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1.  Acute myopia and angle closure glaucoma from topiramate in a seven-year-old: a case report and review of the literature 
BMC Pediatrics  2014;14:96.
Background
A case is reported of acute bilateral myopia and angle closure glaucoma in a 7-year-old patient from topiramate toxicity. This is the second known reported case of topiramate induced acute angle closure glaucoma and third known reported case of topiramate induced acute myopia in a pediatric patient.
Case presentation
This case presents a 7-year-old who had recently begun topiramate therapy for seizures and headache. She developed painless blurred vision and acute bilateral myopia, which progressed to acute bilateral angle closure glaucoma. After a routine eye exam where myopia was diagnosed, the patient presented to the emergency room with symptoms of acute onset blurry vision, tearing, red eyes, swollen eyelids, and photophobia. The symptoms, myopia, and angle closure resolved with topical and oral intraocular pressure lowering medications, topical cyclopentolate, and discontinuation of topiramate.
Conclusion
Acute angle closure glaucoma is a well-known side effect of topiramate, but is rarely seen in children. It cautions providers to the potential ophthalmic side effects of commonly used medications in the pediatric population. It highlights the need to keep a broad differential in mind when encountering sudden onset blurry vision in the primary care clinic, the need for careful consideration of side effects when starting topiramate therapy in a child, and the need for parental counseling of side effects.
doi:10.1186/1471-2431-14-96
PMCID: PMC3991910  PMID: 24712825
Acute angle closure; Drug reaction; Glaucoma; Elevated intraocular pressure; Seizures; Acute myopia
2.  The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure 
Abstract
Microfibrils are macromolecular aggregates located in the extracellular matrix of both elastic and nonelastic tissues that have essential functions in formation of elastic fibers and control of signaling through the transforming growth factor beta (TGFβ) family of cytokines. Elevation of systemic TGFβ and chronic activation of TGFβ signal transduction are associated with diseases caused by mutations in microfibril-associated genes, including FBN1. A role for microfibrils in glaucoma is suggested by identification of risk alleles in LOXL1 for exfoliation glaucoma and mutations in LTBP2 for primary congenital glaucoma, both of which are microfibril-associated genes. Recent identification of a mutation in another microfibril-associated gene, ADAMTS10, in a dog model of primary open-angle glaucoma led us to form the microfibril hypothesis of glaucoma, which in general states that defective microfibrils may be an underlying cause of glaucoma. Microfibril defects could contribute to glaucoma through alterations in biomechanical properties of tissue and/or through effects on signaling through TGFβ, which is well established to be elevated in the aqueous humor of glaucoma patients. Recent work has shown that diseases caused by microfibril defects are associated with increased concentrations of TGFβ protein and chronic activation of TGFβ-mediated signal transduction. In analogy with other microfibril-related diseases, defective microfibrils could provide a mechanism for the elevation of TGFβ2 in glaucomatous aqueous humor. If glaucoma shares mechanisms with other diseases caused by defective microfibrils, such as Marfan syndrome, therapeutic interventions to inhibit chronic activation of TGFβ signaling used in those diseases may be applied to glaucoma.
doi:10.1089/jop.2013.0184
PMCID: PMC3991966  PMID: 24521159
3.  A de novo MYOC mutation detected in juvenile open angle glaucoma causes non-secretion of associated with reduced myocilin protein in aqueous humor 
MYOC mutations were originally identified in patients with juvenile open angle glaucoma (JOAG). Cell culture and mouse studies suggest that MYOC mutations cause glaucoma through a dominant-negative effect on myocilin protein secretion. We tested this hypothesis with patient samples in this study. Glaucoma and control patients underwent complete ocular examination. DNA samples from glaucoma patients, and unaffected relatives and controls were used for DNA sequencing of MYOC. Aqueous humor (AH) samples from glaucoma and control patients were obtained at the time of surgery. Myocilin protein in AH was detected by quantitative Western blot analysis. A de novo Val251Ala mutation of MYOC was found to segregate with disease in a family with autosomal dominant JOAG. Myocilin protein was detected in all control AH samples but not was nearly undetectable in AH samples from a patient heterozygous for the Val251Ala mutation. Our results using human patient samples are consistent with a dominant-negative effect of pathogenic MYOC mutations on myocilin secretion.
doi:10.1016/j.ejmg.2013.03.002
PMCID: PMC3672363  PMID: 23517641
aqueous humor; de novo mutation; glaucoma; myocilin
4.  Multiplex Cytokine Analysis Reveals Elevated Concentration of Interleukin-8 in Glaucomatous Aqueous Humor 
Immune responses are commonly accompanied by localized changes in cytokine expression. To investigate possible immune activation associated with glaucoma, concentrations of multiple cytokines in the aqueous humor of glaucoma patients were determined by microparticle-based immunoassays. An inflammatory cytokine, interleukin-8, was found to be elevated in glaucomatous aqueous humor, consistent with immune activation.
Purpose.
To test the hypothesis that immune activation occurs in glaucoma by comparing concentrations of multiple cytokines in aqueous humor (AH) from patients with primary open angle glaucoma (POAG) and from cataract patients without glaucoma as controls.
Methods.
Cytokine concentrations in AH obtained during surgery were measured using microparticle-based immunoassays. Localized expression of IL-8 protein was investigated by immunohistochemistry of human eyes.
Results.
Eight cytokines (IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12, IFN-γ, and TNF-α) were below the limits of detection, and two cytokines (IL-18 and IL-15) were detected at low levels or in only a few patients. Although IL-6 was detected in 26 of 30 control patients (median, 2.7 pg/mL) and in 23 of 29 POAG patients (median, 1.6 pg/mL), the difference was not statistically significant. IL-8 was detected in 28 of 30 control patients (median, 1.8 pg/mL) and in all 29 POAG patients (median, 4.9 pg/mL). The higher IL-8 concentration in the AH of POAG patients was statistically significant (P < 0.001). In pairs of eyes from patients with asymmetric glaucomatous optic nerve damage, IL-8 concentration was higher in the AH of the more severely affected eye (P < 0.05). Patients with severe visual field defects had higher IL-8 concentrations in the AH than did patients with mild visual field defects. IL-8 protein expression was found in human retina and optic nerve.
Conclusions.
Concentration of the inflammatory cytokine IL-8 is significantly elevated in the AH of POAG patients, supporting the hypothesis that immune activation occurs in glaucoma.
doi:10.1167/iovs.10-5216
PMCID: PMC3055764  PMID: 20592224
5.  Angiopoietin-like 7 Secretion Is Induced by Glaucoma Stimuli and Its Concentration Is Elevated in Glaucomatous Aqueous Humor 
Purpose
To investigate the possibility that Angiopoietin-like 7 (ANGPTL7) protein is involved in the pathogenesis of glaucoma.
Methods
Primary human trabecular meshwork (TM) cells and corneoscleral explants were stimulated with either dexamethasone (DEX) or transforming growth factor β (TGFβ), and ANGPTL7 protein secreted into culture medium was determined by Western blot analysis. The effect of stable overexpression of ANGPTL7 in transfected immortalized TM cell lines on collagen expression was investigated by immunocytochemistry. Localization of ANGPTL7 protein in human eyes was determined by immunohistochemistry. The concentration of ANGPTL7 protein in aqueous humor (AH) from patients with glaucoma and control patients was compared by Western blot analysis. The beagle model of primary open-angle glaucoma (POAG) was used to correlate ANGPTL7 protein levels in canine AH with disease progression.
Results
TGFβ and DEX stimulated secretion of ANGPTL7 protein by TM cells and corneoscleral explants. Overexpression of ANGPTL7 by immortalized TM cell lines increased expression of type I collagen. Expression of ANGPTL7 protein was located in the corneal stroma, near the limbus, and throughout the sclera, with lower expression in the TM. In the lamina cribrosa, ANGPTL7 expression was associated with the cribriform plates. The concentration of ANGPTL7 protein was elevated in AH from patients with glaucoma and increased as disease progressed in POAG beagle dogs.
Conclusions
Induction of ANGPTL7 secretion by glaucoma stimuli and increased concentration of ANGPTL7 in glaucomatous AH suggest that ANGPTL7 is overexpressed in glaucoma. Since overexpression of ANGPTL7 increases collagen expression, a potential disease mechanism, ANGPTL7 could have a pathogenic role in glaucoma, and may serve as a potential therapeutic target.
doi:10.1167/iovs.07-1347
PMCID: PMC2814173  PMID: 18421092
6.  Prospective Retinal and Optic Nerve Vitrectomy Evaluation (PROVE) study: findings at 3 months 
Background
The purpose of this paper is to report the 3-month findings of the Prospective Retinal and Optic Nerve Vitrectomy Evaluation (PROVE) study.
Methods
Eighty eyes of 40 participants undergoing vitrectomy were enrolled. Participants underwent baseline evaluation of the study (surgical) and fellow (control) eye that included: intraocular pressure, central corneal thickness, gonioscopy, cup-to-disc ratio measurement, color fundus and optic disc photography, automated perimetry, and optical coherence tomography of the macula and optic nerve. Evaluation was repeated at 3 months. Main outcome measures were changes in macula and retinal nerve fiber layer (RNFL) thickness and intraocular pressure.
Results
All participants completed follow-up. Mean cup-to-disc ratio of study and fellow eyes at baseline was 0.43 ± 0.2 and 0.46 ± 0.2, respectively, and 13% of participants had undiagnosed narrow angles. There was no significant change in intraocular pressure, cup-to-disc ratio, or pattern standard deviation in study eyes compared with baseline or fellow eyes at 3 months. Vision improved in all study eyes at 3 months compared with baseline (P = 0.013), but remained significantly worse than fellow eyes (P < 0.001). Central subfield and temporal peripapillary RNFL thickness were significantly greater in eyes with epiretinal membrane (P < 0.05), and resolution after surgery correlated with visual improvement (P < 0.05).
Conclusion
The 3-month results do not indicate any increased risk for open-angle glaucoma but suggest that a relatively high percentage of eyes may be at risk of angle closure glaucoma. Temporal RNFL thickness and central subfield were increased in eyes with epiretinal membrane, and resolution correlated with degree of visual recovery.
doi:10.2147/OPTH.S49375
PMCID: PMC3770890  PMID: 24039396
vitrectomy; open-angle glaucoma; intraocular pressure; epiretinal membrane; macular hole
7.  Screening ADAMTS10 in Dog Populations Supports Gly661Arg as the Glaucoma-Causing Variant in Beagles 
Purpose.
Previously, we mapped the disease locus in the beagle model of autosomal recessive primary open angle glaucoma (POAG) to a 4-Mb interval on chromosome 20, and identified a Gly661Arg variant in ADAMTS10 as the candidate disease-causing variant. The purpose of this study was to test the hypothesis that the Gly661Arg variant of ADAMTS10 causes glaucoma by genotyping dogs of various breeds affected and unaffected by primary glaucoma.
Methods.
Dogs of various breeds, affected or unaffected with primary glaucoma, were genotyped for the Gly661Arg variant of ADAMTS10, as well as 7 other nonsynonymous single nucleotide polymorphisms (SNPs) in other genes in the beagle POAG locus that segregate with disease. Alternate allele frequencies were calculated with 95% confidence intervals and comparisons made to expected allele frequency relative to disease prevalence or between cases and controls.
Results.
For the nonsynonymous SNPs other than the ADAMTS10 variant, control dogs were identified that were homozygous for the alternative alleles, ruling out those variants as causative. None of the nonsynonymous SNPs were found associated with primary glaucoma in American cocker spaniels. The Gly661Arg variant of ADAMTS10 was the only variant with minor allele frequency consistent with the prevalence of primary glaucoma in the general beagle population. The only dog found homozygous for the Gly661Arg variant of ADAMTS10 was an affected beagle, unrelated to the POAG colony.
Conclusions.
These findings support the Gly661Arg mutation of ADAMTS10 as the likely cause of POAG in beagles.
Genotyping dogs of various breeds affected or unaffected by primary glaucoma support the Gly661Arg variant of ADAMTS10 as causative for primary open angle glaucoma in beagles.
doi:10.1167/iovs.12-10796
PMCID: PMC3604907  PMID: 23422823
8.  Worsening angle closure glaucoma and choroidal detachments subsequent to closure of a carotid cavernous fistula 
BMC Ophthalmology  2012;12:28.
Background
Carotid cavernous fistulas are abnormal communications between the cavernous sinus and the external or internal carotid arteries. Although rare, closure of carotid cavernous fistulas can lead to immediate ocular complications. To our knowledge, our case represents the first report of worsening angle closure glaucoma and choroidal detachments over an extended period of two months subsequent to closure of a carotid cavernous fistula.
Case presentation
A 70-year-old female with a history of primary angle closure glaucoma presented with 4 mm of proptosis, resistance to retropulsion, tortuous corkscrew blood vessels and an orbital bruit of the right eye. Diagnostic cerebral angiogram showed a small indirect Barrow type D right carotid cavernous fistula. Transarterial embolization was planned but repeat cerebral angiography prior to the procedure demonstrated spontaneous partial closure of the carotid cavernous fistula and the procedure was aborted. One month later, our patient was noted to have worsening vision and choroidal detachments of the right eye. She declined further testing and was thus started on self-administered manual carotid jugular compressions. One month later, she developed progressive worsening of her choroidal detachments and angle closure. She eventually opted for surgical intervention but repeat cerebral angiography showed significant thrombosis of the carotid cavernous fistula and no intervention was warranted. Examination two months later showed complete resolution of the choroidal detachments and open angles of both eyes.
Conclusions
Our patient demonstrated worsening angle closure glaucoma and choroidal detachments after spontaneous closure of her carotid cavernous fistula had been noted. Ocular complications, including acute angle closure, have been reported to occur immediately after closure of carotid cavernous fistulas, but not over months as in our patient. It is imperative that individuals who have undergone apparent closure of a carotid cavernous fistula be carefully monitored for worsening ocular complications.
doi:10.1186/1471-2415-12-28
PMCID: PMC3412712  PMID: 22839357
9.  Proteomics Reveal Cochlin Deposits Associated with Glaucomatous Trabecular Meshwork* S 
The Journal of biological chemistry  2004;280(7):6080-6084.
The etiology of primary open angle glaucoma, a leading cause of age-related blindness, remains poorly defined, although elevated intraocular pressure (IOP) contributes to the disease progression. To better understand the mechanisms causing elevated IOP from aqueous humor circulation, we pursued proteomic analyses of trabecular meshwork (TM) from glaucoma and age-matched control donors. These analyses demonstrated that Cochlin, a protein associated with deafness disorder DFNA9, is present in glaucomatous but absent in normal TM. Cochlin was also detected in TM from the glaucomatous DBA/2J mouse preceding elevated IOP but found to be absent in three other mouse lines that do not develop elevated IOP. Histochemical analyses revealed co-deposits of Cochlin and mucopolysaccharide in human TM around Schlemm’s canal, similar to that observed in the cochlea in DFNA9 deafness. Purified Cochlin was found to aggregate after sheer stress and to induce the aggregation of TM cells in vitro. Age-dependent in vivo increases in Cochlin were observed in glaucomatous TM, concomitant with a decrease in type II collagen, suggesting that Cochlin may disrupt the TM architecture and render components like collagen more susceptible to degradation and collapse. Overall, these observations suggest that Cochlin contributes to elevated IOP in primary open angle glaucoma through altered interactions within the TM extracellular matrix, resulting in cell aggregation, mucopolysaccharide deposition, and significant obstruction of the aqueous humor circulation.
doi:10.1074/jbc.M411233200
PMCID: PMC1483217  PMID: 15579465
10.  Mapping of the Disease Locus and Identification of ADAMTS10 As a Candidate Gene in a Canine Model of Primary Open Angle Glaucoma 
PLoS Genetics  2011;7(2):e1001306.
Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies.
Author Summary
Primary open angle glaucoma (POAG) is a leading cause of vision loss and blindness affecting tens of millions of people. Ocular hypertension is a strong risk factor for the disease and the only effective target of treatment. Ocular hypertension results from increased resistance to outflow of aqueous humor through the trabecular meshwork, a specialized filtration tissue consisting of alternating layers of cells and connective tissue, but the specific reasons for the increased resistance are not known. The animal model for human POAG used in this study was a colony of Beagle dogs that carry an inherited form of the disease in which ocular hypertension is the primary manifestation. We have found a variant in ADAMTS10 that belongs to a family of genes that contribute to formation of extracellular matrix and may itself be involved in formation of elastic microfiber structures. We found that the ADAMTS10 protein is expressed at particularly high levels in the trabecular meshwork. The candidate variant in ADAMTS10 found in the POAG–affected Beagles suggests that altered processing of connective tissue and/or elastic microfiber defects may be involved in raising eye pressure, offering specific biochemical targets for future research and treatment strategies.
doi:10.1371/journal.pgen.1001306
PMCID: PMC3040645  PMID: 21379321

Results 1-10 (10)