Radiation effects on retinal layers revealed by OCT, OCT-A, and perimetry as a function of dose and time from treatment.

Optical coherence tomography (OCT) has become a key method for diagnosing and staging radiation retinopathy, based mainly on the presence of fluid in the central macula. A robust retinal layer segmentation method is required for identification of the specific layers involved in radiation-induced pathology in individual eyes over time, in order to determine damage driven by radiation injury to the microvessels and to the inner retinal neurons. Here, we utilized OCT, OCT-angiography, visual field testing, and patient-specific dosimetry models to analyze abnormal retinal layer thickening and thinning relative to microvessel density, visual function, radiation dose, and time from radiotherapy in a cross-sectional cohort of uveal melanoma patients treated with 125I-plaque brachytherapy. Within the first 24 months of radiotherapy, we show differential thickening and thinning of the two inner retinal layers, suggestive of microvessel leakage and neurodegeneration, mostly favoring thickening. Four out of 13 eyes showed decreased inner retinal capillary density associated with a corresponding normal inner retinal thickness, indicating early microvascular pathology. Two eyes showed the opposite: significant inner retinal layer thinning and normal capillary density, indicating early neuronal damage preceding a decrease in capillary density. At later time points, inner retinal thinning becomes the dominant pathology and correlates significantly with decreased vascularity, vision loss, and dose to the optic nerve. Stable multiple retinal layer segmentation provided by 3D graph-based methods aids in assessing the microvascular and neuronal response to radiation, information needed to target therapeutics for radiation retinopathy and vision loss.

Visualization of Optic Nerve Structural Patterns in Papilledema Using Deep Learning Variational Autoencoders.

Purpose: To visualize and quantify structural patterns of optic nerve edema encountered in papilledema during treatment. Methods: A novel bi-channel deep-learning variational autoencoder (biVAE) model was trained using 1498 optical coherence tomography (OCT) scans of 125 subjects over time from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and 791 OCT scans of 96 control subjects from the University of Iowa. An independent test dataset of 70 eyes from 70 papilledema subjects was used to evaluate the ability of the biVAE model to quantify and reconstruct the papilledema spatial patterns from input OCT scans using only two variables. Results: The montage color maps of the retinal nerve fiber layer (RNFL) and total retinal thickness (TRT) produced by the biVAE model provided an organized visualization of the variety of morphological patterns of optic disc edema (including differing patterns at similar thickness levels). Treatment effects of acetazolamide versus placebo in the IIHTT were also demonstrated in the latent space. In image reconstruction, the mean signed peripapillary retinal nerve fiber layer thickness (pRNFLT) difference ± SD was -0.12 ± 17.34 µm, the absolute pRNFLT difference was 13.68 ± 10.65 µm, and the RNFL structural similarity index reached 0.91 ± 0.05. Conclusions: A wide array of structural patterns of papilledema, integrating the magnitude of disc edema with underlying disc and retinal morphology, can be quantified by just two latent variables. Translational Relevance: A biVAE model encodes structural patterns, as well as the correlation between channels, and may be applied to visualize individuals or populations with papilledema throughout treatment.

Archetypal analysis of longitudinal visual fields for idiopathic intracranial hypertension patients presenting in a clinic setting.

We previously applied archetypal analysis (AA) using visual fields (VF) from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) to derive a model, which quantified patterns (or archetypes [ATs] of VF loss), anticipated recovery, and identified residual VF deficits. We hypothesized that AA could produce similar results using IIH VFs collected in clinical practice. We applied AA to 803 VFs from 235 eyes with IIH from an outpatient neuro-ophthalmology clinic and created a clinic-derived model of ATs, with the relative weight (RW) and average total deviation (TD) for each AT. We also created a combined-derived model from an input dataset containing the clinic VFs and 2862 VFs from the IIHTT. We used both models to decompose clinic VF into ATs of varying percent weight (PW), correlated presentation AT PW with mean deviation (MD), and evaluated final visit VFs considered "normal" by MD ≥ -2.00 dB for residual abnormal ATs. The 14-AT clinic-derived and combined-derived models revealed similar patterns of VF loss previously identified in the IIHTT model. AT1 (a normal pattern) was most prevalent in both models (RW = 51.8% for clinic-derived; 35.4% for combined-derived). Presentation AT1 PW correlated with final visit MD (r = 0.82, p < 0.001 for the clinic-derived model; r = 0.59, p < 0.001 for the combined-derived model). Both models showed ATs with similar patterns of regional VF loss. The most common patterns of VF loss in "normal" final visit VFs using each model were clinic-derived AT2 (mild global depression with enlarged blind spot; 44/125 VFs; 34%) and combined-derived AT2 (near-normal; 93/149 VFs; 62%). AA provides quantitative values for IIH-related patterns of VF loss that can be used to monitor VF changes in a clinic setting. Presentation AT1 PW is associated with the degree of VF recovery. AA identifies residual VF deficits not otherwise indicated by MD.

Neuro-ophthalmic features of patients with spontaneous cerebrospinal fluid leaks.

Background: Increased intracranial pressure is a potential cause of spontaneous cerebrospinal fluid (sCSF) leak. Associated neuro-ophthalmic features have not been well studied, particularly relationships with idiopathic intracranial hypertension (IIH). We hypothesized that neuro-ophthalmic features routinely used in evaluations for IIH can be useful in the investigation of a causal relationship between IIH and sCSF leak. We reviewed the neuro-ophthalmic examination and office-based ophthalmic imaging data of all consecutive patients with sCSF leaks and at least one repair to investigate the clinical and neuro-ophthalmic features of increased intracranial pressure. Methods: We conducted a retrospective longitudinal study at a single institution by querying the electronic medical record system for CSF leak Current Procedural Terminology (CPT) codes (G96.00 and G96.01) from June 1, 2019, to July 31, 2022. For patients with a confirmed diagnosis of sCSF leak, demographic information, eye examination results, and ophthalmic imaging details for both eyes were collected. Results: A total of 189 patients with CSF leaks were identified through CPT coding; 159 had iatrogenic or traumatic CSF leaks, and 30 individuals (3 male, 27 female) had confirmed sCSF leaks. The mean age of patients with sCSF leaks was 46 years (range: 29 - 81), with a mean body mass index of 35.2 kg/m2 (range: 18.2 - 54.1). Only 11 of 30 underwent eye examinations (8 before surgical repair and 10 after). The mean pre-repair and post-repair best-corrected visual acuity were 20/30 (range: 20/20 - 20/55) and 20/25 (range: 20/20 - 20/40), respectively (P = 0.188). The mean retinal nerve fiber layer thickness was 99 µm (range: 96 - 104) pre-repair and 97 µm (range: 84 - 103) post-repair (P = 0.195). The mean ganglion cell complex thickness was 84 µm (range: 72 - 94) pre-repair and 82 µm (range: 71 - 94) post-repair (P = 0.500). Humphrey visual field average mean deviation was -5.1 (range: -12.4 - -1.8) pre-repair and -1.0 (range: -10.1 - 2.1) post-repair (P = 0.063). Conclusions: Serial neuro-ophthalmic examinations are recommended for patients with sCSF leaks to screen for signs of current or prior increased intracranial pressure. Larger studies are required to clarify the longitudinal changes in neuro-ophthalmic features, to investigate the incidence of IIH in cases of sCSF leak development or recurrence after surgical repair, and to explore potential causal relationships to guide post-repair management and prevent recurrent leaks. A multicenter consortium is also suggested to develop a standard clinical protocol for comprehensive management of sCSF leaks.

Reduced blood flow by laser speckle flowgraphy after 125I-plaque brachytherapy for uveal melanoma.

BACKGROUND: To determine whether reductions in retinal and choroidal blood flow measured by laser speckle flowgraphy are detected after 125I-plaque brachytherapy for uveal melanoma. METHODS: In a cross-sectional study, retinal and choroidal blood flow were measured using laser speckle flowgraphy in 25 patients after treatment with 125I-plaque brachytherapy for uveal melanoma. Flow was analyzed in the peripapillary region by mean blur rate as well as in the entire image area with a novel superpixel-based method. Relationships between measures were determined by Spearman correlation. RESULTS: Significant decreases in laser speckle blood flow were observed in both the retinal and choroidal vascular beds of irradiated, but not fellow, eyes. Overall, 24 of 25 patients had decreased blood flow compared to their fellow eye, including 5 of the 6 patients imaged within the first 6 months following brachytherapy. A significant negative correlation between blood flow and time from therapy was present. CONCLUSIONS: Decreases in retinal and choroidal blood flow by laser speckle flowgraphy were detected within the first 6 months following brachytherapy. Reduced retinal and choroidal blood flow may be an early indicator of microangiographic response to radiation therapy.

Utility of Spectral-Domain Optical Coherence Tomography in Differentiating Papilledema From Pseudopapilledema: A Prospective Longitudinal Study.

BACKGROUND: Prospective and longitudinal studies assessing the utility of spectral-domain optical coherence tomography (SD-OCT) to differentiate papilledema from pseudopapilledema are lacking. We studied the sensitivity and specificity of baseline and longitudinal changes in SD-OCT parameters with 3D segmentation software to distinguish between papilledema and pseudopapilledema in a cohort of patients referred for evaluation of undiagnosed optic disc elevation. METHODS: Fifty-two adult patients with optic disc elevation were enrolled in a prospective longitudinal study. A diagnosis of papilledema was made when there was a change in the appearance of the optic disc elevation on fundus photographs as noted by an independent observer at or before 6 months. The degree of optic disc elevation was graded using the Frisen scale and patients with mild optic disc elevation (Frisen grades 1 and 2) were separately analyzed. SD-OCT parameters including peripapillary retinal nerve fiber layer (pRNFL), total retinal thickness (TRT), paracentral ganglion cell layer-inner plexiform layer (GCL-IPL) thickness, and optic nerve head volume (ONHV) at baseline and within 6 months of follow-up were measured. RESULTS: Twenty-seven (52%) patients were diagnosed with papilledema and 25 (48%) with pseudopapilledema. Among patients with mild optic disc elevation (Frisen grades 1 and 2), baseline pRNFL (110.1 µm vs 151.3 µm) and change in pRNFL (ΔpRNFL) (7.3 µm vs 52.3 µm) were greater among those with papilledema. Baseline and absolute changes in TRT and ONHV were also significantly higher among patients with papilledema. The mean GCL-IPL thickness was similar at baseline, but there was a small reduction in GCL-IPL thickness among patients with papilledema. Receiver operator curves (ROCs) were generated; ΔpRNFL (0.93), ΔTRT (0.94), and ΔONHV (0.95) had the highest area under the curve (AUC). CONCLUSIONS: The mean baseline and absolute changes in SD-OCT measurements (pRFNL, TRT, and ONHV) were significantly greater among patients with papilledema, and remained significantly greater when patients with mild optic disc elevation were separately analyzed. ROCs demonstrated that ΔpRNFL, ΔTRT, and ΔONHV have the highest AUC and are best able to differentiate between papilledema and pseudopapilledema.

Association of Optical Coherence Tomography With Longitudinal Neurodegeneration in Veterans With Chronic Mild Traumatic Brain Injury.

Importance: Mild traumatic brain injury (TBI) may predispose individuals to progressive neurodegeneration. Objective: To identify evidence of neurodegeneration through longitudinal evaluation of changes in retinal layer thickness using optical coherence tomography in veterans with a history of mild TBI. Design, Setting, and Participants: This longitudinal cohort study evaluated veterans who were receiving services at the Minneapolis Veterans Affairs Health Care System. Symptomatic or mild TBI was diagnosed according to the Mayo TBI Severity Classification System. Participants in the age-matched control group had no history of TBI. Participants with any history or evidence of retinal or optic nerve disease that could affect retinal thickness were excluded. Data analysis was performed from July 2019 to February 2020. Exposures: The presence and severity of mild TBI were determined through consensus review of self-report responses during the Minnesota Blast Exposure Screening Tool semistructured interview. Main Outcomes and Measures: Change over time of retinal nerve fiber layer (RNFL) thickness. Results: A total of 139 veterans (117 men [84%]; mean [SD] age, 49.9 [11.1] years) were included in the study, 69 in the TBI group and 70 in the control group. Veterans with mild TBI showed significantly greater RNFL thinning compared with controls (mean [SE] RNFL slope, -1.47 [0.24] µm/y vs -0.31 [0.32] µm/y; F1,122 = 8.42; P = .004; Cohen d = 0.52). Functionally, veterans with mild TBI showed greater declines in visual field mean deviation (mean [SE] slope, -0.09 [0.14] dB/y vs 0.46 [0.23] dB/y; F1,122 = 4.08; P = .046; Cohen d = 0.36) and pattern standard deviation (mean [SE] slope, 0.09 [0.06] dB/y vs -0.10 [0.07] dB/y; F1,122 = 4.78; P = .03; Cohen d = 0.39) and high spatial frequency (12 cycles/degree) contrast sensitivity compared with controls. Cognitively, there was a significantly greater decrease in the number of errors over time during the Groton Maze Learning Test (GMLT) in controls compared with veterans with mild TBI (mean [SE] slope, -9.30 [1.48] errors/y vs -5.23 [1.24] errors/y; F1,127 = 4.43; P = .04; Cohen d = 0.37). RNFL tissue loss was significantly correlated with both worsening performance on the GMLT over time (Spearman ρ = -0.20; P = .03) and mild TBI severity (Spearman ρ = -0.25; P = .006). The more severe the mild TBI (larger Minnesota Blast Exposure Screening Tool severity score), the faster the reduction in RNFL thickness (ie, the more negative the slope) across time. Conclusions and Relevance: This cohort study found longitudinal evidence for significant, progressive neural degeneration over time in veterans with mild TBI, as indicated by greater RNFL tissue loss in patients with mild TBI vs controls, as well as measures of function. These results suggest that these longitudinal measures may be useful biomarkers of neurodegeneration. Changes in this biomarker may provide early detection of subsequent cognitive and functional deficits that may impact veterans' independence and need for care.

A Deep-Learning Approach for Automated OCT En-Face Retinal Vessel Segmentation in Cases of Optic Disc Swelling Using Multiple En-Face Images as Input.

Purpose: In cases of optic disc swelling, segmentation of projected retinal blood vessels from optical coherence tomography (OCT) volumes is challenging due to swelling-based shadowing artifacts. Based on our hypothesis that simultaneously considering vessel information from multiple projected retinal layers can substantially increase vessel visibility, in this work, we propose a deep-learning-based approach to segment vessels involving the simultaneous use of three OCT en-face images as input. Methods: A human expert vessel tracing combining information from OCT en-face images of the retinal pigment epithelium (RPE), inner retina, and total retina as well as a registered fundus image served as the reference standard. The deep neural network was trained from the imaging data from 18 patients with optic disc swelling to output a vessel probability map from three OCT en-face input images. The vessels from the OCT en-face images were also manually traced in three separate stages to compare with the performance of the proposed approach. Results: On an independent volume-matched test set of 18 patients, the proposed deep-learning-based approach outperformed the three OCT-based manual tracing stages. The manual tracing based on three OCT en-face images also outperformed the manual tracing using only the traditional RPE en-face image. Conclusions: In cases of optic disc swelling, use of multiple en-face images enables better vessel segmentation when compared with the traditional use of a single en-face image. Translational Relevance: Improved vessel segmentation approaches in cases of optic disc swelling can be used as features for an improved assessment of the severity and cause of the swelling.

The Effect of Acetazolamide and Weight Loss on Intraocular Pressure in Idiopathic Intracranial Hypertension Patients.

PURPOSE: Acetazolamide (ACZ) lowers intraocular pressure (IOP), acutely in normal eyes and both acutely and chronically in eyes with glaucoma, and cerebrospinal fluid pressure (CSFp), chronically in patients with idiopathic intracranial hypertension (IIH). We hypothesize chronic daily ACZ would significantly reduce IOP and contribute to a translaminar pressure gradient change reflected by alteration in the CSFp-IOP difference and the deformation of the neural canal in patients with IIH and no glaucoma. PATIENTS AND METHODS: Before randomization to ACZ or placebo treatment for 6 months, 165 participants in the IIH Treatment Trial had evaluations that included Goldmann applanation, CSFp measurement, and optical coherence tomography determination of the neural canal deformation. These measures were repeated at the 6-month outcome. RESULTS: The IOP was not significantly decreased from baseline at 1, 3, or 6 months in eyes in both treatment groups. At month 6, the amount of ACZ or weight modification did not correlate with any IOP change. The 6-month mean change in neural canal deformation was 0.96 and -0.04 (P=0.001) and in CSFp was -128 and -38 mm H2O (P=0.001), but CSFp-IOP difference change was not significant, in the ACZ and placebo groups, respectively. CONCLUSIONS: ACZ does not reduce the IOP in eyes without glaucoma but does decrease the pathologic elevated CSFp, providing evidence that normal systems can compensate for chronic medication effects. The CSFp-IOP is not a direct marker of translaminar pressure gradient and the ACZ normalization of the neural canal deformation appears due to CSFp reduction alone.

Peripapillary Retinal Pigment Epithelium Layer Shape Changes From Acetazolamide Treatment in the Idiopathic Intracranial Hypertension Treatment Trial.

Purpose: Recent studies indicate that the amount of deformation of the peripapillary retinal pigment epithelium and Bruch's membrane (pRPE/BM) toward or away from the vitreous may reflect acute changes in cerebrospinal fluid pressure. The study purpose is to determine if changes in optic-nerve-head (ONH) shape reflect a treatment effect (acetazolamide/placebo + weight management) using the optical coherence tomography (OCT) substudy of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) at baseline, 3, and 6 months. Methods: The pRPE/BM shape deformation was quantified and compared with ONH volume, peripapillary retinal nerve fiber layer (pRNFL), and total retinal (pTR) thicknesses in the acetazolamide group (39 subjects) and placebo group (31 subjects) at baseline, 3, and 6 months. Results: Mean changes of the pRPE/BM shape measure were significant and in the positive direction (away from the vitreous) for the acetazolamide group (P < 0.01), but not for the placebo group. The three OCT measures reflecting the reduction of optic disc swelling were significant in both treatment groups but greater in the acetazolamide group (P < 0.01). Conclusions: Change in the pRPE/BM shape away from the vitreous reflects the effect of acetazolamide + weight management in reducing the pressure differential between the intraocular and retrobulbar arachnoid space. Weight management alone was also associated with a decrease in optic nerve volume/edema but without a significant change in the pRPE/BM shape, implying an alternative mechanism for improvement in papilledema and axoplasmic flow, independent of a reduction in the pressure differential. (ClinicalTrials.gov number, NCT01003639.).

The Effect of Treatment of Idiopathic Intracranial Hypertension on Prevalence of Retinal and Choroidal Folds.

PURPOSE: We described 3 types of folds in the retina and a crease in the outer retina associated with papilledema owing to idiopathic intracranial hypertension (IIH) at presentation. We report the change in folds relative to treatment of IIH over the 6 months. METHODS: In this substudy of a randomized clinical trial, study eyes of subjects assigned to acetazolamide (ACZ, n = 44) or placebo (PLB, n = 43) had spectral-domain optical coherence tomography (SDOCT) images of the optic disc and macula regions at baseline and at 3 and 6 months. Images were evaluated for peripapillary wrinkles (PPW), retinal folds (RF), choroidal folds (CF), and creases using transaxial and en face views. The optic nerve head (ONH) shape, retinal nerve fiber layer (RNFL) thickness, ONH volume, and papilledema grade were measured. Outcome was determination of the presence or absence of PPW, RF, CF, and creases. RESULTS: At presentation, except for an increase of PPW in ACZ eyes (64% vs 28%), both treatment groups were matched for all OCT features. At 6 months, ACZ-treated, but not PLB-treated, eyes had fewer folds of all types (P < .01), with a 57% reduction in frequency of RF. Creases did not resolve. Resolution of RF, but not of PPW and CF, was associated with significant reduction in RNFL thickness, ONH volume, and papilledema grade. CONCLUSIONS: The various types of retinal folds associated with papilledema reflect biodynamic processes and show an ACZ treatment effect. Persistence of these folds despite marked improvement in ONH swelling suggests permanent changes in the affected retinal tissues.

Retinal Ganglion Cell Layer Thinning Within One Month of Presentation for Non-Arteritic Anterior Ischemic Optic Neuropathy.

PURPOSE: Optical coherence tomography reveals retinal ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thinning in chronic optic nerve injury. With acute optic nerve injury, as in acute nonarteritic anterior ischemic optic neuropathy (NAION), swelling obscures early demonstration of RNFL thinning, which might be used to evaluate therapies. We hypothesized that measurement of GCL plus inner plexiform layer (IPL) thickness and trajectory of thinning would show it is an earlier and more accurate biomarker of early permanent neuronal injury. METHODS: We prospectively studied 29 acute NAION eyes with standard automated perimetry and spectral domain (SD) optical coherence tomography for 6 months. We used a three-dimensional layer segmentation (method 1) and a commercial proprietary (method 2), to compute the combined thickness of macular GCL+IPL and method 2 to compute peripapillary RNFL thickness. RESULTS: At presentation, the mean GCL+IPL thickness (78.7 µm ± 8.9) for NAION eyes, did not differ from unaffected fellow eyes (83 µm ± 6.4), using method 1 while method 2 (66.8 µm ± 18.7) failed in 34% of NAION eyes. At 1 to 2 months, 12% had RNFL loss compared to baseline, while 68% of NAION eyes had GCL+IPL thinning. The ganglion cell layer plus inner plexiform layer reduction was greatest at 1 to 2 months (19.6 µm ± 12.6) and was minimally worse after month 3. Ganglion cell layer plus inner plexiform layer thinning showed moderate to strong significant correlation with the visual acuity and mean deviation at each exam time. The retinal nerve fiber layer was not thinned until month 3. CONCLUSIONS: Ganglion cell layer plus inner plexiform layer is acutely unaffected and provides a reliable measure of retinal neuronal structure using three-dimensional segmentation. Thinning develops within 1 to 2 months of onset, which is prior to RNFL swelling resolution. This suggests GCL+IPL measurement is better than the RNFL thickness to use as biomarker of early structural loss in NAION.

The Pattern of Visual Fixation Eccentricity and Instability in Optic Neuropathy and Its Spatial Relationship to Retinal Ganglion Cell Layer Thickness.

PURPOSE: The purpose of this study was to assess whether clinically useful measures of fixation instability and eccentricity can be derived from retinal tracking data obtained during optical coherence tomography (OCT) in patients with optic neuropathy (ON) and to develop a method for relating fixation to the retinal ganglion cell complex (GCC) thickness. METHODS: Twenty-nine patients with ON underwent macular volume OCT with 30 seconds of confocal scanning laser ophthalmoscope (cSLO)-based eye tracking during fixation. Kernel density estimation quantified fixation instability and fixation eccentricity from the distribution of fixation points on the retina. Preferred ganglion cell layer loci (PGCL) and their relationship to the GCC thickness map were derived, accounting for radial displacement of retinal ganglion cell soma from their corresponding cones. RESULTS: Fixation instability was increased in ON eyes (0.21 deg2) compared with normal eyes (0.06982 deg2; P < 0.001), and fixation eccentricity was increased in ON eyes (0.48°) compared with normal eyes (0.24°; P = 0.03). Fixation instability and eccentricity each correlated moderately with logMAR acuity and were highly predictive of central visual field loss. Twenty-six of 35 ON eyes had PGCL skewed toward local maxima of the GCC thickness map. Patients with bilateral dense central scotomas had PGCL in homonymous retinal locations with respect to the fovea. CONCLUSIONS: Fixation instability and eccentricity measures obtained during cSLO-OCT assess the function of perifoveal retinal elements and predict central visual field loss in patients with ON. A model relating fixation to the GCC thickness map offers a method to assess the structure-function relationship between fixation and areas of preserved GCC in patients with ON.

Retinal ganglion cell layer thinning within one month of presentation for optic neuritis.

BACKGROUND: Spectral domain optical coherence tomography (SD-OCT) reveals retinal ganglion cell layer plus inner plexiform layer (GCL+IPL) and peripapillary retinal nerve fiber layer (pRNFL) thinning in chronic optic nerve injury. At presentation, swelling of the pRNFL confounds evaluation of early axon loss. OBJECTIVE: We studied whether the GCL+IPL thins before the pRNFL, the trajectory of GCL+IPL loss and relationship to vision. METHODS: We prospectively evaluated 33 eyes (study) with new optic neuritis, using perimetry and SD-OCT with investigative three-dimensional layer segmentation and commercial two-dimensional segmentation to compute the GCL+IPL and pRNFL thickness. RESULTS: At presentation, GCL+IPL thickness (82.4±8.8 µm) did not differ from unaffected fellow eyes (81.2±6.7 µm), via the three-dimensional method, while the two-dimensional method failed in 9% of study eyes. At 1-2 months, there was thinning of the pRNFL in 10% and of the GCL+IPL in 93% of study eyes. GCL+IPL reduction was greatest during the first 2 months. GCL+IPL thinning at 1-2 months correlated with GCL+IPL thinning at 6 months (r=0.84, P=0.01) and presentation visual acuity (r=0.48, P=0.006) and perimetric mean deviation (r=0.52, P=0.003). CONCLUSION: GGL+IPL is an early biomarker of structural injury in optic neuritis as thinning develops within 1-2 months of onset, prior to pRNFL thinning.

Retinal and Choroidal Folds in Papilledema.

PURPOSE: To determine the frequency, patterns, associations, and biomechanical implications of retinal and choroidal folds in papilledema due to idiopathic intracranial hypertension (IIH). METHODS: Retinal and choroidal folds were studied in patients enrolled in the IIH Treatment Trial using fundus photography (n = 165 study eyes) and spectral-domain optical coherence tomography (SD-OCT; n = 125). We examined the association between folds and peripapillary shape, retinal nerve fiber layer (RNFL) thickness, disc volume, Frisén grade, acuity, perimetric mean deviation, intraocular pressure, intracranial pressure, and refractive error. RESULTS: We identified three types of folds in IIH patients with papilledema: peripapillary wrinkles (PPW), retinal folds (RF), and choroidal folds (CF). Frequency, with photos, was 26%, 19%, and 1%, respectively; SD-OCT frequency was 46%, 47%, and 10%. At least one type of fold was present in 41% of patients with photos and 73% with SD-OCT. Spectral-domain OCT was more sensitive. Structural parameters related to the severity of papilledema were associated with PPW and RF, whereas anterior deformation of the peripapillary RPE/basement membrane layer was associated with CF and RF. Folds were not associated with vision loss at baseline. CONCLUSIONS: Folds in papilledema are biomechanical signs of stress/strain on the optic nerve head and load-bearing structures induced by intracranial hypertension. Folds are best imaged with SD-OCT. The patterns of retinal and choroidal folds are the products of a complex interplay between the degree of papilledema and anterior deformation of the load-bearing structures (sclera and possibly the lamina cribrosa), both modulated by structural geometry and material properties of the optic nerve head. (ClinicalTrials.gov number, NCT01003639.).

Causes and Prognosis of Visual Acuity Loss at the Time of Initial Presentation in Idiopathic Intracranial Hypertension.

PURPOSE: To determine the etiology and prognosis of visual acuity loss in idiopathic intracranial hypertension (IIH) at presentation and to provide objective measures to predict visual outcome. METHODS: A retrospective review of 660 patients with IIH (2009-2013) identified 31 patients (4.7%) with 48 eyes having best-corrected visual acuity (BCVA) of 20/25 or worse on initial presentation. Fundus photography, optical coherence tomography (OCT) of the optic disc and macula, and perimetry were used to determine the causes and prognosis of vision loss. Segmentation of the macula OCT was performed using the Iowa Reference Algorithm to determine the retinal ganglion cell-inner plexiform layer complex (GCL-IPL) thickness. RESULTS: Outer retinal changes alone caused decreased BCVA at initial presentation in 22 eyes (46%): subretinal fluid in 16, chorioretinal folds in 5, and peripapillary choroidal neovascularization in 1. The vision loss was reversible except for some eyes with chorioretinal folds. Optic neuropathy alone caused decreased BCVA in 10 eyes (21%) and coexisting outer retinal changes and optic neuropathy caused decreased BCVA in 16 eyes (33%). A GCL-IPL thickness less than or equal to 70 µm at initial presentation or progressive thinning of greater than or equal to 10 µm within 2 to 3 weeks compared with baseline correlated with poor visual outcome. CONCLUSIONS: Visual acuity loss in IIH can be caused by both outer retinal changes and optic neuropathy. Vision loss from outer retinal changes is mostly reversible. The outcome of patients with coexisting outer retinal changes and optic neuropathy or optic neuropathy alone depends on the degree of optic neuropathy, which can be predicted by the GCL-IPL thickness.

Multimodal Segmentation of Optic Disc and Cup From SD-OCT and Color Fundus Photographs Using a Machine-Learning Graph-Based Approach.

In this work, a multimodal approach is proposed to use the complementary information from fundus photographs and spectral domain optical coherence tomography (SD-OCT) volumes in order to segment the optic disc and cup boundaries. The problem is formulated as an optimization problem where the optimal solution is obtained using a machine-learning theoretical graph-based method. In particular, first the fundus photograph is registered to the 2D projection of the SD-OCT volume. Three in-region cost functions are designed using a random forest classifier corresponding to three regions of cup, rim, and background. Next, the volumes are resampled to create radial scans in which the Bruch's Membrane Opening (BMO) endpoints are easier to detect. Similar to in-region cost function design, the disc-boundary cost function is designed using a random forest classifier for which the features are created by applying the Haar Stationary Wavelet Transform (SWT) to the radial projection image. A multisurface graph-based approach utilizes the in-region and disc-boundary cost images to segment the boundaries of optic disc and cup under feasibility constraints. The approach is evaluated on 25 multimodal image pairs from 25 subjects in a leave-one-out fashion (by subject). The performances of the graph-theoretic approach using three sets of cost functions are compared: 1) using unimodal (OCT only) in-region costs, 2) using multimodal in-region costs, and 3) using multimodal in-region and disc-boundary costs. Results show that the multimodal approaches outperform the unimodal approach in segmenting the optic disc and cup.

Baseline OCT measurements in the idiopathic intracranial hypertension treatment trial, part I: quality control, comparisons, and variability.

PURPOSE: Optical coherence tomography (OCT) has been used to investigate papilledema in single-site, mostly retrospective studies. We investigated whether spectral-domain OCT (SD-OCT), which provides thickness and volume measurements of the optic nerve head and retina, could reliably demonstrate structural changes due to papilledema in a prospective multisite clinical trial setting. METHODS: At entry, 126 subjects in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) with mild visual field loss had optic disc and macular scans, using the Cirrus SD-OCT. Images were analyzed by using the proprietary commercial and custom 3D-segmentation algorithms to calculate retinal nerve fiber layer (RNFL), total retinal thickness (TRT), optic nerve head volume (ONHV), and retinal ganglion cell layer (GCL) thickness. We evaluated variability, with interocular comparison and correlation between results for both methods. RESULTS: The average RNFL thickness > 95% of normal controls in 90% of eyes and the RNFL, TRT, ONH height, and ONHV showed strong (r > 0.8) correlations for interocular comparisons. Variability for repeated testing of OCT parameters was low for both methods and intraclass correlations > 0.9 except for the proprietary GCL thickness. The proprietary algorithm-derived RNFL, TRT, and GCL thickness measurements had failure rates of 10%, 16%, and 20% for all eyes respectively, which were uncommon with 3D-segmentation-derived measurements. Only 7% of eyes had GCL thinning that was less than fifth percentile of normal age-matched control eyes by both methods. CONCLUSIONS: Spectral-domain OCT provides reliable continuous variables and quantified assessment of structural alterations due to papilledema. (ClinicalTrials.gov number, NCT01003639.).

Baseline OCT measurements in the idiopathic intracranial hypertension treatment trial, part II: correlations and relationship to clinical features.

PURPOSE: The accepted method to evaluate and monitor papilledema, Frisén grading, uses an ordinal approach based on descriptive features. Part I showed that spectral-domain optical coherence tomography (SD-OCT) in a clinical trial setting provides reliable measurement of the effects of papilledema on the optic nerve head (ONH) and peripapillary retina, particularly if a 3-D segmentation method is used for analysis.(1) We evaluated how OCT parameters are interrelated and how they correlate with vision and other clinical features in idiopathic intracranial hypertension (IIH) patients. METHODS: A total of 126 subjects in the IIH Treatment Trial (IIHTT) OCT substudy had Cirrus SD-OCT optic disc and macula scans analyzed by using a 3-D segmentation algorithm to derive retinal nerve fiber layer (RNFL) thickness, total retinal thickness (TRT), retinal ganglion cell layer plus inner plexiform layer (GCL+IPL) thickness, and ONH volume. The SD-OCT parameter values were correlated with high- and low-contrast acuity, perimetric mean deviation, Frisén grading, and IIH features. RESULTS: At study entry, the average RNFL thickness, TRT, and ONH volume showed significant strong correlations (r ≥ 0.90) with each other. The same OCT parameters showed a strong (r > 0.76) correlation with Frisén grade and a mild (r > 0.24), but significant, correlation with lumbar puncture opening pressure. For all eyes at baseline, neither visual acuity (high or low contrast) nor mean deviation correlated with any OCT measure of swelling or GCL+IPL thickness. CONCLUSIONS: In newly diagnosed IIH, OCT demonstrated alterations of the peripapillary retina and ONH correlate with Frisén grading of papilledema. At presentation, OCT measures of papilledema, in patients with newly diagnosed IIH and mild vision loss, do not correlate with clinical features or visual dysfunction. (ClinicalTrials.gov number, NCT01003639.).

Quantitative evaluation of papilledema from stereoscopic color fundus photographs.

PURPOSE: To derive a computerized measurement of optic disc volume from digital stereoscopic fundus photographs for the purpose of diagnosing and managing papilledema. METHODS: Twenty-nine pairs of stereoscopic fundus photographs and optic nerve head (ONH) centered spectral domain optical coherence tomography (SD-OCT) scans were obtained at the same visit in 15 patients with papilledema. Some patients were imaged at multiple visits in order to assess their changes. Three-dimensional shape of the ONH was estimated from stereo fundus photographs using an automated multi-scale stereo correspondence algorithm. We assessed the correlation of the stereo volume measurements with the SD-OCT volume measurements quantitatively, in terms of volume of retinal surface elevation above a reference plane and also to expert grading of papilledema from digital fundus photographs using the Frisén grading scale. RESULTS: The volumetric measurements of retinal surface elevation estimated from stereo fundus photographs and OCT scans were positively correlated (correlation coefficient r(2) = 0.60; P < 0.001) and were positively correlated with Frisén grade (Spearman correlation coefficient r = 0.59; P < 0.001). CONCLUSIONS: Retinal surface elevation among papilledema patients obtained from stereo fundus photographs compares favorably with that from OCT scans and with expert grading of papilledema severity. Stereoscopic color imaging of the ONH combined with a method of automated shape reconstruction is a low-cost alternative to SD-OCT scans that has potential for a more cost-effective diagnosis and management of papilledema in a telemedical setting. An automated three-dimensional image analysis method was validated that quantifies the retinal surface topography with an imaging modality that has lacked prior objective assessment.