Familial Exudative Vitreoretinopathy With and Without Pathogenic Variants of Norrin/ß-Catenin Signaling Genes.

Purpose: To determine the clinical characteristics of familial exudative vitreoretinopathy (FEVR) associated with or without pathogenic variants of the Norrin/ß-catenin genes. Design: This was a multicenter, cross-sectional, observational, and genetic study. Subjects: Two-hundred eighty-one probands with FEVR were studied. Methods: Whole-exome sequence and/or Sanger sequence was performed for the Norrin/ß-catenin genes, the FZD4, LRP5, TSPAN12, and NDP genes on blood collected from the probands. The clinical symptoms of the probands with or without the pathogenic variants were assessed as well as differences in the inter Norrin/ß-catenin genes. Main Outcome Measures: The phenotype associated with or without pathogenic variants of the Norrin/ß-catenin genes. Results: One-hundred eight probands (38.4%) had 88 different pathogenic or likely pathogenic variants in the genes: 24 with the FZD4, 42 with the LRP5, 10 with the TSPAN12, and 12 with the NDP gene. Compared with the 173 probands without pathogenic variants, the 108 variant-positive probands had characteristics of familial predisposition (63.9% vs. 37.6%, P < 0.0001), progression during infancy (75.0% vs. 53.8%, P = 0.0004), asymmetrical severity between the 2 eyes (50.0% vs. 37.6%, P = 0.0472), and nonsyndromic characteristics (10.2% vs. 17.3%, P = 0.1185). The most frequent stage at which the more severe eye conditions was present was at stage 4 in both groups (40.7% vs. 34.7%). However, the advanced stages of 3 to 5 in the more severe eye were found more frequently in probands with variants than in those without variants (83.3% vs. 58.4%, P < 0.0001). Patients with rhegmatogenous retinal detachments progressed from stage 1 or 2 were found less frequently in the variant-positive probands (8.3% vs. 17.3%, P = 0.0346). Nine probands with NDP variants had features different from probands with typical Norrin/ß-catenin gene variants including the sporadic, symmetrical, and systemic characteristics consistent with Norrie disease. Conclusions: The results showed that the clinical characteristics of FEVR of patients with variants in the Norrin/ß-catenin genes are different from those with other etiologies. We recommend that clinicians who diagnose a child with FEVR perform genetic testing so that the parents can be informed on the prognosis of the vision and general health in the child. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome.

Congenital acorea is a rare disease with the absence of a pupil in the eye. To date, only one family and two isolated cases with congenital acorea have been reported. The gene associated with acorea has not been identified. In this study, we recruited a Chinese family acorea-microphthalmia-cataract syndrome. By analyzing the whole-exome sequencing (WES) data of this Chinese family, we revealed the association of a novel heterozygous variant, NM_005267.5:c.137G>A (p.G46E) in the gap junction protein alpha 8 (GJA8) gene encoding connexin 50 or CX50, with familial acorea-microphthalmia-cataract syndrome. Additionally, another variant, NM_005267.5:c.151G>A (p.D51N) in GJA8, was identified to co-segregate with this syndrome in an unrelated Japanese family. Ectopic expression of p.G46E and p.D51N mutant GJA8 genes in cultured cells caused protein mislocalization, suggesting that the p.G46E and p.D51N mutations in GJA8 impaired the function of the gap junction channels. These results established GJA8 as the first gene associated with familial acorea-microphthalmia-cataract syndrome.

An ultralow-cost portable centrifuge from discarded materials for medical applications.

Reliable centrifugation for medical applications has historically required access to expensive, bulky, and electricity-dependent commercial devices, which are generally unavailable in resource-poor settings. Although several portable, low-cost, non-electric centrifuges have been described, these solutions have predominately been designed for diagnostic applications requiring sedimentation of relatively small volumes. Moreover, construction of these devices frequently requires access to specialized materials and tools that are often unavailable in underserved areas. Herein, we describe the design, assembly, and experimental validation of the CentREUSE-an ultralow-cost, portable, discarded material-based, human-powered centrifuge for use in therapeutic applications. The CentREUSE demonstrated a mean centrifugal force of 10.5 relative centrifugal force (RCF) ± 1.3. Sedimentation of 1.0 mL triamcinolone acetonide suspension for intravitreal use after 3 min of CentREUSE centrifugation was comparable to that achieved after 12 h of gravity-mediated sedimentation (0.41 mL ± 0.04 vs. 0.38 mL ± 0.03, p = 0.14). Sediment compactness after 5 min and 10 min of CentREUSE centrifugation was similar to that observed after centrifugation with a commercial device for 5 min at 10 RCF (0.31 mL ± 0.02 vs. 0.32 mL ± 0.03, p = 0.20) and 50 RCF (0.20 mL ± 0.02 vs. 0.19 mL ± 0.01, p = 0.15), respectively. Templates and instructions for construction of the CentREUSE are included as part of this open-source publication.

Retinal Features of Family Members With Familial Exudative Vitreoretinopathy Caused By Mutations in KIF11 Gene.

Purpose: To determine the clinical characteristics of patients and family members with familial exudative vitreoretinopathy (FEVR) caused by mutations in the KIF11 gene. Methods: Twenty-one patients from 10 FEVR families with mutations in the KIF11 gene were studied. The retinal and systemic features were examined. The genetic analyses performed included Sanger sequencing of the KIF11 gene, whole exome sequencing, as well as array comparative genomic hybridization (CGH) analysis and multiple ligation probe assay (MLPA). Results: Sequence analysis revealed seven different KIF11 mutations. Array CGH with MLPA revealed two different exon deletions. All probands had advanced FEVR with retinal detachments (RDs) and microcephaly with or without developmental disabilities. Patients with bilateral RDs were more frequently associated with developmental disabilities (P = 0.023). Multimodal imaging of the family members revealed that six of nine patients without RDs (66%) had varying degrees of chorioretinopathy. The retinal folds in FEVR patients were associated with severe retinal avascularization. However, funduscopic changes in the peripheral retina were unremarkable in family members without RDs. A score representing the peripheral vascular anomalies determined from the fluorescein angiograms was lower than that of control eyes of patients with mutations of the Wnt signaling genes (P = 0.0029). Conclusions: The probands with KIF11 mutations were associated with severe ocular and systemic pathologies, whereas affected family members showed highly variable clinical manifestations. Peripheral vascular anomalies can often be unremarkable in eyes without RDs. Translational Relevance: These findings highlight more diverse mechanisms that underlie the pathological changes in patients with FEVR.

Correlation between improvement in visual acuity and QOL after Ranibizumab treatment for age-related macular degeneration patients: QUATRO study.

BACKGROUND: To evaluate the correlation between visual acuity improvement and vision-related QOL after ranibizumab treatment in Japanese patients with AMD. METHODS: In this one-year prospective, interventional, open-label, multicenter study involving four sites, patients with neovascular AMD were enrolled and observed for 12 months. Treatment-naïve patients received 0.5 mg ranibizumab as needed after three initial monthly doses. The best corrected visual acuity (BCVA) and central macular thickness (CMT) were measured at every visit. Evaluations with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and patient satisfaction questionnaire were performed at baseline and 3 and 12 months after initial treatment. The primary endpoint was change in BCVA and QOL 3 months after ranibizumab treatment. QOL outcomes were also assessed in the better and poor BVCA subgroups. RESULTS: The study enrolled 100 patients. The mean logMAR BCVA after treatment improved significantly from 0.43 to 0.30 at 3 months (p< 0.0001), and 0.28 at 12 months (p< 0.0001). The mean NEI-VFQ-25 composite scores improved from 79.48 to 84.13 at 3 months (p< 0.0001), and 86.0 at 12 months (p< 0.0001). The 3 and 12-month changes in NEI-VFQ-25 score and BCVA showed significant correlation. In the poor baseline visual acuity group (decimal BCVA ≤0.5), there was a significant correlation between the changes in the NEI-VFQ-25 score and BCVA (p=0.02) but not in the better baseline visual acuity group (decimal BCVA > 0.6, p=0.1) at 3 months. There were no significant differences in the satisfaction questionnaire score from baseline to at 3 months (p=0.54) and 12 months (p=0.23). The average CMT improved significantly from 340 to 264 µm at 3 months (p< 0.0001) and to 268 µm at 12 months (p< 0.0001). CONCLUSIONS: Intravitreal ranibizumab treatment resulted in improvement in visual acuity, anatomical change, and visual function change in Japanese AMD patients. Significant improvement was seen in patient visual function, and this was correlated with changes in VA, except immediately after loading dose treatment in patients with higher baseline VA. The patients' satisfaction with the treatment remained unchanged during the study period. TRIAL REGISTRATION: This study is registered at UMIN Clinical Trials Registry ( UMIN000012013 ). Registered October 10, 2013, as prospective study.

ULTRA-WIDE FIELD FUNDUS AUTOFLUORESCENCE IMAGING OF EYES WITH STICKLER SYNDROME.

PURPOSE: To determine the characteristics of fundus autofluorescence (FAF) images and visual functions in eyes with Stickler syndrome using ultra-widefield FAF images. METHODS: Forty-six eyes of 26 patients with mutations in the COL2A1 gene underwent ultra-widefield FAF imaging. The eyes were categorized into three types; no signs of abnormal AF, predominantly hyperfluorescent AF (hyper-AF), and predominantly hypofluorescent AF (hypo-AF). Goldmann perimetry was performed on 34 eyes, and line-scan images of the abnormal AF lesions were obtained by swept-source optical coherence tomography in 4 eyes. RESULTS: Abnormal AF lesions were found in 37 eyes of 21 (80.7%) of the 26 patients. Hyper-AF was found in 15 eyes and hypo-AF was found in 22 eyes. The FAF changes corresponded with the funduscopically observed radial paravascular retinal degeneration. The average age at the examination was significantly younger in patients who had eyes with hyper-AF or no abnormal AF than in those with hypo-AF (12.8 vs. 28.4 years; P = 0.009). Abnormal AF-associated visual field defects were found in 5/10 (50%) eyes with hyper-AF and 17/18 (94%) eyes with hypo-AF. Hyper-AF changes tended to appear before retinal changes were detectable by fluorescein angiography. An absence of the ellipsoid zone and the outer nuclear layer and a thinning of the overall retinal thickness were found corresponding to the hypo-AF lesions in the swept source optical coherence tomography images. CONCLUSION: Abnormal FAF is characteristic of eyes with Stickler syndrome. Age-related alterations of the FAF was associated with visual field defects and disruption of the photoreceptors and retinal pigment epithelial cells.

Polyethylene Glycol-Based Synthetic Hydrogel Sealant for Filtration Bleb Leaks: An In Vivo and Histologic Study.

Purpose: To evaluate the efficacy of polyethylene glycol (PEG)-based synthetic sealant for closing bleb leaks after glaucoma filtration surgery. Methods: Tube shunt surgery that included implantation of a 22-gauge indwelling catheter and intraoperative mitomycin C was performed in the left eyes of 11 New Zealand white rabbits. Seven days postoperatively, all filtration blebs were perforated with an 18-gauge needle to create a bleb hole. In six rabbits, the holes were covered with the sealant and irradiated with blue-green light for 60 seconds; in the five control rabbits, the holes were untreated. For 3 weeks after the tube shunt surgery, the eyes were checked for bleb leaks, and the intraocular pressure (IOP) was measured in both eyes. Finally, the operated eyes were enucleated for histologic examination. Results: The bleb leaks stopped in the eyes in which sealant was used and persisted in the other eyes. The sealant preserved the bleb function; the IOPs in these eyes were significantly (P < 0.05) lower than the right eyes that did not undergo surgery. Hematoxylin and eosin staining showed that the holes were closed and covered with conjunctival epithelial cells in the eyes in which sealant was applied; the holes were open in the control eyes. Immunohistochemical staining showed that the bleb holes in which the sealant was applied had fewer inflammatory cells. Conclusions: The PEG sealant has the potential to seal bleb leaks effectively. Translational Relevance: Application of the PEG sealant can be used as adjunct therapy for bleb leaks in glaucoma surgery.

Detection of retinal microvascular changes in von Hippel-Lindau disease using optical coherence tomography angiography.

PURPOSE: Von Hippel-Lindau (VHL) disease is a hereditary disorder that can lead to ophthalmic manifestations, including retinal capillary hemangioma (RCH). The diagnosis of RCH is often guided by wide-field fluorescein angiography. In some cases, optical coherence tomography angiography (OCT-A) serves as a non-invasive alternative to FA. Herein, we used OCT-A to examine the macular microvasculature in patients with VHL disease. SUBJECTS: Subjects were selected from patients with a diagnosis of VHL. The control group included eyes without retinal diagnosis from patients with an episode of unilateral retinal detachment or trauma and age ≤ 50 years old. METHODS: Subjects were scanned on the Optovue RTVue-XR device to acquire 3mm x 3mm OCT-A images of the superficial (SCP) and deep capillary plexus (DCP). SCP and DCP vessel density (VD) were calculated after the images were binarized. Furthermore, for subjects with RCH, each OCT-A image was divided equally into four quadrants. SCP and DCP VD of quadrants with RCH were compared to those without RCH. T-tests were performed for statistical analysis. RESULTS: 67 eyes with a history of VHL disease were included as study subjects, while 16 eyes were included as controls. Significant increases in VD were found in patients with VHL disease for both the SCP (p = 0.0441) and DCP (p = 0.0344). When comparing quadrants with associated RCH development to those without, we found no significant difference in SCP VD (p = 0.160) or DCP VD (p = 0.484). CONCLUSIONS: OCT-A can detect changes in the retinal microvasculature in the macula of patients with VHL disease. OCT-A imaging may be an additional tool for screening and early detection of patients at risk of developing ocular complications of VHL disease. Future studies should explore subtle progression on OCT-A associated with the pathogenesis and development of RCH, particularly with larger scan patterns.

Electroretinograms of eyes with Stickler syndrome.

PURPOSE: To determine the characteristics of the full-field electroretinograms (ERGs) of eyes with Stickler syndrome. METHODS: Twenty-two eyes of 14 Japanese patients from nine families with Stickler syndrome were studied. All of the patients were found to have mutations in the COL2A1 gene and had undergone ERG recordings. The ERGs from one of the two eyes were compared to 11 eyes of 11 normal control subjects who were matched by age, sex, and refractive error. RESULTS: One patient had non-recordable ERGs under both scotopic and photopic conditions. For the remaining 13 patients, the amplitudes of the b-waves of the scotopic combined, rod, and cone responses were significantly smaller than those of the control subjects (P = 0.0001, P = 0.015, P = 0.0006, respectively). The implicit times of the b-wave of the scotopic combined and photopic responses were significantly prolonged (P = 0.0037 and P = 0.0126). The age was inversely and significantly correlated with the amplitudes of the scotopic combined a-wave (P = 0.0184) and b-wave (P = 0.0076) in 13 eyes. The amplitudes of the scotopic combined b-wave amplitudes were not significantly correlated with the refractive error. CONCLUSIONS: The reduced or absent full-field ERGs in eyes with Stickler syndrome indicate that the physiology of the entire retina was negatively altered. The greater reduction in the ERGs with increasing age suggests that the physiological alterations of the retina are progressive.

Foveal Hypoplasia in Patients with Stickler Syndrome.

PURPOSE: To determine the microstructure of the fovea in patients with Stickler syndrome using imaging by spectral-domain optical coherence tomography (SD OCT) and swept-source OCT. DESIGN: Retrospective case series study. PARTICIPANTS: A total of 39 eyes of 25 patients with genetically confirmed Stickler syndrome were studied. METHODS: All of the patients had mutations in the COL2A1 gene and were diagnosed with Stickler syndrome. Cross-sectional OCT images, OCT angiography (OCTA), and en face OCT images were assessed. The ratio of the foveal inner retinal layer (fIRL) thickness to the parafoveal inner retinal layer (pIRL) thickness, the ratio of the foveal outer retinal layer (fORL) thickness to the parafoveal outer retinal layer (pORL) thickness, and the size of the foveal avascular zone (FAZ) were determined. MAIN OUTCOME MEASURES: The degree of foveal hypoplasia and the best-corrected visual acuity in patients with Stickler syndrome. RESULTS: A persistence of the inner retinal layers in the fovea with an fIRL/pIRL ratio >0.2 was present in 32 of the 39 eyes (82%). Optical coherence tomography angiography showed that the FAZ was smaller, 0 to 0.19 mm2, than that of normal eyes, in 25 eyes of 17 patients who underwent OCTA. There was no significant correlation between the visual acuities and the fIRL/pIRL ratios. CONCLUSIONS: A mild foveal hypoplasia with a persistence of the IRL is characteristic of eyes with Stickler syndrome. The visual acuities were not correlated with the fIRL/pIRL ratios.

Novel mutations in the COL2A1 gene in Japanese patients with Stickler syndrome.

Stickler syndrome is an inherited connective tissue disorder that affects the eyes, cartilage and articular tissues. The phenotypes of Stickler syndrome include congenital high myopia, retinal detachment, premature joint degeneration, hearing impairment and craniofacial anomalies, such as cleft palate and midline facial hypoplasia. The disease is genetically heterogeneous, and the majority of the cases are caused by mutations in the COL2A1 gene. We examined 40 Japanese patients with Stickler syndrome from 23 families to determine whether they had mutations in the COL2A1 gene. This analysis was conducted by examining each patient's genomic DNA by Sanger sequencing. Five nonsense, 4 splicing and 8 deletion mutations in the COL2A1 gene were identified, accounting for 21 of the 23 families. Different mutations of the COL2A1 gene were associated with similar phenotypes but with different degrees of expressivity.

[Ocular disorders associated with occupations].

The ocular disorders associated with occupations include asthenopia caused by VDT work and eye disorders from eye injuries or exposure to organic solvents or ionizing radiation. The factors associated with the eye disorders can be divided into two groups: mechanical factors and non-mechanical factors. Furthermore, the latter factors can be divided into two subgroups: chemical factors and physical factors. It is said that we can prevent most accidents that cause occupation-related eye disorders if all workers wear suitable protective gear. However, the compliance with wearing protective gear is relatively low because of inattention or discomfort. The industrial specialists have to educate the workers about the proper use of the protective gear. Then, the safety and health promoters have to remind the workers to frequently check their field site for potential hazards.

The effects of a convex rear-view mirror on ocular accommodative responses.

Convex mirrors are universally used as rear-view mirrors in automobiles. However, the ocular accommodative responses during the use of these mirrors have not yet been examined. This study investigated the effects of a convex mirror on the ocular accommodative systems. Seven young adults with normal visual functions were ordered to binocularly watch an object in a convex or plane mirror. The accommodative responses were measured with an infrared optometer. The average of the accommodation of all subjects while viewing the object in the convex mirror were significantly nearer than in the plane mirror, although all subjects perceived the position of the object in the convex mirror as being farther away. Moreover, the fluctuations of accommodation were significantly larger for the convex mirror. The convex mirror caused the 'false recognition of distance', which induced the large accommodative fluctuations and blurred vision. Manufactures should consider the ocular accommodative responses as a new indicator for increasing automotive safety.

Reconstruction of a nonfunctional trabeculectomy bleb using an amniotic membrane-wrapped silicone sponge to treat refractory glaucoma.

BACKGROUND: This study was conducted to verify the usefulness of nonfunctional trabeculectomy bleb reconstruction using a silicone sponge wrapped with amniotic membrane. Its purpose was to allow aqueous humor to flow from the flap to the posterior orbital space. METHODS: Seven consecutive patients who had undergone two or more surgeries in one eye for refractory glaucoma followed by our operation were included in this study. Conjunctival adhesion to the sclera was detached with a limbus-based conjunctival incision, followed by reopening the former trabeculectomy flap. A 1.5 × 12 mm silicone sponge used for retinal detachment surgery was wrapped three to four times with amniotic membrane, placed longitudinally on the sclera, and fixed with 10-0 nylon sutures. The anterior end of the amniotic membrane was fixed underneath the scleral flap with sutures, and the conjunctival wound was closed. We periodically checked the intraocular pressure (IOP) and for complications. Follow-up periods ranged from 15 to 30 months (average 19.4 months). Surgical success was defined as a final IOP of ≤ 21 mmHg with or without additional treatment. We defined failure as an IOP of > 21 mmHg on the second of two consecutive visits after the first 4 weeks, or the need for additional glaucoma surgery. RESULTS: Surgery was successful in five of the seven eyes, although bleb needling was performed in two eyes and amniotic membrane patch covering for early aqueous leakage was needed in one eye. In four of the five successful eyes, IOP was well controlled for longer than the period between the previous and present surgeries. One of the unsuccessful eyes, with neovascular glaucoma, had high IOP with hyphema followed by phthisis of the eyeball. The other, with aqueous leakage via the conjunctival wound, required trabeculectomy in a different area. There were no other complications. CONCLUSIONS: Reconstruction of the nonfunctional trabeculectomy bleb using a silicone sponge wrapped with amniotic membrane can be a useful strategy for treating refractory glaucoma.

Potential preventive effects of a new visual intervention for accommodative insufficiency and asthenopia due to sustained near task.

BACKGROUND: The objective of this study was to experimentally investigate whether a new visual intervention with optical and binocular vergence demands prevents accommodative insufficiency and asthenopia after sustained periods of visual task. METHODS: Fourteen female students were given the intervention with optical and binocular vergence demands for 1.5 min immediately after 20 min of a sustained task on a three-dimensional display. Before and after the trial, their ocular functions were measured and their symptoms assessed. A new type of intervention was developed that can vary optical and binocular vergence demands. For control, the subjects rested with eyes closed for 1.5 min after the task instead of the intervention. RESULTS: In the control group, accommodative contraction time (from far to near) and accommodative relaxation time (from near to far) was delayed from 1.13 to 1.68 s and from 1.36 to 1.60 s, respectively, and the symptom of asthenopia increased after rest. In the intervention group, however, changes in those functions were smaller than those in the control group. CONCLUSIONS: These results suggest that the new intervention with optical and binocular vergence demands is effective for the treatment of accommodative insufficiency that follows sustained periods of visual task, and consequently, the symptom of asthenopia induced by accommodative insufficiency may decrease.

Direct inhibition of N-methyl-D-aspartate (NMDA)-receptor function by antiglaucomatous beta-antagonists.

In the present study, we investigated the direct effects of antiglaucoma drugs (timolol, betaxolol, pilocarpine, and latanoprost) on N-methyl-D-aspartate (NMDA)-receptor function using a Xenopus oocytes expression system and electrophysiological techniques. In oocytes expressing wild-type NMDA (NR1a/NR2A) receptors, timolol and betaxolol significantly inhibited glutamate-evoked currents, whereas less inhibition was obtained with pilocarpine, and latanoprost had few effects. Moreover, the effect of timolol and betaxolol was noncompetitive with respect to glutamate. Mutations that changed Asn616 of the NR1a subunit, a critical residue for Mg(2+) blocking of NMDA receptors, to Arg (N616R) or Gln (N616Q) almost eliminated the inhibitory effects of timolol and betaxolol, as well as the blocking effect of Mg(2+). Experiments were also carried out to examine the protective effects of timolol and betaxolol against death of oocytes expressing NMDA receptors. During incubation of oocytes, especially in Mg(2+)-free medium, cell death was induced by addition of glutamate because of the continuous activation of the NMDA receptors expressed. Timolol and betaxolol significantly improved oocyte viability when they were added during the incubation period. These results suggest that timolol and betaxolol may have an additional role that they directly inhibit NMDA-receptor function, possibly via N616 of the NR1a subunit.