Manuele Michelessi

Influence of Disc Size on Optic Nerve Head versus Retinal Nerve Fiber Layer Assessment for Diagnosing Glaucoma

PURPOSE To explore and compare the influence of optic disc size on the diagnostic accuracy of retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) quantitative assessment. DESIGN Observational, cross-sectional evaluation of diagnostic tests. PARTICIPANTS We included 120 eyes from 50 normal subjects and 70 glaucomatous patients classified by the presence of a repeatable visual field defect for the analysis. TESTING The RNFL thickness was measured by scanning laser polarimetry with variable corneal compensator (GDx-VCC, Carl-Zeiss Meditec, Dublin, CA) and spectral-domain optical coherence tomography (Cirrus HD-OCT, Carl Zeiss Meditec, Inc). We obtained ONH imaging by means of confocal scanning laser ophthalmoscopy (HRT3; Heidelberg Engineering, GmbH, Dossenheim, Germany). MAIN OUTCOME MEASURES Sensitivity and specificity for normative classifications, sensitivity at fixed specificity and area under the receiver operating characteristics curve (AUC) for continuous parameters. A logistic marginal regression model and coefficients of variation (CoV) have been used to test and quantify the influence of optic disc size on the diagnostic accuracy of the 3 technologies under investigation. RESULTS Among continuous parameters average RNFL thickness for Cirrus HD-OCT, nerve fiber indicator for GDx-VCC and cup shape measure for the HRT3 showed the best diagnostic accuracy with an AUC of 0.97, 0.94, and 0.94, respectively. Among normative classifications, the highest sensitivity and specificity were found for OCT average RNFL thickness (75.8% and 94.7%), for GDx superior thickness (77.1% and 97.5%), for HRT3 Moorfields regression analysis result (89.4% and 73.7%) and for HRT3 GPS global (92.3% and 76.5%). The diagnostic performance of HRT3 parameters seemed to be significantly influenced by optic disc size, although the same was not true for Cirrus HD-OCT and GDx VCC. The most steady performers for each imaging device across disc size groups were Cirrus HD-OCT average thickness (CoV, 1.6%), GDx-VCC inferior thickness (CoV, 2.5%), and HRT3 GPS temporal and nasal (CoV, 21.4%). CONCLUSIONS The diagnostic accuracy of quantitative RNFL assessment as performed by Cirrus HD-OCT and GDx-VCC is high and virtually unaffected or only minimally affected by the size of the optic disc and may provide more consistent diagnostic outcomes across small and large discs than ONH assessment as performed by HRT3.

Sector-Based Analysis with the Heidelberg Retinal Tomograph 3 Across Disc Sizes and Glaucoma Stages: A Multicenter Study

PURPOSE To investigate the ability of sectorial analysis using the Heidelberg Retinal Tomograph 3 (HRT3) to discriminate between healthy and glaucomatous eyes and to determine whether this is affected by disc size and glaucoma severity. DESIGN Multicenter, cross-sectional evaluation of diagnostic tests. PARTICIPANTS Two hundred thirty-three eyes from 137 normal subjects and 96 glaucoma patients classified by the presence of a repeatable visual field defect. TESTING Participants underwent imaging with the HRT3, and the diagnostic accuracy of stereometric parameters, Moorfields regression analysis (MRA), and glaucoma probability score (GPS) were analyzed sectorially by glaucoma stage and optic disc size. MAIN OUTCOME MEASURES Sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristics curve (AUC). RESULTS Of stereometric parameters, the cup-to-disc area ratio of the inferotemporal sector had the largest AUC (AUC, 0.74). Both MRA and GPS algorithms showed the best diagnostic accuracy in the inferotemporal sector, with a sensitivity and specificity of 63% and 88% for MRA and 80% and 62% for GPS, respectively. In small discs, sectorial MRA analysis had higher diagnostic accuracy than the global optic nerve head (ONH) analysis (sensitivity of 70% and specificity of 82% in the inferonasal sector), and these findings were confirmed in very large discs (sensitivity of 74% and specificity of 85% in the inferotemporal sector). Similarly, stereometric parameters discriminated better sectorially rather than globally, with different parameters giving the best results in different optic disc size subgroups. MRA sensitivity was weak in the early-glaucoma stage, with slightly higher figures if considered sectorially rather than globally. GPS diagnostic accuracy was very consistent across ONH sectors in each disc size and glaucoma stage subgroup, with no single sector demonstrating better diagnostic accuracy than the global analysis. CONCLUSIONS Heidelberg Retinal Tomograph 3 sectorial analysis showed moderate diagnostic performance and may offer potential advantages over global analysis in the clinical diagnostic process. Small discs are classified more accurately by examining the inferonasal sector, whereas larger discs are classified more accurately by examining the inferotemporal sector. Neither HRT parameters nor classification algorithms seem to be good at the earlier stage of the disease. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Effects of Topical Bimatoprost 0.01% and Timolol 0.5% on Circadian IOP, Blood Pressure and Perfusion Pressure in Patients with Glaucoma or Ocular Hypertension: A Randomized, Double Masked, Placebo-Controlled Clinical Trial.

Purpose To compare the 24-hour (24h) effects on intraocular pressure (IOP) and cardiovascular parameters of timolol 0.5% and bimatoprost 0.01% in open angle glaucoma and ocular hypertensive subjects. Methods In this prospective, randomized, double masked, crossover, clinical trial, after washout from previous medications enrolled subjects underwent 24h IOP, blood pressure (BP) and heart rate (HR) measurements and were randomized to either topical bimatoprost 0.01% at night plus placebo in the morning or to timolol 0.5% bid. After 8 weeks of treatment a second 24h assessment of IOP, BP and HR was performed and then subjects switched to the opposite treatment for additional 8 weeks when a third 24h assessment was performed. The primary endpoint was the comparison of the mean 24h IOP after each treatment. Secondary endpoints included the comparisons of IOP at each timepoint of the 24h curve and the comparison of BP, HR, ocular perfusion pressure and tolerability. Results Mean untreated 24h IOP was 20.3 mmHg (95%CI 19.0 to 21.6). Mean 24h IOP was significantly lower after 8 weeks of treatment with bimatoprost 0.01% than after 8 weeks of treatment with timolol 0.5% bid (15.7 vs 16.8 mmHg, p = 0.0003). Mean IOP during the day hours was significantly reduced from baseline by both drugs while mean IOP during the night hours was reduced by -2.3 mmHg (p = 0.0002) by bimatoprost 0.01% plus placebo and by -1.1 mmHg by timolol 0.5% bid (p = 0.06). Timolol 0.5% significantly reduced the mean 24h systolic BP from baseline, the diastolic BP during the day hours, the HR during the night hours, and the mean 24h systolic ocular perfusion pressure. Conclusion Both Bimatoprost 0.01% and Timolol 0.5% are effective in reducing the mean 24h IOP from an untreated baseline but Bimatoprost 0.01% is more effective than timolol 0.5% throughout the 24h. Timolol 0.5% effect on IOP is reduced during the night hours and is associated with reduced BP, HR and ocular perfusion pressure. Trial Registration EU Clinical Trial Register and EudraCT# 2010-024272-26

Cytidine 5'-Diphosphocholine (Citicoline) in Glaucoma: Rationale of Its Use, Current Evidence and Future Perspectives.

Cytidine 5′-diphosphocholine or citicoline is an endogenous compound that acts in the biosynthetic pathway of phospholipids of cell membranes, particularly phosphatidylcholine, and it is able to increase neurotrasmitters levels in the central nervous system. Citicoline has shown positive effects in Parkinson’s disease and Alzheimer’s disease, as well as in amblyopia. Glaucoma is a neurodegenerative disease currently considered a disease involving ocular and visual brain structures. Neuroprotection has been proposed as a valid therapeutic option for those patients progressing despite a well-controlled intraocular pressure, the main risk factor for the progression of the disease. The aim of this review is to critically summarize the current evidence about the effect of citicoline in glaucoma.

STARD 2015 was reproducible in a large set of studies on glaucoma

Aim To investigate the reproducibility of the updated Standards for the Reporting of Diagnostic Accuracy Studies tool (STARD 2015) in a set of 106 studies included in a Cochrane diagnostic test accuracy (DTA) systematic review of imaging tests for diagnosing manifest glaucoma. Methods One senior rater with DTA methodological and clinical expertise used STARD 2015 on all studies, and each of three raters with different training profiles assessed about a third of the studies. Results Raw agreement was very good or almost perfect between the senior rater and an ophthalmology resident with DTA methods training, acceptable with a clinical rater with little DTA methods training, and only moderate with a pharmacology researcher with general, but not DTA, systematic review training and no clinical expertise. The relationship between adherence with STARD 2015 and methodological quality with QUADAS 2 was only partial and difficult to investigate, suggesting that raters used substantial context knowledge in risk of bias assessment. Conclusions STARD 2015 proved to be reproducible in this specific research field, provided that both clinical and DTA methodological expertise are achieved through training of its users.

Combination medical treatment for primary open angle glaucoma and ocular hypertension: A network meta-analysis

This is the protocol for a review and there is no abstract. The objectives are as follows: The objectives of this review are to examine the comparative effectiveness and safety of different glaucoma fixed combination therapies and monotherapies in eyes with primary open angle glaucoma or ocular hypertension and to provide relative rankings of these treatments.

Diagnostic accuracy of optical coherence tomography for diagnosing glaucoma: secondary analyses of the GATE study

Background/Aims To assess the diagnostic performance of retinal nerve fibre layer (RNFL) data of optical coherence tomography (OCT) for detecting glaucoma. Methods Secondary analyses of a prospective, multicentre diagnostic study (Glaucoma Automated Tests Evaluation (GATE)) referred to hospital eye services in the UK were conducted. We included data from 899 of 966 participants referred to hospital eye services with suspected glaucoma or ocular hypertension. We used both eyes’ data and logistic regression-based receiver operator characteristics analysis to build a set of models to measure the sensitivity and specificity of the average and inferior quadrant RNFL thickness data of OCT. The reference standard was expert clinician examination including automated perimetry. The main outcome measures were sensitivity at 0.95 specificity and specificity at 0.95 sensitivity and the corresponding RNFL thickness thresholds. We explored the possibility of accuracy improvement by adding measures of within-eye and between-eye variation, scan quality, intraocular pressure (IOP) and age. Results Glaucoma was diagnosed in at least one eye in 17% of participants. Areas under the curve were between 0.83 and 0.88. When specificity was fixed at 0.95, the sensitivity was between 0.38 and 0.55, and the highest values were reached with models including the inferior quadrant rather than the average RNFL thickness. Fixing sensitivity at 0.95, the specificity was between 0.36 and 0.58. The addition of age, refractive error, IOP or within-subject variation did not improve the accuracy. Conclusion RNFL thickness data of OCT can be used as a diagnostic test, but accuracy estimates remain moderate even in exploratory multivariable modelling of aiming to improve accuracy.

Macular versus nerve fibre layer versus optic nerve head imaging for diagnosing glaucoma at different stages of the disease: Multicenter Italian Glaucoma Imaging Study

To compare the diagnostic accuracy of minimum rim width (MRW), peripapillary retinal nerve fibre layer (pRNFL) and multilayered macular analysis by Spectralis SD‐OCT (Heidelberg Engineering, Germany) in discriminating perimetric glaucoma at different stages of the disease from healthy eyes.

Diagnostic accuracy research in glaucoma is still incompletely reported: An application of Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015

Background Research has shown a modest adherence of diagnostic test accuracy (DTA) studies in glaucoma to the Standards for Reporting of Diagnostic Accuracy Studies (STARD). We have applied the updated 30-item STARD 2015 checklist to a set of studies included in a Cochrane DTA systematic review of imaging tools for diagnosing manifest glaucoma. Methods Three pairs of reviewers, including one senior reviewer who assessed all studies, independently checked the adherence of each study to STARD 2015. Adherence was analyzed on an individual-item basis. Logistic regression was used to evaluate the effect of publication year and impact factor on adherence. Results We included 106 DTA studies, published between 2003–2014 in journals with a median impact factor of 2.6. Overall adherence was 54.1% for 3,286 individual rating across 31 items, with a mean of 16.8 (SD: 3.1; range 8–23) items per study. Large variability in adherence to reporting standards was detected across individual STARD 2015 items, ranging from 0 to 100%. Nine items (1: identification as diagnostic accuracy study in title/abstract; 6: eligibility criteria; 10: index test (a) and reference standard (b) definition; 12: cut-off definitions for index test (a) and reference standard (b); 14: estimation of diagnostic accuracy measures; 21a: severity spectrum of diseased; 23: cross-tabulation of the index and reference standard results) were adequately reported in more than 90% of the studies. Conversely, 10 items (3: scientific and clinical background of the index test; 11: rationale for the reference standard; 13b: blinding of index test results; 17: analyses of variability; 18; sample size calculation; 19: study flow diagram; 20: baseline characteristics of participants; 28: registration number and registry; 29: availability of study protocol; 30: sources of funding) were adequately reported in less than 30% of the studies. Only four items showed a statistically significant improvement over time: missing data (16), baseline characteristics of participants (20), estimates of diagnostic accuracy (24) and sources of funding (30). Conclusions Adherence to STARD 2015 among DTA studies in glaucoma research is incomplete, and only modestly increasing over time.