopsy for establishing a definitive diagnosis.

Lysyl oxidase (LOX) is an enzyme that oxidizes lysine residues in collagens and elastin. It stabilizes or remodels the extracellular matrix and basement membrane of blood vessels. Current oncology studies have revealed that LOX is upregulated in invasive cancer cells and bolstered cell movement, and LOX was observed to promote the angiogenesis and migration of endothelial cells. In the present study, angiogenesis and migration were examined in human umbilical vein endothelial cells (HUVECs). Following cell treatment with 0.1-0.4 mM β-aminoproprionitrile (BAPN), a specific inhibitor of LOX, angiogenesis was analyzed with a fibrin gel in vitro angiogenesis assay kit and migration was examined via a Boyden Chamber assay. Angiogenesis-associated gene expression was investigated with a microarray assay and confirmed with reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results showed that HUVEC angiogenesis substantially increased in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and phorbol 12-myristate 13-acetate (PMA). In addition, LOX inhibition blocked the angiogenesis stimulated by VEGF bFGF and PMA, and the inhibition of LOX reduced the migration of HUVECs. Furthermore, the microarray and RT-qPCR revealed that BAPN downregulated myeloid progenitor inhibitory factor 1, and western blot analysis demonstrated that BAPN decreased the phosphorylation of MAPK and Akt, suggesting that the specific inhibitor of LOX, BAPN, may serve as an alternative strategy for preventing angiogenesis.

PURPOSE: To compare the corneal stromal riboflavin concentration and distribution using 2 transepithelial corneal crosslinking (CXL) systems. SETTING: Absorption Systems, San Diego, California, USA. DESIGN: Experimental study. METHODS: The stromal riboflavin concentration of 2 transepithelial CXL systems was compared in rabbit eyes in vivo. The systems were the Paracel/Vibex Xtra, comprising riboflavin 0.25% solution containing TRIS and ethylenediaminetetraacetic acid and an isotonic solution of riboflavin 0.25%, (Group 1) and the CXLO system (Group 2). Manufacturers' Instructions For Use were followed. The intensity of riboflavin fluorescence by slitlamp observation 10, 15, and 20 minutes after instillation was graded on a scale of 0 to 5. The animals were humanely killed and the corneal stromal samples analyzed with liquid chromatography and mass spectrometry. RESULTS: The mean riboflavin fluorescence intensity grades in Group 1 (4 eyes) were 3.8, 4.8, and 4.8 at 10, 15, and 20 minutes, respectively. The mean grades in Group 2 (3 eyes) were 2.0, 2.3, and 2.0, respectively. The riboflavin distribution was uniform in Group 1 but not in Group 2. The mean riboflavin concentration by liquid chromatography and mass spectrometry was 27.0 μg/g stromal tissue in Group 1 and 6.7 μg/g in Group 2. A stromal riboflavin concentration theoretically adequate for CXL, 15 μg/g, was achieved in all eyes in Group 1 and no eyes in Group 2. Slitlamp grading correlated well with liquid chromatography and mass spectrometry concentration (R = 0.940). CONCLUSIONS: The system used in Group 1 produced corneal riboflavin concentrations that were theoretically adequate for effective transepithelial CXL (≥15 μg/g), while the system in Group 2 did not. Slitlamp grading successfully estimated the corneal riboflavin concentration and can be used to ensure an adequate concentration of riboflavin in the cornea for transepithelial CXL.

PURPOSE: To compare the response of dry eye disease (DED) to treatment with topical steroid in patients with and without graft-vs-host disease (GVHD). DESIGN: Post hoc analysis of a double-masked, randomized clinical trial. METHODS: This single-center study included 42 patients with moderate-to-severe DED associated with (n = 21) or without (n = 21) chronic GVHD. In each group, patients received either loteprednol etabonate 0.5% ophthalmic suspension or artificial tears twice daily for 4 weeks. Clinical data, including Ocular Surface Disease Index (OSDI) questionnaire, corneal fluorescein staining (CFS), conjunctival lissamine green staining, tear break-up time (TBUT), and Schirmer test, were evaluated before and after treatment. RESULTS: There were no significant differences in signs and symptoms of DED between the groups at baseline. In non-GVHD patients receiving loteprednol treatment, the average OSDI score decreased by 34% from 49.5 ± 5.9 to 32.6 ± 4.8 (mean ± standard error of the mean, P = .001) and the average CFS score decreased by 41% from 5.6 ± 0.6 to 3.3 ± 0.9 (P = .02). On the other hand, loteprednol treatment in GVHD patients resulted in minimal change in OSDI (59.2 ± 6.7 to 61.1 ± 7.1, 3% increase, P = .66) and CFS (5.5 ± 0.5 to 5.3 ± 1.1, 4% decrease, P = .85) scores. Treatment with artificial tears resulted in 22% decrease of OSDI (P = .10) and 32% decrease of CFS (P = .02) scores in non-GVHD patients, and had minimal effect in patients with GVHD. CONCLUSIONS: DED patients with ocular GVHD have a less favorable response to a low-dose topical steroid regimen compared with those without ocular GVHD even with similar baseline disease severity.

OBJECTIVE: Retinopathy of prematurity (ROP) is a multifactorial disease linked to low insulin-like growth factor (IGF)-I levels and perhaps to postnatal inflammation. Here, we investigated the longitudinal postnatal serum concentrations of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α in relation to IGF-I levels and ROP. DESIGN: The study cohort included 52 infants born before 31 gestational weeks. The infants were screened for ROP and classified as non-ROP (n=33), non-proliferative ROP (stages 1 and 2; n=10), or proliferative ROP (stage 3, all treated for ROP; n=9). Blood samples were collected at birth, 24h after birth, and then weekly until at least 36weeks postmenstrual age (PMA) (i.e., up to 13weeks after birth). Circulating levels of IL-6 and TNF-α were evaluated in relation to circulating IGF-I levels and ROP. RESULTS: IL-6 levels negatively correlated with IGF-I levels between 5 and 8weeks after birth, (p<0.01 to p<0.05). At birth, the IL-6 and TNF-α levels were similar independent of later ROP. Twenty-four hours after birth, both IL-6 and TNF-α levels had increased in infants later treated for ROP (p<0.05). Postnatal, infants treated for ROP had higher IL-6 levels than infants without ROP. CONCLUSIONS: The pro-inflammatory response is associated with low IGF-I levels and the development of ROP.

Tissue adhesives are gaining popularity in ophthalmology, as they could potentially reduce the complications associated with current surgical methods. An ideal tissue adhesive should have superior tensile strength, be non-toxic and anti-inflammatory, improve efficiency and be cost-effective. Both synthetic and biological glues are available. The primary synthetic glues include cyanoacrylate and the recently introduced polyethylene glycol (PEG) derivatives, while most biological glues are composed of fibrin. Cyanoacrylate has a high tensile strength, but rapidly polymerises upon contact with any fluid and has been associated with histotoxicity. Fibrin induces less toxic and inflammatory reactions, and its polymerisation time can be controlled. Tensile strength studies have shown that fibrin is not as strong as cyanoacrylate. While more research is needed, PEG variants currently appear to have the most promise. These glues are non-toxic, strong and time-effective. Through MEDLINE and internet searches, this paper presents a systematic review of the current applications of surgical adhesives to corneal, glaucoma, retinal, cataract and strabismus surgeries. Our review suggests that surgical adhesives have promise to reduce problems in current ophthalmic surgical procedures.

PURPOSE: The purpose of this study was to examine the effect of corneal biomechanical properties on intraocular pressure (IOP) measurements obtained using a rebound self-tonometer (Icare HOME) compared with Goldmann applanation tonometry (GAT). METHODS: An observational study of 100 patients with glaucoma or ocular hypertension. All had a comprehensive ophthalmic examination and standard automated perimetry. IOP was assessed by GAT, Icare HOME and Ocular Response Analyzer, which was also used to assess corneal hysteresis (CH) and corneal resistance factor (CRF). Central corneal thickness (CCT) was recorded. RESULTS: Mean (±SD) IOP measurements were 14.3±3.9 and 11.7±4.7 mm Hg using GAT and Icare HOME, respectively. Average CCT, CRF, and CH were 534.5±37.3 μm, 9.0±1.7 mm Hg, and 9.4±1.5 mm Hg, respectively. The mean difference between Icare HOME and GAT was -2.66±3.13 mm Hg, with 95% limits of agreement of -8.80 to 3.48 mm Hg, however, there was evidence of proportional bias. There was negative correlation between IOP and CH [5.17 mm Hg higher Icare HOME IOP (P=0.041, R=0.029) and 7.23 mm Hg higher GAT IOP (P=0.008, R=0.080) for each 10 mm Hg lower CH], whereas thinner CCT was significantly associated with lower IOP (P<0.001, R=0.14 for Icare HOME and P<0.001, R=0.08 for GAT). In multivariable analysis, although CRF and CH remained associated with IOP measured using either GAT or Icare HOME, CCT was no longer significant. CONCLUSION: IOP measurements obtained using a self-tonometer, similar to GAT, were more influenced by overall corneal biomechanics than CCT.

BACKGROUND: Endoscopic dacryocystorhinostomies (eDCRs) show patency rates between 81% and 94%. However, dacryocystorhinostomy (DCR) failure and the need for revision remain a significant challenge. One of the principal challenges in revision eDCR is the need to surgically identify the correct osteotomy site and maintain long-term patency in the setting of previously instrumented and potentially scarred tissue. At the same time, the surgeon must assume that the blood supply to the commonly described anterior and posteriorly pedicled flaps has been compromised. OBJECTIVE: The objective of the study is to describe a novel flap technique for revision eDCR. METHODS: The superior based mucosal flap is a novel technique that provides a vascularized mucosa preserving technique in revision eDCR despite previous instrumentation of the lacrimal system. This technique provides wide exposure of the revision osteotomy site while simultaneously allowing a viable mucosal flap to be replaced at the conclusion of the procedure, thereby minimizing bone exposure and cicatricial restenosis. RESULTS: The authors have utilized this technique in 13 procedures with 100% positive identification of the lacrimal sac, a 0% complication rate, and a 100% success rate after a mean follow-up of 26.93 ± 10.33 months (range 6-35 months). CONCLUSION: The eDCR using the superior pedicled mucosal flap provides excellent exposure of the maxillary bone and the lacrimal sac. This method preserves vascularity of the flap using a superiorly based pedicle which is typically inviolate during both open and endoscopic primary DCR. The mucosal flap can then be replaced, thereby minimizing bone exposure and optimizing patency.