The Relationship Between Choroidal Abnormalities and Visual Outcomes in Pediatric Patients With NF1-Associated Optic Pathway Gliomas.

BACKGROUND: Choroidal abnormalities (CAs) visualized on near-infrared reflectance (NIR) imaging are a new diagnostic criterion for neurofibromatosis type 1 (NF1), but the association between the presence of CAs and visual function remains unknown. This study evaluated the relationship between visual acuity (VA) with the presence, number, or total area of CAs visualized by NIR in children with NF1-associated optic pathway gliomas (NF1-OPGs). METHODS: Patients (<18 years) enrolled in a prospective longitudinal study of children with NF1-associated OPGs from 3 institutions were eligible if they had optical coherence tomography (OCT) of the macula (Heidelberg Spectralis) with ≥1 year of follow-up. The central 30° NIR images were reviewed by 2 neuro-ophthalmologists who manually calculated the number and total area of CAs. VA (logMAR) was measured using a standardized protocol. Cross-sectional associations of presence, number, and total area of CAs with VA, retinal nerve fiber layer thickness (RNFL), and ganglion cell-inner plexiform layer thickness were evaluated at the first and most recent visits using regression models. Intereye correlation was accounted for using generalized estimating equations. RESULTS: Eighty-two eyes of 41 children (56% female) were included. The mean ± SD age at the first OCT was 10.1 ± 3.3 years, with a mean follow-up of 20.4 ± 7.2 months. At study entry, CAs were present in 46% of eyes with a mean number of 2.1 ± 1.7 and a mean total area of 2.0 ± 1.7 mm 2 per eye. At the most recent follow-up, CAs were present in 48% of eyes with a mean number of 2.2 ± 1.8 lesions and a mean total area of 2.3 ± 2.1 mm 2 per eye. Neither VA nor OCT parameters at first and follow-up visits were associated with the presence, number, or total area of CAs (all P > 0.05). CONCLUSIONS: CAs are prevalent but not ubiquitous, in children with NF1-OPGs. Although CAs are a diagnostic criterion for NF1, their presence and size do not appear to be associated with visual function.

Optic Disc Cupping in Neuromyelitis Optica Spectrum Disorder, Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease, and Multiple Sclerosis and Its Relationship With Optical Coherence Tomography Parameters: A Multicenter Study.

BACKGROUND: Although cupping of the optic nerve is classically a sign of glaucomatous optic neuropathy, it has been shown that cupping can sometimes occur after an episode of optic neuritis (ON). The purpose of this study was to compare cupping in patients after ON from multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to investigate the relationship between cupping and retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thinning. METHODS: This was a retrospective cohort involving patients (≥18 years) with ON from 3 institutions. Patients were eligible if they had optical coherence tomography (Cirrus, OCT) performed ≥6 months after a single unilateral ON. The amount of thinning and cupping was estimated from the difference in the OCT parameters between affected and unaffected eyes. Univariable and multivariable regressions were used to investigate the relationship between cupping and ON etiology. Pearson correlation was used to investigate the relationship between cupping and RNFL and GCC. RESULTS: Eighty-six subjects (MS: 35, NMOSD: 26, and MOGAD: 25) were included. There was no significant difference in gender and race between the groups, and most patients (86.1%) were female. Patients with NMOSD were significantly older than patients with MS or MOGAD (P = 0.002). In the univariate model, cupping was significantly higher in the NMOSD group (P = 0.017); however, after adjusting for age, GCC, and RNFL of the affected eye, the difference was no longer statistically significant (P = 0.949). The correlation between cupping asymmetry and RNFL and GCC of the affected eye was inversely strong in patients with MS (R = -0.60 and R = -0.64, respectively), inversely moderate in patients with MOGAD (R = -0.34 and R = -0.40, respectively), and weak in patients with NMOSD (R = -0.03 and R = -0.17, respectively). CONCLUSIONS: Our results demonstrated that cupping after ON is correlated with RNFL and GCC thinning; although cupping was overall greater in the NMOSD group, once adjusted for age, RNFL, and GCC, it did not differ among patients with MS, NMOSD, and MOGAD.

Rates of Visual Field Change in Eyes With Optic Disc Drusen.

BACKGROUND: Optic disc drusen (ODD) are calcified deposits in the prelaminar portion of the optic nerve head. Although often asymptomatic, these deposits can cause progressive visual field defects and vision loss. The purpose of this study was to evaluate rates of functional loss in eyes with ODD and to investigate risk factors associated with rates of visual field progression. METHODS: This was a retrospective cohort study including 65 eyes of 43 patients with ODD from the Duke Ophthalmic Registry. All eyes had at least 12 months of follow-up and at least 3 reliable standard automated perimetry (SAP) tests. Linear mixed models were used to estimate rates of SAP mean deviation (MD) loss over time. Univariable and multivariable models were used to assess the effect of clinical variables and intraocular pressure (IOP) on rates of change. RESULTS: Subjects were followed for an average of 7.6 ± 5.3 years. The mean rate of SAP MD change was -0.23 ± 0.26 dB/year, ranging from -1.19 to 0.13 dB/year. Fifty-seven eyes (87.7%) had slow progression (slower than -0.5 dB/year), 6 eyes (9.2%) had moderate progression (between -0.5 dB/year and -1 dB/year), and 2 eyes (3.1%) had fast progression (faster than -1 dB/year). In multivariable models, older age and worse SAP MD at baseline were significantly associated with faster rates of change. Mean IOP was not associated with faster rates of MD change in both univariable and multivariable analyses. CONCLUSIONS: Most eyes with ODD had slow rates of visual field loss over time. Age and baseline severity were significantly associated with faster rates of visual field loss.

Impact of Intraocular Pressure Control on Rates of Retinal Nerve Fiber Layer Loss in a Large Clinical Population.

PURPOSE: To investigate the impact of intraocular pressure (IOP) control on rates of change of spectral-domain OCT (SD-OCT) retinal nerve fiber layer (RNFL) thickness in a large clinical population. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 85 835 IOP measurements and 60 223 SD-OCT tests from 14 790 eyes of 7844 patients. METHODS: Data were extracted from the Duke Glaucoma Registry, a large database of electronic medical records of patients with glaucoma and suspected disease followed over time at the Duke Eye Center and satellite clinics. All records from patients with a minimum of 6 months of follow-up and at least 2 good-quality SD-OCT scans and 2 clinical visits with Goldmann applanation tonometry were included. Eyes were categorized according to the frequency of visits with IOP below cutoffs of 21 mmHg, 18 mmHg, and 15 mmHg over time. Rates of change for global RNFL thickness were obtained using linear mixed models and classified as slow if change was slower than -1.0 µm/year; moderate if between -1.0 and -2.0 µm/year; and fast if faster than -2.0 µm/year. Multivariable models were adjusted for age, gender, race, diagnosis, central corneal thickness, follow-up time, and baseline disease severity. MAIN OUTCOME MEASURES: Rates of change in SD-OCT RNFL thickness according to levels of IOP control. RESULTS: Eyes had a mean follow-up of 3.5±1.9 years. Average rate of change in RNFL thickness was -0.68±0.59 µm/year. Each 1 mmHg higher mean IOP was associated with 0.05 µm/year faster RNFL loss (P < 0.001) after adjustment for potentially confounding variables. For eyes that had fast progression, 41% of them had IOP <21 mmHg in all visits during follow-up, whereas 20% of them had all visits with IOP <18 mmHg, but only 9% of them had all visits with IOP <15 mmHg. CONCLUSIONS: Intraocular pressure was significantly associated with rates of progressive RNFL loss in a large clinical population. Eyes with stricter IOP control over follow-up visits had a smaller chance of exhibiting fast deterioration. Our findings may assist clinicians in establishing target pressures in clinical practice.

Efficacy and Side Effects of Topiramate in Treatment of Children With Pseudotumor Cerebri Syndrome.

BACKGROUND: Topiramate is often considered as a second-line medication for the treatment of pseudotumor cerebri syndrome (PTCS), but limited studies exist that evaluate its efficacy in children. METHODS: Retrospective study of patients aged <21 years with PTCS who were treated with topiramate alone or in combination with acetazolamide was performed. Data regarding clinical courses and visual outcomes were recorded. RESULTS: A total of 46 patients were identified. Three (6.5%) patients were treated with topiramate alone, 31 (67.4%) transitioned to topiramate from acetazolamide, and 12 (26.1%) took both topiramate and acetazolamide concurrently. The median time to resolution of papilledema on topiramate was 0.57 years (interquartile range 0.32 to 0.84). Among eyes with papilledema graded on the Frisen scale at topiramate initiation, 40 of 57 (70.2%) were grade 1, nine of 57 (15.8%) were grade 2, and eight of 57 (14.0%) were grade 3. Twenty-seven of 46 (58.7%) reported headache improvement after starting topiramate. The mean dose of topiramate was 1.3 ± 0.8 mg/kg/day. The most common side effect was patient report of cognitive slowing (10 of 46 [21.7%]). All patients on topiramate monotherapy who were compliant with treatment and follow-up had resolution of papilledema with no evidence of visual function loss. CONCLUSIONS: Topiramate can effectively treat PTCS in children with mild to moderate papilledema or in those unable to tolerate acetazolamide. More research is needed to assess the efficacy of topiramate for higher grade papilledema.

Prevalence, time course, and visual impact of peripapillary hyperreflective ovoid mass-like structures (PHOMS) in pediatric patients with optic nerve pathologies.

BACKGROUND: Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a recently defined optical coherence tomography (OCT) finding. The purpose of this study was to characterize the presence of PHOMS and their visual significance in pediatric patients with and without optic nerve pathologies. METHODS: This retrospective study evaluated 400 patients (<18 years of age) including normal control subjects and patients with optic neuritis, papillitis, optic nerve head drusen (ONHD), and papilledema. Information on demographics, visual function, and structural parameters were obtained. RESULTS: PHOMS were found in 7 of 258 normal control eyes (2.7%), 9 of 59 eyes with optic neuritis (15.3%), 58 of 76 eyes with ONHD (76.3%), 3 of 11 eyes with papillitis (27.3%), and 180 of 308 eyes with papilledema (58.4%). PHOMS were more prevalent in the papilledema (P < 0.001), ONHD (P < 0.001), and optic neuritis (P = 0.028) eyes than in control eyes. We identified 5 cases where PHOMS developed de novo. This occurred over an average of 2.3 years (range, 0.2-7.4 years). Sixteen cases of PHOMS resolved over an average of 1.1 years (range, 0.3-4.0 years). Cross-sectionally, PHOMS were not associated with visual acuity (P = 0.551), retinal nerve fiber layer thickness (P = 0.068), ganglion cell volume (P = 0.375), or visual field mean deviation (P = 0.795). CONCLUSIONS: PHOMS are present in a majority of children with papilledema or ONHD. PHOMS are dynamic and may form de novo over time with optic nerve pathology and may resolve either through treatment or atrophy. There was no relationship between the presence of PHOMS and poor visual function in our study cohort.

Clinical Course and Visual Outcomes of Papilledema in Pediatric Cerebral Venous Sinus Thrombosis.

PURPOSE: Cerebral venous sinus thrombosis (CVST) is a rare but life-threatening event with significant neurologic and visual morbidity. In this study, we report on the natural history and visual outcomes of papilledema in children with CVST. DESIGN: Retrospective case series. METHODS: Patients with CVST evaluated by the Department of Ophthalmology between 2000 and 2023 were included. Records were reviewed for presence and course of papilledema, treatment, and final visual outcomes following papilledema resolution. RESULTS: The study included 35 patients with a mean age of 9 ± 5 years and 40% were female. The most common risk factors for CVST were infection (69%), dehydration (26%), and hypercoagulability (23%). 31 patients (89%) had papilledema. Of these patients, 9 (29%) had progression of papilledema despite treatment, 17 patients (55%) did not have progression, and 5 patients (16%) lacked follow-up records. Initial Frisén grade among all cases was 2 ± 1, and cases with progression reached a grade of 4 ± 1 between 10 and 32 days following initial identification. Most patients (97%) were treated with anticoagulation and 100% required acetazolamide and/or lumbar puncture. Among 26 patients with follow-up, papilledema resolved in 107 ± 128 days. Fifty-four percent of patients had permanent ophthalmic sequelae. An initial Frisén grade ≥3 (odds ratio 7.54, 95% confidence interval 6.53-8.70, P< .001) was significantly associated with eventual optic atrophy. CONCLUSIONS: Children with CVST are at high risk for ophthalmologic sequelae. Papilledema can progress despite appropriate therapy. Our results highlight the importance of ophthalmologic follow-up during treatment course to prevent irreversible vision loss.

Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide.

Importance: Anecdotal experience raised the possibility that semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA) with rapidly increasing use, is associated with nonarteritic anterior ischemic optic neuropathy (NAION). Objective: To investigate whether there is an association between semaglutide and risk of NAION. Design, Setting, and Participants: In a retrospective matched cohort study using data from a centralized data registry of patients evaluated by neuro-ophthalmologists at 1 academic institution from December 1, 2017, through November 30, 2023, a search for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code H47.01 (ischemic optic neuropathy) and text search yielded 16 827 patients with no history of NAION. Propensity matching was used to assess whether prescribed semaglutide was associated with NAION in patients with type 2 diabetes (T2D) or overweight/obesity, in each case accounting for covarying factors (sex, age, systemic hypertension, T2D, obstructive sleep apnea, obesity, hyperlipidemia, and coronary artery disease) and contraindications for use of semaglutide. The cumulative incidence of NAION was determined with the Kaplan-Meier method and a Cox proportional hazards regression model adjusted for potential confounding comorbidities. Data were analyzed from December 1, 2017, through November 30, 2023. Exposures: Prescriptions for semaglutide vs non-GLP-1 RA medications to manage either T2D or weight. Main Outcomes and Measures: Cumulative incidence and hazard ratio of NAION. Results: Among 16 827 patients, 710 had T2D (194 prescribed semaglutide; 516 prescribed non-GLP-1 RA antidiabetic medications; median [IQR] age, 59 [49-68] years; 369 [52%] female) and 979 were overweight or obese (361 prescribed semaglutide; 618 prescribed non-GLP-1 RA weight-loss medications; median [IQR] age, 47 [32-59] years; 708 [72%] female). In the population with T2D, 17 NAION events occurred in patients prescribed semaglutide vs 6 in the non-GLP-1 RA antidiabetes cohort. The cumulative incidence of NAION for the semaglutide and non-GLP-1 RA cohorts over 36 months was 8.9% (95% CI, 4.5%-13.1%) and 1.8% (95% CI, 0%-3.5%), respectively. A Cox proportional hazards regression model showed higher risk of NAION for patients receiving semaglutide (hazard ratio [HR], 4.28; 95% CI, 1.62-11.29); P < .001). In the population of patients who were overweight or obese, 20 NAION events occurred in the prescribed semaglutide cohort vs 3 in the non-GLP-1 RA cohort. The cumulative incidence of NAION for the semaglutide vs non-GLP-1 RA cohorts over 36 months was 6.7% (95% CI, 3.6%-9.7%) and 0.8% (95% CI, 0%-1.8%), respectively. A Cox proportional hazards regression model showed a higher risk of NAION for patients prescribed semaglutide (HR, 7.64; 95% CI, 2.21-26.36; P < .001). Conclusions and Relevance: This study's findings suggest an association between semaglutide and NAION. As this was an observational study, future study is required to assess causality.

Optic neuropathy in craniosynostosis.

Craniosynostosis (CS) or the premature fusion of one or more cranial sutures in utero, or during the first years of life, can present in isolation or as a multisystem clinical disorder with a particular impact on visual function. Among ophthalmic complications, optic neuropathy is a significant cause of irreversible vision loss in these patients. Children with CS are at higher risk of developing elevated intracranial pressure which can lead to papilledema and, ultimately, optic atrophy. In addition, sometimes associated obstructive sleep apnea, abnormalities in central nervous system venous development, and Chiari malformation may contribute to optic neuropathy. Ophthalmologists have an important role in managing a number of coexistent ophthalmologic complications such as strabismus, anisometropia, amblyopia, ptosis, and exposure keratopathy in addition to maintaining surveillance for early signs of optic neuropathy; they play a critical consultative role contributing to the decision for primary or repeat decompressive surgery. In this article, we aim to review the etiology, diagnostic approach, and management of optic neuropathies in patients with craniosynostosis.

Intraocular Pressure and Rates of Macular Thinning in Glaucoma.

PURPOSE: To evaluate the effect of intraocular pressure (IOP) on the rates of macular thickness (ganglion cell layer [GCL] and ganglion cell-inner plexiform layer [GCIPL]) change over time measured by spectral-domain (SD) OCT. DESIGN: Retrospective cohort study. PARTICIPANTS: Overall, 451 eyes of 256 patients with primary open-angle glaucoma. METHODS: Data were extracted from the Duke Ophthalmic Registry, a database of electronic medical records of patients observed under routine clinical care at the Duke Eye Center, and satellite clinics. All records from patients with a minimum of 6 months of follow-up and at least 2 good-quality Spectralis SD-OCT macula scans were included. Linear mixed models were used to investigate the relationship between average IOP during follow-up and rates of GCL and GCIPL thickness change over time. MAIN OUTCOME MEASURES: The effect of IOP on the rates of GCL and GCIPL thickness loss measured by SD-OCT. RESULTS: Eyes had a mean follow-up of 1.8 ± 1.3 years, ranging from 0.5 to 10.2 years. The average rate of change for GCL thickness was -0.220 µm/year (95% confidence interval [CI], -0.268 to -0.172 µm/year) and for GCIPL thickness was -0.231 µm/year (95% CI, -0.302 to -0.160 µm/year). Each 1-mmHg higher mean IOP during follow-up was associated with an additional loss of -0.021 µm/year of GCL thickness (P = 0.001) and -0.032 µm/year of GCIPL thickness (P = 0.001) after adjusting for potentially confounding factors, such as baseline age, disease severity, sex, race, central corneal thickness, and follow-up time. CONCLUSIONS: Higher IOP was significantly associated with faster rates of GCL and GCIPL loss over time measured by SD-OCT, even during relatively short follow-up times. These findings support the use of SD-OCT GCL and GCIPL thickness measurements as structural biomarkers for the evaluation of the efficacy of IOP-lowering therapies in slowing down the progression of glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of an Objective Structural and Functional Reference Standard for Glaucoma with Quality of Life Outcomes.

PURPOSE: To compare self-reported quality-of-life (QoL) outcomes of patients diagnosed as normal, glaucoma suspect, and glaucoma based on an objective reference standard for glaucomatous optic neuropathy (GON). DESIGN: Cross-sectional study. PARTICIPANTS: 1884 eyes of 1019 patients were included in the study. METHODS: The data was sourced from the Duke Glaucoma Registry. Eyes were classified according to the presence and topographic correspondence of functional and structural damage, as assessed by parameters from standard automated perimetry (SAP) and spectral-domain OCT (SD-OCT). The objective diagnosis of the worse eye was used to define patient-level diagnosis. To assess QoL in the diagnostic groups, 14 unidimensional vision-related items of the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) were used to assess QoL in the diagnostic groups. Association between NEI VFQ-25 Rasch-calibrated scores and diagnostic groups was assessed through multivariable regression that controlled for confounding demographic and socioeconomic variables such as age, sex, race, income, marriage status, insurance status, and highest education level. MAIN OUTCOME MEASURES: NEI VFQ-25 Rasch scores compared with objective criteria diagnosis based on SAP mean deviation (MD) and SD-OCT retinal nerve fiber layer (RNFL) thickness. RESULTS: Overall, eyes classified as normal, glaucoma suspect, and glaucoma had decreasing mean scores in SAP MD (0.2 ± 1.0 dB, -0.9 ± 2.4 dB, -6.2 ± 7.0 dB, respectively; P < 0.001) and SD-OCT RNFL thickness (97.8 ± 9.5 µm, 89.0 ± 13.1 µm, 64.5 ± 12.8 µm, respectively; P < 0.001). The mean Rasch-calibrated NEI VFQ-25 score was significantly different among normal, suspect, and glaucoma groups (82.9 ± 13.0, 78.2 ± 14.8, and 72.6 ± 16.2, respectively; P < 0.001). When adjusted for confounding socioeconomic variables, glaucoma patients had significantly worse QoL than those classified as normal (ß = -6.8 Rasch score units; P < 0.001). CONCLUSION: A glaucoma diagnosis, based on an objective reference standard for GON, was significantly associated with worse Rasch-adjusted scores of QoL. Utilization of such objective criteria may provide clinically relevant metrics with potential to improve comparability of research findings and validation of newly proposed diagnostic tools. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Comparison of 10-2 and 24-2 Perimetry to Diagnose Glaucoma Using OCT as an Independent Reference Standard.

PURPOSE: To compare the performance of the 10-2 test versus 24-2 standard automated perimetry (SAP) test for the diagnosis of glaucoma using OCT as an independent standard for glaucomatous damage. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 1375 pairs of 10-2 and 24-2 SAP tests from 569 eyes of 339 subjects were used for the analysis. A total of 440 (77%) eyes had a diagnosis of glaucoma, and 129 (23%) eyes were normal. All participants underwent 10-2 and 24-2 SAP tests within 30 days. METHODS: Glaucomatous severity was quantified based on OCT macula ganglion cell layer (mGCL) and circumpapillary retinal nerve fiber layer. The area under the receiver operating characteristic (ROC) curve (AUC) was used to compare 10-2 and 24-2 metrics for discriminating healthy eyes from those of glaucoma, at different levels of disease severity. MAIN OUTCOME MEASURES: Areas under the ROC curves and sensitivities at fixed specificities of 80% and 95%. RESULTS: The overall AUC for mean deviation (MD) for the 24-2 test (0.808) was significantly higher than that of the 10-2 test (0.742; P < 0.001). When compared at different stages of the disease, the 24-2 test performed generally better than the 10-2 test, notably in the earlier stages of the disease. For early damage (first quartile), the 24-2 MD had an AUC of 0.658 versus 0.590 for 10-2 MD (P = 0.018). For advanced damage (fourth quartile), corresponding values were 0.954 vs. 0.903 (P = 0.013). Similar trends were observed when glaucoma severity was defined based on structural macular damage with mGCL thickness. CONCLUSIONS: The 24-2 SAP test had better diagnostic accuracy compared with that of the 10-2 test for detecting equivalent levels of glaucomatous damage, as measured by quantitative assessment of retinal nerve fiber layer and macula by OCT. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Rates of Glaucomatous Structural and Functional Change From a Large Clinical Population: The Duke Glaucoma Registry Study.

PURPOSE: To investigate rates of structural and functional change in a large clinical population of glaucoma and glaucoma suspect patients. DESIGN: Retrospective cohort. METHODS: Twenty-nine thousand five hundred forty-eight spectral-domain optical coherence tomography (OCT) and 19,812 standard automated perimetry (SAP) tests from 6138 eyes of 3669 patients with ≥6 months of follow-up, 2 good quality spectral-domain OCT peripapillary retinal nerve fiber layer scans, and 2 reliable SAP tests were included. Data were extracted from the Duke Glaucoma Registry, a large database of electronic health records of patients from the Duke Eye Center and satellite clinics. Rates of change for the 2 metrics were obtained using linear mixed models, categorized according to pre-established cutoffs, and analyzed according to the severity of the disease. RESULTS: Average rates of change were -0.73 ± 0.80 µm per year for global retinal nerve fiber layer thickness and -0.09 ± 0.36 dB per year for SAP mean deviation. More than one quarter (26.6%) of eyes were classified as having at least a moderate rate of change by spectral-domain OCT vs 9.1% by SAP (P < .001). In eyes with severe disease, 31.6% were classified as progressing at moderate or faster rates by SAP vs 26.5% by spectral-domain OCT (P = .055). Most eyes classified as fast by spectral-domain OCT were classified as slow by SAP and vice versa. CONCLUSION: Although most patients under routine care had slow rates of progression, a substantial proportion had rates that could potentially result in major losses if sustained over time. Both structural and functional tests should be used to monitor glaucoma, and spectral-domain OCT still has a relevant role in detecting fast progressors in advanced disease.

The Relationship Between Asymmetries of Corneal Properties and Rates of Visual Field Progression in Glaucoma Patients.

PRéCIS:: In this study, asymmetries in corneal hysteresis (CH) between eyes of glaucoma patients were significantly associated with asymmetries in rates of visual field loss, suggesting a role of hysteresis as a risk factor for disease progression. PURPOSE: The purpose of this study was to investigate the relationship between asymmetries in rates of glaucoma progression and asymmetries of corneal properties between eyes of subjects with primary open-angle glaucoma. PARTICIPANTS AND METHODS: This prospective study followed 126 binocular subjects with glaucoma for an average of 4.3±0.8 years. CH was measured at baseline using the Ocular Response Analyzer. Standard automated perimetry (SAP) and intraocular pressure were measured at baseline and every 6 months. Rates of visual field progression were calculated using ordinary least square regression of SAP mean deviation (MD) values over time for each eye. Eyes were defined as "better" and "worse" based on the slopes of SAP MD. Pearson correlation test, and univariable and multivariable regression models were used to investigate the relationship between inter-eye asymmetry in CH and central corneal thickness and inter-eye differences in rates of visual field progression. RESULTS: Only asymmetry of CH was significantly associated with the asymmetry in SAP MD rates of change between eyes (r=0.22; P=0.01). In a multivariable model adjusting for age, race, central corneal thickness, mean intraocular pressure and baseline disease severity, CH asymmetry remained significantly associated with asymmetric progression (P=0.032). CONCLUSION: CH asymmetry between eyes was associated with asymmetry on rates of visual field change, providing further support for the role of CH as a risk factor for glaucoma progression.

Quantification of Retinal Nerve Fibre Layer Thickness on Optical Coherence Tomography with a Deep Learning Segmentation-Free Approach.

This study describes a segmentation-free deep learning (DL) algorithm for measuring retinal nerve fibre layer (RNFL) thickness on spectral-domain optical coherence tomography (SDOCT). The study included 25,285 B-scans from 1,338 eyes of 706 subjects. Training was done to predict RNFL thickness from raw unsegmented scans using conventional RNFL thickness measurements from good quality images as targets, forcing the DL algorithm to learn its own representation of RNFL. The algorithm was tested in three different sets: (1) images without segmentation errors or artefacts, (2) low-quality images with segmentation errors, and (3) images with other artefacts. In test set 1, segmentation-free RNFL predictions were highly correlated with conventional RNFL thickness (r = 0.983, P < 0.001). In test set 2, segmentation-free predictions had higher correlation with the best available estimate (tests with good quality taken in the same date) compared to those from the conventional algorithm (r = 0.972 vs. r = 0.829, respectively; P < 0.001). Segmentation-free predictions were also better in test set 3 (r = 0.940 vs. r = 0.640, P < 0.001). In conclusion, a novel segmentation-free algorithm to extract RNFL thickness performed similarly to the conventional method in good quality images and better in images with errors or other artefacts.

Human Versus Machine: Comparing a Deep Learning Algorithm to Human Gradings for Detecting Glaucoma on Fundus Photographs.

PURPOSE: To compare the diagnostic performance of human gradings vs predictions provided by a machine-to-machine (M2M) deep learning (DL) algorithm trained to quantify retinal nerve fiber layer (RNFL) damage on fundus photographs. DESIGN: Evaluation of a machine learning algorithm. METHODS: An M2M DL algorithm trained with RNFL thickness parameters from spectral-domain optical coherence tomography was applied to a subset of 490 fundus photos of 490 eyes of 370 subjects graded by 2 glaucoma specialists for the probability of glaucomatous optical neuropathy (GON), and estimates of cup-to-disc (C/D) ratios. Spearman correlations with standard automated perimetry (SAP) global indices were compared between the human gradings vs the M2M DL-predicted RNFL thickness values. The area under the receiver operating characteristic curves (AUC) and partial AUC for the region of clinically meaningful specificity (85%-100%) were used to compare the ability of each output to discriminate eyes with repeatable glaucomatous SAP defects vs eyes with normal fields. RESULTS: The M2M DL-predicted RNFL thickness had a significantly stronger absolute correlation with SAP mean deviation (rho=0.54) than the probability of GON given by human graders (rho=0.48; P < .001). The partial AUC for the M2M DL algorithm was significantly higher than that for the probability of GON by human graders (partial AUC = 0.529 vs 0.411, respectively; P = .016). CONCLUSION: An M2M DL algorithm performed as well as, if not better than, human graders at detecting eyes with repeatable glaucomatous visual field loss. This DL algorithm could potentially replace human graders in population screening efforts for glaucoma.

Comparison of Short- And Long-Term Variability in Standard Perimetry and Spectral Domain Optical Coherence Tomography in Glaucoma.

PURPOSE: To assess short- and long-term variability on standard automated perimetry (SAP) and spectral domain optical coherence tomography (SD-OCT) in glaucoma. DESIGN: Prospective cohort. METHODS: Ordinary least squares linear regression of SAP mean deviation (MD) and SD-OCT global retinal nerve fiber layer (RNFL) thickness were fitted over time for sequential tests conducted within 5 weeks (short-term testing) and annually (long-term testing). Residuals were obtained by subtracting the predicted and observed values, and each patient's standard deviation (SD) of the residuals was used as a measure of variability. Wilcoxon signed-rank test was performed to test the hypothesis of equality between short- and long-term variability. RESULTS: A total of 43 eyes of 43 glaucoma subjects were included. Subjects had a mean 4.5 ± 0.8 SAP and OCT tests for short-term variability assessment. For long-term variability, the same number of tests were performed and results annually collected over an average of 4.0 ± 0.8 years. The average SD of the residuals was significantly higher in the long-term than in the short-term period for both tests: 1.05 ± 0.70 dB vs. 0.61 ± 0.34 dB, respectively (P < 0.001) for SAP MD and 1.95 ± 1.86 µm vs. 0.81 ± 0.56 µm, respectively (P < 0.001) for SD-OCT RNFL thickness. CONCLUSIONS: Long-term variability was higher than short-term variability on SD-OCT and SAP. Because current event-based algorithms for detection of glaucoma progression on SAP and SD-OCT have relied on short-term variability data to establish their normative databases, these algorithms may be underestimating the variability in the long-term and thus may overestimate progression over time.

Comparing the Rule of 5 to Trend-based Analysis for Detecting Glaucoma Progression on OCT.

PURPOSE: The rule of 5 is a simple rule for detecting retinal nerve fiber layer (RNFL) change on spectral-domain OCT (SD-OCT), in which a loss of 5 µm of global RNFL on a follow-up test is considered evidence of significant change when compared with the baseline. The rule is based on short-term test-retest variability of SD-OCT and is often used in clinical practice. The purpose of this study was to compare the rule of 5 with trend-based analysis of global RNFL thickness over time for detecting glaucomatous progression. DESIGN: Prospective cohort. PARTICIPANTS: A total of 300 eyes of 210 glaucoma subjects followed for an average of 5.4±1.5 years with a median of 11 (interquartile range, 7-14) visits. METHODS: Trend-based analysis was performed by ordinary least-squares (OLS) linear regression of global RNFL thickness over time. For estimation of specificity, false-positives were obtained by assessing for progression on series of randomly permutated follow-up visits for each eye, which removes any systematic trend over time. The specificity of trend-based analysis was matched to that of the rule of 5 to allow meaningful comparison of the "hit rate," or the proportion of glaucoma eyes categorized as progressing at each time point, using the original sequence of visits. MAIN OUTCOME MEASURES: Comparison between hit rates of trend-analysis versus rule of 5 at matched specificity. RESULTS: After 5 years, the simple rule of 5 identified 37.5% of eyes as progressing at a specificity of 81.1%. At the same specificity, the hit rate for trend-based analysis was significantly greater than that of the rule of 5 (62.9% vs. 37.5%; P < 0.001). If the rule of 5 was required to be repeatable on a consecutive test, specificity improved to 93.4%, but hit rate decreased to 21.0%. At this higher specificity, trend-based analysis still had a significantly greater hit rate than the rule of 5 (47.4% vs. 21.0%, respectively; P < 0.001). CONCLUSIONS: Trend-based analysis was superior to the simple rule of 5 for identifying progression in glaucoma eyes and should be preferred as a method for longitudinal assessment of global SD-OCT RNFL change over time.