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Biomedical subjects

Roger A Hitchings

Publications and source records attributed to Roger A Hitchings.

At least 19 recordsLinked to original sources
PubMed2005

Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene.

PURPOSE: To investigate the clinical features of subjects with glaucoma with the E50K mutation in the optineurin (OPTN) gene and to compare the onset, severity, and clinical course of these patients with a control group of subjects with glaucoma without this mutation. METHODS: The phenotype of well-characterized subjects from Moorfields Eye Hospital, London, who had been identified as carrying the OPTN E50K mutation was examined. A wide range of structural, psychophysical, and demographic factors were then compared with those in a control group of subjects with glaucoma without this mutation. RESULTS: Eleven subjects with glaucoma with the E50K mutation (nine in two families and two sporadic cases) were studied. All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing. Compared with 87 NTG control subjects who did not have this mutation, subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area (+/-SD; 0.5 +/- 0.28 mm2, P = 0.001) at diagnosis. The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields. In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma. CONCLUSIONS: In this study, subjects with glaucoma who had the OPTN E50K mutation were found to have NTG that appeared to be more severe than that in a control group of subjects with NTG without this mutation. The findings emphasize the importance of early detection and treatment of glaucoma in such individuals, to minimize visual loss.

Adult↗
PubMed2004

Associations between the deletion polymorphism of the angiotensin 1-converting enzyme gene and ocular signs of primary open-angle glaucoma.

BACKGROUND: Primary open-angle glaucoma (POAG) is a leading cause of blindness. High intraocular pressure (IOP) has been shown to be a key risk factor for POAG. Topical application of angiotensin 1-converting enzyme (ACE) inhibitors has been shown to lower IOP, and angiotensin-induced increase in vascular tone has been implicated as a pathogenetic mechanism in glaucomatous cupping and damage to the optic nerve. The objective of this study was to investigate the association between the deletion polymorphism in the ACE gene and ocular signs of POAG. METHODS: Baseline data from the Rotterdam Study was used. The ACE genotype was determined in 6,462 subjects. We used univariate and multiple variable statistical techniques to examine associations between ACE genotype and each of ocular hypertension, glaucomatous optic neuropathy, glaucomatous visual field defects and POAG diagnosis. RESULTS: We found no consistent evidence between ACE genotype and ocular signs of POAG. We did, however, find evidence of an association between ACE genotype and optic disc area, subjects homozygous for the deletion allele tending to have fractionally smaller optic disc areas than those with a single deletion allele subjects, who in turn tended to have fractionally smaller optic discs than those with no deletion alleles (P=0.01). CONCLUSIONS: The data provided little evidence of any association between ocular signs of POAG and the deletion polymorphism of ACE. There was, however, evidence that ACE may be associated with optic disc size-this was an unexpected finding.

Aged↗
PubMed2004

Gold standard medical therapy for glaucoma: defining the criteria identifying measures for an evidence-based analysis.

BACKGROUND: Over the past decade, several new medical therapies have become available for the treatment of primary open-angle glaucoma (POAG). A systematic evidence-based approach for identifying an optimal therapeutic agent is lacking. OBJECTIVES: The aims of this review were to critically evaluate published treatment recommendations for POAG and, based on a systematic review of the literature, to develop criteria that would define a "gold standard" medical therapy that reflects new treatment advances and established therapeutic goals. METHODS: A MEDLINE search spanning the years 1966 to 2002 and using the search terms gold standard, drug of choice, agent of choice, benchmark, ophthalmology, eye, and glaucoma was conducted and the results reviewed by a panel of 15 experts in the field of glaucoma. Published treatment recommendations for POAG were discussed. Criteria, anchored to medical evidence, for distinguishing a standard of medical therapy for POAG were defined. RESULTS: The terms connoting a gold standard therapy were found in only 258 of approximately 368,000 ophthalmology-related citations and 53 of almost 23,000 glaucoma citations, validating the need to define therapeutic standards. The lack of recommendations for the use of new classes of ocular hypotensive agents was acknowledged. Criteria identified to evaluate intraocular pressure (IOP)-lowering agents as gold standards included the following: efficacy in reducing IOP consistently over a 24-hour period to a level that will preserve the visual field and protect the optic nerve without inducing tachyphylaxis and tolerance, paucity of local and systemic adverse effects, promotion of patient compliance, and applicability in diverse patient populations. CONCLUSIONS: These criteria should be employed as measures for evidence-based analyses to evaluate available and future IOP-lowering medical therapies for POAG. The conceptual framework presented may be applicable to other therapeutic areas.

Adrenergic beta-Antagonists↗
PubMed2004

Reducing noise in suspected glaucomatous visual fields by using a new spatial filter.

Visual field testing with automated perimetry is hampered by the amount of noise present in the readings. Here, we derive a physiologically accurate spatial filter to be applied to the data after patient examination. The filter was tested by a Virtual Eye computer simulation. By simulating series of stable fields it was shown that specificity of determining visual field changes was improved; while simulating progressing fields (based on a map of the optic nerve head) it was shown that sensitivity was also improved. The filter appears to reduce the noise in glaucomatous visual field data and may be clinically useful.

Computer Simulation↗
PubMed2004

Commingling analysis of intraocular pressure and glaucoma in an older Australian population.

PURPOSE: To test the hypothesis of a major genetic determinant of intraocular pressure (IOP) under the mixed genetic model in a defined population, and to elucidate the relationship between IOP and glaucoma. METHODS: IOP was measured in 3654 persons attending the Blue Mountains Eye Study. A commingling analysis on IOP was performed using a new program, SKUDRIVER. The goodness of fit of 1-, 2- and 3-distribution models was measured. This was repeated after the glaucoma cases had been removed from the dataset, and further repeated on the glaucoma cases in the dataset. RESULTS: The best model was 3-distribution with no evidence for Hardy-Weinberg disequilibrium. The proportion of variance explained by this major effect was 0.18. When glaucoma cases were removed, the best model had 2 distributions. There was no evidence of admixture in glaucoma patients. CONCLUSIONS: The findings of this study are consistent with the presence of a major gene accounting for 18% of the variance of IOP, which could therefore influence the risk of glaucoma, in this population. These findings suggest methods of optimizing strategies for family and association studies to identify quantitative trait loci for IOP. No evidence for distinct IOP-dependent and IOP-independent subgroups of glaucoma was found.

Adult↗
PubMed2004

Magnification changes in scanning laser tomography.

PURPOSE: It is important when evaluating glaucomatous optic disc progression in longitudinal images that image magnification remains unchanged. We studied the effect of changed lens power on magnification in scanning laser tomography. The relative contribution to magnification of axial length, eye-scanner distance, and image-to-image scaling was also assessed. METHODS: A simulated optic disc in a model eye was imaged using the Heidelberg Retina Tomograph. Lens power was alterable by exchanging intraocular lenses (IOL) mounted at the lens plane of the eye to mimic changes in the crystalline lens. IOL power of +20.0D and axial length of 21.5 mm was compatible with emmetropia. The optic disc was imaged through IOLs differing in power (+16.0D to +25.0D) but with axial length kept constant. IOL power was then held constant and imaging was repeated for various axial lengths (17.5-23.5 mm). Model eye-scanner distance was varied with each test sequence. The distances between landmarks on the disc was measured before and after contour lines were exported. RESULTS: Image size varied with IOL power and axial length (r > 0.98; P < 0.0001), with the magnification effect of a +1D increase in lens power equivalent to a third the magnification effect of a 1-mm increase in axial length. Magnification tended to increase with myopia (IOL power > +20.0D) and was accentuated by longer eye-scanner distances. Image-to-image scaling corrected some magnification though this varied with ametropia. CONCLUSIONS: Changed lens power, axial length, and eye-scanner distance can affect the size of the optic disc in scanning laser tomography images. The exported contour line partly compensates for changed magnification.

Disease Progression↗
PubMed2004

Validity of rim area measurements by different reference planes.

PURPOSE: Reference plane description of the neuroretinal rim in scanning laser tomography should correctly represent optic nerve morphology. We evaluated how well rim area analysis by different reference planes agreed with the appearance of rim area in disc images. METHODS: Three expert observers subjectively and repeatedly analyzed rim area in Heidelberg Retina Tomograph (HRT) images so that each optic disc was measured six times in 100 eyes, 50 normal and 50 glaucoma. Rim area was evaluated globally and in 30 degree sectors. Agreement between rim appearance, as subjectively analyzed, and objective analysis by an experimental reference plane, the standard reference plane, and a reference plane fixed 320 microm below the reference ring was assessed in HRT images. RESULTS: Subjective analysis of rim area in HRT images was consistent between expert observers. Their analysis of rim appearance agreed more closely with experimental reference plane analysis than analysis by the standard or 320-microm reference planes; this was true globally and in every region of the nerve (P = 0.000). The experimental reference plane yielded higher estimates of rim area than did the standard or 320-microm reference planes. CONCLUSION: There was closer correspondence between the appearance of the neuroretinal rim in images and description by the experimental reference plane compared with description by the standard and 320-microm reference planes.

Aged↗
PubMed2004

Reversal of disc cupping after intraocular pressure reduction in topographic image series.

PURPOSE: To identify and characterize 'reversal' of optic nerve cupping following intraocular pressure (IOP) lowering in scanning laser tomography (SLT) longitudinal image series. METHODS: Modification was made to a previously described analytical approach to longitudinally study putatively increased rim area following IOP lowering. Sustained IOP reduction of 25% was by topical medication. Forty SLT image series with equivalent follow up were assessed: 10 with ocular hypertension (OHT), 10 with primary open angle glaucoma (POAG), and as controls, 20 normal. Reproducible rim area reversal was identified by sector and its time-course over 1 year examined. RESULTS: By a 2-of-3 reproducibility criterion, reversal following IOP lowering was confirmed in about a third of treated eyes (POAG and OHT) but not in any controls. Rim sectors showing reversal were mostly nasal, with a few occurring superotemporally. Reversal in a fifth of treated eyes persisted for at least 1 year; all these were in the nasal half of the disc. The number of sectors with persisting reversal affected less than 6% of all treated eyes' rim sectors. CONCLUSION: Rim area is not uncommonly increased after IOP lowering and this 'reversal' may persist for at least a year. Within topically treated eyes having IOP lowering of at least 25%, the proportion of rim sectors with persistent reversal appears small. Nevertheless, the effects of IOP reduction on topography, especially in the short term, should be considered when longitudinally assessing progressive rim loss in SLT images.

Aged↗
PubMed2004

Optimizing and validating an approach for identifying glaucomatous change in optic nerve topography.

PURPOSE: To determine and validate optimal parameters for analysis in a previously described approach for identifying glaucomatous optic nerve progression by scanning laser tomography. METHODS: Thirty-degree sectors of rim area, as defined by an experimental reference plane, were analyzed for change with respect to different statistical limits of variability (80%, 90%, 95%, 98%, 99%, and 99.9%) in the longitudinal image series of 62 eyes from 30 ocular hypertension converters and 32 normal control subjects. A criterion requiring that change is repeatable in two of three consecutive tests (the 2-of-3 criterion) was compared with a single-test strategy not requiring confirmation, and four other plausible criteria. The influence of these various parameters on sensitivity and the false-positive rate was evaluated. The same series were also assessed for change by the known method of computer-generated probability maps. RESULTS: More sectors were identified as progressing in converter eyes than in control eyes at every limit of variability. With stricter limits of variability and a requirement of confirmation, fewer sectors were identified as changing, especially in control eyes. The 2-of-3 criterion had the most favorably balanced sensitivity and false-positive rates: these were, for the 90% limit of variability, 90.0% and 6.2%, respectively, and for the 95% limit, 83.3% and 3.1%, respectively. Confirmed rim loss in converter eyes was most frequent in the disc poles and corresponded with the field hemisphere of conversion in 80%. Probability maps detected significant and repeatable change in 26 (86.7%) of 30 converter eyes and 14 (43.8%) of 32 of control eyes. CONCLUSIONS: This study was conducted to optimize and validate an approach for identifying progression. The method distinguished eyes with glaucomatous change from unchanging control eyes.

Adult↗
PubMed2004

Tomographic identification of neuroretinal rim loss in high-pressure, normal-pressure, and suspected glaucoma.

PURPOSE: To identify progressive rim loss and describe patterns of regional change in various clinical presentations of glaucoma by scanning laser tomography (SLT). METHODS: A previously described analytical approach was used to identify progressive rim area loss in SLT disc images of eyes of people with ocular hypertension (OHT, n = 97), early POAG (OHT converters; n = 30), asymmetric normal-pressure glaucoma (NPG, established and suspected in contralateral eyes; n = 26), and normal control subjects (n = 32). Analysis was performed longitudinally in individual image series, and cross-sectionally within groups at different time points. RESULTS: Reproducibly reduced rim area was detected in 2 (6.2%) of 32 normal control subjects, 11 (11%) of 97 OHT subjects, 27 (90%) of 30 OHT converters, 16 (58%) of 26 of suspected NPG eyes, and 15 (54%) of 26 of established NPG eyes (mean MD = -6.5 dB). Of 5 (19%) of 26 of suspected NPG eyes that converted on visual field testing, rim loss was detected in 3 of 5. In all groups, rim loss was common in the disc poles, especially inferiorly. Patterns of rim loss were similar within high-pressure and normal-pressure groups, whether or not eyes had field defects in each. In high-pressure groups, rim loss was more common nasally than temporally. Normal-pressure groups, unlike high-pressure groups, frequently had rim loss temporally. Suspected NPG eyes had more rim loss temporally and their rim area tended to be less compared with OHT and OHT converters, despite the three groups having equivalent baseline fields. CONCLUSIONS: There were similarities and differences in the pattern of rim loss in SLT disc images of high- and normal-pressure presentations of glaucoma. Progressive rim loss was detected in eyes without visual field defects, eyes that progressed to develop field defects, and eyes with established and more severe glaucoma.

Adult↗
PubMed2003

Reasons for rim area variability in scanning laser tomography.

PURPOSE: To determine reasons for rim area variability in scanning laser tomography. METHODS: Regional rim area variability from testing in same and different visits and by same and different observers was characterized in 30 normal and 42 glaucomatous eyes. Variations in (1) optic nerve head (ONH) surface geometry (center of gravity: X, Y, Z), (2) image tilting (horizontally and vertically), and (3) position of the reference plane in relation to the ONH (REF) were analyzed by multiple regression analysis. Whether and how much these factors explain rim area variability was studied in cross-sectional and longitudinal data by using two different reference planes. RESULTS: Variability was higher in glaucoma and in testing by different observers in separate visits. Across a range of eyes, approximately 40% of variability in single-topography images and 60% of variability in mean-topography images was explained. In individual image series, a median 85% of variability was explained, exceeding 90% in at least 25% of eyes. The most frequent contributors to rim area variability were REF (in > or =95%) and Z (in > or =80%); they also usually explained more variability than other factors. The nature of variability differed between reference planes. CONCLUSIONS: A large proportion of rim area variability was explained by variation in the topographical features studied, especially REF and Z. Reference plane definition also influenced variability. Variation in the position of the reference plane in relation to the ONH can affect rim area measurements and should be considered when evaluating the progression of glaucoma.

Aged↗
PubMed2003

Reference plane definition and reproducibility in optic nerve head images.

PURPOSE: To describe and evaluate a new experimental reference plane for measuring rim area in scanning laser tomography. METHODS: The experimental reference plane was positioned so that (1) it always lay entirely below the margin of the optic nerve head (ONH), (2) it remained at a set z-axis distance below the ONH in images of each eye, and (3) it was at a level where variability in rim area is least. Twenty normal control subjects and 20 patients with glaucoma underwent test-retest scanning laser tomographic imaging by same and different operators during same and separate visits. Control subjects had image series spanning at least 3 years. The effect of the positioning of the reference plane on global and regional rim area variability was assessed in intra- and intervisit test-retest images and longitudinal image series and compared with the standard and 320- microm reference planes. RESULTS: Variability in the experimental reference plane was less in test-retest images and longitudinal data (P < 0.05) and more uniform around the ONH than with other reference planes. Variability in the former was not appreciably affected by testing involving different operators and visits, or by the presence of glaucoma. CONCLUSIONS: Variability in rim area by the experimental reference plane was significantly less, more uniform around the ONH, not affected by different operators and visits, and less affected by glaucomatous morphology than other reference planes. This difference was pronounced in sequential data and has implications for detecting progression of glaucoma.

Aged↗
PubMed2003

Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function.

PURPOSE: Mutations in murine and human versions of an ancestrally related gene usually result in similar phenotypes. However, interspecies differences exist, and in the case of two forkhead transcription factor genes (FOXC1 and FOXC2), these differences include corneal or anterior segment phenotypes, respectively. This study was undertaken to determine whether such discrepancies provide an opportunity for identifying novel human-murine ocular phenotypes. METHODS: Four pedigrees with early-onset glaucoma phenotypes secondary to segmental chromosomal duplications or deletions encompassing FOXC1 and 18 individuals from 9 FOXC2 mutation pedigrees underwent detailed ocular phenotyping. Subsequently, mice with mutations in Foxc1 or a related forkhead gene, Foxe3, were assessed for features of the human phenotypes. RESULTS: A significant increase in central corneal thickness was present in affected individuals from the segmental duplication pedigrees compared with their unaffected relatives (mean increase 13%, maximum 35%, P < 0.05). Alterations in corneal thickness were present in mice heterozygous and homozygous for Foxe3 mutations but neither in Foxc1 heterozygotes nor the small human segmental deletion pedigree. Mutations in FOXC2 resulted in ocular anterior segment anomalies. These were more severe and prevalent with mutations involving the forkhead domain. CONCLUSIONS: Normal corneal development is dependent on the precise dose and levels of activity of certain forkhead transcription factors. The altered corneal thickness attributable to increased forkhead gene dosage is particularly important, because it may affect the clinical management of certain glaucoma subtypes and lead to excessive treatment. The FOXC1 and Foxe3 data, taken together with the novel ocular phenotypes of FOXC2 mutations, highlight the remarkable cross-species conservation of function among forkhead genes.

Animals↗
PubMed2003

Approach for identifying glaucomatous optic nerve progression by scanning laser tomography.

PURPOSE: To describe and test an analytical approach for identifying glaucomatous optic nerve change by scanning laser tomography. METHODS: The approach (1). analyzed 30 degrees sectors of rim area by (2). a novel and reproducible experimental reference plane, (3). estimated and accounted for measurement variability in each sector, and (4). required that any change exceeding variability in a single (positive) test should be confirmed as repeatable by a criterion requiring two of three consecutive tests to be positive. The sensitivity and false-positive rate of a single positive test and the two-of-three criterion were assessed in image series of one eye each of 20 ocular hypertension patients who converted to glaucoma (referred to as converters) who had unambiguous disease progression, and in one eye each of 20 normal control subjects. RESULTS: Eighteen of 20 (90% sensitivity) converters and 7 of 20 (35% false-positive responses) control subjects had single positive test results, but with confirmation by the two-of-three criterion, the false-positive rate improved to 5% (1/20) whereas sensitivity was relatively preserved at 85% (17/20). CONCLUSIONS: Estimates of rim area variability in each sector of each nerve allowed change consistent with disease progression to be distinguished from measurement variability. Confirming that change is repeatable by the criterion used in the study resulted in considerably fewer false-positive responses than did testing without confirmation, but with sensitivity not significantly compromised in the former. By this approach, eyes with progressive glaucoma could be distinguished from unchanging normal control eyes.

Diagnostic Techniques, Ophthalmological↗
PubMed2002

Interpreting glaucoma progression by white-on-white perimetry.

Sequential automated static perimetry is commonly used to test whether glaucoma is progressing, but its interpretation depends on analysing complex numerical data and can be complicated. Various methods of analysis - both subjective and objective - can be used, but these methods differ in their interpretation of change. Test fluctuation and media opacities can also confound the evaluation of change. Recently, innovations in perimetric testing and analysis have sought to provide solutions. This article reviews what is known about the nature of visual field progression and examines the usefulness of perimetry in detecting worsening glaucoma.

Disease Progression↗
PubMed2002

Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma.

OPA1, the gene responsible for autosomal dominant optic atrophy, represents a good candidate gene for glaucoma, as there are similarities in the clinical phenotype and OPA1 is expressed in the optic nerve. Single nucleotide polymorphisms on intervening sequence (IVS) 8 of the OPA1gene (genotype IVS8+4 C/T;+32T/C) were recently found to be strongly associated with normal tension glaucoma (NTG). In order to investigate whether this association exists in patients with high-tension glaucoma (HTG), 90 well-characterized HTG patients were examined for the presence of these OPA1polymorphisms by PCR amplification followed by bi-directional sequencing. Five out of 90 HTG subjects (5.6%; 95% CI 1.8-12.5) were found to carry the OPA1 genotype IVS 8+4 C/T; +32 T/C, compared with 32/163 (19.6%; 95% CI 13.8-26.6) NTG subjects [chi(2)=9.2, P=0.002, OR 4.1 (95% CI 1.6-11.1)], and 7/186 (3.8%; 95% CI 1.5-7.6) control subjects [chi(2)=0.47, P=0.49, OR 1.5 (95% CI 0.5-4.9)]. These results indicate that unlike NTG, the OPA1 genotype IVS8+4 C/T,+32T/C is not significantly associated with high-tension primary open angle glaucoma, and suggest genetic heterogeneity between the conditions.

GTP Phosphohydrolases↗