Biomedical subjects

Balwantray C Chauhan

Publications and source records attributed to Balwantray C Chauhan.

17 recordsLinked to original sources

PubMed2004

Detection of glaucoma: the role of new functional and structural tests.

PURPOSE OF REVIEW: It is thought that our current techniques for investigating open-angle glaucoma may not be the most sensitive ones for the earliest detection of the disease. Newly developed psychophysical and imaging techniques may have an important role in clinical practice. This review outlines some of the issues involved in adopting these techniques. RECENT FINDINGS: To date there are many cross-sectional studies that report on the sensitivity and specificity characteristics of these techniques based on our current definitions of open-angle glaucoma. There are a limited number of studies available that show the efficacy of the new techniques for the early detection of open-angle glaucoma. SUMMARY: More longitudinal studies are now needed to demonstrate that the new techniques that are being adopted in clinical practice can detect glaucoma earlier. More importantly, studies are required to prove that early treatment in individuals detected with these new techniques makes a meaningful impact on the patients' prognosis.

Diagnostic Imaging↗

PubMed2004

Model of endothelin-1-induced chronic optic neuropathy in rat.

PURPOSE: To describe a model of chronic endothelin (ET)-1 administration to the optic nerve and evaluate its effect on retinal ganglion cell (RGC) and axon survival in rat. METHODS: Osmotic minipumps were surgically implanted in one eye of 113 Brown Norway rats to deliver 0.05, 0.10, 0.20, or 0.40 microg ET-1 per day (3.3, 6.7, 13.4, and 26.8 microM, respectively), or balanced salt solution (BSS) to the immediate retrobulbar optic nerve; the fellow untreated eye served as the control. Before pump implantation, RGCs were retrogradely labeled with fluorochrome. Animals were killed at 21, 42, or 84 days. RGC survival was expressed as the ratio of RGC counts in experimental versus control eyes in wholemounted retinas, whereas axon survival was expressed similarly from electron micrographs of the optic nerves. Serial optic disc changes were evaluated using scanning laser tomography. The effect of ET-1 (3 microL topical application of 10(-5) M) on blood flow in the surgically exposed optic nerve was measured using laser Doppler flowmetry in a separate group of five animals. RESULTS: ET-1 led to a mean reduction in optic nerve blood flow of 68%. There were no significant differences in RGC survival among the four ET-1 doses used in this study. Pooled across all ET-1 doses, RGC survival decreased incrementally at 21, 42, and 84 days (P < 0.001; mean +/- SD, 0.77 +/- 0.25, 0.60 +/- 0.27, and 0.50 +/- 0.26, respectively) and was statistically significantly lower at each time point than in the BSS-treated animals. The axon survival data also showed a similar time-dependent loss. Only one of 21 animals showed significantly increased disc cupping, and there was no relationship between RGC survival and change in cupping. CONCLUSIONS. Chronic administration of ET-1 to the rat optic nerve results in a time-dependent loss of RGCs and their axons without apparent change in optic disc topography.

Animals↗

PubMed2003

Comparison of data analysis tools for detection of glaucoma with the Heidelberg Retina Tomograph.

PURPOSE: To evaluate the performance of three linear discriminant functions (LDFs) and the Moorfields Regression Analysis (MRA) in classifying optic disc topography images obtained with the Heidelberg Retina Tomograph (HRT) from patients with open-angle glaucoma and normal controls. Furthermore, to investigate whether the classification of glaucomatous eyes is related to the severity of visual field loss or to optic disc size. DESIGN: Prospective comparative observational case series. PARTICIPANTS: One eye of 104 patients with a diagnosis of open-angle glaucoma (mean age, 63.2; range, 30-88 years) and 48 normal controls (mean age, 52.4; range, 33-75 years). TESTING: Subjects were examined with the HRT. MAIN OUTCOME MEASURES: Diagnostic performance was calculated for the LDFs published by Mikelberg et al (LDF1), Burk (LDF2), and Bathija et al (LDF3) and for the MRA. RESULTS: Large differences in sensitivity and specificity were found among the different analyses when using the originally suggested cutoff criteria. When specificity was equalized to 90%, the sensitivities were more similar (LDF1, 55%; LDF2, 61%; and LDF3, 67%). At 95% specificity, the sensitivities decreased further (LDF1, 39%; LDF2, 55%; LDF3, 44%). When treating the "borderline" outcomes as test positives, MRA sensitivity and specificity were 78% and 81%, respectively. When treating the "borderline" outcomes as test negatives, the MRA gave a sensitivity of 58%, with a specificity of 96%. In glaucoma patients, the correlation between the severity of visual field damage, as measured by the mean deviation index, and the outcome of the classification systems was low to moderate (Spearman's r between 0.26 and 0.39). When the entire sample was stratified into equal thirds on the basis of optic disc size, large discs (area > 2.10 mm(2)) tended to be classified with a higher sensitivity but lower specificity than small discs (area < 1.73 mm(2)) with all methods except LDF3. Using a multiple regression model controlling for mean deviation, LDF1, and LDF2, but not LDF3, were significantly influenced by disc size. CONCLUSIONS: The 4 methods of analysis had similar sensitivities once their specificities were equalized. In this sample, the LDFs and MRA generally did not discriminate between glaucoma patients and controls as well as reported in the original respective studies that described the methods.

Adult↗

PubMed2003

Visual field and optic disc progression in patients with different types of optic disc damage: a longitudinal prospective study.

OBJECTIVE: To evaluate the incidence of visual field and optic disc progression in glaucoma patients with distinct patterns of optic disc damage. DESIGN: Prospective, observational case series. PARTICIPANTS: One hundred five patients with open-angle glaucoma. METHODS: Baseline optic disc photographs of 105 study eyes of 105 patients were reviewed by 2 masked observers and classified according to patterns of disc damage into the following categories: focal, myopic, senile sclerotic, and generalized disc damage. Patients were followed up every 6 months with standard automated perimetry (SAP), high-pass resolution perimetry (HRP), and scanning laser tomography (SLT) with the Heidelberg Retina Tomograph. MAIN OUTCOME MEASURES: Visual field (SAP and HRP) and optic disc (SLT) progression were determined according to predefined criteria. RESULTS: Twenty-four eyes were classified into the focal, 8 into the myopic, 12 into the senile sclerotic, and 28 into the generalized group. Eyes from 33 patients could not be classified by the observers into any of these groups and were excluded from further analysis. Although intraocular pressure during follow-up was similar among the four groups, some differences in frequency of progression were observed. Patients with senile sclerotic discs had the lowest rates of visual field progression (both with SAP and HRP) and optic disc progression, although the differences were significant only for optic disc progression (P = 0.05). CONCLUSIONS: Patients with senile sclerotic discs showed a tendency towards less visual field and optic disc progression when compared with patients with other types of disc damage.

Aged↗

PubMed2003

Retinal arterial diameter changes in progressive and nonprogressive glaucoma.

PURPOSE: To determine if the degree of retinal arterial diameter change is different between patients with progressive and nonprogressive open-angle glaucoma. MATERIAL AND METHODS: In this prospective cohort study, 44 eyes of 44 open-angle glaucoma patients (mean age, 67.5 years; age range, 52-84 years; mean follow-up period, 4.9 years; follow-up range, 1.3-7.5 years) were included. The change in arterial diameter between the baseline and the most recent follow-up optic disc photograph was determined. The diameter of the 4 major arteries was measured at the optic disc margin and at the thinnest and broadest locations within 1 optic disc diameter from the disc margin. Patients were stratified into progressing and nonprogressing groups according to visual field and optic disc criteria. RESULTS: Visual field progression was observed in 13 (30%) patients and optic disc progression in 24 (55%) patients. On average, the arterial diameters at the edge of the optic disc decreased significantly by 2.37% (95% CI, -3.31% to -1.41%) per year of follow-up (P<0.001). No significant difference in generalized or focal arterial narrowing was observed between progressive and nonprogressive groups regardless of the criterion used (P>0.462). With this sample, the power to detect a 10% difference in arterial narrowing between the 2 groups was 66%. There was no relationship between the rates of visual field progression and arterial diameter change in the whole group (P = 0.171) or in groups segregated into progressing and nonprogressing patients (P>0.104). CONCLUSION: Arterial diameters decreased in both progressive and nonprogressive glaucoma. In this study, there was little evidence that arterial narrowing was more pronounced in progressive disease.

Aged↗

PubMed2003

Effects of blur and repeated testing on sensitivity estimates with frequency doubling perimetry.

PURPOSE: To investigate the effect of blur and repeated testing on sensitivity with frequency doubling technology (FDT) perimetry. METHODS: One eye of 12 patients with glaucoma (mean deviation [MD] mean, -2.5 dB, range +0.5 to -4.3 dB) and 11 normal control subjects underwent six consecutive tests with the FDT N30 threshold program in each of two sessions. In session 1, blur was induced by trial lenses (-6.00, -3.00, 0.00, +3.00, and +6.00 D, in random order). In session 2, only the effects of repeated testing were evaluated. The MD and pattern standard deviation (PSD) indices were evaluated as functions of blur and of test order. By correcting the data of session 1 for the reduction of sensitivity with repeated testing (session 2), the effect of blur on FDT sensitivities was established, and its clinical consequences evaluated on total- and pattern-deviation probability maps. RESULTS: FDT sensitivities decreased with blur (by <0.5 dB/D) and with repeated testing (by approximately 2 dB between the first and sixth tests). Blur and repeated testing independently led to larger numbers of locations with significant total and pattern deviation. Sensitivity reductions were similar in normal control subjects and patients with glaucoma, at central and peripheral test locations and at locations with high and low sensitivities. However, patients with glaucoma showed larger deterioration in the total-deviation-probability maps. CONCLUSIONS: To optimize the performance of the device, refractive errors should be corrected and immediate retesting avoided. Further research is needed to establish the cause of sensitivity loss with repeated FDT testing.

Adult↗

PubMed2003

Effects of cold-induced vasospasm in glaucoma: the role of endothelin-1.

PURPOSE: Vasospasm has been associated with glaucoma, but its mechanisms have not been elucidated. The present study was designed to evaluate the role of endothelin (ET)-1, a potent endogenous vasoconstrictor, in the genesis of vasospasm in glaucoma. METHODS: Our sample contained patients with open-angle glaucoma (n = 43) and subjects with normal nonglaucomatous eyes and without acral vasospasm (n = 27). After the eligibility visit, all subjects underwent a provocative cooling test, consisting of wearing for 30 minutes a head-vest cooling garment containing coolant fluid. Blood was collected before and after cooling, and plasma ET-1 was determined by immunoassay. In addition, visual fields and retinal blood flow, measured with a confocal scanning laser and Doppler flowmeter, were measured before and after cooling. Peripheral finger flow, skin temperature, and blood pressure were monitored during the experiment. A recovery visit was performed within 1 month, when visual field and retinal blood flow measurements were repeated. RESULTS: Baseline plasma ET-1 levels were similar between patients with glaucoma and control subjects (mean +/- SD: 2.81 +/- 1.29 and 2.56 +/- 1.36 pg/mL, respectively, P = 0.465). Patients with glaucoma, however, had a significant increase in plasma ET-1 after cooling (mean +/- SD increase of 34% +/- 52%, P = 0.001), not observed in control subjects (mean +/- SD increase of 7% +/- 43%, P = 0.750). No significant change in visual fields or retinal blood flow was observed after cooling in either group. Patients with glaucoma who had evidence of acral vasospasm, however, were more likely to show deterioration in visual fields after cooling than patients without acral vasospasm (P = 0.007). CONCLUSIONS: Patients with glaucoma have an abnormal increase in plasma ET-1 after the body cools. It is possible that at least in some patients, increased levels of ET-1 in response to vasospastic stimuli may be involved in the pathogenesis of glaucomatous damage.

Adult↗

PubMed2003

Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma.

PURPOSE: To determine whether retinal glial cells exhibit an activated phenotype in glaucomatous human eyes and whether the mitogen-activated protein kinases (MAPKs) are associated with glial activation in glaucoma. METHODS: Activated phenotypes of retinal macroglia (astrocytes and Müller cells) and microglia were identified by morphologic assessment and immunostaining for the cell markers glial fibrillary acidic protein (GFAP) and HLA-DR, respectively, in 30 eyes obtained from glaucomatous donor eyes in comparison with normal control eyes from 20 age-matched donors. Cellular localization of the activated forms of MAPKs, including extracellular signal-regulated kinases (ERK), c-Jun amino(N)-terminal kinase (JNK), and p38, were studied in the retina of these eyes by immunoperoxidase staining and double immunofluorescence labeling with phosphorylation site-specific antibodies. RESULTS: Retinal astrocytes and Müller cells exhibited a hypertrophic morphology and increased immunostaining for GFAP in the glaucomatous retina. Although an increase was detectable in the number and size of cells positive for HLA-DR immunostaining in the glaucomatous retina compared with the control retina, microglial activation was not as prominent or widespread as the macroglial activation detected in the same eyes. The intensity of immunostaining and the number of immunostained cells for the activated MAPKs were greater in retina sections from glaucomatous eyes than in control eyes, being most prominent for phospho-ERK. Double immunofluorescence labeling demonstrated that the increased retinal immunostaining for phospho-ERK was predominantly, but not exclusively, localized to glial cells, whereas, the immunostaining for phospho-JNK or phospho-p38 was mainly associated with nonglial cells. CONCLUSIONS: These findings provide evidence that retinal glial cells undergo activation in the glaucomatous human retina. A prominent and persistent activation of ERK in activated glial cells suggests that this signaling pathway is probably associated with the induction and/or maintenance of the activated glial phenotype in glaucoma. Because MAPKs are involved in determination of ultimate cell fate, their differential activity in neuronal and activated glial cells in the glaucomatous retina may be associated, in part, with the differential susceptibility of these cell types to glaucomatous injury.

Aged↗

PubMed2003

Comparison of different methods for detecting glaucomatous visual field progression.

PURPOSE: To compare the performance characteristics of seven methods for analyzing glaucomatous visual field progression, using a combination of real patient data and computer simulation techniques. METHODS: The initial and final visual field results, separated by 7 years and measured with the full-threshold 30-2 program of the Humphrey Field Analyzer (Carl Zeiss Meditec, Dublin, CA) of 76 patients with open-angle glaucoma were used. A computer simulation program generated 14 interim semiannual visual fields under conditions of high, moderate, and no variability. Progression was analyzed using the methods of the Advanced Glaucoma Intervention Study (AGIS), the Collaborative Initial Glaucoma Treatment Study (CIGTS), three criteria based on the Glaucoma Change Probability (GCP) analysis, and two criteria based on point-wise linear regression analysis (PLRA). Specificities were calculated by using the same visual field of each patient as both the initial and final field (no progression) under conditions of moderate and high variability. RESULTS: Under the no-variability condition, progression rates were 18% for the AGIS, 36% for CIGTS, 47% to 62% for the three GCP methods, and 72% and 84% for the two PLRA methods. Progression rates increased with greater variability with the three GCP methods and decreased with all other methods. The time to detect confirmed progression was longest for the PLRA methods and shortest for the CIGTS and GCP methods. Under the moderate-variability condition, all methods yielded high specificity. The AGIS, CIGTS, and one of the GCP and PLRA methods were relatively resistant to high variability and maintained high specificities. CONCLUSIONS: The AGIS and CIGTS methods had high specificity, but classified fewer cases of progression than the other methods. The GCP methods determined progression earliest; however, they were generally not as specific. Methods based on PLRA were specific but times to confirmed progression were the longest.

Computer Simulation↗

PubMed2002

Spatial and temporal processing of threshold data for detection of progressive glaucomatous visual field loss.

OBJECTIVE: To evaluate the effect of spatial and temporal filtering of threshold visual field data on the ability of pointwise linear regression (PLR) to detect progressive glaucomatous visual field loss. METHODS: Longitudinal visual field data (Full-Threshold Program 30-2 test point pattern) were simulated using a computer model of glaucomatous visual field progression. This approach permitted construction of a "gold standard" because matching visual field data without variability could be generated and analyzed. Four clustered progressive defects were produced, consisting of 2, 3, 9, and 18 locations, respectively, each with progression rates of -1 and -2.5 dB/y. Pointwise linear regression was used to identify progressive test locations (criterion for progression of statistically significant slope of < or =-1 dB/y, P<.05). Each visual field series was analyzed after the following 3 procedures: (1) no filtering (unprocessed data), (2) Gaussian spatial possessing (3 x 3 grid), and (3) temporal processing (2 field moving average). The effect of spatial and temporal processing on PLR discriminatory power for progression detection was quantified by comparison with the gold standard. RESULTS: Spatial processing reduced PLR sensitivity to levels below that achieved for analysis of unprocessed data for small progressive defects (< or =9 locations) or at the low true progression rate (-1 dB/y). Under these conditions, spatial processing caused small PLR specificity improvement. Spatial processing only improved PLR sensitivity above unprocessed levels when progressive defects were large and changing rapidly (progression rate of -2.5 dB/y). Temporal processing gave consistent PLR improvement in sensitivity for all defect sizes and true progression rates. Pointwise linear regression sensitivity gain provided by temporal processing allowed progression to be detected 2 to 3 visual fields earlier than for analysis of raw data. Specificity dropped slightly as a result of temporal processing but remained at 89% or above for all conditions studied. CONCLUSIONS: Gaussian spatial processing reduces PLR discriminatory power with low true progression rates or small progressive defect sizes and, therefore, is of limited use for detection of progressive visual field loss. Temporal processing improves the sensitivity of PLR and reduces the number of tests required to detect progressive loss with minimal loss of specificity. CLINICAL RELEVANCE: Image processing techniques can be applied to threshold visual field data to enhance sensitivity or specificity of PLR for the determination of progressive change. This investigation demonstrates that temporal processing may assist with the detection of significant progressive visual field loss with fewer test results than unprocessed data.

Computer Simulation↗

PubMed2002

The relationship of visual threshold and reaction time to visual field eccentricity with conventional automated perimetry.

To investigate the relationship between reaction time (RT), stimulus intensity and visual field eccentricity. We generated frequency of seeing (FOS) curves and measured RTs by testing 10 perimetrically experienced normal subjects with a Humphrey perimeter controlled by a custom program. Subjects were tested from 10 degrees to 50 degrees eccentricity along the nasal horizontal meridian in 10 degrees increments. A range of 20 dB, centered on threshold, was tested in 1 dB steps along with 60 and 0 dB intensities as catch trials. Twenty repetitions for each intensity at each location were used. Linear regression showed a significant increase in suprathreshold RT (to the 0 dB stimulus) with increasing eccentricity. The RT at the calculated FOS 50% threshold was prolonged by about 200 ms compared with the RT using the 0 dB target at the equivalent eccentricities. Also, when the difference between the RT at 0 dB stimulus and the RT at threshold was regressed against visual field eccentricity there was a significant decrease with eccentricity. When the RT(pi) (RT prolongation from threshold relative to the 0 dB stimulus) was plotted as a function of decreasing stimulus attenuation, the results fit the function RT(pi)=a+bi(3) (i=stimulus intensity) with r(2)>0.94 at all eccentricities. However, the slope of the function flattened with increasing eccentricity. Using conventional automated perimetry stimuli in perimetrically experienced young subjects, suprathreshold RT increases but threshold RT prolongation decreases with increasing visual field eccentricity. RT fits a power function with decreasing stimulus attenuation but the slope flattens with eccentricity. This relationship found along the nasal horizontal meridian may allow use of RT to cross-check threshold results or to define response windows for reliability indices of conventional automated perimetry.

Adult↗

PubMed2002

Sensitivity differences between real-patient and computer-stimulated visual fields.

PURPOSE: The authors sought to verify computer simulation of visual fields by comparing thresholds of real and corresponding simulated visual fields. METHODS: Four patients with stable glaucomatous visual fields and three patients with progressing glaucomatous visual fields were chosen for the study. Visual fields had been recorded at 6-month intervals for 5 to 7.5 years. A previously described computer simulation program was used to generate a corresponding simulated visual field for each of the real fields. Twenty different levels of response variability and long-term variability were used in the simulations. Pointwise sensitivity differences between real and simulated fields were calculated. The average difference and 95% interval of the differences were analyzed for the different simulation conditions, for the pointwise sensitivities in the real patient fields, and to determine whether the field was stable or progressing. RESULTS: In almost all simulation conditions, the average pointwise sensitivity differences ranged from -1 to 1 dB and were not significantly different among different simulation conditions. The 95% interval of the average difference increased significantly with response variability, whereas long-term variability failed to show any apparent effect. Average pointwise differences and the 95% intervals were greatest in locations where the real-patient field had reduced sensitivity of 14 dB or worse. CONCLUSION: The simulation program provided good estimates of visual field sensitivities. Increasing amounts of response, but not long-term variability, produced a linear increase in the variability of threshold sensitivities. This finding implies that short-term rather than long-term fluctuation is the most important factor determining the variability of thresholds.

Aged↗

PubMed2002

Timolol concentrations in rat ocular tissues and plasma after topical and intraperitoneal dosing.

PURPOSE: Topical beta-blockers, such as timolol, have been used extensively in the medical treatment of glaucoma to lower intraocular pressure (IOP). Recently, these drugs have been shown to have effects on the retinal and optic nerve circulation as well as potential neuroprotective properties. In the current study, the concentration of timolol attained in the cornea, iris-ciliary body, retina, vitreous, and plasma was measured after topical or intraperitoneal administration in rats to determine the relative contributions of each route to intraocular timolol concentrations. MATERIALS AND METHODS: One group of rats received one drop of commercially available 0.5% timolol in the right eye and two drops in the left eye for 3 to 12 days. Another group of rats received one drop of 0.5% timolol in one eye only and concentrations were studied in the ocular tissues at 15, 30, 60, 120, and 240 minutes after instillation. The final group of rats received a single intraperitoneal injection of timolol ranging in concentration from 5 to 75 mg/kg after which tissue and plasma concentrations were measured 30 minutes after injection. All tissue and plasma concentrations were measured by high performance liquid chromatography. RESULTS: Rats that received topical timolol daily for 3 to 12 consecutive days accumulated timolol concentrations of 2.3 to 4.4 microg/g in cornea, 198 to 326 microg/g in iris, 0.05 to 0.11 microg/ml in vitreous, and 0.17 to 0.77 microg/g in retina. In rats that received a single drop of timolol in one eye, the tissue concentrations were higher in the treated eye than in the untreated eye in all cases except for vitreous. In these experiments, timolol levels in plasma were either low or not detectable. Increasing timolol doses administered intraperitoneally resulted in corresponding increased tissue and plasma concentrations. CONCLUSIONS: Absorption of drug into the systemic circulation plays a significant role in delivering timolol to the retina and vitreous in addition to a local ocular route. A clear dose-response relationship exists in all ocular tissues studied after an intraperitoneal dose of timolol. High doses of timolol were required to achieve measurable concentrations of drug in the ocular tissues via our high performance liquid chromatography assay suggesting that a significant hepatic first-pass effect may be involved after an intraperitoneal injection of timolol.

Absorption↗

PubMed2002

Properties of perimetric threshold estimates from Full Threshold, SITA Standard, and SITA Fast strategies.

PURPOSE: To investigate the distributions of threshold estimates with the Swedish Interactive Threshold Algorithms (SITA) Standard, SITA Fast, and the Full Threshold algorithm (Humphrey Field Analyzer; Zeiss-Humphrey Instruments, Dublin, CA) and to compare the pointwise test-retest variability of these strategies. METHODS: One eye of 49 patients (mean age, 61.6 years; range, 22-81) with glaucoma (Mean Deviation mean, -7.13 dB; range, +1.8 to -23.9 dB) was examined four times with each of the three strategies. The mean and median SITA Standard and SITA Fast threshold estimates were compared with a "best available" estimate of sensitivity (mean results of three Full Threshold tests). Pointwise 90% retest limits (5th and 95th percentiles of retest thresholds) were derived to assess the reproducibility of individual threshold estimates. RESULTS: The differences between the threshold estimates of the SITA and Full Threshold strategies were largest ( approximately 3 dB) for midrange sensitivities ( approximately 15 dB). The threshold distributions of SITA were considerably different from those of the Full Threshold strategy. The differences remained of similar magnitude when the analysis was repeated on a subset of 20 locations that are examined early during the course of a Full Threshold examination. With sensitivities above 25 dB, both SITA strategies exhibited lower test-retest variability than the Full Threshold strategy. Below 25 dB, the retest intervals of SITA Standard were slightly smaller than those of the Full Threshold strategy, whereas those of SITA Fast were larger. CONCLUSIONS: SITA Standard may be superior to the Full Threshold strategy for monitoring patients with visual field loss. The greater test-retest variability of SITA Fast in areas of low sensitivity is likely to offset the benefit of even shorter test durations with this strategy. The sensitivity differences between the SITA and Full Threshold strategies may relate to factors other than reduced fatigue. They are, however, small in comparison to the test-retest variability.

Adult↗

PubMed2002

Comparison of the neuroprotective effects of adrenoceptor drugs in retinal cell culture and intact retina.

PURPOSE: The efficacy of beta1-adrenoceptor (AR)-selective (betaxolol and metoprolol) and nonselective (timolol) antagonists and the alpha2-AR agonist UK14,304 as retinal neuroprotectants was compared and contrasted in an in vitro glutamate excitotoxicity model. The ability of UK14,304, brimonidine, and betaxolol to alter glutamate-receptor-induced changes in intracellular calcium ([Ca2+]i) was also determined in isolated retinal neurons and retinal ganglion cells (RGCs) in an intact retina preparation. METHODS: Neuronal survival was measured in mixed retinal cell cultures treated for 24 hours with media containing 100 microM glutamate, with or without the addition of each of the drugs (1-1000 microM). Effects of glutamate on glia were also investigated in a C6 glioma cell line. Glutamate-induced changes in [Ca2+]i with and without UK14,304, and its analogue brimonidine were assessed by calcium-imaging techniques in retinal neurons in culture. The effect of betaxolol on [Ca2+]i was investigated in RGCs in intact rabbit retina. RESULTS: In cell cultures, 10-1000 microM glutamate resulted in a dose-dependent loss of neurons, but not of glia. The absence of glutamate toxicity in glia was confirmed in C6 glioma cells. Betaxolol, but not timolol or metoprolol, significantly increased survival (from 52% of control in glutamate-only to 78% with 10 microM betaxolol) after excitotoxic insult. UK14,304 also increased survival (from 62% of control in glutamate only to 109% and 101% of control with 10 and 100 microM UK14,304, respectively). This effect was blocked by the specific alpha2-antagonist, yohimbine. Both UK14,304 and brimonidine (10-100 microM) reduced glutamate-induced [Ca2+]i increases in retinal neurons in culture. The actions of the alpha2-agonists in reducing glutamate-induced [Ca2+]i increases were reduced by yohimbine (1 microM). Betaxolol (100 microM) reduced N-methyl-D-aspartate (NMDA)-induced increases of [Ca2+]i in RGCs in intact retina. CONCLUSIONS: Betaxolol reduced glutamate excitotoxicity in retinal neurons in vitro through a mechanism independent of beta-AR interactions. UK14,304, acting through alpha2-ARs, was also neuroprotective in vitro. The neuroprotective actions of betaxolol and the alpha2-agonists on retinal neurons may be due, at least in part, to a direct reduction of glutamate receptor-mediated increases of [Ca2+]i.

Adrenergic alpha-Agonists↗

PubMed2002

Effect of intraocular pressure on optic disc topography, electroretinography, and axonal loss in a chronic pressure-induced rat model of optic nerve damage.

PURPOSE: To characterize the effect of intraocular pressure (IOP) on optic disc topography, retinal function, and axonal survival in a model of IOP-induced optic nerve damage in rat. METHODS: Hypertonic (1.75 M) saline was injected into an episcleral vein of one eye of 49 Brown Norway rats, with the fellow untreated eye serving as the control. During the 1 to 3 months of follow-up, IOP was measured twice weekly in conscious animals with a handheld tonometer, and changes in disc topography and retinal function were monitored with scanning laser tomography and electroretinography (ERG), respectively. Peak IOP elevation in the experimental eye compared with the fellow control eye (peak deltaIOP), integral of IOP elevation over time (deltaIOP integral), and days of IOP elevation were calculated. Axon counts were obtained from electron micrographs of the sectioned optic nerves. RESULTS: Progressive cupping was found in 9 (56.3%) of 16 eyes with peak deltaIOP of more than 15 mm Hg and in none of 21 eyes with peak deltaIOP less than 15 mm Hg. A strong correlation between deltaIOP integral and progressive cupping was also found, but not with days of IOP elevation. ERG abnormalities (limited to the b-wave) were found in 11 (64.7%) of 17 eyes with peak deltaIOP of more than 15 mm Hg and in 2 (8.7%) of 23 eyes with peak deltaIOP of less than 15 mm Hg. Neither of the other IOP parameters was predictive of ERG damage. The proportion of surviving axons was negatively correlated to both deltaIOP and deltaIOP integral (P <or= 0.001). Progressive cupping was evident only with more than 55% axonal loss. Similarly, ERG results remained mostly within normal limits for low to moderate axonal loss, but were markedly abnormal with more than 70% axonal loss. CONCLUSIONS: Structural and functional changes in this model are best correlated to peak deltaIOP and not to duration of IOP elevation, suggesting the existence of an IOP-related damage threshold.

Animals↗

PubMed2002

Optic disc movement with variations in intraocular and cerebrospinal fluid pressure.

PURPOSE: To determine the effect of intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFP) on optic disc movement and lamina cribrosa displacement using confocal scanning laser tomography (CSLT). METHODS: The anterior chamber and lateral ventricles were cannulated in mixed-breed dogs (n = 8) to allow modulation and control of IOP and CSFP, respectively. Optic disc topography was determined after baseline (set at IOP 15 mm Hg and CSFP of 0 mm Hg) and with each step-wise increase in IOP (steps of 3-5 mm Hg up to an average of 32 mm Hg) with CSFP fixed at 0 mm Hg. After the pressure returned to baseline, images were obtained after each step-wise increase in CSFP (steps of 2 to 4 mm Hg up to an average of 12 mm Hg) with IOP fixed at 15 mm Hg. Data were analyzed by a new probabilistic method for CSLT and global parameters generated by the instrument software. The global parameter changes from baseline were analyzed as a function of the translaminar pressure difference (IOP minus CSFP). RESULTS: Elevation in IOP resulted in significant posterior displacement of the disc surface, whereas elevation in CSFP resulted in significant anterior displacement. For a given degree of pressure change, an increase in CSFP resulted in larger changes than a corresponding increase in IOP. The deepest 5% of locations within the disc surface were displaced nonlinearly (with an inverse exponential function, r = 0.92) as a function of the difference in translaminar pressure. Most displacement occurred at low translaminar pressure differences, with little extra movement at differences higher than 15 mm Hg. The change in the volume subtended by the anterior lamina cribrosa showed a nonlinear relationship similar to the translaminar pressure difference (r = 0.98), with negligible volume change at high difference in pressures. CONCLUSIONS: Most optic disc movement occurs with pressure changes in the low range of translaminar pressure differences. This is consistent with the mechanical properties of collagen.

Animals↗