Optic Nerve Function Research Articles

Evaluation of Retinal Nerve Fiber Layer and Optic Nerve Function in Patients with Obstructive Sleep Apnea Syndrome

Evaluation of Retinal Nerve Fiber Layer and Optic Nerve Function in Patients with Obstructive Sleep Apnea Syndrome

Copper deficiency anemia: review article.

Copper is a crucial micronutrient needed by animals and humans for proper organ function and metabolic processes such as hemoglobin synthesis, as a neurotransmitter, for iron oxidation, cellular respiration, and antioxidant defense peptide amidation, and in the formation of pigments and connective tissue. Multiple factors, either hereditary or acquired, contribute to the increase in copper deficiency seen clinically over the past decades. The uptake of dietary copper into intestinal cells is via the Ctr1 transporter, located at the apical membrane aspect of intestinal cells and in most tissues. Copper is excreted from enterocytes into the blood via the Cu-ATPase, ATP7A, by trafficking the transporter towards the basolateral membrane. Zinc is another important micronutrient in animals and humans. Although zinc absorption may occur by direct interaction with the Ctr1 transporter, its absorption is slightly different. Copper deficiency affects physiologic systems such as bone marrow hematopoiesis, optic nerve function, and the nervous system in general. Detailed pathophysiology and its related diseases are explained in this manuscript. Diagnosis is made by measuring serum copper, serum ceruloplasmin, and 24-h urine copper levels. Copper deficiency anemia is treated with oral or intravenous copper replacement in the form of copper gluconate, copper sulfate, or copper chloride. Hematological manifestations are fully reversible with copper supplementation over a 4- to 12-week period. However, neurological manifestations are only partially reversible with copper supplementation.

Using the Anterior Visual System to Assess Neuroprotection and Remyelination in Multiple Sclerosis Trials.

Clinical trials using agents directed at neuroprotection and remyelination in multiple sclerosis (MS) are needed. As optic neuritis (ON) is common in people with MS and the pathology of ON is similar to other MS lesions in the brain, measurements of the anterior visual system are frequently utilized in neuroprotection and remyelination trials. Understanding the strengths and weaknesses of the measurements is vital when interpreting the results of this research. Techniques such as visual evoked potentials (VEP) and optical coherence tomography (OCT) are well established in MS and are thought to measure axonal integrity and myelination. Novel imaging techniques can also be used in conjunction with these measurements to provide better insight into optic nerve structure and function. Magnetization transfer imaging (MTR) together with optic nerve area and volume measures neurodegeneration; diffusion tensor imaging (DTI) measures myelination status and neurodegeneration. However, these techniques require various levels of experience to interpret, and all can be confounded by ocular motion and surrounding fat and bone. This article provides a review of established and novel techniques to measure the anterior visual system in multiple sclerosis with a focus on the evidence to support their use as outcome measures in clinical trials focused on neuroprotection and remyelination therapies.

Structural and visual functional deficits in a rat model of neuromyelitis optica spectrum disorders related optic neuritis

Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune astrocytopathies in the central nervous system, which are mainly caused by immunoglobulin G (IgG) against astrocyte water channel aquaporin-4 (AQP4). In this study, we aimed to establish a model of NMOSD-related optic neuritis (NMOSD-ON) and to evaluate the progressive changes of the optic nerve and visual function. AQP4 IgG-positive serum from NMOSD patients was injected into the subarachnoid space of the rat optic nerve to induce the NMOSD-ON model (AQP4 + group), and healthy serum was injected as the control. The visual evoked potential, pupillary light reflex and optical coherence tomography were monitored every week for 3 weeks after induction. Compared with the control group, the amplitude of the N1-P1 peak and pupillary light reflex in the AQP4+ group were reduced within the first week and then remained low thereafter. Consistent with the functional deficits, the thickness of the peripapillary retinal nerve fiber layer in the AQP4 + group was also greatly reduced. At the end of 3 weeks, there was a loss of retinal ganglion cells and the optic nerves showed characteristic NMOSD-like pathologic changes, including deposition of AQP4 IgG, local astrocyte damage, demyelination, microglia activation, macrophage infiltration and axonal injury. Thus, we have established an NMOSD-ON rat model with deficits in the optic nerve and visual function that may be a valuable tool for exploring the mechanism of NMOSD-ON and evaluating its potential therapeutic treatment.

Continuous Positive Airway Pressure Treatment May Improve Optic Nerve Function in Obstructive Sleep Apnea: An Electrophysiological Study.

Obstructive sleep apnea (OSA) is a sleep disorder frequently associated with optic nerve diseases. Moreover, untreated patients with severe OSA may show optic nerve dysfunction as documented by electrophysiological studies using visual evoked potentials (VEP). Because continuous positive airway pressure (CPAP) treatment has proved to restore the physiologic nocturnal breathing, thus preventing nocturnal hypoxemia and reducing inflammation, in this study we tested whether 1-year CPAP treatment may modify VEP responses in patients with severe OSA. VEP were recorded at baseline and after 1 year of CPAP treatment in 20 patients with severe OSA, divided in two groups on the basis of CPAP adherence, and compared to a healthy control group. Patients with good adherence to CPAP therapy (CPAP+; n = 10) showed VEP P100 amplitude significantly higher than patients with poor adherence to CPAP therapy (CPAP-; n = 10). Moreover, the CPAP+ group showed VEP responses similar to those in the control group (n = 26). Considering the mean difference of VEP responses between baseline and follow-up, the CPAP+ group showed a significant increase in VEP P100 amplitude and a significant decrease in VEP P100 latency compared to the CPAP- group. This study documented that CPAP therapy significantly improves VEP in patients with OSA who are adherent to the treatment. We hypothesize that CPAP treatment, minimizing the metabolic, inflammatory and ischemic consequences of OSA, may normalize the altered VEP responses in patients with OSA by restoring and preserving optic nerve function.

Optic Nerve Head Drusen: The Relationship Between Intraocular Pressure and Optic Nerve Structure and Function.

To determine whether at the time of diagnosis, the intraocular pressure (IOP) in patients with optic nerve head drusen (ONHD) correlates with the perimetric mean deviation (PMD) and the mean retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT). This retrospective chart review included adults with ONHD from 2 academic medical centers. Inclusion criteria were age older than 18 years, definitive diagnosis of ONHD, measurement of IOP, and an automated visual field (VF) within 3 months of diagnosis. Exclusion criteria were unreliable VFs, use of IOP-lowering therapy, and visually significant ocular comorbidities. Data were collected from the initial visit. Age, IOP, method of diagnosis of ONHD, mean RNFL thickness, and PMD were recorded. Multiple and logistic regression models were used to control for potential confounders in statistical analyses. Chart review identified 623 patients, of which 146 patients met inclusion criteria. Mean age was 44.2 years (range: 19-82 years). Average PMD of 236 eyes was -5.22 dB (range, -31.2 to +1.21 dB). Mean IOP was 15.7 mm Hg (range: 6-24 mm Hg). Forty eyes (16.9%) underwent RNFL measurement using OCT; mean RNFL thickness was 79.9 μm (range: 43-117 μm). There was no statistically significant association between IOP and PMD (P = 0.13) or RNFL thickness (P = 0.65). Eyes with ocular hypertension tended to have less depressed PMD than those without (P= 0.031). Stratified analyses of visible and buried subgroups yielded similar results. Lowering IOP in patients with ONHD has been proposed as a means to prevent progression of optic neuropathy. Our study demonstrated that among predominately normotensive eyes, higher IOP was not associated with greater VF loss or thinner RNFL at the time of presentation. This suggests that lowering IOP may not be beneficial in preventing visual loss in normotensive eyes with ONHD.

Early isolated optic neuropathy caused by cyclosporine.

To examine, for the first time, whether cyclosporine intake has an early isolated effect on the optic nerve. This observational case series consisted of 192 eyes of 98 patients treated with cyclosporine. Patient age and duration and dosage of cyclosporine were recorded, and visual acuity, optic nerve function, visual fields, and visual evoked potential (VEP) were tested. Fundus examination was also performed. Patients with glaucoma, vascular retinopathies, and deep amblyopia were excluded. Mean patient age was 46years, average duration of treatment was 6years, and median dosage of cyclosporine was 200mg daily. VEP was tested in 73 patients (142 eyes) and yielded a delayed P100 wave in 9 (12.32%) (14 eyes). Among these 9 patients, abnormal findings were also noted on the Ishihara colour test in 42.86% of the eyes, and on the visual field test in 64.3% of the eyes. Abnormal VEP showed a significant correlation (p < 0.05) with older age (> 46years) and a non-significant correlation with longer duration of treatment. Higher abnormal VEP potential was not correlated with higher cyclosporine dose, and there was no correlation between abnormal VEP and blood level of cyclosporine. Optic neuropathy was significantly associated with older age in cyclosporine-treated patients. A correlation between optic neuropathy with longer duration of cyclosporine treatment was noted but was not statistically significant. We suggest that tests of optic nerve function, including VEP, be a part of the follow-up of patients receiving cyclosporine.

Target and untargeted GC–MS based metabolomic study of mouse optic nerve and its potential in the study of neurological visual diseases

The optic nerve is made of highly specialized neurons and the energetic supply to their axons is crucial due to their great demand. The energy comes basically through the oxidative phosphorylation in the mitochondria, supported by glial cells metabolism. Mitochondrial dysfunction is a shared feature encountered within the optic neuropathies, including Leber’s Hereditary Optic Neuropathy, Leigh’s Syndrome, or Kjer’s syndrome.In an effort to investigate the metabolic alterations produced within the optic nerve in a mutant mouse model of Neurological Visual Disease (NVD), a rapid, robust, and efficient one-single phase extraction methodology has been developed and validated for the GC–MS platform. Once the method was successfully validated for lactic acid and pyruvic acid as markers of an adequate optic nerve function, the protocol was applied to unveil the metabolomic signature of the wild-type mouse optic nerve. Along the chromatographic profile of the optic nerve, 94 peaks were identified and, to our knowledge, for the first time. Afterwards, a targeted metabolomics analysis was performed to quantify lactic acid and pyruvic acid in the NDV mice group (n = 8) and its corresponding wild-type (n = 8). Finally, an untargeted metabolomic study was carried out and univariate and multivariate data analyses showed 34 compounds modified in the optic nerve of the mouse with NVD mutation. Then, the metabolic reaction network of the identified metabolites highlighted alterations in the catabolism of proteins, TCA cycle, and urea cycle, reflecting a mitochondrial energetic dysfunction. Taken together, this metabolomic study has proven to be suited for the study of optic neuropathies.

Monitoring of optic nerve function in Neurofibromatosis 2 children with optic nerve sheath meningiomas using multifocal visual evoked potentials

Monitoring optic nerve sheath meningiomas (ONSM) in Neurofibromatosis type 2 (NF2) patients remains difficult. Other ocular manifestations of NF2 may obscure ophthalmic assessment of optic nerve function in these patients. Serial magnetic resonance imaging (MRI) used to assess the optic nerve is not without limitations, being expensive and often requiring general anaesthetic in children, with associated risks. This study was undertaken to describe the use of multifocal visual evoked potentials (multifocal VEP, mfVEP) in the regular monitoring of NF2 patients with ONSM. This study involved three NF2 patients with ONSM who undertook mfVEP testing at an academic ophthalmic centre. Same day mfVEP and routine ophthalmic testing were undertaken. Topographical function of the optic nerve was assessed, utilising tools such as asymmetry deviation and accumap severity index. Results were assessed alongside MRI and visual acuity (VA). From the three patients, five eyes had ONSMs, of which two caused unilateral blindness. The remaining three affected eyes had initial VAs 6/6, 6/24, and 6/18. Over follow up, ranging from 5 to 12 years, all tumours progressed, and VA declined for all patients. Multifocal VEP detected optic nerve functional loss corresponding with visual decline. This case series suggests mfVEP is effective in the objective topographic monitoring of optic nerve function in NF2 patients with ONSM. Due also to its safety in a paediatric population, the test may be considered in the routine monitoring of these patients, to be used to assist regular ophthalmic review and MRI scans.

Advances in etiological study of non-arterial inflammatory ischemic optic neuropathy (NAION)

Non-arterial Inflammatory ischemic optic neuropathy (NAION) is a common ocular disease in middle and old ages. Symptoms of optic nerve dysfunction in NAION are caused by cerebral ischemia, which leads to optic atrophy. Recent studies have focused on the early interventions targeting NAION′s risk factors to protect the optic nerve and retinal ganglion cells. This article reviews recent progress in studies on the etiology and risk factors of NAION and potential therapies that may help to preserve optic nerve function in NAION. Key words: Optic neuropathy, ischemic; Risk factors; Pathologic processes

The Prevalence of diabetic optic neuropathy in type 2 diabetes mellitus

Background and objective: As diabetes mellitus a common health problem, it is well known that it can lead to optic neuropathy that affects the optic nerve functions. It is important to monitor the effect of this metabolic disease on the optic nerve that can lead ultimately to decrease visual acuity that can be irreversible. This study aimed to find out the prevalence of diabetic optic nerve diseases and to evaluate the patient characteristics and fundus findings. Methods: Screening examination was done for 2213 patients with type 2 diabetic patients presented to the diabetic center from October 2007 to September 2009. The examination includes visual acuity test using conventional E chart, slit lamp exam, followed by installing short acting Mydriatics (tropicamide 1%) eye drops for fundoscopy examination using +76.D or +90 D. Results: Eighty eight patients (approximately 4%) had optic nerve problems; 50 females and 38 males. The mean age was 59 years. A total of 58 (116 eyes) patients were bilaterally affected, 42 patients with optic papillopathy, 8 patients with anterior ischemic optic neuropathy and profound loss of vision, 8 with glaucomatous cupping and pallor and 30 patients with end stage optic atrophy. A total of 63 (71.5%) patients had poor metabolic control. Conclusions: Patients with type 2 diabetes mellitus have 4% prevalence of diabetic optic neuropathy.

The Evolving Role of the Relationship between Optic Nerve Structure and Function in Glaucoma

The relationship between functional vision loss and structural changes of the optic nerve head and retinal ganglion cells is the hallmark of glaucoma diagnosis. Understanding and measuring this relationship has been the focus of numerous studies, the goal of which have been to improve glaucoma diagnosis and detection of glaucoma worsening. In this review, a historical perspective is used to understand structure-function relationships in glaucoma and their application to improve glaucoma diagnosis and monitoring. Initially, histologic studies that link visual field sensitivity to retinal ganglion cell count are discussed. Additionally, those studies that determined the mathematical relationship between visual field sensitivity and ganglion cell number are reviewed. Next, those studies that attempt to create a map of the structure-function relationship using fundus photography and visual field sensitivity are examined. Subsequently, studies that use more recent imaging technology, such as optical coherence tomography, confocal scanning laser ophthalmoscopy, or scanning laser perimetry, to measure structure quantitatively invivo and to correlate these measures with automated perimetry are explored. Among these studies that use advanced imaging, those that use cross-sectional data to explore structure-function relationships to improve glaucoma diagnosis first are discussed. Second, those studies that use longitudinal data to improve detection of worsening are reviewed. Finally, areas of further research and steps needed to implement structure-function relationships clinically are explored.

The Effect of a Decrease in Intraocular Pressure on Optic Nerve Function in Patients with Optic Nerve Drusen

Purpose: The aim of the study was to compare optic nerve function in eyes with brinzolamide-reduced intraocular pressure (IOP) and the fellow eyes of patients with optic disk drusen (ODD). Methods: The study comprised 34 patients with bilateral ODD but no signs of any other ocular disease. The eyes with more advanced optic neuropathy were selected for treatment with an IOP-lowering drug, carbonic anhydrase inhibitor (brinzolamide); the fellow eyes served as the control. Static perimetry, pattern electroretinography (PERG), pattern visual-evoked potentials (PVEP), and retinal nerve fiber layer (RNFL) thickness were analyzed. The observation period was 12 months. Results: The eyes with brinzolamide-reduced IOP exhibited a statistically significant decrease in the mean defect index of static visual field (p = 0.03), an increase in PERG N95 amplitude (from 2.94 to 4.41 µV; p = 0.0047), and RNFL thickness stabilization. A statistically significant decrease in RNFL thickness (from 83.21 to 79.85 µm; p = 0.0017) was found in the control eyes. Conclusions: A decrease in IOP in eyes with ODD results in improvement of retinal ganglion cell function and delays the progression of optic neuropathy. PERG should be performed in patients with ODD as it is a sensitive test for monitoring optic neuropathy.

Differences in pupillary light reflex between optic neuritis and ischemic optic neuropathy.

ObjectivesTo determine the differences in pupillary light reflex (PLR) between the acute and chronic phases of optic neuritis (ON) and nonarteritic anterior ischemic optic neuropathy (NAION).MethodsThe study included 30 patients with ON and 22 patients with NAION whose PLR were measured by a dynamic pupillometer (PLR-200; NeurOptics Inc., Irvine, USA). Age-matched controls included 58 healthy individuals with normal vision and optic nerve function. Pupil diameters, latency, constriction ratio, constriction velocity and dilation velocity were noted. The differences in PLR measurements were compared among the acute and chronic phases of ON and NAION, and in age-matched controls. Regression analysis determined factors associated with PLR measurements, including visual acuity, color vision defect, visual field defects and retinal nerve fiber layer thickness measurements on optical coherence tomography.ResultsPupillary constriction velocity, constriction ratio and latency were all significantly decreased in the acute phase of ON and NAION. ON showed significantly delayed constriction latency compared to NAION (P = 0.047). Pupillary constriction velocity, constriction ratio and latency were recovered in the chronic phase of ON (P = 0.038, 0.018, and 0.045), however, these parameters were not recovered in NAION (P = 0.693, 0.173 and 0.994).ConclusionsPupillary constriction velocity, constriction ratio, and latency were significantly decreased in the acute phase of ON and NAION compared to normal controls. ON showed delayed constriction latency compared to NAION. Decreased PLR were recovered in the chronic phase of ON, but not in NAION.

Optic disc swelling in a patient with tuberculous meningitis: a diagnostic challenge

We discuss the diagnostic challenge in an adult patient presented with purely ocular symptoms diagnosed with tuberculous meningitis (TBM). A 38-year-old woman presented with bilateral painless blurring of vision. There...

Optic neuropathies: the tip of the neurodegeneration iceberg.

The optic nerve and the cells that give origin to its 1.2 million axons, the retinal ganglion cells (RGCs), are particularly vulnerable to neurodegeneration related to mitochondrial dysfunction. Optic neuropathies may range from non-syndromic genetic entities, to rare syndromic multisystem diseases with optic atrophy such as mitochondrial encephalomyopathies, to age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease where optic nerve involvement has, until recently, been a relatively overlooked feature. New tools are available to thoroughly investigate optic nerve function, allowing unparalleled access to this part of the central nervous system. Understanding the molecular pathophysiology of RGC neurodegeneration and optic atrophy, is key to broadly understanding the pathogenesis of neurodegenerative disorders, for monitoring their progression in describing the natural history, and ultimately as outcome measures to evaluate therapies. In this review, the different layers, from molecular to anatomical, that may contribute to RGC neurodegeneration and optic atrophy are tackled in an integrated way, considering all relevant players. These include RGC dendrites, cell bodies and axons, the unmyelinated retinal nerve fiber layer and the myelinated post-laminar axons, as well as olygodendrocytes and astrocytes, looked for unconventional functions. Dysfunctional mitochondrial dynamics, transport, homeostatic control of mitobiogenesis and mitophagic removal, as well as specific propensity to apoptosis may target differently cell types and anatomical settings. Ultimately, we can envisage new investigative approaches and therapeutic options that will speed the early diagnosis of neurodegenerative diseases and their cure.

Volume-staged gamma knife surgery for the treatment of large skull base meningioma surrounding the optical apparatus: A snowman-shape design

BackgroundIn cases of meningioma surrounding the optical apparatus, this study sought to reduce the incidence of radiation-induced optical neuropathy resulting from gamma knife surgery (GKS) by dividing the treatment volume into 2 or 3 fractions. MethodsFour patients with a large skull base meningioma (1 male and 3 females; median age: 42 years; range: 33–43 yrs) were treated using volume-staged GKS. In stage I, the large basal part of the tumor (13.2 mL; range: 3.9–54.7 mL) was treated with a marginal dose of 13.5 Gy (range: 12–15 Gy). In stage II, treatment focused on the smaller upper portion of the tumor located close to the optical apparatus (4.3 mL; range: 1.5–16.2 mL), and the marginal dose was 9 Gy (range: 8–10 Gy). ResultsAll patients tolerated the treatments well, and tumors regressed over a median follow-up period of 100.5 months (range: 42–122 mos). Specifically, a 34–46% reduction in tumor volume was observed. All four patients presented improvements in the neurological deficits observed prior to GKS treatment, albeit to varying degrees. No adverse effects of radiation or new visual deterioration were observed during the follow-up period. Furthermore, no evidence of new endocrine dysfunction or new cranial nerve neuropathy was observed within a follow-up period of 100.5 months. ConclusionThe application of volume-staged GKS using snowman-shape design appears to be an effective approach to control tumor growth when treating benign meningiomas surrounding the optical apparatus. This approach enables the application of higher radiation dosages to facilitate tumor control while still preserving optic nerve function.

Relationship of Optic Nerve Structure and Function to Peripapillary Vessel Density Measurements of Optical Coherence Tomography Angiography in Glaucoma.

To evaluate the sectoral and global structure-structure (vessel density-retinal nerve fiber layer thickness) and structure-function (vessel density-visual sensitivity loss) relationships of peripapillary vessel density measurements on optical coherence tomography angiography in primary open-angle glaucoma and to determine if fractional polynomial (FP) models characterize the relationships better than linear models. In a cross-sectional study, structure-structure and structure-function relationships of peripapillary vessel densities were determined in 227 eyes of 143 subjects (63 control and 164 primary open-angle glaucoma eyes) who had undergone standard automated perimetry and optical coherence tomography testing within 6 months of each other, using linear and FP models. FP model evaluates the relationship between the dependent and the best-fitting fractional powers of the independent variable. Strength of relationship was reported as coefficient of determination (R). R values for structure-structure associations using linear models (0.53 for superotemporal sector, 0.61 for inferotemporal, and 0.53 for average measurements) were significantly less (P<0.05) than that determined using FP models (0.57, 0.65, and 0.55, respectively). R values for structure-function associations using linear models (0.35 for superotemporal vessel density-inferotemporal visual sensitivity loss, 0.49 for inferotemporal vessel density-superotemporal visual sensitivity loss, and 0.39 for average vessel density-average visual sensitivity loss) were significantly less than that determined using FP models (0.43, 0.58, and 0.47, respectively). The inferotemporal peripapillary vessel density showed the strongest association with the corresponding retinal nerve fiber layer thickness and visual sensitivity loss in the global and sectoral regions studied. The FP models were significantly better than linear models in describing these relationships.

Quantitatively Measured Anatomic Location and Volume of Optic Disc Drusen: An Enhanced Depth Imaging Optical Coherence Tomography Study.

Optic disc drusen (ODD) are found in up to 2.4% of the population and are known to cause visual field defects. The purpose of the current study was to investigate how quantitatively estimated volume and anatomic location of ODD influence optic nerve function. Anatomic location, volume of ODD, and peripapillary retinal nerve fiber layer and macular ganglion cell layer thickness were assessed in 37 ODD patients using enhanced depth imaging optical coherence tomography. Volume of ODD was calculated by manual segmentation of ODD in 97 B-scans per eye. Anatomic characteristics were compared with optic nerve function using automated perimetric mean deviation (MD) and multifocal visual evoked potentials. Increased age (P = 0.015); larger ODD volume (P = 0.002); and more superficial anatomic ODD location (P = 0.007) were found in patients with ODD visible by ophthalmoscopy compared to patients with buried ODD. In a multivariate analysis, a worsening of MD was significantly associated with larger ODD volume (P < 0.0001). No association was found between MD and weighted anatomic location, age, and visibility by ophthalmoscopy. Decreased ganglion cell layer thickness was significantly associated with worse MD (P = 0.025) and had a higher effect on MD when compared to retinal nerve fiber layer thickness. Large ODD volume is associated with optic nerve dysfunction. The worse visual field defects associated with visible ODD should only be ascribed to larger ODD volume and not to a more superficial anatomic ODD location.

Phenotype Analysis of Early Risk Factors from Electronic Medical Records Improves Image-Derived Diagnostic Classifiers for Optic Nerve Pathology.

We examine imaging and electronic medical records (EMR) of 588 subjects over five major disease groups that affect optic nerve function. An objective evaluation of the role of imaging and EMR data in diagnosis of these conditions would improve understanding of these diseases and help in early intervention. We developed an automated image-processing pipeline that identifies the orbital structures within the human eyes from computed tomography (CT) scans, calculates structural size, and performs volume measurements. We customized the EMR-based phenome-wide association study (PheWAS) to derive diagnostic EMR phenotypes that occur at least two years prior to the onset of the conditions of interest from a separate cohort of 28,411 ophthalmology patients. We used random forest classifiers to evaluate the predictive power of image-derived markers, EMR phenotypes, and clinical visual assessments in identifying disease cohorts from a control group of 763 patients without optic nerve disease. Image-derived markers showed more predictive power than clinical visual assessments or EMR phenotypes. However, the addition of EMR phenotypes to the imaging markers improves the classification accuracy against controls: the AUC improved from 0.67 to 0.88 for glaucoma, 0.73 to 0.78 for intrinsic optic nerve disease, 0.72 to 0.76 for optic nerve edema, 0.72 to 0.77 for orbital inflammation, and 0.81 to 0.85 for thyroid eye disease. This study illustrates the importance of diagnostic context for interpretation of image-derived markers and the proposed PheWAS technique provides a flexible approach for learning salient features of patient history and incorporating these data into traditional machine learning analyses.