Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma

PURPOSE: To examine families ascertained for late-onset primary open-angle glaucoma (POAG) to determine mutations in the gene coding for myocilin. METHODS: The diagnosis of late-onset POAG was defined as age at diagnosis more than 35 years, intraocular pressure (IOP) 22 mm Hg or more in both eyes or 19 mm Hg or more while the patient was taking two glaucoma medications, glaucomatous optic neuropathy in both eyes, and visual field loss consistent with optic nerve damage in at least one eye of the proband. Two of three criteria were required in other family members. DNA from all families was screened for polymorphisms in myocilin using single-strand conformation polymorphism analysis. All polymorphisms were sequenced for mutations. RESULTS: Eighty-three affected people in 29 families with late-onset POAG were screened for mutations. Three mutations, two novel missense (Thr377Met and Glu352Lys) and one nonsense (Gln368STOP), were identified. The missense mutations did not segregate with the disease phenotype in these families. The nonsense mutation was found in 3 of 29 unrelated families with POAG. All affected family members and 8 of 12 in whom glaucoma was suspected had the Gln368STOP mutation. All people with this mutation had elevated IOP, and 78% had POAG by age 70. CONCLUSIONS: Three mutations were identified in the gene coding for myocilin in families with late-onset POAG. Of these, the Gln368STOP mutation was highly associated with the development of glaucoma. All people with this mutation had glaucoma or elevated IOP by age 70. In the United States, the Gln368STOP mutation in myocilin is strongly associated with the development of late-onset POAG. However, factors in addition to the presence of this mutation seem to play a role in the development of ocular hypertension and glaucoma in these families.     

Family history in primary open-angle glaucoma

A family history of glaucoma was found in 50% of patients with primary open-angle glaucoma (POAG) and 43% of patients with ocular hypertension (OH). Positive family history was twice as prevalent in those with OH and either HLA-B7 or B12 antigens than in OH with neither antigen (P less than .01). Although POAG occurred equally in men and women, the prevalence of a positive family history of glaucoma on the maternal side of the family in POAG patients was six to seven times greater than on the paternal side (P less than .0005). However, in patients with OH, but no glaucomatous field loss, there was no difference in prevalence of maternal and paternal family history. Even in OH with HLA-B7 or B12 antigens, there was no predominance of maternal family history. The implication that offspring were more likely to develop POAG when their mother's side of the family rather than their father's side had the disease has provided an additional potentially useful risk factor in patients with OH. In addition, it has raised interesting questions as to possible maternal cytoplasmic factors in the transmission and pathogenesis of POAG.     

Spectrum of trabecular pigmentation in open-angle glaucoma: a clinicopathologic study

In eight patients with chronic open-angle glaucoma and associated trabecular pigmentation, trabeculectomy and peripheral iridectomy specimens were studied by light and electron microscopy. Clinically, three patients displayed signs of classic pigmentary glaucoma (Group 1). In the other cases chronic open-angle glaucoma was associated with varying degrees of expression of the full pigmentary glaucoma syndrome (Group 2). Histopathologic examination of peripheral iridectomy and trabeculectomy specimens from Group 1 showed: (1) marked focal atrophy and hypopigmentation of iris pigmented epithelium with an apparent delay in melanogenesis. The dilator muscle was thickened except for occasional thinned areas. (2) The trabeculectomy specimens revealed excessive amounts of pigmented epithelial melanosomes and moderate accumulation of electron-dense basement membrane-like material in the juxtacanalicular meshwork. Similar specimens from Group 2 showed: (1) minimal hypopigmentation of the iris pigmented epithelium with normal melanogenesis. The iris stroma and dilator muscle were normal. (2) Trabeculectomy specimens displayed excessive electron-dense basement membrane-like material in the juxtacanalicular meshwork and minimal to moderate accumulation of melanosomes.     

HLA antigens and primary open-angle glaucoma in black Americans

Black patients with primary open-angle glaucoma, when compared to nonglaucomatous individuals, demonstrate significantly increased prevalences of the HLA antigens B7 and B12 and significantly decreased frequencies of A1 and A11. White patients with primary open-angle glaucoma have in common with blacks the increases in B7 and B12 and the decrease in A11, but present no deficit of A1. In addition, white patients with primary open-angle glaucoma demonstrate a significant increase of A3 and a decrease of Bw35, both of which are not found in blacks.     

Immunohemostatic mechanisms in the development of primary open-angle glaucoma

The charts of 247 allergic patients (all ages) who were receiving immunotherapy were studied retrospectively. They belong to a private setting at the city of Santa Ana Chiautempan, Tlax (Mexico). We looked at whether they were compliant or noncompliance. Compliance was considered as those who did not stop immunotherapy during a 18-month period, and shorter periods s noncompliance. One hundred and fifty two (62%) were compliant and 95 (38%) were not. Noncompliance causes were: 29 patients felt better soon, 19 claimed high costs, 8 changed to alternative medicine. 6 felt worse because of immunotherapy, 6 moved to other cities, 2 preferred other allergists and 25 did not answer the questionnaire. Forty six per cent stopped during the first 2 to 6 months and 56% within 8 and 14 with a median of 5.4. Eighty per cent from those who were compliant claimed they felt much better and 18% only slightly better. The average length-compliance was 29.7 months.     

Prevalence of primary chronic open-angle glaucoma in Ivory Coast

BACKGROUND: The aim of this study was to determine and analyze the rate of chronic open-angle glaucoma in C?te d'Ivoire. METHODS: The prevalence of chronic glaucoma (POAG) was retrospectively evaluated in a population of 33,000 patients attending a private clinic including 24,751 black subjects and 8,249 white subjects. Patients with a cup/disc superior to 0.5 and an abnormal Goldmann's kinetic perimetry, associated with (POAG with "elevated" pressure or not (POAG with normal pressure) with an intraocular hypertension (intra ocular pressure superior to 21 mmHg) were distinguished. RESULTS: Prevalence was from 2.1% for the black subjects and 0.75% for the white subjects. Mean age was 46.4 +/- 12.5 years for blacks subjects versus 52.8 +/- 12.2 years for white subjects. This prevalence increased with age in both populations. Out of 571 cases of POAG, 465 (81.4%) were previously known and 450 of them were treated; 38.5% of the POAG cases had normal pressure. CONCLUSION: Primary open-angle glaucoma is a major health care problem emphasizing the need for detection and prevention in C?te d'Ivoire.     

Diabetes in primary open-angle glaucoma patients with inferior visual field defects

We reviewed the charts of 144 randomly selected patients with primary open-angle glaucoma who had Aulhorn's stage 1, 2, or 3 visual field defects to investigate whether primary open-angle glaucoma patients with predominantly inferior visual field defects had a higher prevalence of diabetes mellitus than primary open-angle glaucoma patients without such visual field defects. Of the 59 patients with mainly inferior visual field defects in one or both eyes, 19 (32%) had diabetes mellitus, while 11 of 85 (13%) patients without such defects had diabetes mellitus. This difference was statistically significant (P = 0.0096). These results suggest that primary open-angle glaucoma patients with predominantly inferior visual field defects in one or both eyes are more likely to have diabetes and that such patients with no known history of diabetes may benefit from glucose tolerance testing to detect occult impaired glucose tolerance or diabetes mellitus.     

Influence of axial length on visual field defects in primary open-angle glaucoma

With the high frequency of myopia in Taiwan, potential complications or associated conditions, such as glaucoma, are of great concern. To investigate the role of axial length in glaucoma, we enrolled 307 primary open-angle glaucoma (POAG) patients from 1986 through 1996. For the control group, 124 persons were recruited from a survey of a non-glaucoma population and the Ophthalmology Out-patient Department of the National Taiwan University Hospital. Routine eye examination, stereophotography of the optic disc, automated visual field tests, and A-scan ultrasonography were performed on each patient. The Glaucoma Hemifield test was used for analysis of visual field results. The mean axial length was longer in the POAG group than in the control group, especially in the younger age groups (40-59 yr). The POAG group was divided into a short-axial-length (SAL, axial length < 26 mm) group and a long-axial-length (LAL, axial length > or = 26 mm) group. Both subgroups had the deepest visual field defects in the upper and lower nasal areas. The LAL group had deeper visual field defects and the defects were more frequently involved in all sectors analyzed than the SAL group defects. The upper visual field had deteriorated more in the SAL group, whereas the depth of scotoma was similar in the upper and lower hemifields in the LAL group. Our results support the idea that glaucoma patients have a longer axial length than people without glaucoma, and that visual field defects are more pronounced in patients with LAL than in those with SAL.     

A comparative study of visual field damage in low-tension and primary open-angle glaucoma

Methods to encapsulate biological materials are now widely used. Sometimes bioencapsulation is considered as a universal technique conducting to identical results independently on the biological material used. For instance, a similar behavior is frequently waited for different strains of immobilized microorganisms without taking into account substantial differences in its physiological and morphological characteristics. Often interactions with the matrix support are also neglected. Thus, some concepts developed throughout all these years working in bioencapsulation merits to be revisited.     

Genetic mapping of autosomal dominant primary open-angle glaucoma (POAG) in Sardinia

Primary open-angle glaucoma (POAG) can be subdivided into two groups according to age of onset: (1) the more prevalent middle to late-age-onset chronic open-angle glaucoma (COAG) diagnosed after age 40, and (2) the less common form, juvenile open-angle glaucoma (JOAG), which occurs between 3 years of age and early adulthood. Susceptibility to either COAG or JOAG has been found to be inherited. The discovery of several genetic markers spanning the region 1q21-q24 in genetic linkage with autosomal dominant juvenile open-angle glaucoma (adJOAG) represents a major breakthrough towards the localisation of gene(s) responsible for the disease. Linkage analysis is a powerful means of distinguishing disease loci in large families with dominant disease. However the size of the group of families may represent a crucial factor for the linkage analysis. Sardinia is an island with a relatively isolated ethnic group showing a relatively high frequency of ad JOAG and COAG (Fossarello et al, 1994) and it is genetically more homogeneous than most Western populations. Therefore it represents an ideal ethnic group to search for linkage. We identified 18 families affected by POAG in which the disease appears to be inherited as autosomic dominant trait. In all families but two, occurrence of both JOAG and COAG in the same kindred was observed. Identification of adPOAG locus was performed by linkage analysis using 9 microsatellite markers spanning the region 1q21-q24. No significant linkage was observed. Our findings provide further evidence for genetic heterogeneity in autosomal dominant primary open angle glaucoma, even in a geographic area where a relatively homogeneous genetic background exists.     

Human and monkey trabecular meshwork accumulate alpha B-crystallin in response to heat shock and oxidative stress

PURPOSE: Oxidative stress and other forms of injury to trabecular meshwork (TM) cells may contribute to changes seen with age and primary open-angle glaucoma. This study was designed to investigate if TM expresses alpha B-crystallin, a small heat-shock protein with chaperone activity, and whether it might be overexpressed under stress conditions. METHODS: The TM from human and monkey eyes, as well as organ and primary cell cultures derived from these eyes, were investigated for alpha B-crystallin by immunohistochemistry, two-dimensional gel electrophoresis, Northern and Western blot analysis. The TM cell cultures were stressed by heat shock (44 degrees C for 15 minutes) or hydrogen peroxide (200 mumol for 1 hour). Semiquantitation of alpha B-crystallin messenger RNA (mRNA) or protein was obtained by densitometry. RESULTS: In both species, alpha B-crystallin could be detected in fresh and cultured TM by two-dimensional gel electrophoresis in conjunction with Western blot analysis. Immunohistochemistry of fresh samples showed that alpha B-crystallin was expressed predominantly in the cribriform area. Protein expression was enhanced in 4- to 7-day organ cultures. Primary cultures from human TM cells expressed two sizes (approximately 0.8 and 1.1 kb) of alpha B-crystallin mRNA in Northern blots. In monkey TM cultures, a 0.8-kb band was observed, which comigrated with lens alpha B-crystallin. In both species, heat shock caused a significant increase in alpha B-crystallin mRNA with a peak after 4 hours. An increase in alpha B-crystallin mRNA also was observed after oxidative stress; however, the onset of mRNA induction was slower. After heat shock, but not after oxidative stress, a transient change in mRNA mobility was observed. Western dot blot analysis showed a 3.4-fold increase in protein 24 hours after heat shock and a 20-fold increase after 48 hours. No constitutive mRNA expression and only a minimal increase 4 hours after heat shock could be observed in simian virus 40 transformed cell lines from human TM. CONCLUSIONS: Overexpression of alpha B-crystallin might be an important mechanism for TM to prevent cellular damage associated with various stress conditions.     

Experimental erbium: YAG laser photoablation of trabecular meshwork in rabbits: an in-vivo study

Photoablative laser trabecular surgery has been proposed as an outflow-enhancing treatment for open-angle glaucoma. The aim of the study was to investigate the time course of repair response following low-thermal Erbium: YAG laser trabecular ablation. In 20 anaesthetized rabbits gonioscopically controlled ab-interno photoablation of the ligamenta pectinata and underlying trabecular meshwork (TM) was performed with a single-pulsed (200 microseconds) Erbium: YAG (2.94 microns) laser. The right eye received 12-15 single laser pulses (2 mJ) delivered through an articulated zirconium fluoride fiberoptic and a 200 microns (core diameter) quartz fiber tip, the left unoperated eye served as control. At time intervals of 30 minutes, 2, 10, 30, and 60 days after laser treatment, eyes were processed for light- and scanning electron microscopy. The applied energy density of 6-4 J cm-2 resulted in visible dissection of the ligamenta pectinata and reproducible microperforations of the TM exposing scleral tissue accompanied by blood reflux from the aqueous plexus. The initial ablation zones measured 154 +/- 36 microns in depth and 45 +/- 6 microns in width. Collateral thermal damage zones were 22 +/- 8 microns. At two days post-operative, ablation craters were still blood- and fibrin-filled. The inner surface of the craters were covered with granulocytes. No cellular infiltration of the collateral thermal damage zone was observed. At 10 days post-operative, progressive fibroblastic proliferation was observed, resulting in dense scar tissue formation with anterior synechiae, proliferating capillaries and loss of intertrabecular spaces inside the range of former laser treatment at 60 days post-operative. Trabecular microperforations were closed 60 days after laser treatment in all rabbits. IOP in treated and contralateral eyes did not significantly change its level during whole period of observation. Low-thermal infrared laser energy with minimal thermal damage to collateral structures could not effectively prevent early scarring of trabecular surgery in rabbits.     

Non-penetrating deep sclerectomy combined with a collagen implant in primary open-angle glaucoma. Medium-term retrospective results

PURPOSE: To evaluate the middle term tonometric results of a new filtering procedure, the non penetrating deep sclerectomy with collagen device, in primary open-angle glaucoma. This technique aims to eliminate or minimize the complications of classical trabeculectomy. MATERIAL AND METHOD: This procedure has been developed by Koslov et al. Under a limbal-base conjunctival flap and a superficial scleral flap, the ablation of a deep scleral flap takes away the external wall of Schlemm's canal, leaving only the Descemet membrane. A visible filtration across the opened Schlemm's canal and Descemet membrane is obtained. To improve the aqueous filtration, a cylindric collagen device, made from biocompatible porcine scleral tissue, known for its high water content, is fixed in the deep scleral bed with a 10/0 nylon suture. This device provides a support for the elimination route of aqueous humor and acts like a sponge, carrying the liquid by capillary action. It is sterilized by irradiation. Full guarantee against viral contamination is provided. This procedure ends in one suture (40/0 nylon) of superficial scleral flap and conjunctival closing suture. We conducted a retrospective study. Our material included 159 patients (92 males, 65 females), 2/9 eyes. The mean age was 65 years (11-91). The mean follow-up : 8 months (3-20). The types of glaucoma were: POAG: 183 eyes; juvenile POAG: 18 eyes: pigmentary glaucoma: 11 eyes; capsular glaucoma: 7 eyes, 58 eyes (40 patients) presented one or several risk factors of failure for filtering surgery. RESULTS: The mean pre-operative IOP was 24 mmHg +/- 6.60; 15.7 +/- 5.30 at the end of the follow-up (delta average IOP: 9.1 +/- 7.1). The probability success rate (IOP < or = 20 mmHg), according to the Kaplan-Meier Method, was 89% at six months, 75.6% at 16 months. With monotherapy with beta blockers, 79% at 16 months. It was better in the without risk factors group. The mean change in visual acuity was inferior to 0.1 at the end of the follow-up. Except several hyphemas, no complications of the trabeculectomy were observed. The reelevation of IOP was due to an internal obstruction (goniosynechiae or bad filtration), it was treated with Nd-Yag laser with a 2/3 of success rate. External obstruction was treated by 5FU injections into the bleb. CONCLUSION: Non penetrating deep sclerectomy with collagen device can be an excellent alternative to trabeculectomy in open and wide angles. It does not modify visual actuity. It carries less complications than trabeculectomy and the use of antimitotic agents is safer.     

The cyclopentolate provocative test in suspected or untreated open-angle glaucoma. IV. Fluorescein angiography of the vessels of the iris in open-angle glaucoma eyes with a positive cyclopentolate response

Fluorescein angiography of the iris (IFAG) was performed on 15 patients with a positive cyclopentolate response (IOP elevation greater than or equal to 8 mmHg) in 17 eyes to the cyclopentolate provocative test. The chamber angles were open in all the eyes. Seven of the responder eyes had capsular glaucoma undergoing treatment, six had simple glaucoma, two had pigmentary glaucoma and two suspicion of open-angle glaucoma. The object was to study with IFAG whether vascular changes can be established in the iris of the responder eyes such as could have a role in the elevation of IOP. All the eyes with capsular glaucoma displayed vascular changes, vasoproliferation and fluorescein leakage from the iris vessles. No other vascular changes were seen in the irises of the responder eyes. IFAG revealed no differences in the iris vasculature between responder and non-responder eyes. A vascular aetiology for the IOP elevation in responders is improbable.     

Quantitative differences between the optic nerve head and peripapillary retina in low-tension and high-tension primary open-angle glaucoma

Anti-IgE antibodies directed against the Fc epsilon RI-binding region on IgE inhibit binding of IgE to IgE receptors without inducing mediator release from IgE sensitized cells. In mice these antibodies selectively reduce serum IgE, inhibit antigen induced skin reactions, cytokine production by lung Th2 cells, and pulmonary eosinophil infiltration. Clinical trials in humans reveal that such antibodies are well tolerated and reduce rhinitis symptoms and early and late phase bronchoconstriction responses. Thus interruption of the allergic cascade at the IgE antibody level with non-anaphylactogenic anti-IgE antibodies is effective and represents an attractive intervention for the treatment of allergic diseases.     

Effect of orally administered hydrocortisone on the ocular tension in primary open-angle glaucoma subjects. Preliminary report

We studied the possible influence on the pattern of diurnal ocular tension curve by peroral hydrocortisone in 16 eyes of 16 subjects with primary open-angle glaucoma. The baseline diurnal curve was determined by Schiotz tonometry six times daily starting at 10 a.m. and repeated every four hours. The baseline curve showed a significant rise in the daytime with a fall during the night. On another day, 20 mg hydrocortisone was given perorally at 5 p.m., for a repeat 24-h measurement period. A significant rise in ocular tension over the baseline resulted in the following night-time tonometric readings, i.e. at 10 p.m. (P less than 0.01) and 2 a.m. (P less than 0.001). The results seem to strongly indicate that plasma cortico-steroid levels dictate the pattern of diurnal variation of ocular tension.