Sleep disorders: a risk factor for normal-tension glaucoma?

PURPOSE: To determine the prevalence of sleep-related symptoms and sleep-related breathing disorders by polysomnography in patients with normal-tension glaucoma (NTG). PATIENTS AND METHODS: This comparative case series included 23 patients with NTG, 14 NTG suspects, and 30 comparison patients without NTG. A sleep history was obtained and determined to be positive or negative. Polysomnography was offered for patients with a positive sleep history. Prevalence of a positive sleep history and prevalence of sleep disorders were the main outcome measures. RESULTS: The NTG, NTG suspect, and comparison groups did not differ with respect to age, body mass index, systemic disease, gender, or race. Thirteen (57%) of 23 patients with NTG, 6 (43%) of 14 NTG suspects, and 1 (3%) of 30 comparison patients had a positive sleep history (P = 0.001). Nine of 13 patients with NTG and four of six NTG suspects with a positive sleep history chose to undergo polysomnography. Seven (78%) of nine patients with NTG and all four NTG suspects undergoing polysomnography were diagnosed with a sleep disorder. Five patients with NTG had sleep apnea and two had sleep hypopnea. Two NTG suspects had sleep apnea; one had sleep hypopnea; and one had upper airway resistance syndrome. The one comparison patient with a positive sleep history had upper airway resistance syndrome by polysomnography. CONCLUSIONS: Sleep-disturbed breathing may be a risk factor for NTG. Although we do not provide evidence for a cause-and-effect relationship, various physiologic factors produced by sleep-disturbed breathing may play a significant role in the pathogenesis of this optic neuropathy. We recommend obtaining a sleep history from patients with NTG and performing polysomnography in those patients with sleep disturbance symptoms.

Morphological sequelae of intracameral hydrogen peroxide after inhibition of glutathione synthesis.

The morphological sequelae of intracameral injections of hydrogen peroxide on the corneal endothelium were examined under different conditions. In animals pretreated with either intravenous 3-aminotriazole (3AT) alone, to suppress catalase activity, or intravitreal buthionine sulfoximine alone (BSO), to inhibit gamma-glutamyl synthetase activity, the endothelium was normal. The intracameral administration of 10 microliters of 10 mM hydrogen peroxide caused no response after 3AT and some small morphological but not physiological changes after BSO pretreatment. The intracameral injection of 10 microliters of 25 mM hydrogen peroxide caused no additional change in 3AT pretreated rabbits, but caused substantial morphological and physiological changes in BSO pretreated rabbits. The correlation between the present morphological changes and those seen earlier in physiological studies is excellent. The data confirm that the glutathione redox system may be more important than catalase in maintaining the integrity of the corneal endothelium at low aqueous humor concentrations of hydrogen peroxide while catalase assumes greater importance at higher peroxide concentrations.

Roles of catalase and the glutathione redox cycle in the regulation of anterior-chamber hydrogen peroxide.

The effects of inhibition of both glutathione synthesis and of glutathione reductase and catalase activities have been determined in the regulation of hydrogen peroxide (H2O2) in the anterior chamber of pigmented rabbits. Glutathione reductase inhibition using intravitreal 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) did not significantly alter either total glutathione or the percent oxidized glutathione fraction in the iris-ciliary body. Intravitreal buthionine sulfoximine (BSO) significantly reduced the total glutathione content of iris-ciliary body and corneal endothelium, while not altering the oxidized fraction. BCNU increased the oxidized fraction of glutathione in the aqueous humor from 22 to 63% without significantly altering total glutathione levels. BSO, however, reduced total glutathione by 70% in the aqueous humor, and the oxidized fraction doubled. Decreases in the reduced glutathione concentration caused by BSO correlate with increases in the normally stable ratio of H2O2 to ascorbate concentrations in the aqueous humor, strongly suggesting that glutathione metabolism is correlated with H2O2 regulation at endogenous levels of this oxidant. Both BSO and 3-aminotriazole (3AT) separately increased the half-time for the loss of exogenously added H2O2 from the anterior chamber. BSO increased the half-time by 77% after 10 microliters of 10 mM H2O2 was injected intracamerally, while suppression of catalase activity with 3AT increased it by only 40%. With intracameral injections of 10 microliters of either 25 or 50 mM H2O2, however, 3AT had a greater effect than BSO. The half-time values after 3AT pretreatment were 61 and 135% greater than control values at the concentrations of 25 and 50 mM H2O2, respectively; those after BSO pretreatment were at 14 and 78%. From these data we conclude that the glutathione redox system protects the anterior segment tissues from hydrogen peroxide at low concentrations of this oxidant, while catalase assumes a greater role at higher concentrations of hydrogen peroxide.

Role of glutathione in the regulation of anterior chamber hydrogen peroxide.

Catalase inhibition leads to an increase in the t 1/2 for hydrogen peroxide loss from the anterior chamber and increased tissue damage. BCNU (1,3-bis-(2-chloroethyl)-l-nitrosourea) and BSO (buthionine sulfoxamine) were used to suppress glutathione reductase and glutathione synthesis, respectively. Intravitreal BSO (1 to 4 mg) reduced total glutathione levels of iris by 80%, and aqueous glutathione levels by 70%. BSO caused the t 1/2 for hydrogen peroxide disappearance from the anterior chamber to increase after 10 microliters of 10 mM peroxide was injected intracamerally but not after 25 or 50 mM peroxide injections. Catalase inhibition, however, had more influence at 50 mM than with 10 or 25 mM injections. The glutathione redox system is operative at low aqueous hydrogen peroxide concentrations and catalase is of greater importance at higher peroxide concentrations.

The effects of endotoxin, glucocorticoids and prostaglandin metabolism in the rabbit iris.

Superoxide dismutase activity (SOD) was measured in the irides of control animals (n = 16) and 24 hours after the intravitreal administration of endotoxin (n = 12). Nearly a twofold increase in SOD was noted in the endotoxin-treated animals (p less than 0.001). In order to assess the induction of SOD while protecting against the inflammatory process, topical dexamethasone (dex) was administered t.i.d. for 2 days before and 1 day after endotoxin (n = 6). Dex prevented the conjunctival hyperemia, vascular injection and iritis seen with endotoxin treatment alone and blocked the induction of SOD. A similar medrysone (med) application (n = 4) failed to prevent the visible signs of ocular inflammation yet also blocked the elevation of SOD. Pretreatment with either of the cyclooxygenase inhibitors, indomethacin (n = 4) or aspirin (n = 7), failed to block the induction in SOD (p less than 0.001 and p less than 0.01, respectively). However, the induction of SOD was prevented by the phospholipase A2 inhibitor, quinacrine, and the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA). The data indicate that a product of the lipoxygenase pathway may be mediating the induction of SOD seen with endotoxin-induced ocular inflammation.

The effects of ascorbate, 3-aminotriazole, and 1,3-bis-(2-chloroethyl)-1-nitrosourea on hydrogen peroxide levels in the rabbit aqueous humor.

3-aminotriazole (3-AT), a catalase inhibitor, given to pigmented rabbits in 0.2% drinking solution for 43 days, produced cataractous changes and over a 50% reduction in iris and ciliary process catalase activity. Aqueous H2O2 levels were suppressed by 60% which correlated with a 77% reduction in aqueous ascorbate concentration. Intravenous 3-AT at 1.0 g/kg body weight had no effect on either aqueous ascorbate or H2O2 levels. BCNU (1,3-bis-(2-chloroethyl)-1-nitrosourea) was given intravitreally to rabbits: 3.0 mg suppressed iris glutathione reductase activity by 80%, but only increased the oxidized glutathione/total glutathione ratio to 26% from 18%. Both aqueous ascorbate and H2O2 levels were unaltered at 48 hours. Buthionine sulfoximine (BSO) was given intravitreally; at 48 hours after 4.0 mg BSO, iris-ciliary body total glutathione levels were reduced by 80%, aqueous ascorbate levels were reduced by 53%, and aqueous H2O2 levels were unaltered. A direct correlation seems to exist between aqueous humor ascorbate and H2O2 concentrations, even during suppression of tissue catalase activity. Changes in glutathione status cause peroxide levels to be greater than predicted from the aqueous ascorbate concentration.

Hydrogen peroxide in the rabbit anterior chamber: effects on glutathione, and catalase effects on peroxide kinetics.

Intracameral hydrogen peroxide (H2O2) is cleared at a faster rate in young (t1/2, 93 seconds) than in adult (t1/2, 109 seconds) rabbits. Extrapolated zero time concentrations of H2O2 were 3.3 mM in adults and 3.2 mM in young. The more rapid disappearance of H2O2 correlated with greater catalase levels in iris (35%) and corneal endothelium (50%) in young as compared to adult animals. Catalase levels have been found to be reduced in ocular tissues with 3-amino-1H-1,2,4-triazole (3AT) in a dose-related manner up to 6 ml/kg of an intravenous 3M solution. Iris and ciliary processes showed a linear reduction with dose, while corneal endothelium, liver and lung reached near maximal decreases in catalase activity at 2, 4, and 6 ml/kg, respectively. 3AT caused a significant dose-dependent extension of the rate of clearance of H2O2 from the anterior chamber, that was directly related to catalase loss. The t1/2 for H2O2 disappearance in adult animals increased from 109 seconds with no 3AT, to 147 seconds after 2 ml/kg 3M 3AT, to 161 seconds after 4 ml/kg 3M 3AT and 184 seconds after 6 ml/kg 3M 3AT. Corneal endothelial oxidized glutathione levels were transiently increased after intracameral hydrogen peroxide. Considering the sum total of all tissues of the anterior segment, specific incremental decreases of catalase generated by intravenous 3AT caused the t1/2 of H2O2 clearance from the anterior chamber to become longer, while the reducing power of anterior segment tissues excluding lens epithelium is related clearly to the systemic dose of 3AT.(ABSTRACT TRUNCATED AT 250 WORDS)

3-amino-triazole effects on the eye of young and adult rabbits in the presence and absence of hydrogen peroxide.

3-aminotriazole (3AT) is known to reduce catalase levels in ocular tissues when given intravenously or orally. Rabbits were given either 4 ml/kg of a 3M solution of 3AT intravenously or a 2% solution as drinking fluid. Intravenous 3AT administration was followed at 4 hrs by an intracameral injection of hydrogen peroxide (H2O2) to give an aqueous humor concentration of 3.2 mM in young (4-6 weeks of age) and a 3.3 mM in adult (6 months of age) rabbits. Tissues were taken for microscopy at either 6 or 24 hours after intracameral H2O2. Neither oral nor intravenous 3AT alone in adult rabbits, or intravenous 3AT in young rabbits, had any effect on either iris, ciliary process, or corneal endothelial morphology. After oral 3AT in adult rabbits, H2O2 caused highly edematous ciliary processes with dilated vessels; corneal endothelial cells were swollen. Previous studies in adult and young rabbits have shown that intracameral H2O2 alone caused few morphological changes in young, but marked changes in the adult that correlated with the 35 to 50% lower catalase levels found in iris and corneal endothelium, respectively, in adult ocular tissues. Young rabbits pre-treated with intravenous 3AT, when examined at 6 and 24 hours after intracameral H2O2, showed swollen ciliary processes, vessel dilation, alteration of the pigment epithelium and corneal endothelial damage. In non 3AT-treated young rabbits, H2O2 caused only minor morphological changes. In adult animals at 6 and 24 hours after intracameral H2O2 the ciliary processes were edematous in the absence of 3AT; after intravenous 3AT and intracameral H2O2 the changes were even more marked, with very severe swelling of ciliary processes and corneal endothelial damage. It is apparent that the decrease in catalase caused by 3AT allows H2O2 to induce damage even in young animals where it usually does not induce morphological changes. In adult animals, the effects of H2O2 are enhanced in the presence of 3AT.