Pattern electroretinogram, blue-yellow visual evoked potentials and the risk of developing visual field defects in glaucoma suspects: a longitudinal "survival" analysis with a very long follow-up.

PURPOSE: Estimating glaucoma suspects' risk for visual field defects helps to avoid under- and over-treatment. In this retrospective, longitudinal cohort study with a very long follow-up, we studied whether pattern electroretinograms (PERG) amplitudes and blue-on-yellow visual evoked potential (BY-VEP) latencies can predict visual field defects. METHODS: Participants of the Erlangen Glaucoma Study were examined with PERG and BY-VEP between 9/1991 and 8/2001. Stimuli were created using an optical bench with Maxwellian view and consisted of vertical gratings (0,88 cpd) in a 32° field for both PERG and BY-VEP. Patients were treated according to clinical standards and performed standard automated perimetry (SAP) annually. Retrospectively, patients with normal SAP at baseline were selected. Primary endpoint was conversion to perimetric glaucoma. Predictive value was modeled using Kaplan-Meier analyses and a multivariate cox proportional hazards model with the continuous variables PERG amplitude, BY-VEP peak time and SAP square-root of loss variance (sLV) after stratification for Jonas classification of the optic discs. RESULTS: Of 412 patients (288: Jonas 0, 103: I, and 21: II; baseline age: 20-60 years), 65 converted to perimetric glaucoma during follow-up (0.5-23.3 years; median 5.5 years). Optic disc classification was a strong risk factor for conversion (log rank p < 0.0001), and patients with more advanced changes progressed earlier. In the multivariate analysis (log rank p = 0.005), only PERG amplitude remained an independent risk factor after stratification for optic disc morphology (p = 0.021), with a ~ 30% higher risk per µV amplitude decrease. CONCLUSIONS: PERG helps to estimate glaucoma suspects' risk for visual field defects.

Differential Effects of Aging in the Macular Retinal Layers, Neuroretinal Rim, and Peripapillary Retinal Nerve Fiber Layer.

PURPOSE: We determined the differential aging effects of the inner 6 layers of the macula in contrast to the minimum neuroretinal rim width (MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness. DESIGN: Cross-sectional, multicenter study. PARTICIPANTS: An approximately equal number of white subjects with a normal ocular and visual field examination in each decade group from 20 to 90 years. METHODS: OCT of the macula, optic nerve head, and peripapillary retina. MAIN OUTCOME MEASURES: Sectoral measurements of the inner 6 layers of the macula; age-related decline of each of these layers; strength of the associations with age of the macular parameters, MRW, and peripapillary RNFL thickness; and association between ganglion cell layer (GCL) thickness and MRW and peripapillary RNFL thickness. RESULTS: The study sample comprised 1 eye of 246 subjects with a median (range) age of 52.9 (19.8-87.3) years. Of the 6 layers, there was a statistically significant decline with age of only the GCL, inner plexiform layer, and inner nuclear layer thickness with rates of -0.11 µm/year, -0.07 µm/year, and -0.03 µm/year, respectively. These rates corresponded to 2.82%, 2.10%, and 0.78% loss per decade, respectively, and were generally uniform across sectors. The rate of loss of MRW and peripapillary RNFL thickness was -1.22 µm/year and -0.20 µm/year, corresponding to 3.75% and 2.03% loss per decade. However, the association of GCL thickness change with age (R2 = 0.28) was approximately twice that of MRW and RNFL thickness (R2 = 0.14 for each). CONCLUSIONS: In concordance with histopathologic studies showing age-related loss of retinal ganglion cell axons, we showed a significant decline in GCL thickness, as well as MRW and peripapillary RNFL thickness. The stronger relationship between aging and GCL thickness compared with the rim or peripapillary RNFL may indicate that GCL thickness could be better suited to measure progression of structural glaucomatous loss.

OCT Angiography: Measurement of Retinal Macular Microvasculature with Spectralis II OCT Angiography - Reliability and Reproducibility.

AIM: The aim of the present study was to investigate the reliability of macular microvasculature measurements in normal subjects by Heidelberg Spectralis II optical coherence tomography angiography (OCT-A) in combination with a newly made software. SUBJECTS AND METHODS: This prospective study included 23 eyes of 23 persons from the Erlangen Glaucoma Registry (ISSN 2191-5008, CS-2011; NTC00494923). The subjects underwent a complete clinical, standardized ophthalmologic examination to rule out any eye disease. En face OCT-A imaging was done using Heidelberg Spectralis II OCT (Heidelberg, Germany). Images were recorded with a 15 × 15° angle and a lateral resolution of 5.7 µm/pixel, resulting in a retinal section of 2.9 × 2.9 mm. The Erlangen-Angio-Tool (EA-Tool) OCT-A application performed multiple segmentations, allowing analysis of the vessel density in 12 segments. The software was coded in MATLAB. Macular data on the superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP) were exported into the application and analyzed separately. The EA-Tool calculated the percentage of "white area" in the "total area" of the region of interest, called vessel density. Foveolar avascular zones (FAZs) of the SVP, ICP, and DCP were calculated manually. To investigate the reproducibility of the new software, individual scans (SVP, ICP, and DCP) were analyzed twice with the EA-Tool and intraclass coefficients (ICCs) of the vessel density values were calculated. Statistical analysis was performed with SPSS version 21.0. RESULTS: The mean vessel density of the SVP ranged between 30.4 and 33.5, that of the ICP between 20.9 and 24.7, and that of the DCP between 23.5 and 27.6. Bland-Altman plots showed a good reliability of two consecutive scans of each sector (S1-S12) in the SVP, ICP, and DCP. Testing reproducibility, no statistically significantly different sectorial coefficients of variation of the SVP, ICP, and DCP were observed (p > 0.05). The mean FAZ area of the SVP was 0.43 ± 0.16 mm2, that of the ICP 0.28 ± 0.1 mm2, and that of the DCP 0.44 ± 0.12 mm2. CONCLUSIONS: Spectralis OCT II, in combination with the semiautomated vessel density software EA-Tool, showed good or even excellent ICCs in 75% of all segments of the SVP, ICP, and DCP. The ICCs for the FAZ area in the SVP, ICP, and DCP were excellent.

Structural changes of macular inner retinal layers in early normal-tension and high-tension glaucoma by spectral-domain optical coherence tomography.

PURPOSE: Assessment of the diagnostic ability of segmented macular inner retinal layer thickness and peripapillary retinal nerve fiber layer (pRNFL) measured by spectral-domain optical coherence tomography (SD-OCT) in patients with normal-tension (NT) and high-tension (HT) perimetric and preperimetric glaucoma. METHODS: The 212 participants included 45 healthy subjects, 55 patients with ocular hypertension, 56 patients with preperimetric glaucoma, and 56 patients with perimetric glaucoma. The preperimetric and perimetric groups were further subdivided into NT and HT groups. Sectoral and global thickness of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (mGCL), inner plexiform layer (mIPL), ganglion cell complex (mGCC), and pRNFL were measured using SD-OCT (Spectralis, Heidelberg Engineering, Germany). Diagnostic performance was ascertained by sectoral and global comparison of the sensitivities at specificity ≥ 95%. RESULTS: For all layers, the largest thickness decrease was reported in the HT perimetric group. In all groups, the sensitivities of mGCL showed a comparable diagnostic value to pRNFL in order to distinguish between healthy subjects and glaucoma patients. In the perimetric group, mGCL (85.7%) exhibited higher sensitivities than mRNFL (78.6%) and mGCC (78.6%). Both mRNFL and pRNFL demonstrated equal diagnostic performance in the HT perimetric group (88.5 and 96.2%), in the NT groups, mRNFL was inferior to all other layers. CONCLUSION: The sensitivities of mGCL and mRNFL were comparable to the sensitivities of pRNFL. In clinical application, mGCL and mRNFL, with a focus on the temporal and inferior sectors, may provide a convincing supplementation to pRNFL. CLINICAL TRIAL REGISTRATION: Erlangen Glaucoma Registry www.clinicaltrials.gov ID: NCT00494923.

Comparison of frequency doubling and flicker defined form perimetry in early glaucoma.

PURPOSE: To compare perimetric data based on the second-generation frequency doubling technology (FDT) and on flicker defined form (FDF) stimulation in early glaucoma patients. METHODS: Seventy-two experienced glaucoma patients and 50 healthy subjects of the Erlangen Glaucoma Registry participated in the study. The definition of glaucoma was solely based on optic disc appearance. All patients underwent FDF perimetry (HEP), FDT perimetry (Matrix), standard automated perimetry (SAP, Octopus), and peripapillar measurements of the RNFL thickness (Spectralis OCT). Exclusion criteria were: mean defect (MD) in SAP > 6 dB, eye diseases other than glaucoma, or non-reliable FDF or FDT measurements. Statistical analyses included comparison of the standard indices and correlations between methods. Venn-diagrams show the number of patients with abnormal results in HEP, Matrix, SAP, and mean RNFL thickness. RESULTS: Mean defect data from FDT and FDF perimetry were strongly correlated (R = -0.85, P <0.001). In this cohort of early glaucoma patients, the MD values were 6.1 ± 5.0 dB (FDF) and 4.5 ± 4.1 dB (FDT). Sensitivity in this patient group was 65 % for FDF-MD, 60 % for FDT-MD, and 60 % for RNFL-thickness, all at a specificity of 95 %. The correlation analysis between local RNFL thickness and corresponding visual defects revealed significant Spearman correlation coefficients for the arcuate bundles of the visual field (FDF-inferior: R = -0.65, FDF-superior: R = -0.74, FDT-inferior: R = -0.55, FDT-superior: R = -0.72). CONCLUSION: FDF and FDT stimulations can be used to detect patients with early glaucoma. Combined consideration of RNFL thickness and results from one of these perimetric tests can increase the total number of detected patients.

Bruch's Membrane Opening Minimum Rim Width and Retinal Nerve Fiber Layer Thickness in a Normal White Population: A Multicenter Study.

PURPOSE: Conventional optic disc margin-based neuroretinal rim measurements lack a solid anatomic and geometrical basis. An optical coherence tomography (OCT) index, Bruch's membrane opening minimum rim width (BMO-MRW), addresses these deficiencies and has higher diagnostic accuracy for glaucoma. We characterized BMO-MRW and peripapillary retinal nerve fiber layer thickness (RNFLT) in a normal population. DESIGN: Multicenter cross-sectional study. PARTICIPANTS: Normal white subjects. METHODS: An approximately equal number of subjects in each decade group (20-90 years of age) was enrolled in 5 centers. Subjects had normal ocular and visual field examination results. We obtained OCT images of the optic nerve head (24 radial scans) and peripapillary retina (1 circular scan). The angle between the fovea and BMO center (FoBMO angle), relative to the horizontal axis of the image frame, was first determined and all scans were acquired and analyzed relative to this eye-specific FoBMO axis. Variation in BMO-MRW and RNFLT was analyzed with respect to age, sector, and BMO shape. MAIN OUTCOME MEASURES: Age-related decline and between-subject variability in BMO-MRW and RNFLT. RESULTS: There were 246 eyes of 246 subjects with a median age of 52.9 years (range, 19.8-87.3 years). The median FoBMO angle was -6.7° (range, 2.5° to -17.5°). The BMO was predominantly vertically oval with a median area of 1.74 mm(2) (range, 1.05-3.40 mm(2)). Neither FoBMO angle nor BMO area was associated with age or axial length. Both global mean BMO-MRW and RNFLT declined with age at a rate of -1.34 µm/year and -0.21 µm/year, equivalent to 4.0% and 2.1% loss per decade of life, respectively. Sectorially, the most rapid decrease occurred inferiorly and the least temporally; however, the age association was always stronger with BMO-MRW than with RNFLT. There was a modest relationship between mean global BMO-MRW and RNFLT (r = 0.35), whereas sectorially the relationship ranged from moderate (r = 0.45, inferotemporal) to nonexistent (r = 0.01, temporal). CONCLUSIONS: There was significant age-related loss of BMO-MRW in healthy subjects and notable differences between BMO-MRW and RNFLT in their relationship with age and between each other. Adjusting BMO-MRW and RNFLT for age and sector is important in ensuring optimal diagnostics for glaucoma.

Short-term fluctuation of intraocular pressure is higher in patients with pseudoexfoliation syndrome despite similar mean intraocular pressure: a retrospective case-control study.

PURPOSE: Higher levels of short-term fluctuation of intraocular pressure (IOP) are characteristic of pseudoexfoliation syndrome (PEX). However, it is not known whether they are just a side effect of the higher mean intraocular pressure (IOP) or an independent feature. The purpose of this study was to compare short-term fluctuation of IOP between eyes with PEX and control eyes that were matched as closely as possible for mean IOP. METHODS: In this retrospective case-control study, all patients with confirmed PEX were identified from the database of the Erlangen Glaucoma Registry. From the same database, matched control eyes with similar treatment, age, glaucoma stage, and mean IOP were identified. For each patient, data from multiple extended diurnal IOP profiles were available. RESULTS: Seventy-eight eyes were included in the study (39 with PEX and 39 matched control eyes). Although a very close match was achieved, a small but statistically significant difference in mean IOP was still present, but this did not seem to explain the differences in IOP fluctuation levels. Eyes with PEX had significantly higher short-term IOP fluctuations (SD of IOP and range of IOP). CONCLUSIONS: The higher levels of short-term fluctuation in IOP appear to be an independent feature of PEX and not merely a secondary effect of the higher mean IOP. We suggest that this may have practical implications, even if IOP fluctuation levels should not prove to be an independent risk factor for development/progression of glaucoma, because more frequent measurements are needed in these patients to obtain good estimates of mean IOP and changes in IOP under treatment.

Flicker-defined form perimetry in glaucoma patients.

PURPOSE: To assess the potential of flicker-defined form (FDF) perimetry to detect functional loss in patient groups with beginning glaucoma, and to evaluate the dynamic range of the FDF stimulus in individual patients and at individual test positions. METHODS: FDF perimetry and standard automated perimetry (SAP) were performed at identical test locations (adapted G1 protocol) in 60 healthy subjects and 111 glaucoma patients. All patients showed glaucomatous optic disc appearance. Grouping within the glaucoma cohort was based on SAP-performance: 33 "preperimetric" open-angle glaucoma (OAG) patients, 28 "borderline" OAG (focal defects and SAP-mean defect (MD) <2 dB), 33 "early" OAG (SAP-MD < 5 dB), 17 "advanced" OAG. All participants were experienced in psychophysical and perimetric tests. Defect values and the areas under receiver operating characteristic curves (ROC) in patient groups were statistically compared. RESULTS: The values of FDF-MD in the preperimetric, borderline, and early OAG group were 2.7 ± 3.4 dB, 5.5 ± 2.6 dB, and 8.5 ± 3.4 dB respectively (all significantly above normal). The percentage of patients exceeding normal FDF-MD was 27.3 %, 60.7 %, and 87.9 % respectively. The age-adjusted FDF-mean defect (MD) of the G1X-protocol was not significantly correlated with refractive error, lens opacity, pupil size, or gender. Occurrence of ceiling effects (inability to detect targets at highest contrast) showed a high correlation with visual field losses (R = 0.72, p < 0.001). Local analysis indicates that SAP losses exceeding 5 dB could not be distinguished with the FDF technique. CONCLUSION: The FDF stimulus was able to detect beginning glaucoma damage. Patients with SAP-MD values exceeding 5 dB should be monitored with conventional perimetry because of its larger dynamic range.

Common genetic determinants of intraocular pressure and primary open-angle glaucoma.

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Variants in ASB10 are associated with open-angle glaucoma.

The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765C>T (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0%) compared with 9 in 13 controls (13 of 461; 2.8%; P = 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by ∼50% compared with control-infected anterior segments (P = 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.

Longitudinal stability of the diurnal rhythm of intraocular pressure in subjects with healthy eyes, ocular hypertension and pigment dispersion syndrome.

BACKGROUND: The diurnal fluctuation of intraocular pressure may be relevant in glaucoma. The aim of this study was to find out whether the timing of diurnal fluctuation is stable over the years. METHODS: Long-term IOP data from the Erlangen Glaucoma Registry, consisting of several annual extended diurnal IOP profiles for each patient, was retrospectively analyzed. Normal subjects, patients with ocular hypertension and with pigment dispersion syndrome were included because these subjects had not been treated with antiglaucomatous medications at the time of data acquisition. A cosine curve was fitted to the IOP data and the stability of individual rhythms over the years was tested using the Rayleigh test. To compare the peak times among groups, means were calculated only from subjects with a significant Rayleigh test. RESULTS: Of the fifty-two eligible subjects, a total of 364 extended diurnal IOP profiles measured in a sitting position had been collected over a period of 114 ± 39 months. The Rayleigh test indicated intraindividual stability of phase timing only in 19 subjects (36%). In subjects with pigment dispersions syndrome, peak IOP occurred on average two hours and seven minutes later during the day compared with subjects without this condition (p = 0.05). CONCLUSIONS: Fitting of cosine curves to the clinical IOP profiles was generally feasible, although careful interpretation is warranted due to lack of measurements in supine position and between midnight and 7 am. The interesting observation of a phase lag in eyes with pigment dispersion syndrome warrants confirmation and exploration in future prospective studies. The analysis of the IOP data showed no stable individual rhythm in the long term in a majority of patients.

Optical Coherence Tomographic Optic Nerve Head Morphology in Myopia III: The Exposed Neural Canal Region in Healthy Eyes-Implications for High Myopia.

PURPOSE: To determine the prevalence and magnitude of optical coherence tomography (OCT) exposed neural canal (ENC), externally oblique choroidal border tissue (EOCBT), and exposed scleral flange (ESF) regions in 362 non-highly myopic (spherical equivalent -6.00 to 5.75 diopters) eyes of 362 healthy subjects. DESIGN: Cross-sectional study. METHODS: After OCT optic nerve head (ONH) imaging, Bruch membrane opening (BMO), the anterior scleral canal opening (ASCO), and the scleral flange opening (SFO) were manually segmented. BMO, ASCO, and SFO points were projected to the BMO reference plane. The direction and magnitude of BMO/ASCO offset as well as the magnitude of ENC, EOCBT, and ESF was calculated within 30° sectors relative to the foveal-BMO axis. Hi-ESF eyes demonstrated an ESF ≥100 µm in at least 1 sector. Sectoral peri-neural canal choroidal thickness (pNC-CT) was measured and correlations between the magnitude of sectoral ESF and proportional pNC-CT were assessed. RESULTS: Seventy-three Hi-ESF (20.2%) and 289 non-Hi-ESF eyes (79.8%) were identified. BMO/ASCO offset as well as ENC, EOCBT, and ESF prevalence and magnitude were greatest inferior temporally where the pNC-CT was thinnest. Among Hi-ESF eyes, the magnitude of each ENC region correlated with the BMO/ASCO offset magnitude, and the sectors with the longest ESF correlated with the sectors with proportionally thinnest pNC-CT. CONCLUSIONS: ONH BMO/ASCO offset, either as a cause or result of ONH neural canal remodeling, corresponds with the sectoral location of maximum ESF and minimum pNC-CT in non-highly myopic eyes. Longitudinal studies to characterize the development and clinical implications of ENC Hi-ESF regions in non-highly myopic and highly myopic eyes are indicated.

Common genetic variants associated with open-angle glaucoma.

Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

APSified OCT-angiography analysis: Macula vessel density in healthy eyes during office hours.

PURPOSE: Optical coherence tomography angiography (OCT-A) can visualize retinal capillary microcirculation non-invasively. In order to investigate potential factors influencing OCT-A diagnostics, the aim of the present study was to determine circadian changes in macular vessel density (VD) in healthy adults during office hours, considering axial length (AL) and subfoveal choroidal thickness (CT). METHODS: In the prospective study 30 eyes of 30 healthy subjects (mean age 28.7 ± 11.8, range 19-60 years) were recruited who underwent repeated measurements of AL, subfoveal CT and three-layer macula VD (superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP)) on a single day at three predetermined timepoints (9 AM, 3 PM, and 9 PM). For better intra- and interindividual scan comparability, the new Anatomic Positioning System function (APS, part of Glaucoma Module Premium Edition [GMPE], Heidelberg Engineering, Germany) allowing analysis of identical retinal areas, was used for quantitative OCT-A analysis. RESULTS: Overall mean macula VD was unchanged during office hours in SVP, ICP and DCP, respectively (p>0.05). In addition, AL and CT showed no statistically significant changes over time (p>0.05). Rather, a large interindividual variance of VD with different peak time was observed. Contrary to the overall data, sectorial VD changed in dependency of office hours in all layers with an increase of VD in SVP between 9 AM and 9 PM (p = 0.003), in ICP between 3 PM and 9 PM (p = 0.000), in DCP between 9 AM and 9 PM (p = 0.048), and 3 PM and 9 PM (p = 0.000), respectively. CONCLUSION: Overall mean macula VD, subfoveal CT and AL tended not to show statistically significant changes over time in this cohort, whereas a regional analysis of VD did. Therefore, a circadian influence on capillary microcirculation should be kept in mind. Moreover, the results highlight the importance of a more detailed analysis of VD in different sectors and different vascular layers. In addition, the pattern of diurnal variation could vary inter-individually, thus a patient-specific fluctuation pattern would need to be considered when evaluating these parameters in clinical practice.

Asymmetry of Peripapillary Retinal Blood Vessel and Retinal Nerve Fiber Layer Thickness Between Healthy Right and Left Eyes.

Purpose: The purpose of this study was to determine if there is asymmetry in retinal blood vessel (RBV) position and thickness between right and left eyes (R-L) and evaluate whether R-L asymmetry in RBV thickness is related to R-L asymmetry of retinal nerve fiber layer thickness (RNFLT). Methods: We analyzed peripapillary circle scan optical coherence tomography (OCT) examinations from healthy White subjects to measure RNFLT and RBV thickness and position relative to the fovea to Bruch's membrane opening axis, for all visible RBV. The R-L asymmetries of RNFLT and RBV thickness were computed for each A-scan. Four major vessels (superior temporal artery [STA] and superior temporal vein [STV], inferior temporal artery [ITA], and vein [ITV]) were identified using infrared images. Results: We included 219 individuals. The mean (standard deviation) number of RBV measured per eye was 15.0 (SD = 2.2). The position of the STV and STA was more superior in left eyes than in right eyes, by 2.4 degrees and 3.7 degrees, respectively (P < 0.01). There was no region with significant R-L asymmetry in RBV thickness. RNFLT was thicker in right eyes in the temporal superior region and thicker in left eyes in the superior and nasal superior regions, with the asymmetry profile resembling in a "W" shape. This shape was also present in post hoc analyses in two different populations. The R-L asymmetries of RBV and RNFLT at each A-scan were not significantly associated (P = 0.37). Conclusions: There is little R-L asymmetry in RBV, and it is not related to RNFLT asymmetry. This study suggests that R-L RNFLT asymmetry is due to factors other than RBV.

Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma.

Glaucoma, a main cause of blindness in the developed world, is characterized by progressive degeneration of retinal ganglion cells (RGCs), resulting in irreversible loss of vision. Although members of the neurotrophin gene family in various species are known to support the survival of numerous neuronal populations, including RGCs, it is less clear whether they are also required for survival and maintenance of adult neurons in humans. Here, we report seven different heterozygous mutations in the Neurotrophin-4 (NTF4) gene accounting for about 1.7% of primary open-angle glaucoma patients of European origin. Molecular modeling predicted a decreased affinity of neurotrophin 4 protein (NT-4) mutants with its specific tyrosine kinase receptor B (TrkB). Expression of recombinant NT-4 carrying the most frequent mutation was demonstrated to lead to decreased activation of TrkB. These findings suggest a pathway in the pathophysiology of glaucoma through loss of neurotrophic function and may eventually open the possibility of using ligands activating TrkB to prevent the progression of the disease.

Canine multifocal retinopathy in the Australian Shepherd: a case report.

A 1-year-old Australian Shepherd (AS) was presented for a routine hereditary eye examination. During the examination multiple raised, brown to orange lesions were noted in the fundus, which could not be attributed to a known retinal disease in this breed. As they clinically most closely resembled canine multifocal retinopathy (cmr) and no indication of an acquired condition was found, genetic tests for BEST1 gene mutations were performed. These showed the dog to be homozygous for the cmr1 (C73T/R25X) gene defect. Furthermore, ultrasound (US), electroretinography (ERG), and optical coherence tomography were performed, confirming changes typical for cmr. Subsequently, the AS pedigree members were genetically and clinically tested, demonstrating autosomal recessive inheritance with no clinical symptoms in carrier animals, as was previously described for cmr. To our knowledge, this is the first reported case of canine multifocal retinopathy in the AS breed. Further investigations are under way.

On and off responses of the photopic fullfield ERG in normal subjects and glaucoma patients.

Recent studies suggest a diagnostic value of the photopic negative response (PhNR) with a long-duration stimulus. The aim of this study was to record the on and off responses of the photopic fullfield electroretinogram (ERG) in normal subjects and glaucoma patients. We focused on different waves of the responses after onset and offset of the long-duration stimulus ERG. Photopic fullfield ERGs were recorded in response to a white bright LED flash on a white 20 cd/m(2) background. Stimulus luminances were 40, 60 and 80 cd/m(2). Responses were averaged using a flash duration of 240 ms and an offset period of 500 ms. We examined 19 healthy subjects, 27 patients with glaucomatous optic disc atrophy and 7 ocular hypertensive patients. The amplitudes and implicit times of the on and off responses of the human ERG depended on flash luminance. Comparing patients with glaucoma and healthy subjects for the 60 cd/m² flash, there was a significant change in the PhNRs (at onset: P < 0.01, at offset: P < 0.001) of the d-wave and of the i-wave at offset (P < 0.01). No significant difference was found for peak times of the fullfield ERG and for a- and b-wave amplitudes. PhNR amplitudes were significantly correlated with mean thickness of retinal nerve fibre layer as measured with OCT. In comparison with the normal photopic long-flash ERG, glaucoma patients showed changes in the PhNR amplitude following stimulus onset and in waves following stimulus offset.

Detection of nerve fiber atrophy in apparently effectively treated papilledema in idiopathic intracranial hypertension.

BACKGROUND: Since papilledema in idiopathic intracranial hypertension is a passive event not primarily affecting the visual tract, resolution with restitution ad integrum is expected if intracranial pressure is rebalanced. Retinal nerve fiber swelling due to papilledema in the acute phase and possible axon loss after long-lasting elevated intracranial pressure was investigated in a controlled cross-sectional study by scanning laser polarimetry. METHODS: A cohort of 23 patients with idiopathic intracranial hypertension according to the modified Dandy diagnostic criteria, and 23 controls matched for age and gender were investigated. All patients received neurological and ophthalmologic examination including scanning laser polarimetry (GDx VCC). Patients were divided into groups depending on the presence of a papilledema (group 1) or the regression of the papilledema after initiation of therapy (group 2). Therapy was based on recommendations of the German Society of Neurology. RESULTS: Scanning laser polarimetry showed an increase of nerve fiber thickness in group 1, and a decrease of the nerve fiber thickness in group 2 compared to controls. Ten of 13 patients showed signs of a regional axon loss in the deviation map of the GDx report, and six had a Nerve Fiber Index above 30. All patients with regressive papilledema and coincidence of visual field damage and pale optic disc appearance had a pathologic result in the GDx examination, but only four of ten patients with a pathologic GDx examination showed coincidence of pale optic disc appearance and visual field damage as sign of underlying optic disc atrophy. CONCLUSION: In patients with apparently effective treatment of clinical symptoms and a regression of papilledema in idiopathic intracranial hypertension, a retinal axon loss was detected by scanning laser polarimetry. Axon loss was even present in patients without clinical evidence of optic nerve atrophy.

Peripapillary Scleral Bowing Increases with Age and Is Inversely Associated with Peripapillary Choroidal Thickness in Healthy Eyes.

PURPOSE: To use optical coherence tomography (OCT) to 3-dimensionally characterize the optic nerve head (ONH) in peripapillary scleral bowing in non-highly myopic healthy eyes. DESIGN: Cross-sectional, multicenter study. METHODS: A total of 362 non-highly myopic (+6 diopters [D] > spherical equivalent > -6D) eyes of 362 healthy subjects from 20-90 years old underwent OCT ONH radial B-scan imaging. Bruch's membrane (BM), BM opening (BMO), anterior scleral canal opening (ASCO), and the peripapillary scleral surface were segmented. BMO and ASCO planes were fit, and their centroids, major axes, ovality, areas and offsets were determined. Peripapillary scleral bowing was characterized by 2 parameters: peripapillary scleral slope (ppSS) of 3 anterior peripapillary scleral segments (0-300, 300-700, and 700-1,000 µm from the ASCO centroid); and ASCO depth relative to a peripapillary scleral reference plane (ASCOD-ppScleral). Peripapillary choroidal thickness (ppCT) was calculated relative to the ASCO as the minimum distance between the anterior scleral surface and BM. RESULTS: Both ppSS and ASCOD-ppScleral ranged from slightly inward through profoundly outward in direction. Both parameters increased with age and were independently associated with decreased ppCT. CONCLUSIONS: In non-highly myopic healthy eyes, outward peripapillary scleral bowing achieved substantial levels, was markedly increased with age, and was independently associated with decreased peripapillary choroidal thickness. These findings provide a normative foundation for characterizing this anatomy in cases of high myopia and glaucoma and in eyes with optic disc tilt, torsion, and peripapillary atrophy.