Simvastatin downregulates adipogenesis in 3T3-L1 preadipocytes and orbital fibroblasts from Graves' ophthalmopathy patients.

BACKGROUND: Smoking is a strong risk factor for the development of Graves' ophthalmopathy (GO). Immediate early genes (IEGs) are overexpressed in patients with active GO compared to healthy controls. The aim of this study was to study the effects of tobacco smoking and simvastatin on preadipocytes and orbital fibroblasts (OFs) in the adipogenic process. METHODS: Cigarette smoke extract (CSE) was generated by a validated pump system. Mouse 3T3-L1 preadipocytes or OFs were exposed to 10% CSE with or without simvastatin. Gene expression was studied in preadipocytes and OFs exposed to CSE with or without simvastatin and compared to unexposed cells or cells treated with a differentiation cocktail. RESULTS: In 3T3-L1 preadipocytes, Cyr61, Ptgs2, Egr1 and Zfp36 expression levels were two-fold higher in cells exposed to CSE than in unexposed cells. Simvastatin downregulated the expression of these genes (1.6-fold, 5.5-fold, 3.3-fold, 1.4-fold, respectively). CSE alone could not stimulate preadipocytes to differentiate. Scd1, Ppar-γ and adipogenesis were downregulated in simvastatin-treated preadipocytes compared to nontreated preadipocytes 18-, 35- and 1.7-fold, respectively. In OFs, similar effects of CSE were seen on the expression of CYR61 (1.4-fold) and PTGS2 (3-fold). Simvastatin downregulated adipogenesis, PPAR-γ (2-fold) and SCD (27-fold) expression in OFs. CONCLUSION: CSE upregulated early adipogenic genes in both mouse 3T3-L1 preadipocytes and human OFs but did not by itself induce adipogenesis. Simvastatin inhibited the expression of both early and late adipogenic genes and adipogenesis in preadipocytes and human OFs. The effect of simvastatin should be investigated in a clinical trial of patients with GO.

Increased TRAb and/or low anti-TPO titers at diagnosis of graves' disease are associated with an increased risk of developing ophthalmopathy after onset.

Patients with low thyroid peroxidase antibodies (anti-TPO) and increased TSH-receptor antibodies (TRAb) at diagnosis of Graves' disease (GD) have been suggested to have an increased risk to develop Graves' ophthalmopathy (GO). The aim was to evaluate if GO development can be predicted.This is an observational study with registration of possible GD and GO risk factors.399 patients with GD were registered 2003-2008 in Malmö, Sweden and out of these 310 were retrospectively followed up to 6 years. The main outcome measures were anti-TPO titer, TRAb titer, smoking habits, radioiodine treatment and GO development.TRAb was assessed with a third generation assay at GD diagnosis in 231 patients. The proportion of patients with GO increased above the median 6.3 IU/L both at diagnosis of GD (p=0.001) and at follow-up (p=0.0001).The distribution of GO patients anti-TPO above or below 20 kIU/L at diagnosis of GD was similar between groups (p=0.239). However at follow-up anti-TPO<20 kIU/L was associated with an increased proportion of newly developed GO as compared to the cohort with anti-TPO>20 kIU/L (p=0.018).87% of patients who developed GO after GD diagnosis had TRAb above 6.3 IU/L and/or anti-TPO below 20 kIU/L. The proportion of GO was doubled in GD patients treated with radioiodine but could not explain the described findingsAnti-TPO<20 kIU/L and/or TRAb>6.3 IE/L at the time of GD diagnosis were associated with an increased risk to develop GO after diagnosis of GD.

Comparison of ranked segment analysis (RSA) and cup to disc ratio in computer-assisted optic disc evaluation.

PURPOSE: Ranked segment analysis is a new method for evaluation of optic nerve head topography with the Heidelberg Retina Tomograph. This analysis ranks sector measurements around the optic disc and compares these measurements with rank specific significance limits. We evaluated the diagnostic precision of the ranked segment analysis in a large clinical sample and compared with vertical cup/disc ratio measurements. Vertical cup/disc ratio measurements were not corrected for disc size. METHODS: We analysed optic disc images from 153 normal and 75 glaucomatous eyes using the Heidelberg Retina Tomograph (software version 2.01). Ranked segment analyses and vertical cup/disc ratio measurements were obtained from each optic disc image, and ROC curves were plotted. RESULTS: At the 95% specificity level, sensitivity was significantly lower for ranked segment analysis (70%) compared to vertical cup/disc ratio measurements (85%). Almost 30% of the discs in the glaucoma group were classified as normal using the ranked segment analysis. DISCUSSION: Ranked segment analysis yielded unacceptably poor discrimination, in fact, worse than cup/disc ratio with its known clinical limitations Glaucomatous disc damage typically occurs at the vertical poles of the disc. High rank measurements (low sector values) in normal eyes, on the other hand, are more common in the temporal disc sectors. Important spatial information is lost during the ranking procedure. This may partly explain the low sensitivity of the ranked segment analysis observed in our study. The results raise serious concerns regarding the clinical usefulness of ranked segment analysis.

Kinetic and static fixation methods in automated threshold perimetry.

PURPOSE: Static fixation is the standard method for stabilizing the eye during automated perimetry. Kinetic fixation is an alternative for fixation control in which the eye follows a moving target. This study was conducted to evaluate the fixation accuracy of static and kinetic fixation perimetry and to determine their ability to detect the absolute scotoma of the physiologic blind spot. METHODS: The 71 patients with early glaucomatous field loss (mean age 65 years) and 45 control subjects (mean age 57 years) recruited from five clinical sites underwent threshold testing on the Dicon perimeter (kinetic fixation; Vismed, San Diego, CA) and Humphrey Field Analyzer (static fixation). The frequency of Heijl-Krakau fixation catch-trial errors was used as an indicator of fixation accuracy, and the measured sensitivity at the physiologic blind spot was used as an indicator of perimetric accuracy. RESULTS: In patients with glaucoma, the frequency of fixation errors was significantly greater for kinetic fixation (17.2%) than for static fixation (10.2%). In the control group, the frequency of fixation errors also was significantly greater for kinetic fixation (27.5%) than for static fixation (12.6%). The threshold at the presumed location of the blind spot (15 degrees temporal, 3 degrees inferior from fixation) was 14.8 dB using kinetic fixation versus 4.0 dB with static fixation in patients with glaucoma, and 18.5 dB using kinetic fixation versus 2.5 dB using static fixation in the control group. CONCLUSION: Relative to static fixation, kinetic fixation was associated with fixation inaccuracy and underestimation of the absolute scotoma at the physiologic blind spot.

Perimetric probability maps to separate change caused by glaucoma from that caused by cataract.

We describe a new method for analysis of change in glaucomatous visual fields with the object to differentiate between changes caused by glaucoma from those caused by cataract. New pattern deviation change probability maps were developed from a prospectively collected glaucoma material and designed to be sensitive to changes in localized field loss, but to be unaffected by media-induced perimetric change. We compared the new change probability maps with the commercially available total deviation change probability maps in series of Humphrey perimetric tests in a glaucoma material of 43 eyes of 35 patients, who had undergone cataract surgery. When using the total deviation maps, considerable differences were seen between fields obtained before and after cataract surgery. Much smaller differences were seen when using the new change probability maps, that almost eliminated the common and disturbing effect of increasing cataract. This new tool could be of considerable help in differentiation between progressive glaucomatous visual field loss and deterioration caused by increasing media opacities.

Giant cell arteritis presenting with oculomotor nerve palsy.

We present a case of histologically proven giant cell arteritis presenting as an acute unilateral oculomotor nerve palsy without pupillary dilatation. The etiology and mechanisms involved in this uncommon phenomenon are discussed. It is emphasized that a giant cell arteritis with cranial nerve involvement is a medical emergency, and that swift diagnosis and treatment is necessary to avoid permanent disability.

Comparison of diagnostic performance and fixation control of two automated perimeters.

BACKGROUND: The Humphrey perimeter and its Statpac (analysis programs have been widely used and studied. Another statistical analysis program, FieldView, is used with the Dicon perimeter. The purpose of this study was to compare the diagnostic performance of the two perimeters and their statistical analysis packages. METHODS: Twenty-three normal subjects (age range, 27 to 83 years) and 31 patients with glaucoma or cerebrovascular disease (age range, 28 to 87 years) experienced in automated perimetry were examined using the Dicon and the Humphrey perimeters. RESULTS: The total number of significant points identified on the Humphrey total deviation probability maps was in close agreement with statistical expectations, while the Dicon total deviation probability maps yielded significantly more false-positive defects than expected for normals. Fixation loss ratios were almost twice as high with the Dicon perimeter (mean, 16%) as compared with the Humphrey perimeter (mean, 9%). The Humphrey perimeter was more reliable than the Dicon in measuring the defect depth of the physiological blind spot. CONCLUSION: The Dicon perimeter appears to yield excessive false-positive findings in normal subjects, resulting in poor sensitivity/specificity combinations, while at the same time failing to properly measure defect depth in scotomas.

A perimetric learner's index.

PURPOSE: Certain individuals need earlier perimetric experience before producing normal fields on automated static threshold perimetry. Mid-peripheral depressions and an unaffected central field are typical findings in such cases. We have devised a learner's index, to detect defect patterns that may be due to such perimetric inexperience. METHODS: The central visual field was partitioned into 5 concentric zones and averages of deviations from the age-corrected normal threshold values were studied in each zone. The third test session in 74 randomly selected normal subjects provided an experienced reference material. Visual field results typical of normal individuals lacking perimetric experience were represented by the first field test obtained from each of 7 subjects ('learners') from the same group, who showed significant learning during three test sessions. A linear discriminant function, learner's index, was constructed that discriminates between typically experienced and typically inexperienced field results in normals. RESULTS: Average deviation from age-corrected normal threshold increased with increasing eccentricity in the learner's initial fields. Clinical examples illustrate the intended use of the new index. CONCLUSIONS: The learner's index highlights those first field tests from eyes with normal visual fields, that deviate significantly from a normal experienced result in the direction of a learner's result. Patients showing significant learner's index are candidates for repeated visual field testing.

Physiology of cumulative defect curves; consequences in glaucoma perimetry.

Purely diffuse field loss is a controversial sign of early glaucoma. Cumulative defect curves have been proposed to distinguish between diffuse and localized visual field loss. In such curves, pointwise deviations from the normal reference field are ranked. The deviations are then compared with normative limits for each rank. The ranking leads to a complete loss of spatial information and ignoration of pointwise physiological threshold variability. We believed that this might impair the curves' intended ability to distinguish diffuse and localized types of defects. The lower 5% normative limit was estimated for each rank in the cumulative defect curve using Humphrey 30-2 tests of 88 subjects from the Statpac normal database. For each rank we identified those two test points (among the total of 6512 (74 test points in each of 88 subjects)) from which the 5% limit was calculated. The average eccentricity, eccrank, of those two points was then determined at each rank. For lower to intermediate ranks eccrank was spread out from center to periphery. When instead the 20 highest ranks (most depressed points) were considered eccrank was much concentrated peripherally. Our normative limits were subsequently used to evaluate field results in 101 patients with glaucoma. In this glaucoma evaluation group, the largest deviations were often encountered in central or paracentral scotomas, in sharp contrast to the more peripheral position in the normative group. These deviations often failed to reach the cumulative defect curve limits which originated from points in the mid-periphery where normal variability is large. At present, cumulative defect curves are not optimized to distinguish diffuse and localized field loss.

Pitfalls of automated perimetry in glaucoma diagnosis.

Perimetry is a cornerstone in glaucoma management. The detection of glaucomatous visual field loss is of crucial importance for diagnosing the disease. Automated threshold perimetry makes thorough testing of the central visual field very possible and high-quality data are often achieved. Certain factors, however, may hamper the visual field examination or visual field interpretation. Many diseases other than glaucoma are known to influence the visual field in more or less predictable ways. Of interest is also low patient reliability, learning and fatigue effects, as well as test artifacts and suboptimal test strategies or parameters. Finally, statistical aids provided by the built-in computer of the perimeter must be judged keeping in mind the population from which the patient is derived. We describe such pitfalls in glaucoma perimetry, how they can be identified, and dealt with clinically.

Diffuse visual field loss and glaucoma.

It is often claimed that general reduction, or diffuse loss, of perimetric sensitivity is an early sign of glaucoma. Our clinical experience and the results of a few other studies led us to believe otherwise. To investigate factors associated with diffuse field loss we reviewed 4222 Humphrey 30-2 threshold tests from 1582 eyes of 862 patients followed at our department. Most of these patients had ocular hypertension or glaucoma. Each field test was evaluated with the Glaucoma Hemifield Test of the Statpac 2 program. The Glaucoma Hemifield Test classifies field test results as within or outside normal limits regarding localized field loss and general shifts in sensitivity. General reduction of sensitivity without concomitant localized loss was found in 117 tests from 81 eyes of 69 patients. Corresponding patient records were found for 60 eyes of 60 patients. Media opacities or miotic therapy were noted in 46 eyes (77%), 10 eyes (17%) had end-stage field loss, and in 2 eyes (3%) other non-glaucomatous ocular pathology explained the diffuse loss of sensitivity. Thus, general reduction of differential light sensitivity as an isolated finding was almost always associated with reasons other than early to moderate glaucoma in this material mainly consisting of patients with glaucoma or increased intraocular pressure. Since only 2 out of the 1582 eyes had general reduction of sensitivity that was not explained by non-glaucomatous reasons, we conclude that purely diffuse field loss was not a sign of glaucoma.

Arcuate cluster analysis in glaucoma perimetry.

Typical glaucomatous visual field defects are often contiguous areas of diminished differential light sensitivity presenting as clusters of abnormally depressed points in the visual field chart. We investigated the value of recognizing arcuate cluster patterns, corresponding to the anatomy of the normal retinal nerve fiber layer. Cluster sizes were quantified using cluster volume and surface area. Clusters were analyzed separately in different regions of the visual field. Central 30 degrees static threshold fields from 87 eyes of 87 normal subjects and 101 eyes of 101 patients with glaucoma were studied. The two groups were discriminated with logistic regression. Central and nasal clusters were more indicative of glaucoma than were equally large clusters in other areas. Discrimination of normal and glaucoma eyes was significantly better with arcuate cluster analysis than with a traditional cluster analysis, which did not take cluster shape into account. Thus, arcuate cluster analysis was more sensitive to early central, paracentral, or nasal glaucomatous field loss and at the same time capable of deemphasizing common test artifacts and nondiagnostic field disturbances. Arcuate cluster volume gave better classification than did arcuate surface area. The results indicate that analysis of arcuate clusters offers substantial advantages as compared with traditional cluster analysis for recognition of early glaucomatous visual field loss.

Weighting according to location in computer-assisted glaucoma visual field analysis.

In recent years several aids for automated interpretation of visual field data have been suggested. We believed that incorporation of thorough knowledge of normal visual field variability would allow improvements in the performance of such aids since more attention would be paid to field results in areas with low physiological variability. Two visual field models for classification of fields in glaucoma based on comparisons of sensitivity values in the upper and lower hemifields and on analysis of test point clusters with diminished sensitivity were compared. Both models were constructed using logistic regression analysis in 101 normal eyes and 101 eyes with glaucoma. The first, more traditional model assumed Gaussian distributions of deviations from age-corrected normal thresholds and constant variability across the field (non-weighted model). The second model took into account empirically determined variability of pointwise threshold results and of cluster volumes in various visual field regions (weighted model). The two models were subsequently tested on an independent material of 163 normal eyes and 76 eyes with glaucoma. The weighted model gave significantly better classification of the fields in both materials. Accounting for physiological threshold variability can offer significant advantages in the construction of perimetric analysis aids for detection of glaucoma.

Spatial analyses of glaucomatous visual fields; a comparison with traditional visual field indices.

Interpretation of numeric automated threshold visual field results is often difficult. A large amount of data is obtained for every single field tested. Various approaches to summarize this data have been suggested, most commonly the mean and standard deviation of departures from age-corrected normal threshold values. These visual field indices differ substantially from subjective field interpretation where spatial relationships are important. We have previously devised two methods for automated field interpretation which take spatial information into account--regional up-down comparisons and arcuate cluster analysis. We now studied the merits of using these new spatial methods and compared them to traditional visual field indices for discrimination between normal and glaucomatous field results. Central static 30 degree field results in 101 eyes of 101 normal subjects and 101 eyes of 101 patients with glaucoma were discriminated using logistic regression analysis. The best field classification was obtained with a spatial visual field model combining up-down differences and arcuate clusters. The advantages of the spatial model were confirmed in an independent material of 163 eyes of 163 normal subjects and 76 eyes of 76 patients with glaucoma where eyes with large field defects had been removed. In this material the spatial model gave 87% sensitivity and 83% specificity while the best non-spatial model gave 82% sensitivity and 80% specificity. Visual field interpretation in glaucoma may be significantly enhanced if detection is focused on circumscribed field loss rather than on averages of differential light sensitivities and similar indices which do not take spatial relationships into consideration.

Glaucoma Hemifield Test. Automated visual field evaluation.

We have developed an algorithm, the Glaucoma Hemifield Test (GHT), for automated evaluation of single static threshold visual field test results in glaucoma. The GHT uses empirically determined limits of normality for up-down differences in the Statpac probability maps of the Humphrey Field Analyzer to detect localized visual field loss. It is also constructed to detect field loss that is symmetric around the horizontal meridian. Analysis is done in five corresponding pairs of sectors that are based on the normal anatomy of the retinal nerve fiber layer. Deviations from the age-corrected normal threshold in the most sensitive portions of the visual field are used to detect general reductions of sensitivity or abnormally high sensitivities. The GHT provides brief visual field evaluations printed on the field chart as plain text. The aim of this article is to describe the fundamentals of the analysis program and to provide clinical examples.

Evaluation of methods for automated Hemifield analysis in perimetry.

A new aid to perimetric analysis, the Glaucoma Hemifield Test, primarily evaluates up-down differences in automated static visual field tests. We analyzed the visual fields of 163 eyes of 163 normal subjects and 77 eyes of 77 patients with glaucoma diagnosed on bases other than perimetry using the Glaucoma Hemifield Test and a similar, previously developed, hemifield analysis method. The performance of the Glaucoma Hemifield Test was compared with that of the earlier method and the differences in test design were evaluated individually. The Glaucoma Hemifield Test allowed significantly improved separation between the normal group and the group with glaucoma than did the earlier method. This improvement was due to an increase in sensitivity, and was associated with the use of test point significances instead of threshold values, and a large normal database alone in the determination of normal limits.

Computer-assisted interpretation of visual fields in glaucoma.

Visual field abnormality is an important diagnostic sign in glaucoma. Therefore, the presence or absence of visual field loss most often strongly influences diagnostic and therapeutic decisions in glaucoma management. Interpretation of visual field results is often difficult, however. Physiological variability of perimetric sensitivity values contributes to these difficulties. It has been our aim to develop improved computer-assisted methods for the recognition of early glaucomatous field loss. Our approach has therefore been to design techniques that are highly sensitive to small but significant departures from normality. We have investigated normal physiological variability in perimetric results and combined the obtained knowledge with pathophysiological models which are sensitive to the spatial patterns of field loss commonly seen in glaucoma. Thus, we have devised probability scores in order to take the complex physiological variability into account, and developed a hemifield analysis and an arcuate cluster analysis based on the normal anatomy of the retinal nerve fibre layer. A fundamental approach in the collection of normative data and the selection of glaucoma cases used in this project has been to select subjects using non-perimetric criteria (except for the removal of large field defects). Our objective here was to reduce bias from pre-conceived ideas of visual fields. This approach was used for (1) empirical studies on physiological variability, (2) development of analysis methods, and (3) evaluation of such methods. Glaucoma patients were selected based on evaluations of optic disc appearance. Normal subjects were never eliminated on the basis of perimetric results alone. The new methods developed in these studies have significantly improved discrimination between normal and glaucomatous field results, as compared with previously available techniques. Our results indicated that the usage of probability scores was the main source of this improvement, and that the location of observed field abnormalities and spatial modelling were other important factors. Candidate methods which did not properly combine spatial and normative analyses resulted in false positive defects in the mid-periphery and/or underestimated paracentral glaucomatous field defects. Similar approaches based on classification of visual field results in terms of significances, and on recognition of specific spatial patterns of field loss could be used for other groups of diseases having visual field abnormality as an important diagnostic sign.(ABSTRACT TRUNCATED AT 400 WORDS)

Visual field interpretation with empiric probability maps.

Automated visual field charts may be difficult to interpret partly because of the magnitude and complex nature of normal threshold variability. We devised two types of empiric probability maps in which this variability is taken into account and the significances of measured threshold values are displayed. These maps are highly sensitive to nonobvious but significant paracentral field loss but will at the same time deemphasize false-positive patterns commonly found more peripherally. They also frequently show field defects before these are obvious in conventional threshold printouts. In addition, they differentiate between generalized loss of sensitivity and localized field defects.

A clinical study of perimetric probability maps.

Perimetric probability maps depict visual field results in terms of the frequency with which the measured findings are seen in a normal population. We tested clinically the importance of the model of the normal visual field used to calculate such maps. Forty-one eyes of 41 normal subjects and 58 eyes of 46 glaucomatous patients were studied. Probability maps were calculated by means of two different models of the normal visual field. The first model assumed gaussian threshold distributions with constant variability across the field. The second used empirically determined nongaussian location-dependent threshold distributions. Probability maps using the empiric model allowed better separation between glaucomatous and normal eyes, and the number of significant points in normal subjects was in better agreement with the theoretically expected number. The gaussian model yielded an unacceptably high frequency of significant points in normal fields, particularly in the midperiphery. The clinical usefulness of perimetric probability maps depends critically on the choice of normal visual field model.