Aschard H, Kang JH, Iglesias AI, Hysi P, Cooke Bailey JN, Khawaja AP, Allingham RR, Ashley-Koch A, Lee RK, Moroi SE, Brilliant MH, Wollstein G, Schuman JS, Fingert JH, Budenz DL, Realini T, Gaasterland T, Scott WK, Singh K, Sit AJ, Igo RP, Song YE, Hark L, Ritch R, Rhee DJ, Gulati V, Haven S, Vollrath D, Zack DJ, Medeiros F, Weinreb RN, Cheng C-Y, Chasman DI, Christen WG, Pericak-Vance MA, Liu Y, Kraft P, Richards JE, Rosner BA, Hauser MA, Hauser MA, Klaver CCW, van Duijn CM, Haines J, Wiggs JL, Pasquale LR. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis. Eur J Hum Genet 2017;25(11):1261-1267.Abstract
Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.
Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.
The purpose of this study was to describe a possible causal relationship between ocular cicatricial pemphigoid (OCP) and ocular surface squamous neoplasia. Two middle-aged female patients with already diagnosed OCP were studied in regard to the subsequent onset of conjunctival squamous neoplasia. Their clinical histories, ocular examinations, clinical photographs, and results of biopsies and any ancillary immunofluorescent laboratory evaluation studies were carefully reviewed. One patient had a preinvasive squamous dysplasia and the other an invasive squamous cell carcinoma, both in the unequivocal setting of OCP with bilateral conjunctivitis, symblephara, and forniceal foreshortening. The patients had been receiving intensive immunotherapy consisting of some combination of corticosteroids, rituximab, and interferon alpha. Both patients had a positive immunofluorescent study demonstrating immunoreactants at the level of the epithelial basement membrane. Each patient had 2 earlier negative immunofluorescent studies before a third was positive. While rare, there is 1 previous report of an association between OCP and conjunctival squamous neoplasia. The current report provides more data supporting the proposal that this conjunction is more than a random event. Repeat immunofluorescent studies after an initial negative result in a patient with strong clinical signs of OCP are imperative due to the frequency of false negative studies in the context of clinically persuasive disease.
PURPOSE OF REVIEW: Recent advances in experimental studies of optic nerve regeneration to better understand the pathophysiology of axon regrowth and provide insights into the future treatment of numerous optic neuropathies. RECENT FINDINGS: The optic nerve is part of the central nervous system and cannot regenerate if injured. There are several steps that regenerating axons of retinal ganglion cells (RGCs) must take following optic nerve injury that include: maximizing the intrinsic growth capacity of RGCs, overcoming the extrinsic growth-inhibitory environment of the optic nerve, and optimizing the reinnervation of regenerated axons to their targets in the brain. Recently, some degree of experimental optic nerve regeneration has been achieved by factors associated with inducing intraocular inflammation, providing exogenous neurotrophic factors, reactivating intrinsic growth capacity of mature RGCs, or by modifying the extrinsic growth-inhibitory environment of the optic nerve. In some experiments, regenerating axons have been shown to reinnervate their central targets in the brain. SUMMARY: Further approaches to the combination of aforementioned treatments will be necessary to develop future therapeutic strategy to promote ultimate regeneration of the optic nerve and functional vision recovery after optic nerve injury.
PURPOSE: To assess the sensitivity of corneal cold receptors to a known transient receptor potential melastatin 8 (TRPM8) agonist, menthol, in dry eye and normals, and to determine whether factors such as disease duration or age affect responses. METHODS: Dry eye disease (DED) (N = 33) and normal (N = 15) subjects were randomly assigned to receive Rohto® Hydra (0.01% menthol) or Systane® Ultra treatments (OU) in a prospective, double-blind, crossover study. DED subjects had documented disease and symptom response scores >2 on a 0- to 5-point scale. Normals had no history of DED and scores <2 on the same scale. Endpoints included mean cooling score (0 = not cool and 10 = very cool) evaluated at 0, 0.5, 1, 2, 3, and 4 min post-instillation, sum cooling scores (5 time points, range 0-60), and ocular signs and symptoms. RESULTS: Mean (±SD) ages were similar, 62.2 ± 8.6-year (DED) versus 53.5 ± 7.6-year (normal). Corneal sensitivity scores were not different between groups. Mean cooling scores at 0.5-4 min post-menthol instillation were significantly higher in DED subjects (P ≤ 0.03). Sum cooling scores were significantly higher (P = 0.04) in DED subjects with a disease duration <10 years (N = 18, 28.3 ± 2.58) versus ≥10 years (N = 15, 20.2 ± 2.76). Age did not affect cooling response in either group. CONCLUSION: DED subjects had greater sensitivity to cold than normal subjects. DED duration, and not age, was critical to cooling sensitivity. The finding that cooling scores were higher in subjects with DED for less than 10 years compared to more than 10 years suggests that corneal cold receptor sensitivity decreases as the duration of DED increases.
PURPOSE: V-pattern strabismus observed with syndromic craniosynostosis has been attributed to disparate causes. We compared severity of V pattern with degree of excyclorotation of rectus muscles to appraise significance of this proposed aetiology. METHODS: 43 patients with Apert, Crouzon or Pfeiffer syndrome referred to Boston Children's Hospital Department of Ophthalmology were identified. 28 met inclusion criteria for retrospective cohort study, specifically: (1) sensorimotor measurements in minimum of seven cardinal gazes, (2) quantified fundus torsion and (3) orbital CT imaging sufficient to measure rectus muscle cyclorotation in coronal and quasicoronal planes, posteriorly (near orbital apex) and anteriorly (near pulleys). Patients were placed in one of four V-pattern severity groups. The most severe group demonstrated inability to elevate abducted eye above midline with characteristic 'seesaw' misalignment during horizontal saccades. Rectus muscle cyclorotation was measured by paediatric neuroradiologist blinded to group placement. Primary outcome was correlation of severity of V pattern with degree of excyclorotation. Secondary outcome was correlation of severity with craniosynostosis syndrome. RESULTS: Increasing severity of V pattern correlated with greater excyclorotation in anterior coronal (p=0.009), anterior quasicoronal (p=0.021), posterior coronal (p=0.014) and posterior quasicoronal (p=0.040) planes for moderate-to-severe V pattern. Even greater excyclorotation was associated with seesaw V pattern in anterior quasicoronal (p=0.004) and posterior quasicoronal (p=0.001) views. Highly significant association was found between Apert syndrome and severity of V pattern (p=0.004). CONCLUSIONS: Severity of V pattern is associated with magnitude of excyclorotation. More severe V pattern and seesaw strabismus noted with Apert syndrome may relate to distinctive orbital morphology.
OBJECTIVE: Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5'-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5'-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5'-phosphate oxidase deficiency. METHODS: A series of six patients with homozygous mutations of PNPO, the gene coding pyridox(am)ine 5'-phosphate oxidase, were evaluated in our center over the course of two years for phenotyping of neurological and systemic manifestations. RESULTS: Five of six were born prematurely, three had anemia and failure to thrive, and two had elevated alkaline phosphatase. A movement disorder was observed in two children, and a reversible retinopathy was observed in the most severely affected infant. All patients had neonatal-onset epilepsy and were on a continuum of developmental delay to profound encephalopathy. Electroencephalographic features included background slowing and disorganization, absent sleep features, and multifocal and generalized epileptiform discharges. All the affected probands carried a homozygous PNPO mutation (c.674 G>T, c.686 G>A and c.352G>A). CONCLUSION: In addition to the well-described epileptic encephalopathy, pyridox(am)ine 5'-phosphate oxidase deficiency causes a range of neurological and systemic manifestations. A movement disorder, developmental delay, and encephalopathy, as well as retinopathy, anemia, and failure to thrive add to the broadening clinical spectrum of P5P dependent epilepsy.
PURPOSE: To investigate choroidal involvement in acute posterior multifocal placoid pigment epitheliopathy (APMPPE). METHODS: A retrospective observational case series using multimodal imaging including optical coherence tomography (OCT) angiography. RESULTS: Five patients with APMPPE were included. In most acute lesions, OCT angiography revealed outer retinal and retinal pigment epithelium (RPE) hyperreflective lesions with attenuated OCT signal in the underlying choroid, but careful examination allowed us to identify a single lesion with decreased choriocapillaris flow outside the signal attenuation. Optical coherence tomography angiography obtained after healing of lesions revealed areas of hypointense circular flow voids clustered in groups surrounded by either isointense or hyperintense signal background. Point-by-point evaluation revealed these flow voids did not correspond to areas of RPE thickening or focal pigmentary changes. Larger hypointense lesions were observed and did correlate with pigmentary changes. CONCLUSION: Our case series demonstrates choriocapillaris flow abnormalities in acute APMPPE extending beyond the OCT lesions, and distinct residual vascular abnormalities in healed APMPPE lesions on OCT angiography. Our findings support a primary ischemic insult to the photoreceptors and RPE, but choriocapillaris flow abnormalities could be secondary to (OCT invisible) retinal and RPE involvement. The lack of understanding of the etiology along with the inability to visualize most of the choroid in acute lesions precludes definite conclusions about the true pathogenesis of APMPPE.
PURPOSE: The qualities that applicants value in the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) fellowship programs have been studied, but the availability of this information on program websites has not yet been reviewed. The authors evaluated the availability of resident-valued ASOPRS fellowship program information on the Internet. METHODS: The authors performed an Internet search of the 53 ASOPRS fellowship program websites and evaluated websites for 20 characteristics of interest to ASOPRS fellowship applicants such as teaching faculty, program description, rotation schedule, operative cases, and interview information. RESULTS: Of the 53 ASOPRS fellowship programs, 43 (81.1%) had a fellowship program-dedicated website. The fellowship websites contained a mean 7.6 characteristics (38.1%, range 0-15). Faculty listing, program description, and case diversity were the most commonly included data (74.4%, 72.1%, and 69.8%, respectively). Fellow selection process, interview information, and graduate job placement were least commonly included (7.0%, 2.3%, and 0.0%, respectively). There was no significant difference in website inclusiveness based on fellowship region or faculty number. Programs affiliated with an ophthalmology residency were more complete than those that were not (40.3% vs. 20.0%, p = 0.0098). CONCLUSIONS: This review found that most programs had websites and contained a reasonable number of characteristics. However, applicant-valued information regarding surgical volume, procedure variety, application information, and postgraduate employment history were often missing. American Society of Ophthalmic Plastic and Reconstructive Surgery fellowship programs may improve match outcomes by providing and enhancing program websites with details that their applicants seek.
PURPOSE: Advances in surgical techniques allow implantation of intraocular lenses (IOL) with cataract extraction, even in young children. However, there are several challenges unique to the pediatric population that result in greater degrees of postoperative refractive error compared to adults. METHODS: Literature review of the techniques and outcomes of pediatric cataract surgery with IOL implantation. RESULTS: Pediatric cataract surgery is associated with several sources of postoperative refractive error. These include planned refractive error based on age or fellow eye status, loss of accommodation, and unexpected refractive errors due to inaccuracies in biometry technique, use of IOL power formulas based on adult normative values, and late refractive changes due to unpredictable eye growth. CONCLUSIONS: Several factors can preclude the achievement of optimal refractive status following pediatric cataract extraction with IOL implantation. There is a need for new technology to reduce postoperative refractive surprises and address refractive adjustment in a growing eye.
A 66-year-old man developed a painless 2 mm to 3 mm recurrent nodule at the left upper eyelid margin. Excision disclosed a spindle cell lesion without frank atypia or mitotic activity growing in a twisted fascicular pattern often referred to as storiform. All the surgical margins were involved with tumor. Immunohistochemistry demonstrated that many of the constituent spindle and dendritic tumor cells were CD34, factor XIIIa, and CD 163, the latter 2 being biomarkers for monocytic lineage. The lesion was diagnosed as a dermatofibroma rather than a fibrous histiocytoma, a term that should be reserved for more aggressive lesions of deeper fascial planes. Facial dermatofibromas are rarer and more likely than those of the extremities to recur and therefore deserve wider local excision at first surgery with careful and frequent clinical follow ups. Eyelid dermatofibroma has probably often been misdiagnosed as another tumor in the past. Immunohistochemistry can supply valuable biomarker criteria for diagnosis.
Most bony and cartilaginous lesions of the orbit and periorbital compartments are benign, grow endophytically, and are composed of dense lamellar bone (eburnated or ivory osteomas). An 87-year-old woman had a well-circumscribed, firm, round, and exophytic lesion of the brow region for at least 15 years. Excisional surgery disclosed an osteocartilaginous lesion with an enveloping pseudocapsule (periosteum/perichondrium) and a narrow stalk connecting it to the frontal bone. The periphery of the lesion displayed lamellar bone which appeared to be replacing a central cartilaginous zone. The adjacent deep preaponeurotic fat displayed nodules of collagen with myxoid change and occasional CD34 spindle cells suggestive of a spindle cell lipoma. Because of the osteochondroma's deep location in the preaponeurotic fat, the lesion differs from an osteoma cutis found in the dermis which fails to exhibit a cartilaginous component or a periosteum. Other clinically simulating lesions are described.
PURPOSE OF REVIEW: Congenital anomalies of the optic nerve are rare but significant causes of visual dysfunction in children and adults. Accurate diagnosis is dependent on a thorough funduscopic examination, but can be enhanced by imaging information garnered from optical coherence tomography (OCT). We review common congenital optic nerve anomalies, including optic disc pit, optic nerve coloboma, morning glory disc anomaly, and hypoplasia of the optic nerve, review their systemic associations, and discuss insights from OCT imaging. RECENT FINDINGS: Optic disc pits are a result of a defect in the lamina cribrosa and abnormal vitreomacular adhesions have been shown to cause maculopathy. In patients with optic nerve colobomas, OCT can be instrumental in diagnosing choroidal neovascularization, a rare but visually devastating complication. The pathogenesis of morning glory disc anomaly has been more clearly elucidated by OCT as occurring from a secondary postnatal mesenchymal abnormality rather than only the initial neuroectodermal dysgenesis of the terminal optic stalk in isolation. OCT studies of optic nerve hypoplasia have demonstrated significant thinning of the inner and outer retinal layers of the perifoveal region and thicker layers in the fovea itself, resulting in a foveal hypoplasia-like pathology, that is, significantly correlated to poorer visual outcomes. SUMMARY: OCT provides detailed in-vivo analysis of these anatomic anomalies and their resulting pathologies, shedding new insights on the pathogenesis, diagnosis, and potential visual outcomes of these conditions in children. Further study employing OCT to elucidate structure-function relationships of congenital optic nerve anomalies will help expand the role of OCT in clinical practice related to diagnosis, prognosis, and management of these entities.
Primary orbital natural killer T-cell lymphoma (NKTCL) is a rare condition with only a few published cases in the literature. Over 1 month, an 81-year-old man developed progressive left periocular inflammation unresponsive to treatment. Clinical examination and imaging studies demonstrated a left lacrimal gland enlargement. Bilateral anterior uveitis and erythematous nontender cutaneous lesions were also found. Biopsies of the skin and lacrimal gland on the back revealed histopathologic and immunohistochemical findings confirming Epstein-Barr virus-positive NKTCL. Metastatic work up disclosed multifocal involvement in the pancreas, stomach, and chest wall. Palliative treatment consisting of nonanthracycline-based chemotherapy and radiation was instituted, but the patient died 5 months after the onset of symptoms. This is the first example of acute dacryoadenitis, and the second of bilateral anterior uveitis, in the setting of NKTCL. Absence of naso-sinus involvement in the current case is rare in NKTCL. Despite treatment, the prognosis remains dismal. Orbital specialists should include NKTCL in the differential diagnosis of lacrimal gland/orbital masses and perform an incisional biopsy if the clinical scenario so dictates.
Learning to read causes the development of a letter- and word-selective region known as the visual word form area (VWFA) within the human ventral visual object stream. Why does a reading-selective region develop at this anatomical location? According to one hypothesis, the VWFA develops at the nexus of visual inputs from retinotopic cortices and linguistic input from the frontotemporal language network because reading involves extracting linguistic information from visual symbols. Surprisingly, the anatomical location of the VWFA is also active when blind individuals read Braille by touch, suggesting that vision is not required for the development of the VWFA. In this study, we tested the alternative prediction that VWFA development is in fact influenced by visual experience. We predicted that in the absence of vision, the "VWFA" is incorporated into the frontotemporal language network and participates in high-level language processing. Congenitally blind (n = 10, 9 female, 1 male) and sighted control (n = 15, 9 female, 6 male), male and female participants each took part in two functional magnetic resonance imaging experiments: (1) word reading (Braille for blind and print for sighted participants), and (2) listening to spoken sentences of different grammatical complexity (both groups). We find that in blind, but not sighted participants, the anatomical location of the VWFA responds both to written words and to the grammatical complexity of spoken sentences. This suggests that in blindness, this region takes on high-level linguistic functions, becoming less selective for reading. More generally, the current findings suggest that experience during development has a major effect on functional specialization in the human cortex.SIGNIFICANCE STATEMENT The visual word form area (VWFA) is a region in the human cortex that becomes specialized for the recognition of written letters and words. Why does this particular brain region become specialized for reading? We tested the hypothesis that the VWFA develops within the ventral visual stream because reading involves extracting linguistic information from visual symbols. Consistent with this hypothesis, we find that in congenitally blind Braille readers, but not sighted readers of print, the VWFA region is active during grammatical processing of spoken sentences. These results suggest that visual experience contributes to VWFA specialization, and that different neural implementations of reading are possible.
PURPOSE: To review the most current treatment recommendations and outcomes for delayed suprachoroidal hemorrhages. METHODS: Article review of management and outcomes of suprachoroidal hemorrhages, with emphasis on delayed suprachoroidal hemorrhages in the setting of glaucoma surgery. CONCLUSION: Time of drainage of suprachoroidal hemorrhages remains controversial. Earlier drainage should be considered with high intraocular pressure, expulsion of intraocular content, or retinal detachment. In clinically stable eyes with suprachoroidal hemorrhage, recommendations range from observation to immediate drainage. Clot lysis occurs at roughly 14 days.
PURPOSE: To compare structural features in prelaminar and laminar tissues of the optic nerve head (ONH) in chronic angle closure glaucoma (CACG), primary open angle glaucoma (POAG), and control subjects. MATERIALS AND METHODS: ONH imaging was performed using swept-source optical coherence tomography (SS-OCT) for measurements of minimum rim width at Bruch's membrane opening (BMO-MRW), horizontal, and vertical lamina cribrosa depth (LCD). Prelaminar defects, categorized as hole and wedge, and lamina cribrosa (LC) defects were identified. Enhanced depth imaging spectral domain OCT (EDI-OCT) customized to perform high-resolution volume scans was used in conjunction to further characterize prelaminar holes. One eye per subject was analyzed. RESULTS: Eighty subjects (20 CACG, 40 POAG, and 20 controls) were included in the study. CACG and POAG groups had similar mean deviation on Humphrey visual field testing (-6.9 ± 5.1 vs. -6.3 ± 6.0 dB, p > 0.05) and IOP on the day of imaging (14.0 ± 3.1 vs. 13.8 ± 2.7 mmHg, p > 0.05). Thinnest and global BMO-MRW in CACG (120.3 ± 44.8, 225.5 ± 53.9 μm) and POAG (109.7 ± 56.3, 213.8 ± 59.7 μm) groups were lower than controls (200.1 ± 40.8, 308.3 ± 70.8 μm; p < 0.001 for both). Prelaminar holes were most frequent in CACG (65.0%) than POAG (25.0%, p=0.008) or control groups (20.0%, p=0.01). After adjusting for demographic and ophthalmic covariates, CACG was associated with increased odds of having prelaminar holes compared to POAG (odds ratio, 9.79; 95% CI, 2.12-45.19; p=0.003). Hole volume was similar between CACG and POAG (p > 0.05), but the CACG group had more holes per scan than POAG (maximum 2.5 ± 1.9 vs. 1.2 ± 0.4, p=0.02). Prelaminar wedge defects were less common in the CACG than the POAG group (5.0% vs. 37.5%, p=0.02). The CACG group did not differ from controls in laminar characteristics, such as LCD and LC defects. CONCLUSIONS: SS-OCT evaluation of the ONH revealed more frequent prelaminar holes in CACG compared to POAG and control patients.