Sex-Specific Differences in Circumpapillary Retinal Nerve Fiber Layer Thickness.

PURPOSE: To investigate the role of sex on retinal nerve fiber layer (RNFL) thickness at 768 circumpapillary locations based on OCT findings. DESIGN: Population-based cross-sectional study. PARTICIPANTS: We investigated 5646 eyes of 5646 healthy participants from the Leipzig Research Centre for Civilization Diseases (LIFE)-Adult Study of a predominantly white population. METHODS: All participants underwent standardized systemic assessments and ocular imaging. Circumpapillary RNFL (cRNFL) thickness was measured at 768 points equidistant from the optic nerve head using spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). To control ocular magnification effects, the true scanning radius was estimated by scanning focus. Student t test was used to evaluate sex differences in cRNFL thickness globally and at each of the 768 locations. Multivariable linear regression and analysis of variance were used to evaluate individual contributions of various factors to cRNFL thickness variance. MAIN OUTCOME MEASURES: Difference in cRNFL thickness between males and females. RESULTS: Our population consisted of 54.8% females. The global cRNFL thickness was 1 µm thicker in females (P < 0.001). However, detailed analysis at each of the 768 locations revealed substantial location specificity of the sex effects, with RNFL thickness difference ranging from -9.98 to +8.00 µm. Females showed significantly thicker RNFLs in the temporal, superotemporal, nasal, inferonasal, and inferotemporal regions (43.6% of 768 locations), whereas males showed significantly thicker RNFLs in the superior region (13.2%). The results were similar after adjusting for age, body height, and scanning radius. The superotemporal and inferotemporal RNFL peaks shifted temporally in females by 2.4° and 1.9°, respectively. On regions with significant sex effects, sex explained more RNFL thickness variance than age, whereas the major peak locations and interpeak angle explained most of the RNFL thickness variance unexplained by sex. CONCLUSIONS: Substantial sex effects on cRNFL thickness were found at 56.8% of all 768 circumpapillary locations, with specific patterns for different sectors. Over large regions, sex was at least as important in explaining the cRNFL thickness variance as was age, which is well established to have a substantial impact on cRNFL thickness. Including sex in the cRNFL thickness norm could therefore improve glaucoma diagnosis and monitoring.

Reversal of Glaucoma Hemifield Test Results and Visual Field Features in Glaucoma.

PURPOSE: To develop a visual field (VF) feature model to predict the reversal of glaucoma hemifield test (GHT) results to within normal limits (WNL) after 2 consecutive outside normal limits (ONL) results. DESIGN: Retrospective cohort study. PARTICIPANTS: Visual fields of 44 503 eyes from 26 130 participants. METHODS: Eyes with 3 or more consecutive reliable VFs measured with the Humphrey Field Analyzer (Swedish interactive threshold algorithm standard 24-2) were included. Eyes with ONL GHT results for the 2 baseline VFs were selected. We extracted 3 categories of VF features from the baseline tests: (1) VF global indices (mean deviation [MD] and pattern standard deviation), (2) mismatch between baseline VFs, and (3) VF loss patterns (archetypes). Logistic regression was applied to predict the GHT results reversal. Cross-validation was applied to evaluate the model on testing data by the area under the receiver operating characteristic curve (AUC). We ascertained clinical glaucoma status on a patient subset (n = 97) to determine the usefulness of our model. MAIN OUTCOME MEASURES: Predictive models for GHT results reversal using VF features. RESULTS: For the 16 604 eyes with 2 initial ONL results, the prevalence of a subsequent WNL result increased from 0.1% for MD < -12 dB to 13.8% for MD ≥-3 dB. Compared with models with VF global indices, the AUC of predictive models increased from 0.669 (MD ≥-3 dB) and 0.697 (-6 dB ≤ MD < -3 dB) to 0.770 and 0.820, respectively, by adding VF mismatch features and computationally derived VF archetypes (P < 0.001 for both). The GHT results reversal was associated with a large mismatch between baseline VFs. Moreover, the GHT results reversal was associated more with VF archetypes of nonglaucomatous loss, severe widespread loss, and lens rim artifacts. For a subset of 97 eyes, using our model to predict absence of glaucoma based on clinical evidence after 2 ONL results yielded significantly better prediction accuracy (87.7%; P < 0.001) than predicting GHT results reversal (68.8%) with a prescribed specificity 67.7%. CONCLUSIONS: Using VF features may predict the GHT results reversal to WNL after 2 consecutive ONL results.

Degeneration and Regeneration of Subbasal Corneal Nerves after Infectious Keratitis: A Longitudinal In Vivo Confocal Microscopy Study.

PURPOSE: To investigate the longitudinal alterations of subbasal corneal nerves in patients with infectious keratitis (IK) during the acute phase, cessation of treatment, and the recovery phase by in vivo confocal microscopy (IVCM). DESIGN: Prospective, longitudinal, case-control, single-center study. PARTICIPANTS: Fifty-six eyes of 56 patients with the diagnosis of bacterial (n=28), fungal (n=15), or Acanthamoeba (n=13) keratitis were included in the study. Thirty eyes of 30 normal volunteers constituted the control group. METHODS: Corneal sensation and serial IVCM of the central cornea were performed prospectively using the Heidelberg Retina Tomograph 3/Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany). The IVCM images were assessed at 3 time points: at the acute phase (first visit to the cornea service), at cessation of antimicrobial treatment, and up to 6 months after the resolution of infection. MAIN OUTCOME MEASURES: Total nerve number and length, main nerve trunks, branching, and corneal sensation were assessed during the follow-up period. RESULTS: Corneal nerves were reduced significantly during the acute phase in eyes with IK compared with controls across all subgroups, with total nerve length of 5.47±0.69 mm/mm2 versus 20.59±1.06 mm/mm2 (P<0.0001). At the cessation of treatment, corneal nerves in patients with IK had regenerated, including total nerve length (8.49±0.94 mm/mm2; P=0.02) and nerve branch length (4.80±0.37 mm/mm2; P=0.005). During the recovery phase, after resolution of infection, corneal nerves regenerated further, including total nerve length (12.13±1.97 mm/mm2; P=0.005), main nerve trunk length (5.80±1.00 mm/mm2; P=0.01), and nerve branch length (6.33±0.76 mm/mm2; P=0.003) as compared with the acute phase, but were still significantly lower when compared with controls (P<0.05 for all parameters). Corneal degeneration and regeneration correlated with corneal sensation (r=0.47; P=0.0009). CONCLUSIONS: Patients with IK who sustain profound loss of corneal nerves during the acute phase of infection demonstrate increased corneal nerve density during the first 6 months after the resolution of infection. However, despite significant nerve regeneration, corneal nerve density does not recover fully and remains low compared to controls. By providing an objective methodology to monitor corneal re-innervation, IVCM adds potentially important findings that may have implications for clinical management and surgical planning.

The Effect of Ametropia on Glaucomatous Visual Field Loss.

Myopia has been discussed as a risk factor for glaucoma. In this study, we characterized the relationship between ametropia and patterns of visual field (VF) loss in glaucoma. Reliable automated VFs (SITA Standard 24-2) of 120,019 eyes from 70,495 patients were selected from five academic institutions. The pattern deviation (PD) at each VF location was modeled by linear regression with ametropia (defined as spherical equivalent (SE) starting from extreme high myopia), mean deviation (MD), and their interaction (SE × MD) as regressors. Myopia was associated with decreased PD at the paracentral and temporal VF locations, whereas hyperopia was associated with decreased PD at the Bjerrum and nasal step locations. The severity of VF loss modulated the effect of ametropia: with decreasing MD and SE, paracentral/nasal step regions became more depressed and Bjerrum/temporal regions less depressed. Increasing degree of myopia was positively correlated with VF depression at four central points, and the correlation became stronger with increasing VF loss severity. With worsening VF loss, myopes have increased VF depressions at the paracentral and nasal step regions, while hyperopes have increased depressions at the Bjerrum and temporal locations. Clinicians should be aware of these effects of ametropia when interpreting VF loss.

Effect of partial posterior vitreous detachment on spectral-domain optical coherence tomography retinal nerve fibre layer thickness measurements.

BACKGROUND/AIMS: To assess the effect of partial posterior vitreous detachment (pPVD) on spectral-domain optical coherence tomography (OCT) peripapillary retinal nerve fibre layer thickness (RNFL) measurements. METHODS: Spectral-domain OCT RNFL thickness measurements were obtained from 684 consecutive patients who were seen in the Massachusetts Eye and Ear Glaucoma Service. Of these patients, we compared RNFL thickness measurements between 101 eyes of 101 glaucoma suspects who met inclusion criteria (55 eyes with and 46 eyes without pPVD). RESULTS: Among all 684 patients, 253 (37%) had pPVD in at least one eye. Among a subset of 101 eyes of 101 glaucoma suspects, average RNFL thickness was greater in eyes with compared to eyes without pPVD (p=0.02). Measurements were significantly greater in the inferior (p=0.004) and superior quadrants (p=0.008), but not in the nasal (p=0.10) and temporal quadrants (p=0.25). The difference in average RNFL thickness remained significant (p=0.05) even when corrected for expected age-related decline in RNFL thickness. CONCLUSION: Over a third of patients were found on peripapillary spectral-domain OCT to have a pPVD, which was associated with greater RNFL thickness measurements. Judicious clinical interpretation of this finding on spectral-domain OCT RNFL thickness scans should be factored into the assessment of glaucoma suspects.

Norms of Interocular Circumpapillary Retinal Nerve Fiber Layer Thickness Differences at 768 Retinal Locations.

Purpose: The onset and progression of optic neuropathies like glaucoma often occurs asymmetrically between the two eyes of a patient. Interocular circumpapillary retinal nerve fiber layer thickness (cpRNFLT) differences could detect disease earlier. To apply such differences diagnostically, detailed location specific norms are necessary. Methods: Spectral-domain optical coherence tomography cpRNFLT circle scans from the population-based Leipzig Research Centre for Civilization Diseases-Adult study were selected. At each of the 768 radial scanning locations, normative interocular cpRNFLT difference distributions were calculated based on age and interocular radius difference. Results: A total of 8966 cpRNFLT scans of healthy eyes (4483 patients; 55% female; age range, 20-79 years) were selected. Global cpRNFLT average was 1.53 µm thicker in right eyes (P < 2.2 × 10-16). On 96% of the 768 locations, left minus right eye differences were significant (P < 0.05), varying between +11.6 µm (superonasal location) and -11.8 µm (nasal location). Increased age and difference in interocular scanning radii were associated with an increased mean and variance of interocular cpRNFLT difference at most retinal locations, apart from the area temporal to the inferior RNF bundle where cpRNFLT becomes more similar between eyes with age. Conclusions: We provide pointwise normative distributions of interocular cpRNFLT differences at an unprecedentedly high spatial resolution of 768 A-scans and reveal considerable location specific asymmetries as well as their associations with age and scanning radius differences between eyes. Translational Relevance: To facilitate clinical application, we implement these age- and radius-specific norms across all 768 locations in an open-source software to generate patient-specific normative color plots.

Characterization of Central Visual Field Loss in End-stage Glaucoma by Unsupervised Artificial Intelligence.

Importance: Although the central visual field (VF) in end-stage glaucoma may substantially vary among patients, structure-function studies and quality-of-life assessments are impeded by the lack of appropriate characterization of end-stage VF loss. Objective: To provide a quantitative characterization and classification of central VF loss in end-stage glaucoma. Design, Setting, and Participants: This retrospective cohort study collected data from 5 US glaucoma services from June 1, 1999, through October 1, 2014. A total of 2912 reliable 10-2 VFs of 1103 eyes from 1010 patients measured after end-stage 24-2 VFs with a mean deviation (MD) of -22 dB or less were included in the analysis. Data were analyzed from March 28, 2018, through May 23, 2019. Main Outcomes and Measures: Central VF patterns were determined by an artificial intelligence algorithm termed archetypal analysis. Longitudinal analyses were performed to investigate whether the development of central VF defect mostly affects specific vulnerability zones. Results: Among the 1103 patients with the most recent VFs, mean (SD) age was 70.4 (14.3) years; mean (SD) 10-2 MD, -21.5 (5.6) dB. Fourteen central VF patterns were determined, including the most common temporal sparing patterns (304 [27.5%]), followed by mostly nasal loss (280 [25.4%]), hemifield loss (169 [15.3%]), central island (120 [10.9%]), total loss (91 [8.3%]), nearly intact field (56 [5.1%]), inferonasal quadrant sparing (42 [3.8%]), and nearly total loss (41 [3.7%]). Location-specific median total deviation analyses partitioned the central VF into a more vulnerable superonasal zone and a less vulnerable inferotemporal zone. At 1-year and 2-year follow-up, new defects mostly occurred in the more vulnerable zone. Initial encroachments on an intact central VF at follow-up were more likely to be from nasal loss (11 [18.4%]; P < .001). One of the nasal loss patterns had a substantial chance at 2-year follow-up (8 [11.0%]; P = .004) to shift to total loss, whereas others did not. Conclusions and Relevance: In this study, central VF loss in end-stage glaucoma was found to exhibit characteristic patterns that might be associated with different subtypes. Initial central VF loss is likely to be nasal loss, and 1 specific type of nasal loss is likely to develop into total loss.

An Artificial Intelligence Approach to Detect Visual Field Progression in Glaucoma Based on Spatial Pattern Analysis.

Purpose: To detect visual field (VF) progression by analyzing spatial pattern changes. Methods: We selected 12,217 eyes from 7360 patients with at least five reliable 24-2 VFs and 5 years of follow-up with an interval of at least 6 months. VFs were decomposed into 16 archetype patterns previously derived by artificial intelligence techniques. Linear regressions were applied to the 16 archetype weights of VF series over time. We defined progression as the decrease rate of the normal archetype or any increase rate of the 15 VF defect archetypes to be outside normal limits. The archetype method was compared with mean deviation (MD) slope, Advanced Glaucoma Intervention Study (AGIS) scoring, Collaborative Initial Glaucoma Treatment Study (CIGTS) scoring, and the permutation of pointwise linear regression (PoPLR), and was validated by a subset of VFs assessed by three glaucoma specialists. Results: In the method development cohort of 11,817 eyes, the archetype method agreed more with MD slope (kappa: 0.37) and PoPLR (0.33) than AGIS (0.12) and CIGTS (0.22). The most frequently progressed patterns included decreased normal pattern (63.7%), and increased nasal steps (16.4%), altitudinal loss (15.9%), superior-peripheral defect (12.1%), paracentral/central defects (10.5%), and near total loss (10.4%). In the clinical validation cohort of 397 eyes with 27.5% of confirmed progression, the agreement (kappa) and accuracy (mean of hit rate and correct rejection rate) of the archetype method (0.51 and 0.77) significantly (P < 0.001 for all) outperformed AGIS (0.06 and 0.52), CIGTS (0.24 and 0.59), MD slope (0.21 and 0.59), and PoPLR (0.26 and 0.60). Conclusions: The archetype method can inform clinicians of VF progression patterns.

Quantifying positional variation of retinal blood vessels in glaucoma.

We studied the relationship between major retinal blood vessel (BV) positions and glaucoma parameters based on pairs of Cirrus optical coherence tomography scans and Humphrey visual fields of 445 eyes from 445 glaucoma patients in our cross-sectional study. A trained observer marked the major superior and inferior temporal BV (artery and vein) positions on four concentric circles around the optic disc. Analysis of variance was performed to analyze the group differences of BV positions related to the factors of radius, BV type, myopia status and glaucoma stage. Subsequent t-tests were implemented to further study the effect of glaucoma stage on BV positions. The radial variations of BV positions were correlated to mean deviation and circumpapillary retinal nerve fiber layer thickness (cpRNFLT). We found significant main effects of BV type, radius and myopia status for superior and inferior BV positions and of glaucoma stage for superior BV positions (all p≤0.006) with significant superior artery nasalization in advanced compared to mild glaucoma on the two smallest circles (subsequent t-tests, p<0.05). In addition, MD (r = -0.10, p = 0.04) and cpRNFLT (r = -0.12, p = 0.02) were significantly correlated to the angle difference of superior arteries between the innermost and outermost circles. In conclusion, we demonstrated that peripapillary superior artery positions are significantly nasalized for advanced glaucoma.

The Interrelationship between Refractive Error, Blood Vessel Anatomy, and Glaucomatous Visual Field Loss.

PURPOSE: We quantified the interrelationship between retinal blood vessel (BV) anatomical variation, spherical equivalent (SE) of refractive error, and functional diagnostic parameters in glaucoma to identify optimal parameters for the improvement of optical coherence tomography (OCT) retinal nerve fiber layer thickness (RNFLT) norms. METHODS: A trained observer marked the intersections of the main superior/inferior temporal arteries and veins with concentric circles around the optic nerve head (ONH) center on fundus images. The interrelationship of BV, SE, and visual field global parameters was analyzed by multivariate regression and model comparison. RESULTS: A total of 445 eyes of 445 patients in a large glaucoma practice were selected. Of all investigated BV parameters, interartery angles (IAA) between superior and inferior arteries at a radius of 1.73 mm around the ONH center demonstrated the strongest relationship to SE (Bayesian information criterion difference to null model, 11.9). SE and BV parameters are unrelated to functional parameters, including mean deviation (MD), pattern standard deviation, and glaucoma hemifield test results. CONCLUSIONS: BV locations outside the ONH are sufficiently stable over glaucoma severity to represent individual eye anatomy, and the IAA at 1.73 mm eccentricity is the optimal parameter to be considered for novel OCT RNFLT norms. TRANSLATIONAL RELEVANCE: Among a large set of BV location parameters, considering IAA may improve RNFLT norms optimally and thereby increase the accuracy of clinical glaucoma diagnosis.

Associations between Optic Nerve Head-Related Anatomical Parameters and Refractive Error over the Full Range of Glaucoma Severity.

PURPOSE: To evaluate the associations between optic disc (OD)-related anatomical parameters (interartery angle [IAA] between superior and inferior temporal retinal arteries, OD tilt [TL], rotation [ROT], and torsion [TO], OD surface curvature [CUR], and central retinal vessel trunk entry point location [CRVTL] on OD) and the spherical equivalent of refractive error (SE), and to assess the impact of glaucoma severity on these relationships. METHODS: Cirrus optical coherence tomography (OCT) fundus images and 24-2 visual fields of 438 patients were included. Ellipses were fitted to OD borders. IAA was calculated between marked retinal artery locations on a circle around OD. Blood vessel entry point on OD was marked to locate CRVTL. TL was measured as the angle between the lines fitted to OD clinical boundary and the Bruch's membrane edges on the horizontal B-scans. Ellipse rotation relative to the vertical axis defined ROT. Angle between the long axis of OD and the interartery line defined TO. CUR was determined by the inner limiting membrane on the horizontal B-scans. Linear regression models evaluated by Bayes Factors (BF) were used to determine the covariance structure between the parameters and SE as well as possible impacts of mean deviation (MD). RESULTS: Our results showed that CRVTL had the strongest relationship with SE, followed by ROT, TL, and IAA (BFs: 3.59 × 107, 2645, 1126, and 248, respectively). MD did not significantly modulate the relationship between ONH parameters and SE. CONCLUSION: Our results suggest that SE should be considered when interpreting the OD and its circumpapillary region for diagnostic purposes. TRANSLATIONAL RELEVANCE: The reported relationships between OD-related parameters and ametropia may help to decrease false-positive clinical diagnoses of optic neuropathies.

Ametropia, retinal anatomy, and OCT abnormality patterns in glaucoma. 1. Impacts of refractive error and interartery angle.

Retinal nerve fiber layer thickness (RNFLT) measured by optical coherence tomography (OCT) is widely used in clinical practice to support glaucoma diagnosis. Clinicians frequently interpret peripapillary RNFLT areas marked as abnormal by OCT machines. However, presently, clinical OCT machines do not take individual retinal anatomy variation into account, and according diagnostic biases have been shown particularly for patients with ametropia. The angle between the two major temporal retinal arteries (interartery angle, IAA) is considered a fundamental retinal ametropia marker. Here, we analyze peripapillary spectral domain OCT RNFLT scans of 691 glaucoma patients and apply multivariate logistic regression to quantitatively compare the diagnostic bias of spherical equivalent (SE) of refractive error and IAA and to identify the precise retinal locations of false-positive/negative abnormality marks. Independent of glaucoma severity (visual field mean deviation), IAA/SE variations biased abnormality marks on OCT RNFLT printouts at 36.7%/22.9% of the peripapillary area, respectively. 17.2% of the biases due to SE are not explained by IAA variation, particularly in inferonasal areas. To conclude, the inclusion of SE and IAA in OCT RNFLT norms would help to increase diagnostic accuracy. Our detailed location maps may help clinicians to reduce diagnostic bias while interpreting retinal OCT scans.

Ametropia, retinal anatomy, and OCT abnormality patterns in glaucoma. 2. Impacts of optic nerve head parameters.

Clinicians use retinal nerve fiber layer thickness (RNFLT) measured by optical coherence tomography (OCT) as an adjunct to glaucoma diagnosis. Ametropia is accompanied by changes to the optic nerve head (ONH), which may affect how OCT machines mark RNFLT measurements as abnormal. These changes in abnormality patterns may bias glaucoma diagnosis. Here, we investigate the relationship between OCT abnormality patterns and the following ONH-related and ametropia-associated parameters on 421 eyes of glaucoma patients: optic disc tilt and torsion, central retinal vessel trunk location (CRVTL), and nasal and temporal retinal curvature adjacent to ONH, quantified as nasal/temporal slopes of the inner limiting membrane. We applied multivariate logistic regression with abnormality marks as regressands to 40,401 locations of the peripapillary region and generated spatial maps of locations of false positive/negative abnormality marks independent of glaucoma severity. Effects of torsion and temporal slope were negligible. The effect of tilt could be explained by covariation with ametropia. For CRVTL/nasal slope, abnormality pattern shifts at 7.2%/23.5% of the peripapillary region were detected, respectively, independent of glaucoma severity and ametropia. Therefore, CRVTL and nasal curvature should be included in OCT RNFLT norms. Our spatial location maps may aid clinicians to improve diagnostic accuracy.

Relationship Between Central Retinal Vessel Trunk Location and Visual Field Loss in Glaucoma.

PURPOSE: To study the relationship between horizontal central retinal vessel trunk location (CRVTL) on glaucomatous optic discs and sector-specific visual field (VF) loss. DESIGN: Retrospective cross-sectional study. METHODS: CRVTL of 421 eyes from 421 patients was manually tracked on the horizontal optic disc axis on fundus images. Focal circumpapillary retinal nerve fiber layer thickness (cpRNFLT) measurements were extracted from optical coherence tomography (OCT). The relationship between focal visual field (VF) loss and CRVTL and focal cpRNFLT was studied by linear regression models. Furthermore, we related central VF loss to CRVTL and focal cpRNFLT separately for mild (VF mean deviation [MD] ≥-6 dB), moderate (-12 dB ≤ MD <-6 dB), and severe (MD <-12 dB) glaucoma. RESULTS: CRVTL nasalization was significantly correlated only to central VF loss (Garway-Heath scheme [central 6 locations, C6]: correlation: r = -0.16, P < .001; macular vulnerability zone [central 2 locations, C2]: r = -0.14, P = .003; central 4 locations [C4]: r = -0.17, P < .001). While focal cpRNFLT at the sectors corresponding to C2 and C6 was significantly correlated to the respective VF sectors as well (C2: r = 0.15, P = .002; C6: r = 0.10, P = .03), multivariate models combining cpRNFLT and CRVTL substantially improved structure-function models compared with cpRNFLT alone (likelihood ratio tests, C2 and C6: P < .001). The correlations between CRVTL and central VF loss of C4 were -0.11 (P = .04), -0.39 (P = .01), and -0.63 (P = .002) for mild, moderate, and severe glaucoma, respectively. CONCLUSIONS: CRVTL nasalization is significantly and exclusively correlated to central VF loss for all glaucoma severities independent of cpRNFLT, and thus might be a structural biomarker of central VF loss.

Age, ocular magnification, and circumpapillary retinal nerve fiber layer thickness.

Optical coherence tomography (OCT) manufacturers graphically present circumpapillary retinal nerve fiber layer thickness (cpRNFLT) together with normative limits to support clinicians in diagnosing ophthalmic diseases. The impact of age on cpRNFLT is typically implemented by linear models. cpRNFLT is strongly location-specific, whereas previously published norms are typically restricted to coarse sectors and based on small populations. Furthermore, OCT devices neglect impacts of lens or eye size on the diameter of the cpRNFLT scan circle so that the diameter substantially varies over different eyes. We investigate the impact of age and scan diameter reported by Spectralis spectral-domain OCT on cpRNFLT in 5646 subjects with healthy eyes. We provide cpRNFLT by age and diameter at 768 angular locations. Age/diameter were significantly related to cpRNFLT on 89%/92% of the circle, respectively (pointwise linear regression), and to shifts in cpRNFLT peak locations. For subjects from age 42.1 onward but not below, increasing age significantly decreased scan diameter (r=-0.28, p<0.001), which suggests that pathological cpRNFLT thinning over time may be underestimated in elderly compared to younger subjects, as scan diameter decrease correlated with cpRNFLT increase. Our detailed numerical results may help to generate various correction models to improve diagnosing and monitoring optic neuropathies.

Patterns of Retinal Nerve Fiber Layer Loss in Different Subtypes of Open Angle Glaucoma Using Spectral Domain Optical Coherence Tomography.

PURPOSE OF THE STUDY: The purpose of the study was to determine whether there are different patterns of retinal nerve fiber layer (RNFL) thinning as measured by spectral domain optical coherence tomography (SD-OCT) for 4 subtypes of open angle glaucoma (OAG): primary OAG (POAG), normal tension glaucoma (NTG), pseudoexfoliation glaucoma (PXG), and pigmentary glaucoma (PDG) and to compare them with normal controls. MATERIALS AND METHODS: SD-OCT RNFL thickness values were measured for 4 quadrants and for 4 sectors (ie, superior-nasal, superior-temporal, inferior-nasal, and inferior-temporal). Differences in RNFL thickness values between groups were analyzed using analysis of variance. Paired t tests were used for quadrant comparisons. RESULTS: Two hundred eighty-five participants (102 POAG patients, 33 with NTG, 48 with PXG, 13 with PDG, and 89 normal patients) were included in this study. All 4 subtypes of OAG showed significant RNFL thinning in the superior, inferior, and nasal quadrants as well as the superior-temporal and inferior-temporal sectors (all P-values <0.0001) compared with normals. POAG and NTG patients had greater RNFL thinning inferiorly and inferior-temporally than superiorly (P-values: 0.002 to 0.018 and 0.006, respectively) compared with PXG patients. In contrast, PDG patients had greater RNFL thinning superiorly and superior-nasally than inferiorly compared with other OAG subtypes (ie, POAG, NTG, PXG groups, with P-values: 0.009, 0.003, 0.009, respectively). Of the 4 OAG subtypes, PXG patients exhibited the greatest degree of inter-eye RNFL asymmetry. CONCLUSIONS: This study suggests that SD-OCT may be able to detect significant differences in patterns of RNFL thinning for different subtypes of OAG.

Facilitating Glaucoma Diagnosis With Intereye Retinal Nerve Fiber Layer Asymmetry Using Spectral-Domain Optical Coherence Tomography.

PURPOSE: To test whether increased intereye retinal nerve fiber layer (RNFL) asymmetry may be indicative of glaucoma. To determine the best statistical methods and intereye RNFL cutoffs for differentiating between normal and glaucoma subjects to better alert clinicians to early glaucomatous damage. METHODS: Sixty-six primary open-angle glaucoma (OAG) and 40 age-matched normal subjects had both eyes imaged at the Massachusetts Eye and Ear Infirmary with a commercially available spectral-domain optical coherence tomography (OCT) machine. Statistical methodologies were used to find cutoffs that achieved the best sensitivities and specificities for differentiating OAG from normal subjects. RESULTS: Intereye RNFL asymmetry for global average, all quadrants, and all sectors was significantly greater in OAG than normal subjects. Intereye RNFL asymmetry for global average showed the greatest statistical difference (P<0.001) between OAG (23.64 ± 14.90 µm) and normal eyes (3.58 ± 3.96 µm), with 6.60 times greater asymmetry in OAG eyes. The inferior quadrant showed the second greatest difference, with 3.91 times greater asymmetry in OAG eyes. Using a statistically determined cutoff of 6.0 µm as abnormal, intereye RNFL asymmetry for global average achieved a sensitivity of 74.24% and specificity of 90% in differentiating between normal and OAG subjects, achieving a better combination of sensitivity and specificity than intereye RNFL asymmetry of any quadrant or sector. CONCLUSIONS: Intereye RNFL asymmetry may be a useful clinical OCT measurement to provide quantitative assessment of early glaucomatous damage. Newly developed algorithms for intereye RNFL asymmetry may improve the ability to detect glaucoma.

Contralateral Clinically Unaffected Eyes of Patients With Unilateral Infectious Keratitis Demonstrate a Sympathetic Immune Response.

PURPOSE: To analyze the contralateral unaffected eyes of patients with microbial keratitis (MK) for any immune cell or nerve changes by laser in vivo confocal microscopy (IVCM). METHODS: A prospective study was performed on 28 patients with MK, including acute bacterial, fungal, and Acanthamoeba keratitis, as well as on their contralateral clinically unaffected eyes and on control groups, which consisted of 28 age-matched normal controls and 15 control contact lens (CL) wearers. Laser IVCM with the Heidelberg Retinal Tomograph 3/Rostock Cornea Module and Cochet-Bonnet esthesiometry of the central cornea were performed. Two masked observers assessed central corneal dendritiform cell density and subbasal corneal nerve parameters. RESULTS: The contralateral clinically unaffected eyes of patients with MK demonstrated significant diminishment in nerve density (15,603.8 ± 1265.2 vs. 24,102.1 ± 735.6 µm/mm²), total number of nerves (11.9 ± 1.0 vs. 24.9 ± 1.2/frame), number of branches (1.7 ± 0.2 vs. 19.9 ± 1.3/frame), and branch nerve length (5775.2 ± 757.1 vs. 12,715.4 ± 648.4 µm/mm²) (P < 0.001 for all parameters) compared to normal controls and CL wearers. Further, dendritiform cell density in the contralateral unaffected eyes was significantly increased as compared to that in controls (117.5 ± 19.9 vs. 24.2 ± 3.5 cells/mm², P < 0.001). CONCLUSIONS: We demonstrate a subclinical involvement in the contralateral clinically unaffected eyes in patients with unilateral acute MK. In vivo confocal microscopy reveals not only a diminishment of the subbasal corneal nerves and sensation, but also an increase in dendritiform cell density in the contralateral unaffected eyes of MK patients. These findings show bilateral immune alterations in a clinically unilateral disease.

Correlation of retinal nerve fiber layer thickness and visual fields in glaucoma: a broken stick model.

PURPOSE: To determine the retinal nerve fiber layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss. DESIGN: Retrospective cross-sectional study. METHODS: Eighty-seven healthy and 108 glaucoma subjects (1 eye per subject) were recruited from an academic institution. All patients had VF examinations (Swedish Interactive Threshold Algorithm 24-2 test of the Humphrey Visual Field Analyzer 750i) and spectral-domain optical coherence tomography RNFL scans. Comparison of RNFL thickness values with VF threshold values showed a plateau of VF threshold values at high RNFL thickness values and then a sharp decrease at lower RNFL thickness values. A broken stick statistical analysis was used to estimate the tipping point at which RNFL thickness values are associated with VF defects. The slope for the association between structure and function was computed for data above and below the tipping point. RESULTS: The mean RNFL thickness value that was associated with initial VF loss was 89 µm. The superior RNFL thickness value that was associated with initial corresponding inferior VF loss was 100 µm. The inferior RNFL thickness value that was associated with initial corresponding superior VF loss was 73 µm. The differences between all the slopes above and below the aforementioned tipping points were statistically significant (P < .001). CONCLUSIONS: In open-angle glaucoma, substantial RNFL thinning or structural loss appears to be necessary before functional visual field defects become detectable.