Mimickers of anterior uveitis, scleritis and misdiagnoses- tips and tricks for the cornea specialist.

BACKGROUND: Anterior uveitis, inflammation of the anterior chamber and related structures, is a cohort of diseases that can present to almost any general or sub-specialty Ophthalmology practice. Its features classically involve anterior chamber cell and flare. Below the surface of these two signs exist a panoply of diagnoses. BODY: The purpose of this review is to provide a general framework for diagnoses of anterior uveitis that are often missed as well as non-uveitic pathologies that often mimic anterior uveitis. Diagnostic deviation in either direction can have vision-threatening and rarely life-threatening consequences for patients. Using a comprehensive literature review we have collected a broad spectrum of etiologies of anterior uveitis that are easily missed and non-uveitic pathologies that can masquerade as anterior uveitis. CONCLUSIONS: We present a focused review on specific misdiagnosed anterior uveitis pathologies and some of the conditions that can masquerade as anterior uveitis and scleritis.

Coagulase-negative staphylococcal endophthalmitis: clinical severity and outcomes based on speciation.

OBJECTIVE: To identify characteristics and visual outcomes of coagulase-negative staphylococcal (CoNS) endophthalmitis in the era after the Endophthalmitis Vitrectomy Study. DESIGN: Single-centre retrospective analysis. PARTICIPANTS: Forty-two samples from 40 patients with documented CoNS endophthalmitis. METHODS: Visual acuity outcomes of CoNS endophthalmitis were assessed in relation to species and type of treatment instituted (i.e., pars plana vitrectomy [PPV] versus vitreous tap and injection of intravitreal antibiotics [T&I]) on 42 samples from 40 patients. RESULTS: Staphylococcus epidermidis was the most prevalent CoNS in our study. Cataract surgery and intravitreal injections were the most common sources for acute CoNS endophthalmitis. Eyes presenting with hand motion or better vision had similar mean final vision after either intravitreal antibiotics or PPV, whereas those with light perception or worse vision at onset had better outcomes after PPV only. Subanalysis showed that patients with S. epidermidis endophthalmitis (n = 39 eyes) had similar visual outcomes with either intravitreal injections or PPV regardless of visual acuity. Hypopyon and vitritis are not always present. CONCLUSIONS: Patients with S. epidermidis endophthalmitis may benefit similarly from either early vitrectomy or intravitreal antibiotic injections regardless of visual acuity. This finding may be a supplement to the complements the management standards set forth by the Endophthalmitis Vitrectomy Study.

OCT Angiography in Noninfectious Uveitis: A Description of Five Cases and Clinical Applications.

BACKGROUND: Optical coherence tomography angiography (OCTA) is a noninvasive imaging modality used to analyze the retinochoroidal vasculature and detect vascular flow. The resulting images can be segmented to view each vascular plexus individually. While fluorescein angiography is still the gold standard for the diagnosis of posterior uveitis, it has limitations, and can be replaced by OCTA in some cases. METHODS: This case series describes five patients with posterior noninfectious uveitis and their description by OCTA. RESULTS: Cases included lupus retinopathy (n = 1) for which OCTA showed ischemic maculopathy as areas of flow deficit at the superficial and deep capillary plexus; choroidal granulomas (n = 1) with a non-detectable flow signal in the choroid; active punctate inner choroiditis and multifocal choroiditis (n = 1) with OCTA that showed active inflammatory chorioretinal lesions as non-detectable flow signals in choriocapillaris and choroid; dense type 2 inflammatory secondary neovascularization (n = 1) associated with active choroiditis; and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (n = 1) without flow abnormalities at the superficial and deep retinal plexuses but non-detectable flow at the levels of the choriocapillaris and choroid. CONCLUSIONS: Ophthalmologists can use OCTA to identify inflammatory changes in retinal and choroidal vasculature, aiding in the diagnosis, management, and monitoring of posterior uveitis.

Autofluorescent hyperreflective foci on infrared autofluorescence adaptive optics ophthalmoscopy in central serous chorioretinopathy.

Purpose: To test the hypothesis that hyperreflective foci in central serous chorioretinopathy (CSCR) are autofluorescent and may represent macrophages that have engulfed outer retinal fluorophores from the retinal pigment epithelium (RPE) and photoreceptors. Methods: Enrolled subjects underwent spectral domain and swept-source optical coherence tomography, adaptive optics flood-illumination, and adaptive optics scanning laser ophthalmoscopy (AOSLO), including near-infrared autofluorescence (AO-IRAF). For the AO-IRAF imaging, retinal fluorophores were excited using 795 nm light and collected in an emission band from 814 to 850 nm. Results: In 2 of 3 eyes, a hyperautofluorescent signal was detected with an elliptical shape and punctate, granular aspects surrounded by a hypoautofluorescent halo. The size of these structures in the active case was measured to be 17 ± 4 µm in diameter, with at least 45 individual hyperautofluorescent foci identified from the AO-IRAF montage in the active stage of patient 2. In the asymptomatic case there were fewer structures visible (∼10) and their size was smaller (11 ± 4 µm). These hyper-AF foci were colocalized with hyperreflective foci on OCT and visible in simultaneously acquired confocal AOSLO images in active stage. The hyperautofluorescent foci in the patient with active CSCR disappeared coincident with clinical resolution. Conclusion and importance: We show here the first AO-IRAF images from patients with CSCR, demonstrating hyper-autofluorescent punctate foci, colocalized with hyper-reflective foci on confocal AOSLO images and in OCT. The autofluorescence of these foci may be driven by the accumulation of photoreceptor and RPE fluorophores within macrophages during the active stage of the disease.

MULTIMODAL IMAGING OF MULTIFOCAL CHOROIDITIS WITH ADAPTIVE OPTICS OPHTHALMOSCOPY.

PURPOSE: To describe longitudinal, anatomical, and functional alterations caused by inflammatory and neovascular lesions of idiopathic multifocal choroiditis/punctate inner choroidopathy using adaptive optics imaging and microperimetry. METHODS: Longitudinal case study using multiple imaging modalities, including spectral-domain optical coherence tomography, fluorescein angiography, indocyanine green angiography, optical coherence tomography angiography, flood illumination adaptive optics, and microperimetry. RESULTS: A 21-year-old myopic Asian man presented with blurred vision in the right eye. Clinical examination was notable for an isolated hypopigmented, perifoveal lesion in each eye. Multimodal imaging showed inflammatory lesions in the outer retina, retina pigment epithelium, and inner choroid lesions of both eyes. The right eye additionally exhibited active Type-2 macular neovascularization with loss of cone mosaic regularity that was associated with reduced sensitivity on microperimetry. The clinical picture was consistent with multifocal choroiditis/punctate inner choroidopathy. The patient was treated with oral steroids and three injections of intravitreal bevacizumab in the right eye. After therapy, imaging showed reestablishment of the cone mosaic on flood illumination adaptive optics and improvement in sensitivity on microperimetry. CONCLUSION: Adaptive optics imaging and microperimetry may detect biomarkers that help to characterize the nature and activity of multifocal choroiditis lesions and to help monitor response to therapy. With timely intervention, structural abnormalities in the outer retina and choroid can be treated, and anatomical improvements precede improvements in visual function.

Super U-Net: a modularized generalizable architecture.

Objective: To develop and validate a novel convolutional neural network (CNN) termed "Super U-Net" for medical image segmentation. Methods: Super U-Net integrates a dynamic receptive field module and a fusion upsampling module into the classical U-Net architecture. The model was developed and tested to segment retinal vessels, gastrointestinal (GI) polyps, skin lesions on several image types (i.e., fundus images, endoscopic images, dermoscopic images). We also trained and tested the traditional U-Net architecture, seven U-Net variants, and two non-U-Net segmentation architectures. K-fold cross-validation was used to evaluate performance. The performance metrics included Dice similarity coefficient (DSC), accuracy, positive predictive value (PPV), and sensitivity. Results: Super U-Net achieved average DSCs of 0.808±0.0210, 0.752±0.019, 0.804±0.239, and 0.877±0.135 for segmenting retinal vessels, pediatric retinal vessels, GI polyps, and skin lesions, respectively. The Super U-net consistently outperformed U-Net, seven U-Net variants, and two non-U-Net segmentation architectures (p < 0.05). Conclusion: Dynamic receptive fields and fusion upsampling can significantly improve image segmentation performance.

Near infrared autofluorescence imaging of retinal pigmented epithelial cells using 663 nm excitation.

PURPOSE: Fundus autofluorescence (AF) using adaptive optics scanning laser ophthalmoscopy (AOSLO) enables morphometric analysis of individual retinal pigmented epithelial (RPE) cells. However, only a few excitation wavelengths in the visible and near-infrared have been evaluated. Visible light excitation (<600 nm) presents additional safety hazards and is uncomfortable for patients. Near-infrared excitation (>700 nm) overcomes those problems but introduces others, including decreased AF signal and cone signatures that obscure RPE structure. Here we investigated the use of an intermediate wavelength, 663 nm, for excitation and compared it to 795 nm. METHODS: Subjects were imaged using AOSLO equipped with a detection channel to collect AF emission between 814 and 850 nm. Two light sources (663 and 795 nm) were used to excite the retinal fluorophores. We recorded 90 s videos and registered them with custom software to integrate AF images for analysis. RESULTS: We imaged healthy eyes and an eye with pattern dystrophy. Similar AF microstructures were detected with each excitation source, despite ~4 times lower excitation power with 663 nm. The signal-to-noise values showed no meaningful difference between 663 nm and 795 nm excitation and a similar trend was observed for image contrast between the two excitation wavelengths. CONCLUSIONS: Lower light levels can be used with shorter wavelength excitation to achieve comparable images of the microstructure of the RPE as have been obtained using higher light levels at longer wavelengths. Further experiments are needed to fully characterize AF across spectrum and determine the optimal excitation and emission bandwidths that balance efficiency, patient comfort, and efficacy.

Clinical Features and Multimodal Imaging in Atypical Posterior Uveitis Secondary to Bartonella Henselae Infection.

PURPOSE: To characterize an unusual presentation of infectious posterior uveitis using multimodal imaging, and discuss the clinical decision-making involved in diagnosis and treatment. METHODS: Wide-field fundus photography, swept-source optical coherence tomography (OCT), swept-source OCT angiography, fluorescein angiography, and indocyanine green angiography. RESULTS: This patient presented with cyclical fevers and blurry vision. Fundus examination revealed bilateral optic disc edema, macular intraretinal white spots and many scattered yellow-white chorioretinal lesions. Multimodal imaging characteristics suggested that many of these lesions represent choroidal granulomas. Extensive systemic workup was only notable for borderline elevated Bartonella henselae IgG titers (1:128), however convalescent IgG titers were elevated at 38 days (1:512) supporting the diagnosis of Bartonella chorioretinitis. CONCLUSION: Ocular manifestations of Bartonella henselae infection are varied and may include choroidal granulomas. Multimodal imaging characteristics may help identify etiologies of infectious uveitis. Convalescent titers are important when evaluating patients with suspected Bartonellosis, especially patients with atypical presentations.

Choriocapillaris: Fundamentals and advancements.

The choriocapillaris is the innermost structure of the choroid that directly nourishes the retinal pigment epithelium and photoreceptors. This article provides an overview of its hemovasculogenesis development to achieve its final architecture as a lobular vasculature, and also summarizes the current histological and molecular knowledge about choriocapillaris and its dysfunction. After describing the existing state-of-the-art tools to image the choriocapillaris, we report the findings in the choriocapillaris encountered in the most frequent retinochoroidal diseases including vascular diseases, inflammatory diseases, myopia, pachychoroid disease spectrum disorders, and glaucoma. The final section focuses on the development of imaging technology to optimize visualization of the choriocapillaris as well as current treatments of retinochoroidal disorders that specifically target the choriocapillaris. We conclude the article with pertinent unanswered questions and future directions in research for the choriocapillaris.

Review of the Current Literature and Our Experience on the Value of OCT-angiography in White Dot Syndromes.

PURPOSE: To describe the application of OCT-A in various posterior uveitis disorders in our experience and to compare it with the available literature. METHODS: Eighteen eyes with the diagnoses of multifocal choroiditis (MFC), multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), tuberculous serpiginous-like choroiditis (SLC), serpiginous choroiditis (SC), and birdshot chorioretinopathy (BSCR) were studied. RESULTS: We found flow void of the choriocapillaris in patients with APMPPE, SC, MFC, BSCR, and in SLC. In contrast, perfusion of the choriocapillaris seemed normal in patients with MEWDS. CONCLUSIONS: We confirmed that OCT-A contributes new information on the physiopathology of white dot syndromes and inflammatory chorioretinopathies, notably on whether or not the choriocapillaris is involved. Comparing the OCT-A features allowed us to suggest that both APMPPE and SLC might be part of the same spectrum of inflammatory disease with primary involvement at the level of the choriocapillaris and secondary RPE damage.

Multimodal Imaging of Torpedo Maculopathy With Fluorescence Adaptive Optics Imaging of Individual Retinal Pigmented Epithelial Cells.

Torpedo maculopathy (TM) is a rare congenital defect of the retinal pigment epithelium (RPE). The RPE is often evaluated clinically using fundus autofluorescence (AF), a technique that visualizes RPE structure at the tissue level from the intrinsic AF of RPE fluorophores. TM lesions typically emit little or no AF, but this macroscopic assessment is unable to resolve the RPE cells, leaving the organization of the RPE cell mosaic in TM unknown. We used fluorescence adaptive optics scanning laser ophthalmoscopy (AOSLO) to show here for the first time the microscopic cellular-level structural alterations to the RPE cell mosaic in TM that underlie the tissue-level changes seen in conventional clinical imaging. We evaluated two patients with TM using conventional clinical imaging techniques and adaptive optics (AO) infrared autofluorescence (IRAF) in AOSLO. Confocal AOSLO revealed relatively normal cones outside the TM lesion but altered cone appearance within it and along its margins in both patients. We quantified cone topography and RPE cell morphometry from the fovea to the margin of the lesion in case 1 and found cone density to be within the normal range across the locations imaged. However, RPE morphometric analysis revealed disrupted RPE cells outside the margin of the lesion; the mean RPE cell area was greater than two standard deviations above the normative range up to approximately 1.5 mm from the lesion margin. Similar morphometric changes were seen to individual RPE cells in case 2. Multi-modal imaging with AOSLO reveals that RPE cells are abnormal in TM well beyond the margins of the characteristic TM lesion boundary defined with conventional clinical imaging. Since the TM fovea appears to be fully formed, with normal cone packing, it is possible that the congenital RPE defect in TM occurs relatively late in retinal development. This work demonstrates how cellular level imaging of the RPE can provide new insight into RPE pathologies, particularly for rare conditions such as TM.

A New Method for Visualizing Drusen and Their Progression in Flood-Illumination Adaptive Optics Ophthalmoscopy.

Purpose: Drusen are dynamic sub-RPE deposits that are risk factors for late-stage age-related macular degeneration (AMD). Here we show a new imaging method using flood-illumination adaptive optics (FIAO) that reveal drusen with high contrast and resolution. Methods: A fovea-centered 4° × 4° FIAO image and eight surrounding images with gaze displaced by ±2° vertically and horizontally were acquired. Clinical color fundus and spectral-domain optical coherence tomography were acquired for clinical grading and comparison. Custom software registered overlapping FIAO images and fused the data statistically to generate a fovea-centered 4° × 4° gaze-dependent image. Our dataset included 15 controls (aged 31-72) and 182 eyes from 104 AMD patients (aged 56-92), graded as either normal aging (n = 7), and early (n = 12), intermediate (n = 108) and late AMD (n = 42); 27 had subretinal drusenoid deposits (SDDs), and 83 were imaged longitudinally. Results: No gaze varying structures were detected in young eyes. In aging eyes with no evidence of age-related changes, putative drusen <20 µm in diameter were visible. Gaze-dependent images revealed more drusen and many smaller drusen than visible in color fundus images. Longitudinal images showed expansion and fusion of drusen. SDDs were lower contrast, and RPE atrophy did not yield a consistent signal. Conclusions: Gaze-dependent imaging in a commercially available FIAO fundus camera combined with image registration and postprocessing permits visualization of drusen and their progression with high contrast and resolution. Translational Relevance: This new technique offers promise as a robust and sensitive method to detect, map, quantify, and monitor the dynamics of drusen in aging and AMD.

Eye trauma in falls presenting to the emergency department from 2006 through 2015.

AIMS: To characterise the epidemiology of eye trauma in the event of falls presenting to the emergency departments (ED) in the USA. METHOD: Retrospective cohort study. Nationwide Emergency Department Sample was used to analyse fall encounters presenting to the ED with eye trauma from 2006 to 2015. National estimates of the leading diagnoses were determined, and multivariable regression was used to determine the relationship between factors involved in fall encounters presenting with eye trauma. RESULTS: From 2006 to 2015, an estimated 87 991 036 fall encounters presented to the ED, of which 952 781 encounters had eye trauma as either a primary or secondary diagnosis. The overall incidence of fall encounters with eye trauma per 100 000 US population increased from 30.7 encounters in 2006 to 33.8 encounters per 100 000 population in 2014 with a decrease seen in 2015. Eye trauma, including vision-threatening type, was highest in females (n=500 520, 52.5%), elderly (n=400 209, 42%) and children (n=2 06 741, 21.7%). Elderly were more likely to have eye trauma in the setting of falls (adjusted OR (aOR) 2.06, 95% CI 2.02 to 2.11) and be admitted (aOR 1.89, 95% CI 1.86 to 1.91) than adults (reference). The leading types of eye trauma were contusion of orbital tissues (n=174 292, 18.3%), laceration of eyelid and periocular area (n=172 361, 18.1%) and orbital fractures (n=151 013, 15.8%). CONCLUSIONS: Falls are preventable, yet the incidence of falls and resulting eye trauma are increasing despite our best efforts. As ophthalmologists, we should not only develop guidelines to recognise and counsel at-risk groups under our care but also strategies for prevention of eye trauma secondary to falls.

Microstructure of the retinal pigment epithelium near-infrared autofluorescence in healthy young eyes and in patients with AMD.

Retinal pigmented epithelial (RPE) cells are essential for maintaining normal visual function, especially in their role in the visual cycle, and are thought to be one of the first cell classes affected by age-related macular degeneration (AMD). Clinical imaging systems routinely evaluate the structure of the RPE at the tissue level, but cellular level information may provide valuable RPE biomarkers of health, aging and disease. In this exploratory study, participants were imaged with 795 nm excitation in adaptive optics scanning laser ophthalmoscopy (AOSLO) to observe the microstructure of the near-infrared autofluorescence (AO-IRAF) from the RPE layer in healthy retinas and patients with AMD. The expected hexagonal mosaic of RPE cells was only sometimes seen in normal eyes, while AMD patients exhibited highly variable patterns of altered AO-IRAF. In some participants, AO-IRAF structure corresponding to cones was observed, as we have demonstrated previously. In some AMD patients, marked alterations in the pattern of AO-IRAF could be seen even in areas where the RPE appeared relatively normal in clinical imaging modalities, such as spectral domain optical coherence tomography (SD-OCT). AO-IRAF imaging using AOSLO offers promise for better detection and understanding of early RPE changes in the course of AMD, potentially before clinical signs appear.

Ophthalmology Practice During the Coronavirus Disease 2019 Pandemic: The University of Pittsburgh Experience in Promoting Clinic Safety and Embracing Video Visits.

The coronavirus disease 2019 pandemic has led to widespread change as public health strategies for containment have emphasized social distancing and remaining at home. These policies have led to downscaled clinic volumes, cancellation of elective procedures, enhanced personal protective strategies in the clinic, and adoption of telemedicine encounters. We describe the evidence-based practical approach taken in our ophthalmology department to continue delivering eye care during the pandemic by rescheduling visits, enhancing clinic safety, and adopting virtual video encounters.

Eye-Related Emergency Department Visits and The Opioid Epidemic: a 10-Year Analysis.

PURPOSE: To describe the epidemiology of Emergency Department (ED) visits related to opioid abuse with primary ophthalmic diagnoses in the United States (US). METHODS: This retrospective cross-sectional study used National ED Sample (NEDS) (2006-2015), a representative sample of all US EDs, to analyze and compare the epidemiology of primary ophthalmic diagnoses in opioid abusers and a control group of non-opioid users. National incidence and descriptive statistics were calculated for demographics and prevalent diagnoses. Multivariable logistic regression was used to compare outcomes between primary ophthalmic diagnoses in opioid and non-opioid abusers. RESULTS: An estimated 10,617 visits had a primary ophthalmic diagnosis and an accompanying opioid abuse diagnosis, and the incidence increased from 0.2 in 2006 to 0.6 per 100,000 US population in 2015. Opioid abuse group had more adults (6,747:63.5%) and middle-aged (3,361:31.7%) patients, while in controls adults (7,905,003:40.4%) and children (4,068,534:20.8%) were affected more. Leading etiologies were similar: traumatic and infectious etiologies were most common; however, opioid abuse patients had more severe ophthalmic diagnoses such as orbital fractures (8.4%), orbital cellulitis (7.4%), globe injury (3.4%) and endophthalmitis (3.2%) compared to controls. Patients in the opioid abuse group were also more likely to be admitted (adjusted Odds Ratio [aOR], 28.38 [95% CI, 24.50-32.87]). CONCLUSIONS: In the era of opioid crisis, an increase in ED visits with ophthalmic complaints is seen, with increasing direct and indirect costs on the healthcare system. More research is needed to establish causality and devise strategies to lower this burden.

CHOROIDAL MORPHOLOGY IN EYES WITH PERIPAPILLARY POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: This study analyzes a subset of patients with peripapillary polypoidal choroidal vasculopathy (PCV) to determine whether quantifiable pachychoroid features colocalize with disease foci. METHODS: Patients with PCV diagnosed by indocyanine green angiography were identified for the analysis of medical records and multimodal imaging and classified as having peripapillary or macular PCV. The ratio of Haller layer thickness to total choroidal thickness was calculated at the fovea and at the site of dilated Haller vessels that showed spatial correlation with the origin of neovascularization. Choroidal thickness was measured horizontally across the fovea and circumferentially around the temporal side of the disk to study its relationship to neovascularization. RESULTS: Three hundred and fourteen eyes of 299 patients with PCV were identified, of which 17 eyes (5%) had peripapillary disease. Although eyes with peripapillary PCV exhibited thinner subfoveal choroids than those with macular PCV, at the extrafoveal disease foci, choroidal thickness, Haller's layer thickness, and its ratio to total choroidal thickness were relatively high. CONCLUSION: Quantitative indices of choroidal structure previously identified in macular PCV performed consistently when applied to a peripapillary PCV cohort, thus supporting the hypothesis that inner choroidal thinning and Haller vessel enlargement are mechanistically relevant to these related entities.

Choroidal imaging biomarkers.

The choroid is the vascular coat of the eye, and its role has been studied in multiple chorioretinal disorders. Recent advancements in choroidal imaging techniques, including enhanced depth imaging optical coherence tomography, swept source optical coherence tomography, en face optical coherence tomography, and optical coherence tomography angiography have facilitated an in-depth analysis of the choroid. The gradual shift from manual to automated segmentation and binarization methods have led to precise and reproducible measurements of choroidal parameters. These qualitative and quantitative parameters, called choroidal imaging biomarkers, have evolved over the past decade from a simple linear subfoveal choroidal thickness to more complex 3D choroidal reconstruction, thus widening the spectrum encompassing multiple parameters. These biomarkers have provided a better understanding of the pathogenesis, are helpful in diagnostic dilemmas, and, in the future may also help to devise treatment options. The lack of normative data, absence of standardized parameters, and limitations of the imaging techniques, however, have led to ambiguity and difficulty in the interpretation of these variables. We attempt to address these lacunae in the literature and provide a basic understanding of the choroid in both health and disease using these choroidal biomarkers.

Classification and Quantification of Retinal Cysts in OCT B-Scans: Efficacy of Machine Learning Methods.

The automatic segmentation of fluid spaces in optical coherence tomography (OCT) imaging facilitates clinically relevant quantification and monitoring of eye disorders over time. Eyes with florid disease are particularly challenging to segment, as the anatomy is often highly distorted from normal. In this context, we propose an end-to-end machine learning method consisting of near perfect detection of retinal fluid using random forest classifier and an efficient DeepLab algorithm for quantification and labeling of the target fluid compartments. In particular, we achieve an average Dice score of 86.23% with reference to manual delineations made by a trained expert.