Progressive Retinal Nerve Fiber Layer Thinning Research Articles

Rapid Retinal Nerve Fiber Layer Thinning in the Unaffected Contralateral Eyes of Patients with Unilateral Normal-Tension Glaucoma: A Retrospective Observational Study

PurposeTo observe the rate of progressive retinal nerve fiber layer (RNFL) thinning in the unaffected eyes of patients with unilateral normal-tension glaucoma (NTG), in comparison with that of healthy subjects, and to identify the factors associated with progressive RNFL thinning. DesignRetrospective, longitudinal, observational study. ParticipantsNinety-five patients with unilateral NTG and 61 healthy controls MethodsThis study included unilateral NTG and healthy control subjects who were followed up for longer than 4 years and in whom at least 5 reliable RNFL thickness (RNFLT) measurements were performed using optical coherence tomography. Factors associated with the rate of thinning of the unaffected eyes of unilateral NTG patients were identified using regression analysis. Main Outcome MeasuresThe rate of progressive RNFL thinning and the associated factors. ResultsRNFLT decreased significantly in both the unaffected eyes of unilateral NTG patients and the healthy eyes (both P<0.001). The RNFL thinning was significantly faster in the unaffected eyes of unilateral NTG patients than in the healthy eyes (P<0.001), specifically in the temporal-inferior sector (P=0.003). Factors associated with faster RNFL thinning in the unaffected eyes of unilateral NTG patients were thicker baseline RNFL of the unaffected eyes (P=0.002) and a worse visual field (VF) mean deviation (MD) in the NTG eyes (P=0.040). In the healthy controls, the rate of RNFL thinning in the contralateral eyes was the only factor associated with faster thinning (P=0.007). ConclusionsThe unaffected eyes of unilateral NTG patients showed faster RNFL thinning than healthy control eyes, more obviously in the temporal-inferior sector, and were likely to progress faster when they had a thicker baseline RNFL, and when the NTG eyes had a worse VF MD. In unilateral NTG patients, initiation of prophylactic treatment could be considered for the unaffected eyes when they are accompanied by a risk of developing glaucoma.

Comparison of Patterns of Structural Progression in Primary Open Angle Glaucoma and Pseudoexfoliation Glaucoma.

Primary open angle glaucoma and pseudoexfoliation glaucoma showed different progression patterns of the retinal nerve fiber layer and ganglion cell-inner plexiform layer thinning in OCT-guided progression analysis. To compare the patterns of progression of retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thinning by guided progression analysis (GPA) of optical coherence tomography (OCT) in primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG). The progression of RNFL and GCIPL thinning was assessed by the GPA of Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). By overlaying the acquired images of the RNFL and GCIPL thickness-change maps, the topographic patterns of progressive RNFL and GCIPL thinning were evaluated. The rates of progression of RNFL and GCIPL thinning were analyzed and compared between patients with POAG and those with PXG. Of the 248 eyes of 248 patients with POAG (175 eyes of 175 patients) or PXG (73 eyes of 73 patients) enrolled, 156 POAG eyes and 48 PXG eyes were included. Progressive RNFL thinning was significantly more common in PXG than in POAG ( P =0.005). According to the RNFL progression-frequency maps, progression appeared mainly in the superotemporal and inferotemporal areas in POAG, whereas it had invaded more into the temporal area in PXG. According to the GCIPL maps, progression was most common in the inferotemporal area in both POAG and PXG. The average progression rate of GCIPL thinning was faster in PXG than in POAG ( P =0.013), and when analyzed in 2 halves (superior/inferior), the progression rate of the inferior half was faster in PXG than in POAG ( P =0.011). OCT GPA showed progression patterns of RNFL and GCIPL thinning in POAG and PXG. Understanding the specific patterns of progressive RNFL and GCIPL thinning according to glaucoma type may prove helpful to glaucoma-patient treatment and monitoring.

Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures

To assess longitudinal relationships among visual function and anatomical measures of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). Phase 1 clinical trial. This was a single-institution study of patients with G11778A LHON. Patients with chronic bilateral visual loss >12 months (group 1, n=11), acute bilateral visual loss <12 months (group 2, n=9), or unilateral visual loss (group 3, n=8) were administered unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. Oucome measures were best-corrected visual acuity (BCVA), visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and ganglion cell+inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores. Mean follow-up was 33.6 months (range=18-36 months). Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of group 3, and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes, with some eyes having modest improvement that may be related to natural history or to gene therapy. Mean NEI-VFQ-25 scores declined in group 3 subjects (P=.023), CONCLUSION: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of effective neuroprotection given reduced GCIPL and SS-PERG. Randomization of patients to an untreated control group would help to assess treatment effect by accounting for variable natural history. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Risk of Normal Tension Glaucoma Progression From Automated Baseline Retinal-Vessel Caliber Analysis: A Prospective Cohort Study

To determine the relationship between baseline retinal-vessel calibers computed by a deep-learning system and the risk of normal tension glaucoma (NTG) progression. Prospective cohort study. Three hundred and ninety eyes from 197 patients with NTG were followed up for at least 24 months. Retinal-vessel calibers (central retinal arteriolar equivalent [CRAE] and central retinal venular equivalent [CRVE]) were computed from fundus photographs at baseline using a previously validated deep-learning system. Retinal nerve fiber layer (RNFL) thickness and visual field (VF) were evaluated semiannually. The Cox proportional-hazards model was used to evaluate the relationship of baseline retinal-vessel calibers to the risk of glaucoma progression. Over a mean follow-up period of 34.36 ± 5.88 months, 69 NTG eyes (17.69%) developed progressive RNFL thinning and 22 eyes (5.64%) developed VF deterioration. In the multivariable Cox regression analysis adjusting for age, gender, intraocular pressure, mean ocular perfusion pressure, systolic blood pressure, axial length, standard automated perimetry mean deviation, and RNFL thickness, narrower baseline CRAE (hazard ratio per SD decrease [95% confidence interval], 1.36 [1.01-1.82]) and CRVE (1.35 [1.01-1.80]) were associated with progressive RNFL thinning and narrower baseline CRAE (1.98 [1.17-3.35]) was associated with VF deterioration. In this study, each SD decrease in the baseline CRAE or CRVE was associated with a more than 30% increase in the risk of progressive RNFL thinning and a more than 90% increase in the risk of VF deterioration during the follow-up period. Baseline attenuation of retinal vasculature in NTG eyes was associated with subsequent glaucoma progression. High-throughput deep-learning-based retinal vasculature analysis demonstrated its clinical utility for NTG risk assessment.

Nicotinamide riboside as a neuroprotective therapy for glaucoma: study protocol for a randomized, double-blind, placebo-control trial

BackgroundWhereas lowering the intraocular pressure (IOP) can slow optic nerve degeneration in glaucoma, many patients with glaucoma continue to develop progressive loss in vision despite a significant reduction in IOP. No treatment has been shown to be effective for neuroprotection in glaucoma. We set out to conduct a randomized controlled trial to investigate whether nicotinamide riboside (NR), a nicotinamide adenine dinucleotide precursor, is effective to slow optic nerve degeneration in patients with primary open-angle glaucoma (POAG). We hypothesize that patients treated with NR have a slower rate of progressive retinal nerve fiber layer (RNFL) thinning compared with those treated with placebo.MethodsThis is a randomized, double-blind, placebo-controlled, parallel-group, multi-center study including 125 patients with POAG. Patients will be randomized to receive 300 mg NR or placebo for 24 months. Clinical examination, optical coherence tomography imaging of the RNFL, and visual field (VF) test will be performed at the baseline, 1 month, 4 months, and then at 2-month intervals until 24 months. The primary outcome measure is the rate of RNFL thinning measured over 24 months. The secondary outcome measures include (1) time to VF progression, (2) time to progressive RNFL/ganglion cell inner plexiform layer (GCIPL) thinning, and (3) the rate of change of VF sensitivity over 24 months (to investigate neuroprotection) and 1 month (to investigate neuroenhancement). The rates of RNFL thinning and VF sensitivity decline between treatment groups will be compared with linear mixed modeling. Survival analysis will be performed to compare the differences in time from baseline to VF progression and time from baseline to progressive RNFL/GCIPL thinning between treatment groups using Cox proportional hazards models.DiscussionOutcome measures in glaucoma neuroprotection trials have been centered on the detection of VF progression, which may take years to develop and confirm. In addition to addressing whether NR has a neuroprotective/neuroenhancement effect in glaucoma patients, this study will demonstrate the feasibility of studying neuroprotection in a relatively short trial period (24 months) by comparing the rates of progressive RNFL thinning, a more reproducible and objective outcome measure compared with VF endpoints, between treatment groups.Trial registrationChinese Clinical Trial Registry 1900021998

Intraocular Pressure Control Predicts Retinal Nerve Fiber Layer Thinning in Primary Angle Closure Disease: The CUPAL Study

To determine the relationship of intraocular pressure (IOP) control with subsequent retinal nerve fiber layer (RNFL) thinning in patients with primary angle closure disease (PACD). Prospective cohort study. The study monitored 517 treated PACD eyes from 280 Chinese patients at least 24 months. IOP was measured every 3 months using Goldmann applanation tonometry, and RNFLs were measured by spectral-domain optical coherence tomography (Spectralis, Heidelberg Engineering) every 6 months. IOP mean and fluctuation were calculated as the average and the coefficient of variation of IOP measurements during the first 18 months of the study period. The relationship between IOP and subsequent RNFL changes over time were examined using multivariable linear mixed models. Intraclass correlations at the patient and eye levels were also controlled using nested random intercepts in the models. IOP mean (β=-1.20 µm/y per 1 mm Hg, P < .001) and IOP fluctuation (β=-3.10 µm/y per 10% unit change in the coefficient of variation, P < .001) were independently negatively associated with subsequent progressive global RNFL changes, after adjustment for age, sex, and baseline RNFL thickness. In the sectoral analysis, both higher mean IOP and IOP fluctuation predicted progressive RNFL thinning in the inferotemporal, superotemporal, superonasal, and temporal sectors in the order of strength of association. In the subgroup analysis by disease category, IOP fluctuation showed greater association with global RNFL thinning in eyes with primary angle closure glaucoma (P=.010) than in eyes without glaucomatous changes (P=.07). In treated PACD eyes, large IOP fluctuation is an independent predictor for subsequent progressive RNFL thinning in addition to high mean IOP during follow-up.

Detection of Primary Angle Closure Glaucoma Progression by Optical Coherence Tomography.

To compare the role of spectral-domain optical coherence tomography (SD-OCT) in regard to retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) assessment in the detection of primary angle-closure glaucoma (PACG) and primary open-angle glaucoma (POAG) progression. In the prospective study, 131 subjects with PACG and POAG were examined during 72 months with follow-up visits every 6 months. Visual field (VF) progression was detected using the Guided Progression Analysis (GPA) of the Humphrey visual field analyzer and structural change using SD-OCT while a significant negative trend for the RNFL and GCC was gauged. The diagnostic accuracy of RNFL and GCC thinning in the detection of glaucoma progression was compared between PACG and POAG eyes using the Kaplan-Meier method with the calculation of the log-rank test. Progression was detected in 57% of eyes with POAG and 59% of eyes with PACG. The rate of thinning of RNFL (-2.95±1.85 μm/y) and GCC (-3.22±2.96 μm/y) was significantly higher in PACG progression eyes compared with POAG [-1.64±2.00 μm/y (P=0.018) and -1.74±2.05 μm/y (P=0.046), respectively]. The progression was associated with initial pattern standard deviation in both glaucoma subtypes, while only in PACG-with long-term intraocular pressure fluctuations (cutoff >5.2 mm Hg) and lens thickness (cutoff >4.92 mm), and only in POAG-with initial focal loss volume of GCC (cutoff >1.5%).In PACG, the rate of the visual function deterioration correlated with GCC thinning rate (r=0.330, P=0.027), but not with the RNFL thinning rate (r=-0.010, P=0.79), while in POAG, it was significant for both RNFL thinning (r=0.296, P=0.039) and GCC thinning (r=0.359, P=0.011). In PACG patients with progressive GCC thinning, functional progression was detected earlier (log-rank test P≤0.001) than in patients with progressive RNFL thinning (log-rank test P=0.457), while for POAG, these results were P=0.012 and ≤0.001 for GCC and RNFL thinning, respectively. SD-OCT plays an important role in detecting PACG progression. In contrast to POAG, GCC thinning predicted functional loss better than RNFL thinning in PACG.

Longitudinal Macular Ganglion Cell–Inner Plexiform Layer Measurements to Detect Glaucoma Progression in High Myopia

To investigate whether progressive macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thinning are predictive for detecting visual field (VF) progression in eyes with high myopia. Cohort study. A total of 104 primary open-angle glaucoma (POAG) eyes with high myopia and 104 age- and VF severity-matched POAG eyes without high myopia (mean follow-up, 5.4 years) were included. High myopia was defined as a spherical equivalent <-6.0 diopters or axial length >26.5mm. Progressive GCIPL, RNFL, and VF deterioration were determined by Guided Progression Analysis (GPA) in optical coherence tomography and standard automated perimetry. The risk of VF progression was evaluated using Cox proportional hazard models. Highly myopic eyes with progressive GCIPL thinning had a significantly higher risk of developing VF progression after adjusting for the baseline intraocular pressure (HR 4.00; P= .001) or peak intraocular pressure (HR 3.11; P= .011) in the multivariable Cox proportional hazard model, whereas highly myopic eyes with progressive RNFL thinning were not significantly associated with VF progression. In eyes without high myopia, both progressive GCIPL (HR 4.67 or 3.62; P= .008 or .037, respectively) and RNFL (HR 6.60 or 3.97; P= .001 or .016, respectively) thinning were associated with a significantly higher risk of developing VF progression after adjusting for the baseline or peak intraocular pressure. Monitoring macular GCIPL thickness was effective for predicting glaucoma progression regardless of the presence of high myopia.

Risk Factors Associated with Structural Progression in Normal-Tension Glaucoma: Intraocular Pressure, Systemic Blood Pressure, and Myopia.

PurposeTo determine risk factors associated with structural progression in medically treated normal-tension glaucoma (NTG).MethodsThis retrospective cohort study included 166 NTG patients (average age, 56.5 years; average mean deviation, −4.2 dB). The structural progression endpoint was determined by optical coherence tomography; significant thickness differences in the peripapillary retinal nerve fiber layer (RNFL) or macular ganglion cell inner plexiform layer (GCIPL) that exceeded baseline test-retest variability were identified with event-based guided-progression analysis. Intraocular pressure and systemic blood pressure (BP) were measured at each visit throughout the follow-up period, and the risk for progression was evaluated with Cox regression. Myopic disc features and antihypertensives were also analyzed. Tree analysis was used to determine the cutoff values and elucidate influential risk factors.ResultsStructural progression, defined as progressive peripapillary RNFL or macular GCIPL thinning, was identified in 62 eyes. Occurrence of disc hemorrhages, presence of diabetes, and lower minimum systolic BP were associated with progression (hazard ratio [HR]: 2.116, P = 0.005; HR: 1.998, P = 0.031; HR: 0.968, P = 0.005; respectively). The cutoff value derived from the tree analysis of minimum systolic BP was 108 mm Hg. The tree analysis revealed systolic and diastolic BP to be the most influential risk factors for progressive peripapillary RFNL thinning and progressive macular GCIPL thinning, respectively.ConclusionsLow BP measured during follow-up correlated with structural progression in medically treated NTG eyes, indicating that the evaluation of hypotension is required during the management of NTG patients. The tree analysis identified BP target values that may help prevent glaucoma progression.

Wide-field Trend-based Progression Analysis of Combined Retinal Nerve Fiber Layer and Ganglion Cell Inner Plexiform Layer Thickness: A New Paradigm to Improve Glaucoma Progression Detection

Evaluation of glaucoma progression with OCT has been centered on the analysis of progressive retinal nerve fiber layer (RNFL) thinning over the parapapillary region and/or progressive ganglion cell inner plexiform layer (GCIPL) thinning over the macula. We investigated (1) whether combining the RNFL and GCIPL as a single layer (i.e., RNFL-GCIPL) for wide-field progression analysis outperforms wide-field progression analysis of the RNFL or the GCIPL, and (2) whether eyes with progressive RNFL-GCIPL thinning are at risk of visual field (VF) progression. Prospective, longitudinal study. A total of 440 eyes from 236 glaucoma patients; 98 eyes from 49 healthy individuals. OCT RNFL/GCIPL/RNFL-GCIPL thickness and VF measurements were obtained at ∼4-month intervals for ≥3 years. Progressive changes of the RNFL/GCIPL/RNFL-GCIPL thicknesses were analyzed over a wide field (12×9 mm2) covering the parapapillary region and the macula with trend-based progression analysis (TPA) controlled at a false discovery rate of 5%. VF progression was determined by the Early Manifest Glaucoma Trial criteria. Proportions of eyes with progressive RNFL/GCIPL/RNFL-GCIPL thinning; hazard ratios (HRs) for development of VF progression. More eyes showed progressive RNFL-GCIPL thinning (127 eyes; 28.9%, 95% confidence interval [CI]: 23.9%-33.8%) than progressive RNFL thinning (74 eyes; 16.8%, 95% CI: 13.1%-20.6%) and progressive GCIPL thinning (26 eyes; 5.9%, 95% CI: 3.7%-8.1%) in the glaucoma group over the study follow-up. Progressive RNFL-GCIPL thinning was almost always detected before or simultaneously with progressive RNFL thinning or progressive GCIPL thinning. The specificity of TPA (estimated from the healthy group) for detection of progressive RNFL-GCIPL thinning, progressive RNFL thinning, and progressive GCIPL thinning was 83.7% (95% CI: 74.9%-92.4%), 94.9% (95% CI: 90.6%-99.2%), and 96.9% (95% CI: 93.5%-100.0%), respectively. Eyes with progressive RNFL-GCIPL thinning had a higher risk to develop possible (HR: 2.4, 95% CI: 1.2-5.0) or likely (HR: 4.6, 95% CI: 1.5-14.0) VF progression, with adjustment of covariates, compared with eyes without progressive RNFL-GCIPL thinning. Progression analysis of RNFL-GCIPL thickness reveals a significant portion of progressing eyes that neither progression analysis of RNFL thickness nor GCIPL thickness would identify. Wide-field progression analysis of RNFL-GCIPL thickness is effective to inform the risk of VF progression in glaucoma patients.

Hierarchical Cluster Analysis of Peripapillary Retinal Nerve Fiber Layer Damage and Macular Ganglion Cell Loss in Open Angle Glaucoma.

PurposeTo categorize the structural progression pattern of glaucoma, as detected by optical coherence tomography guided progression analysis, with respect to the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL).MethodsOne hundred sixty-four eyes with primary open-angle glaucoma were studied. The structural progression pattern evaluated by optical coherence tomography guided progression analysis was classified using hierarchical cluster analysis. The clinical parameters, patterns of structural progression, and visual field (VF) changes were compared among the groups.ResultsThree groups were included: stable, progressive peripapillary RNFL thinning without macular GCIPL involvement, and progressive thinning of both the peripapillary RNFL and macular GCIPL. The third group, those with progressive peripapillary RNFL and macular GCIPL thinning, showed more progressive peripapillary RNFL thinning in the inferotemporal area and VF progression in the parafoveal area. Conversely, the 12 and 6 o'clock areas were the most common locations of progressive peripapillary RNFL thinning in the group without macular GCIPL involvement.ConclusionsStructural progression patterns of glaucoma can be categorized into three groups. The location of progressive peripapillary RNFL thinning is associated with progressive macular GCIPL thinning and pattern of VF changes in the affected area. Our results indicate that the use of only macular GCIPL analysis is inadequate for analyzing the structural progression of glaucoma.

Risk factors associated with progressive nerve fiber layer thinning in open-angle glaucoma with mean intraocular pressure below 15\u2009mmHg

The purpose of this study was to identify risk factors associated with progressive retinal nerve fiber layer(RNFL) thinning of open-angle glaucoma(OAG) in patients whose intraocular pressure(IOP) was maintained low with medical treatment. Based on a retrospective review of medical records, OAG patients with ≥60 months of follow-up and mean IOP below 15 mmHg were recruited. All eyes underwent IOP measurement with Goldmann applanation tonometer(GAT), standard automated perimetry(SAP), and cirrus optical coherence tomography(cirrus OCT) at 6 month or 1 year intervals. RNFL thinning was assessed using the Guided Progression Analysis(GPA) software. Forty-one eyes of 41 patients (mean age 54.9 ± 13.5) were followed up for 77.8 ± 7.8 months. GPA detected 20 eyes (48.8%) with progressive RNFL thinning(−1.5 ± 0.5 um/year), who were subsequently classified as the ‘rapid progression group.’ Those whose rate of change in RNFL thickness was slower than −1.00 µm/year was classified as the ‘slow progression group’ (n = 21, −0.0 ± 0.4 um/year, P < 0.001). Mean IOP after initiating therapy was 13.2 ± 1.1 mmHg in the rapid progression group and 13.1 ± 1.3 mmHg in the slow progression group (P = 0.300; 14.8 ± 10.0% vs. 19.6 ± 12.4% reduction, P = 0.155). Disc hemorrhage was found to more frequently occur in the rapid progression group (P = 0.001). Multivariate logistic regression analysis showed that patients with disc hemorrhage were at a higher risk for progressive RNFL thinning in OAG (OR 37.529 95% CI 2.915–483.140) after adjusting for baseline co-variates (P = 0.005). In conclusion, disc hemorrhage is associated with progressive RNFL thinning in OAG with well-maintained IOP. Factors other than IOP appear to also play a role in OAG progression.

Ganglion Cell-Inner Plexiform Layer and Retinal Nerve Fiber Layer Changes in Glaucoma Suspects Enable Prediction of Glaucoma Development

To investigate whether progressive macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thinning predict development of visual field (VF) defects in glaucoma suspects. Retrospective cohort study. This study included 541 eyes of 357 glaucoma suspects with a mean follow-up of 5.7 years. Progressive GCIPL and RNFL thinning were determined using Guided Progression Analysis (GPA) in optical coherence tomography (OCT). The development of VF defect was defined as the presence of three consecutive abnormal VFs. The risk of developing VF defect was evaluated using Cox proportional hazard models. A total of 74 eyes (13.7%) and 87 eyes (16.1%) showed progressive GCIPL and RNFL thinning by OCT GPA, respectively, and 40 eyes (7.4%) developed VF defects. Eyes with progressive GCIPL (hazard ratio [HR], 7.130; 95% confidence interval [CI], 3.137-16.205) and RNFL (HR, 7.525; 95% CI, 3.272-17.311) thinning showed a significantly higher risk of developing VF defects. The rate of change in the average GCIPL and RNFL thickness was significantly higher in the eyes that developed VF defects (-0.71 and-1.13μm/y, respectively) than the eyes that did not (-0.19 and-0.27 μm/y, respectively; all P < 0.05). Progressive GCIPL (43.1 vs. 63.1 months, respectively; P < 0.001) and RNFL (50.9 vs. 66.7months, respectively; P < 0.001) thinning were detected significantly earlier than the development of VF defects. Monitoring progressive change in GCIPL, as well as RNFL, effectively predicts the development of VF defects in glaucoma suspects.

Influence of Choroidal Microvasculature Dropout on the Rate of Glaucomatous Progression: A Prospective Study

To determine the prognostic significance of choroidal microvasculature dropout (MvD) to predict the future rate of progressive retinal nerve fiber layer (RNFL) thinning in eyes with primary open-angle glaucoma (POAG). Prospective, longitudinal case series. This study enrolled 101 eyes of 101 patients with POAG who underwent OCT angiography (OCTA) imaging of the optic nerve head at baseline and were followed up for at least 2 years thereafter, during which RNFL thickness was measured by serial spectral-domain OCT. The peripapillary microvasculature was evaluated by examining en face OCTA images. Choroidal MvD was defined as a focal sectoral capillary dropout with no visible microvascular network in the choroidal layer. The rate of RNFL thinning was determined by linear regression of serial OCT RNFL thickness measurements. Influence of the presence of an MvD on the rate of subsequent RNFL thinning. Microvasculature dropout was identified in 48 eyes (47.5%). The rate of global RNFL thinning was significantly faster in eyes with MvD than eyes without MvD (-1.6±0.8 vs.-1.2±0.9 μm/year, P= 0.018). Eyes with MvD in the inferior hemisphere (n= 41) showed a faster rate of inferior RNFL thinning than eyes without MvD (P= 0.036). Eyes with MvD in both the superior and inferior hemispheres (n= 5) showed faster rates of superior (P= 0.027) and inferior (P= 0.016) RNFL thinning than eyes without MvD. Multivariate regression analysis showed that MvD at baseline (P= 0.003) and the presence of disc hemorrhage during follow-up (P= 0.001) were independently associated with a faster rate of global RNFL thinning. Microvasculature dropout was an independent predictor of a faster rate of progressive RNFL thinning in patients with POAG. Microvasculature dropout location was topographically associated with the location of faster RNFL thinning.

Elucidation of the Strongest Factors Influencing Rapid Retinal Nerve Fiber Layer Thinning in Glaucoma.

To determine which groupings of prognostic factors best explain the rapid progressive retinal nerve fiber layer (RNFL) thinning in patients with primary open-angle glaucoma (POAG). Optic nerves of 111 POAG patients who were followed for at least 2.5 years, during which the RNFL thickness was measured by serial spectral-domain optical coherence tomography (OCT) were included. Eyes were imaged using enhanced depth-imaging spectral-domain OCT and swept-source OCT angiography to determine the lamina cribrosa curvature index (LCCI), and the presence of a choroidal microvasculature dropout (cMvD), respectively. The rate of RNFL thinning was determined by linear regression of serial OCT RNFL thickness measurements. A regression tree model was used to find groupings of factors that best explain the rate of future RNFL thinning. Disc hemorrhage, larger LCCI, and presence of cMvD were associated with faster global RNFL thinning in the multivariate regression analysis. The regression tree analysis revealed three stratified groups based on the rate of RNFL thinning, divided by the LCCI and the presence of cMvD. Eyes with LCCI ≥11.87 had the fastest RNFL thinning (-2.4 ± 0.8 μm/year, mean ± SD). Among eyes with LCCI <11.87, the presence of cMvD was the strongest factor influencing faster RNFL thinning (-1.5 ± 0.8 μm/year). Eyes with LCCI <11.87 and without a cMvD exhibited the slowest RNFL thinning (-0.8 ± 0.9 μm/year). Our regression tree model demonstrated that larger LCCI, and then the presence of cMvD were the first and second strongest prognostic factors for faster progressive RNFL thinning. Further studies may be needed to confirm these findings.

Evaluation of Parapapillary Choroidal Microvasculature Dropout and Progressive Retinal Nerve Fiber Layer Thinning in Patients With Glaucoma

Parapapillary choroidal microvasculature dropout (MvD) is considered one of pathophysiological manifestations of glaucomatous damage. To evaluate the longitudinal change in the parapapillary choroidal MvD in patients with primary open-angle glaucoma (POAG), and to determine whether this change is associated with progressive retinal nerve fiber layer (RNFL) thinning. This prospective observational case series was conducted at a tertiary referral center in Korea and included 68 patients with POAG who exhibited parapapillary choroidal MvD in en face optical coherence tomography (OCT) angiography (OCTA) images who were enrolled from the ongoing Investigating Glaucoma Progression Study from January 1, 2016, through July 31, 2018. The mean (SD) follow-up period was 2.5 (0.2) years and observers were masked to the clinical characteristics of the participants for measurements. The OCTA images were obtained twice at an interval of at least 2 years, during which the RNFL thickness was measured at least 4 times in serial OCT examinations. Microvasculature dropout was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. The MvD area was measured in the OCTA images obtained at the baseline and the final follow-up. The significance of changes in the MvD area was defined using the 95% Bland-Altman limits of agreement. The rate of RNFL thinning was determined by linear regression of the serial OCT RNFL thickness measurements. The association between the change in the MvD area and the rate of RNFL thinning. Of 68 Korean participants, 37 (54.5%) were women, and the mean (SD) age was 54.3 (13.1) years. Among 68 eyes, 22 (32.4%) showed increases in the MvD area during the follow-up. Faster global RNFL thinning was associated with a larger baseline parapapillary atrophy β-zone (β = -0.55; 95% CI, -0.96 to -0.14; P = .01), disc hemorrhage detection during the follow-up period (β = -0.75; 95% CI, -1.67 to -0.34; P = .001), and a larger increase in the MvD area (β = -4.74; 95% CI, -7.72 to -1.75; P = .002). The MvD area was not associated with the rate of RNFL thinning at baseline or the final follow-up. Microvasculature dropout enlargement was associated with progressive RNFL thinning in POAG.

Comparison between Lamina Cribrosa Depth and Curvature as a Predictor of Progressive Retinal Nerve Fiber Layer Thinning in Primary Open-Angle Glaucoma

To compare the ability of lamina cribrosa (LC) depth (LCD) and LC curvature to predict the rate of progressive retinal nerve fiber layer (RNFL) thinning in patients with primary open-angle glaucoma (POAG). Observational case series. A total of 114 eyes of 114 patients diagnosed with POAG, in which RNFL thickness had been measured by serial spectral-domain (SD) OCT for at least 2.5 years. The optic nerves of all participants underwent enhanced depth imaging volume scanning, and their circumpapillary RNFL thickness was measured using SD OCT, followed by regular serial measurements of RNFL thickness at intervals of ≥6 months. The LCD from the levels of Bruch's membrane (BM, LCD-BM) and the anterior sclera (AS, LCD-AS), and LC curvature index (LCCI) were measured by SD OCT at 3 locations: superior midperipheral, midhorizontal, and inferior midperipheral. The rate of RNFL thinning over time was determined by linear regression of serial OCT measurements of RNFL thickness. Factors associated with the rate of OCT RNFL thinning. Univariate analysis showed that larger LCD-BM (P= 0.001), LCD-AS (P < 0.001), and LCCI (P < 0.001) were all significantly associated with a faster rate of global RNFL thinning. The LCCI showed a stronger correlation with the rate of global RNFL thinning than LCD-BM (P < 0.001) or LCD-AS (P < 0.001). Of the 3 variables, only LCCI remained significant on multivariate analysis (P < 0.001). Disc hemorrhage during follow-up (P= 0.003), wider parapapillary atrophy β-zone (P= 0.017), and greater global RNFL thickness (P= 0.040) were also significantly associated with a faster rate of global RNFL thinning. Morphology of LC was significantly associated with the rate of progressive RNFL thinning. Curvature of LC better predicted progressive RNFL thinning than did LCD measured from the BM or AS.

Integrating Macular Ganglion Cell Inner Plexiform Layer and Parapapillary Retinal Nerve Fiber Layer Measurements to Detect Glaucoma Progression

To investigate the temporal relationship among progressive macular ganglion cell inner plexiform layer (GCIPL) thinning, progressive parapapillary retinal nerve fiber layer (RNFL) thinning, and visual field (VF) progression in patients with primary open-angle glaucoma (POAG). Prospective study. One hundred thirty-six POAG patients (231 eyes) followed up for ≥5 years. OCT imaging of the macular GCIPL and parapapillary RNFL and perimetry were performed at ∼ 4-month intervals. Progressive GCIPL and RNFL thinning were determined by Guided Progression Analysis (GPA) of serial GCIPL and RNFL thickness maps. The specificities of GPA were calculated from the proportions of eyes with progressive GCIPL or RNFL thinning in 67 eyes of 36 healthy individuals followed up for ≥5 years. Visual field progression (likely or possible) was determined by the Early Manifest Glaucoma Trial criteria. Hazard ratios for VF progression, progressive RNFL thinning, and progressive GCIPL thinning, as determined by time-varying Cox models. GPA detected 57 eyes (24.7%) with progressive GCIPL thinning and 66 eyes (28.6%) with progressive RNFL thinning at a specificity of 95.5% and 91.0%, respectively. Thirty-five eyes (15.2%) demonstrated progressive RNFL and GCIPL thinning, whereas 53 eyes (22.9%) demonstrated progressive RNFL or GCIPL thinning. Eyes with progressive GCIPL thinning had a higher risk for progressive RNFL thinning (HR, 5.27; 95% confidence interval [CI], 2.89-9.62), whereas eyes with progressive RNFL thinning were also at a higher risk for progressive GCIPL thinning (HR, 2.99; 95% CI, 1.48-6.02), after adjusting for baseline covariates. The HRs for likely and possible VF progression were 3.48 (95% CI, 1.51-8.01) and 2.74 (95% CI, 1.26-5.98), respectively, on detection of progressive GCIPL thinning and 3.66 (95% CI, 1.68-7.97) and 2.54 (95% CI, 1.23-5.21), respectively, on detection of progressive RNFL thinning after adjusting for baseline covariates. Eyes with VF progression were not at risk of progressive RNFL or GCIPL thinning (P ≥ 0.493). Progressive macular GCIPL thinning and progressive parapapillary RNFL thinning are mutually predictive. Because progressive RNFL thinning and progressive GCIPL thinning are both indicative of VF progression, integrating macular GCIPL and parapapillary RNFL measurements is relevant to facilitate early detection of disease deterioration in glaucoma patients.

Ganglion Cell–Inner Plexiform Layer Change Detected by Optical Coherence Tomography Indicates Progression in Advanced Glaucoma

To examine the performance of Guided Progression Analysis (GPA; Carl Zeiss Meditec, Dublin, CA) in spectral-domain optical coherence tomography (OCT) in detecting progressive thinning of ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) in glaucoma. Longitudinal, observational study. A total of 196 eyes of 123 primary open-angle glaucoma patients (mean follow-up, 5.0 years). Macular GCIPL and peripapillary RNFL thicknesses were measured by Cirrus HD-OCT (Zeiss, Dublin, CA), and progressive GCIPL and RNFL thinning were assessed by GPA. The reference standard of glaucoma progression was determined by visual field (VF) progression. Glaucomatous eyes were classified into mild (117 eyes) or moderate to advanced (79 eyes) groups based on VF defects. Ganglion cell-inner plexiform layer and RNFL thinning rates were compared between progressors and nonprogressors. Visual field survival estimates in eyes with and without progressive GCIPL and RNFL thinning were evaluated by Kaplan-Meier survival analysis and compared with the log-rank test. Progressive GCIPL and RNFL thinning assessed by OCT GPA. Seventy-six eyes (38.8%) and 43 eyes (21.9%) demonstrated progressive GCIPL and RNFL thinning, respectively, and 48 eyes (24.5%) were classified as progressors by reference standard. The rate of change in the average GCIPL thickness was significantly higher in progressors (-1.05±0.98 μm/year for mild glaucoma and-0.66±0.30 μm/year for moderate to advanced glaucoma) than in nonprogressors (-0.47±0.54 μm/year for mild glaucoma and-0.31±0.50 μm/year for moderate to advanced glaucoma), regardless of glaucoma severity (P < 0.05). Eyes with progressive GCIPL thinning had lower VF survival estimates than eyes without, regardless of glaucoma severity. However, the rate of change in the average RNFL thickness did not differ significantly in moderate to advanced glaucoma (P= 0.765; -0.26±0.55 μm/year for progressors and-0.33±0.92 μm/year for nonprogressors), and VF survival estimates did not differ significantly between eyes with and without progressive RNFL thinning in moderate to advanced glaucoma (P= 0.781). Ganglion cell-inner plexiform layer GPA provides a new approach for evaluating glaucoma progression. It may be more useful for detecting progression in the advanced stages of glaucoma than RNFL GPA.

Influence of the lamina cribrosa on the rate of global and localized retinal nerve fiber layer thinning in open-angle glaucoma.

The advent of optical coherence tomography (OCT) imaging allows identification of the structural contribution of the lamina cribrosa (LC) to glaucoma progression. This study aimed to determine the role of various LC features, such as the LC depth (LCD), LC thickness (LCT), and focal LC defects, on the future rate of progressive retinal nerve fiber layer (RNFL) thinning in patients with glaucoma. One hundred eighteen patients with glaucoma who had undergone at least 4 OCT examinations were included. Features of LC, including the LCD, LCT, and presence of focal LC defects, from serial scan of the optic disc using the enhanced depth imaging of Spectralis OCT; were analyzed at baseline. Eyes were classified as those with or without progressive RNFL thinning using the guided progression analysis of Cirrus OCT. Factors associated with the rate of RNFL thinning (linear regression analysis against time for global average, inferior, and superior RNFL thicknesses, μm/year) were evaluated using a general linear model. Greater baseline LCD and thinner baseline LCT were significantly associated with the rate of superior RNFL thinning. Focal LC defects were significantly more frequent in eyes with progressive inferior RNFL thinning (93.8%) and the location of the focal LC defect was only related to the location of progression RNFL thinning in the inferior region (P < 0.001). A deeper and thinner LC was related to the rate of superior RNFL thinning, and the presence of focal LC defects was related to the rate of inferior RNFL thinning.