The entry point of the central retinal artery into the outer meningeal sheath of the optic nerve.

INTRODUCTION: The entry point of the central retinal artery (CRA) into the outer meningeal sheath of the optic nerve posterior to the globe has been studied and debated for more than one hundred years. The authors have supervised an orbital anatomy course for more than two decades. This article summarizes previous studies of the CRA and presents the results of dissections of 67 orbits. MATERIALS AND METHODS: Heads were hemisected prior to dissection at the Vagelos College of Physicians and Surgeons of Columbia University. The authors measured the entry point of the CRA with a caliper and noted the meridional orientation of the CRA. RESULTS: The mean entry point was 10.65 mm posterior to the globe, with a range of 5 to 18 mm. Most commonly, the CRA entered the sheath in the inferior meridian, but some entered slightly inferomedially or inferolaterally. CONCLUSIONS: The entry point of the CRA into the sheath of the optic nerve is variable, and without detailed angiography the clinician cannot know the course of the CRA prior to performing invasive intraorbital procedures. Knowledge of common variations in CRA entry into the outer meningeal sheath of the optic nerve should help to minimize injury during surgery.

Schimmelpenning-Feuerstein-Mims syndrome with orbital choristoma and KRAS mutation: a current review and novel case report.

INTRODUCTION: Schimmelpenning-Feurstein-Mims Syndrome (SFMS) is a rare neurocutaneous disorder. Herein, we describe a novel case and review the phenotypic spectrum and molecular findings of SFMS from an ophthalmology perspective. METHODS: Clinical case including presentation, management, pathology, and genetic analysis is described. A literature search on Schimmelpenning-Feuerstein-Mims and its synonyms, Linear nevus sebaceous syndrome, Organoid nevus syndrome, Jadassohn nevus phacomatosis, and Solomon syndrome, was conducted. An updated review and description of published cases with identified genetic mutations are described. RESULTS: A 13-year-old boy with SFMS presented with acute right eye pain and an enlarging orbital mass. Excisional biopsy of the mass revealed an orbital choristoma. Genetic analysis of the orbital tumor confirmed a KRAS c.35 G>A, p.G12D mutation. A literature search revealed 19 cases of SFMS with mutations in the RAS-pathway. KRAS, HRAS, and NRAS mutations were identified in 74%, 21%, and 5% of patients, respectively. Ophthalmic pathology was seen in 83% of patients. Systemic findings varied and involved the skin, central nervous system, and eyes most commonly. DISCUSSION: SFMS, a rare neurocutaneous disorder, results from postzygotic mosaic mutations in the RAS/MAPK pathway. Patients present with various systemic findings and ophthalmic manifestations occur in most cases. This is the first case description of a KRAS mutation identified in an orbital choristoma in SFMS. The disease is described under various names in the literature, and we propose that all syndromic cases with mosaic RAS mutations be reported under the eponym, SFMS.

Plus disease in retinopathy of prematurity: diagnostic impact of field of view.

PURPOSE: To examine the impact of retinal field of view and magnification on interexpert reliability of plus disease diagnosis in retinopathy of prematurity. METHODS: Fifteen wide-angle images from infants with retinopathy of prematurity were cropped and adjusted in magnification to create 2 additional image categories: medium angle (40°-50°) and narrow angle (20°-30°). These 45 images were uploaded to a Web-based system and interpreted independently by 13 experts of retinopathy of prematurity using a 3-level (plus, preplus, neither) and 2-level (plus, not plus) classification. Absolute agreement and kappa statistics were calculated to compare interexpert reliability. RESULTS: In the 3-level classification, ≥ 70% experts agreed on the same diagnosis in 8 of the 15 wide-angle images (53%), but only in 3 of the 15 medium-angle (20%) and 3 of the 15 narrow-angle (20%) images. In the 2-level classification, ≥ 80% experts agreed on the same diagnosis in 11 of the 15 wide-angle images (73%), but only in 9 of the 15 medium-angle (60%) and 3 of the 15 narrow-angle (20%) images. Mean kappa of each expert compared with all other experts was 0.40 to 0.59 in 8 of 13 experts (62%) using wide-angle images, was 0 to 0.19 in 7 of 13 experts (54%) using medium-angle images, and was 0.20 to 0.39 in 9 of 13 experts (69%) using narrow-angle images. CONCLUSION: Interexpert agreement in plus disease diagnosis in wide-angle images is higher than from medium-angle and narrow-angle images. Plus disease is defined using a narrow-angle standard published photograph, yet this study suggests that peripheral findings also contribute to diagnosis.

Extracellular vesicles of human diabetic retinopathy retinal tissue and urine of diabetic retinopathy patients are enriched for the junction plakoglo bin protein.

Introduction: Diabetic Retinopathy (DR) is a potentially blinding retinal disorder that develops through the pathogenesis of diabetes. The lack of disease predictors implies a poor prognosis with frequent irreversible retinal damage and vision loss. Extracellular Vesicles (EVs) present a novel opportunity for pre-symptomatic disease diagnosis and prognosis, both severely limited in DR. All biological fluids contain EVs, which are currently being studied as disease biomarkers. EV proteins derived from urine have emerged as potential noninvasive biomarkers. Methods: In this study, we isolated EVs from DR retinal tissue explants and from DR patients' urine, and characterized the vesicles, finding differences in particle number and size. Next, we performed proteomic analysis on human explanted DR retinal tissue conditioned media, DR retinal EVs and DR urinary EVs and compared to normal human retinal tissue, retinal EVs, and urinary EVs, respectively. Results: Our system biology analysis of DR tissue and EV expression profiles revealed biological pathways related to cell-to-cell junctions, vesicle biology, and degranulation processes. Junction Plakoglobin (JUP), detected in DR tissue-derived EVs and DR urinary EVs, but not in controls, was revealed to be a central node in many identified pathogenic pathways. Proteomic results were validated by western blot. Urinary EVs obtained from healthy donors and diabetic patient without DR did not contain JUP. Conclusion: The absence of JUP in healthy urinary EVs provide the basis for development of a novel Diabetic Retinopathy biomarker, potentially facilitating diagnosis.

Representation of ophthalmology concepts by electronic systems: intercoder agreement among physicians using controlled terminologies.

OBJECTIVE: To assess intercoder agreement for ophthalmology concepts by 3 physician coders using 5 controlled terminologies (International Classification of Diseases 9, Clinical Modification [ICD9CM]; Current Procedural Terminology, fourth edition; Logical Observation Identifiers, Names, and Codes [LOINC]; Systematized Nomenclature of Medicine, Clinical Terms [SNOMED-CT]; and Medical Entities Dictionary). DESIGN: Noncomparative case series. PARTICIPANTS: Five complete ophthalmology case presentations selected from a publicly available journal. METHODS: Each case was parsed into discrete concepts. Electronic or paper browsers were used independently by 3 physician coders to assign a code for every concept in each terminology. A match score representing adequacy of assignment for each concept was assigned on a 3-point scale (0, no match; 1, partial match; 2, complete match). For every concept, the level of intercoder agreement was determined by 2 methods: (1) based on exact code matching with assignment of complete agreement when all coders assigned the same code, partial agreement when 2 coders assigned the same code, and no agreement when all coders assigned different codes, and (2) based on manual review for semantic equivalence of all assigned codes by an independent ophthalmologist to classify intercoder agreement for each concept as complete agreement, partial agreement, or no agreement. Subsequently, intercoder agreement was calculated in the same manner for the subset of concepts judged to have adequate coverage by each terminology, based on receiving a match score of 2 by at least 2 of the 3 coders. MAIN OUTCOME MEASURES: Intercoder agreement in each controlled terminology: complete, partial, or none. RESULTS: Cases were parsed into 242 unique concepts. When all concepts were analyzed by manual review, the proportion of complete intercoder agreement ranged from 12% (LOINC) to 44% (SNOMED-CT), and the difference in intercoder agreement between LOINC and all other terminologies was statistically significant (P<0.004). When only concepts with adequate terminology were analyzed by manual review, the proportion of complete intercoder agreement ranged from 33% (LOINC) to 64% (ICD9CM), and there were no statistically significant differences in intercoder agreement among any pairs of terminologies. CONCLUSIONS: The level of intercoder agreement for ophthalmic concepts in existing controlled medical terminologies is imperfect. Intercoder reproducibility is essential for accurate and consistent electronic representation of medical data.

Representation of ophthalmology concepts by electronic systems: adequacy of controlled medical terminologies.

OBJECTIVE: To assess the adequacy of 5 controlled medical terminologies (International Classification of Diseases 9, Clinical Modification [ICD9-CM]; Current Procedural Terminology 4 [CPT-4]; Systematized Nomenclature of Medicine, Clinical Terms [SNOMED-CT]; Logical Identifiers, Names, and Codes [LOINC]; Medical Entities Dictionary [MED]) for representing concepts in ophthalmology. DESIGN: Noncomparative case series. PARTICIPANTS: Twenty complete ophthalmology case presentations were sequentially selected from a publicly available ophthalmology journal. METHODS: Each of the 20 cases was parsed into discrete concepts, and each concept was classified along 2 axes: (1) diagnosis, finding, or procedure and (2) ophthalmic or medical concept. Electronic or paper browsers were used to assign a code for every concept in each of the 5 terminologies. Adequacy of assignment for each concept was scored on a 3-point scale. Findings from all 20 case presentations were combined and compared based on a coverage score, which was the average score for all concepts in that terminology. MAIN OUTCOME MEASURES: Adequacy of assignment for concepts in each terminology, based on a 3-point Likert scale (0, no match; 1, partial match; 2, complete match). RESULTS: Cases were parsed into 1603 concepts. SNOMED-CT had the highest mean overall coverage score (1.625+/-0.667), followed by MED (0.974+/-0.764), LOINC (0.781+/-0.929), ICD9-CM (0.280+/-0.619), and CPT-4 (0.082+/-0.337). SNOMED-CT also had higher coverage scores than any of the other terminologies for concepts in the diagnosis, finding, and procedure categories. Average coverage scores for ophthalmic concepts were lower than those for medical concepts. CONCLUSIONS: Controlled terminologies are required for electronic representation of ophthalmology data. SNOMED-CT had significantly higher content coverage than any other terminology in this study.

Image analysis for retinopathy of prematurity diagnosis.

PURPOSE: To review findings from the authors' published studies involving telemedicine and image analysis for retinopathy of prematurity (ROP) diagnosis. METHODS: Twenty-two ROP experts interpreted a set of 34 wide-angle retinal images for presence of plus disease. For each image, a reference standard diagnosis was defined from expert consensus. A computer-based system was used to measure individual and linear combinations of image parameters for arteries and veins: integrated curvature (IC), diameter, and tortuosity index (TI). Sensitivity, specificity, and receiver operating characteristic areas under the curve (AUC) for plus disease diagnosis were determined for each expert. Sensitivity and specificity curves were calculated for the computer-based system by varying the diagnostic cutoffs for arterial IC and venous diameter. Individual vessels from the original 34 images were identified with particular diagnostic cutoffs, and combined into composite wide-angle images using graphics editing software. RESULTS: For plus disease diagnosis, expert sensitivity ranged from 0.308-1.000, specificity from 0.571-1.000, and AUC from 0.784 to 1.000. Among computer system parameters, one linear combination had AUC 0.967, which was greater than that of 18 of 22 (81.8%) experts. Composite computer-generated images were produced using the arterial IC and venous diameter values associated with 75% under-diagnosis of plus disease (ie, 25% sensitivity cutoff), 50% under-diagnosis of plus disease (ie, 50% sensitivity cutoff), and 25% under-diagnosis of plus disease (ie, 75% sensitivity cutoff). CONCLUSIONS: Computer-based image analysis has the potential to diagnose severe ROP with comparable or better accuracy than experts, and could provide added value to telemedicine systems. Future quantitative definitions of plus disease might improve diagnostic objectivity.

Plus disease in retinopathy of prematurity: development of composite images by quantification of expert opinion.

PURPOSE: To demonstrate a methodology for generating composite wide-angle images of plus disease in retinopathy of prematurity (ROP), using quantitative analysis of expert opinions. METHODS: Thirty-four wide-angle retinal images were independently interpreted by 22 ROP experts as "plus" or "not plus." All images were processed by the computer-based Retinal Image multiScale Analysis (RISA) system to calculate two parameters: arterial integrated curvature (AIC) and venous diameter (VD). Using a reference standard defined by expert consensus, sensitivity and specificity curves were calculated by varying the diagnostic cutoffs for AIC and VD. From these curves, individual vessels from multiple images were identified with particular diagnostic cutoffs, and were combined into composite wide-angle images using graphics-editing software. RESULTS: The values associated with 75% underdiagnosis of true plus disease (i.e., 25% sensitivity cutoff) were AIC 0.061 and VD 4.272, the values associated with 50% underdiagnosis of true plus disease (i.e., a 50% sensitivity cutoff) were AIC 0.049 and VD 4.088, and the values associated with 25% underdiagnosis of true plus disease (i.e., 75% sensitivity cutoff) were AIC 0.042 and VD 3.795. Composite wide-angle images were generated by identifying and combining individual vessels with these characteristics. CONCLUSIONS: Computer-based image analysis permits quantification of retinal vascular features, and a spectrum of abnormalities is seen in ROP. Selection of appropriate vessels from multiple images can produce composite plus disease images corresponding to expert opinions. This method may be useful for educational purposes, and for development of future disease definitions based on objective, quantitative principles.

Reliability of SNOMED-CT coding by three physicians using two terminology browsers.

SNOMED-CT has been promoted as a reference terminology for electronic health record (EHR) systems. Many important EHR functions are based on the assumption that medical concepts will be coded consistently by different users. This study is designed to measure agreement among three physicians using two SNOMED-CT terminology browsers to encode 242 concepts from five ophthalmology case presentations in a publicly-available clinical journal. Inter-coder reliability, based on exact coding match by each physician, was 44% using one browser and 53% using the other. Intra-coder reliability testing revealed that a different SNOMED-CT code was obtained up to 55% of the time when the two browsers were used by one user to encode the same concept. These results suggest that the reliability of SNOMED-CT coding is imperfect, and may be a function of browsing methodology. A combination of physician training, terminology refinement, and browser improvement may help increase the reproducibility of SNOMED-CT coding.

Evaluation of lenticonus in Alport's syndrome: quantitative Scheimpflug analysis.

Anterior lenticonus is an ocular abnormality that can occur in Alport's syndrome. In this study, Scheimpflug slit imaging analyses were employed for quantitative and objective evaluation of lens changes associated with Alport's syndrome. It was determined that while the apices of the lenticular protrusions are central in the vertical plane, they are nasally displaced in the horizontal meridian. The eccentricity and dimensions of the diameters and thicknesses of the conical aberration are highly correlated in both eyes. Lens thickness and anterior chamber depth do not differ between eyes. Densitometrically similar differences are apparent in the cortex and nuclear regions although evidence of overt opacification may or may not be present. The data strongly suggest that the physical parameters of the lenticonus are consistent with the constraints imposed by the pupil. Changes observed in the cornea and the vitreous may be associated with the syndrome.