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Tisdale AK, Chwalisz BK. Neuro-ophthalmic manifestations of coronavirus disease 19. Curr Opin Ophthalmol 2020;31(6):489-494.Abstract
PURPOSE OF REVIEW: To provide a summary of the neuro-ophthalmic manifestations of coronavirus disease 19 (COVID-19), documented in the literature thus far. RECENT FINDINGS: A small but growing literature documents cases of new onset neuro-ophthalmic disease, in the setting of COVID-19 infection. Patients with COVID-19 have experienced acute onset vision loss, optic neuritis, cranial neuropathies, and Miller Fisher syndrome. In addition, COVID-19 increases the risk of cerebrovascular diseases that can impact the visual system. SUMMARY: The literature on COVID-19 continues to evolve. Although COVID-19 primarily impacts the respiratory system, there are several reports of new onset neuro-ophthalmic conditions in COVID-infected patients. When patients present with new onset neuro-ophthalmic issues, COVID-19 should be kept on the differential. Testing for COVID-19 should be considered, especially when fever or respiratory symptoms are also present. When screening general patients for COVID-19-associated symptoms, frontline physicians can consider including questions about diplopia, eye pain, pain with extraocular movements, decreased vision, gait issues, and other neurologic symptoms. The presence of these symptoms may increase the overall probability of viral infection, especially when fever or respiratory symptoms are present. More research is needed to establish a causal relationship between COVID-19 and neuro-ophthalmic disease, and better understand pathogenesis.
Sobrin L, Yu Y, Susarla G, Chan W, Xia T, Kempen JH, Hubbard RA, VanderBeek BL. Risk of Noninfectious Uveitis with Female Hormonal Therapy in a Large Healthcare Claims Database. Ophthalmology 2020;127(11):1558-1566.Abstract
PURPOSE: To determine if female hormonal therapy (FHT) increases the incidence of noninfectious uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Women exposed to FHT and matched women unexposed to FHT enrolled in a national insurance plan. METHODS: Estimation of noninfectious uveitis incidence used multivariable Cox proportional hazards regression. To account for differences between the exposed and unexposed cohorts, a propensity score for being prescribed FHT was created using logistic regression, and inverse probability of treatment weighting was performed. MAIN OUTCOME MEASURES: Incidence of noninfectious uveitis. For the primary outcome, incident noninfectious uveitis was defined as a new diagnosis code for noninfectious uveitis followed by a second instance of a noninfectious uveitis code within 120 days. For the alternative outcome definition, a corticosteroid prescription or code for an ocular corticosteroid injection within 120 days of the uveitis diagnosis code was used instead of the second uveitis diagnosis code. RESULTS: There were 217 653 women exposed to FHT and 928 408 women not unexposed to FHT. For the primary outcome, the hazard ratio (HR) for incident noninfectious uveitis was not significantly different between the FHT and unexposed cohorts (HR, 0.99; 95% confidence interval [CI], 0.83-1.17; P = 0.87). With the alternative outcome definition, the FHT cohort was more likely to develop uveitis (HR, 1.21; 95% CI, 1.04-1.41; P = 0.01). When examined by anatomic subtype, for anterior uveitis there was a greater likelihood of incident uveitis in the exposed cohort (HR, 1.23; 95% CI, 1.05-1.45; P = 0.01) for the alternative outcome definition but not for the primary outcome. With age stratification, women exposed to FHT aged ≥45 years at the time of FHT prescription were more likely to develop uveitis (HR, 1.23; 95% CI, 1.03-1.47; P = 0.03) for the alternative outcome definition. A similar HR (1.22) was seen for women aged ≤44 years at the time of prescription, but this association did not meet statistical significance (P = 0.20). CONCLUSIONS: Exposure to FHT increases the rate of incident noninfectious uveitis when uveitis is defined on the basis of both diagnostic codes and documentation of corticosteroid treatment. However, the risk is modest and FHT is likely safe with regard to noninfectious uveitis risk in the majority of patients exposed to these drugs.
Agrawal R, Betzler BK, Testi I, Mahajan S, Agarwal A, Gunasekeran DV, Raje D, Aggarwal K, Murthy SI, Westcott M, Chee S-P, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Cunningham ET, Kempen JH, Nguyen QD, Pavesio C, Gupta V. The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Review of 447 Patients with Tubercular Intermediate Uveitis and Panuveitis. Ocul Immunol Inflamm 2020;:1-11.Abstract
Tubercular intermediate uveitis (TIU) and panuveitis (TBP) are difficult to manage because of limitations in diagnostic tools and lack of evidence-based treatment guidelines. The Collaborative Ocular Tuberculosis Study (COTS) analyzed treatment regimens and therapeutic outcomes in patients with TIU and TBP. Multicentre retrospective analysis. A total of 138 TIU and 309 TBP patients were included. A total of 382 subjects received antitubercular therapy (ATT) (n = 382/447; 85.4%) and 382 received corticosteroids (n = 382/447; 85.4%). Treatment failure was observed in 78 individuals (n = 78/447; 17.4%), occurring less frequently in patients receiving ATT (n = 66/382; 17.2%) compared to those who did not (n = 12/65; 18.5%). The study did not show any statistically significant therapeutic effect of ATT in patients with TIU and TBP. Taking into account the limitations of the retrospective, non-randomized study design, resultant reliance on reported data records, and unequal size of the samples, the current study cannot provide conclusive evidence on the therapeutic benefit of ATT in TIU and TBP.
Hicks PM, Haaland B, Feehan M, Crandall AS, Pettey JH, Nuttall E, Self W, Hartnett ME, Bernstein P, Vitale A, Shakoor A, Shulman JP, Sieminski SF, Kim I, Owen LA, Murtaugh MA, Noyes A, Deangelis MM. Systemic Disease and Ocular Comorbidity Analysis of Geographically Isolated Federally Recognized American Indian Tribes of the Intermountain West. J Clin Med 2020;9(11)Abstract
BACKGROUND: The American Indian Navajo and Goshute peoples are underserved patient populations residing in the Four Corners area of the United States and Ibupah, Utah, respectively. METHODS: We conducted a cross-sectional study of epidemiological factors and lipid biomarkers that may be associated with type II diabetes, hypertension and retinal manifestations in tribal and non-tribal members in the study areas (n = 146 participants). We performed multivariate analyses to determine which, if any, risk factors were unique at the tribal level. Fundus photos and epidemiological data through standardized questionnaires were collected. Blood samples were collected to analyze lipid biomarkers. Univariate analyses were conducted and statistically significant factors at < 0.10 were entered into a multivariate regression. RESULTS: Of 51 participants for whom phenotyping was available, from the Four Corners region, 31 had type II diabetes (DM), 26 had hypertension and 6 had diabetic retinopathy (DR). Of the 64 participants from Ibupah with phenotyping available, 20 had diabetes, 19 had hypertension and 6 had DR. Navajo participants were less likely to have any type of retinopathy as compared to Goshute participants (odds ratio (OR) = 0.059; 95% confidence interval (CI) = 0.016-0.223; < 0.001). Associations were found between diabetes and hypertension in both populations. Older age was associated with hypertension in the Four Corners, and the Navajo that reside there on the reservation, but not within the Goshute and Ibupah populations. Combining both the Ibupah, Utah and Four Corners study populations, being American Indian ( = 0.022), residing in the Four Corners ( = 0.027) and having hypertension ( < 0.001) increased the risk of DM. DM ( < 0.001) and age ( = 0.002) were significantly associated with hypertension in both populations examined. When retinopathy was evaluated for both populations combined, hypertension ( = 0.037) and living in Ibupah ( < 0.001) were associated with greater risk of retinopathy. When combining both American Indian populations from the Four Corners and Ibupah, those with hypertension were more likely to have DM ( < 0.001). No lipid biomarkers were found to be significantly associated with any disease state. CONCLUSIONS: We found different comorbid factors with retinal disease outcome between the two tribes that reside within the Intermountain West. This is indicated by the association of tribe and with the type of retinopathy outcome when we combined the populations of American Indians. Overall, the Navajo peoples and the Four Corners had a higher prevalence of chronic disease that included diabetes and hypertension than the Goshutes and Ibupah. To the best of our knowledge, this is the first study to conduct an analysis for disease outcomes exclusively including the Navajo and Goshute tribe of the Intermountain West.
Hui P-C, Pereira LA, Dore R, Chen S, Taniguchi E, Chodosh J, Dohlman CH, Paschalis EI. Intrinsic Optical Properties of Boston Keratoprosthesis. Transl Vis Sci Technol 2020;9(12):10.Abstract
Purpose: To benchmark the optical performance of Boston Keratoprosthesis (B-KPro). Methods: Back focal lengths (BFL) of B-KPros for various eye axial lengths were measured using an optical bench, International Organization for Standardization-certified for intraocular lens characterization, and compared against manufacturer's specification. The modulation transfer function (MTF) and the resolution efficiencies were measured. The theoretical geometry-dependent higher-order aberrations (HOA) were calculated. The devices were characterized with optical profilometry for estimating the surface scattering. Aberration correction and subsequent image quality improvement were simulated in CODE-V. Natural scene-imaging was performed in a mock ocular environment. Retrospective analysis of 15 B-KPro recipient eyes were presented to evaluate the possibility of achieving 20/20 best-corrected visual acuity (BCVA). Results: BFL measurements were in excellent agreement with the manufacturer-reported values (r = 0.999). The MTF specification exceeded what is required for achieving 20/20 visual acuity. Astigmatism and field curvature, correctable in simulations, were the primary aberrations limiting imaging performance. Profilometry of the anterior surface revealed nanoscale roughness (root-mean-square amplitude, 30-50 nm), contributing negligibly to optical scattering. Images of natural scenes obtained with a simulated B-KPro eye demonstrated good central vision, with 10/10 visual acuity (equivalent to 20/20). Full restoration of 20/20 BCVA was obtainable for over 9 years in some patients. Conclusions: Theoretical and experimental considerations demonstrate that B-KPro has the optical capacity to restore 20/20 BCVA in patients. Further image quality improvement can be anticipated through correction of HOAs. Translational Relevance: We establish an objective benchmark to characterize the optics of the B-KPro and other keratoprosthesis and propose design changes to allow improved vision in B-KPro patients.
Dohlman JC, Cestari DM, Freitag SK. Orbital disease in neuro-ophthalmology. Curr Opin Ophthalmol 2020;31(6):469-474.Abstract
PURPOSE OF REVIEW: Orbital disease represents a diverse spectrum of pathology and can result in a variety of neuro-ophthalmic manifestations. The aim of this review is to provide updates on recent advances in our understanding of orbital disease secondary to thyroid eye disease, myositis, IgG4-related disease, sarcoidosis, granulomatosis with polyangiitis and various tumours. RECENT FINDINGS: With regards to thyroid eye disease, there have been recent advances in the development of steroid-sparing therapies, new modalities for objectively monitoring disease activity and increased understanding of the role of environmental risk factors. There has been interest in characterizing the clinical course and underlying mechanism of optic nerve disease secondary to orbital disorders, which has led to advances in how we monitor for and prevent permanent vision loss. Increased knowledge of orbital tumour subtype histopathology and the development of novel classification systems has had prognostic value and aided medical decision-making. SUMMARY: Orbital disease occurs secondary to a wide variety of diseases and can lead to neuro-ophthalmic manifestations with significant morbidity. Advances in our understanding of different subtypes of orbital disease have improved our ability to treat these potentially debilitating conditions.
Hu Z, Riquelme MA, Gu S, Jiang JX. Regulation of Connexin Gap Junctions and Hemichannels by Calcium and Calcium Binding Protein Calmodulin. Int J Mol Sci 2020;21(21)Abstract
Connexins are the structural components of gap junctions and hemichannels that mediate the communication and exchange of small molecules between cells, and between the intracellular and extracellular environment, respectively. Connexin (Cx) 46 is predominately expressed in lens fiber cells, where they function in maintaining the homeostasis and transparency of the lens. Cx46 mutations are associated with impairment of channel function, which results in the development of congenital cataracts. Cx46 gap junctions and hemichannels are closely regulated by multiple mechanisms. Key regulators of Cx46 channel function include Ca and calmodulin (CaM). Ca plays an essential role in lens homeostasis, and its dysregulation causes cataracts. Ca associated CaM is a well-established inhibitor of gap junction coupling. Recent studies suggest that elevated intracellular Ca activates Cx hemichannels in lens fiber cells and Cx46 directly interacts with CaM. A Cx46 site mutation (Cx46-G143R), which is associated with congenital Coppock cataracts, shows an increased Cx46-CaM interaction and this interaction is insensitive to Ca, given that depletion of Ca reduces the interaction between CaM and wild-type Cx46. Moreover, inhibition of CaM function greatly reduces the hemichannel activity in the Cx46 G143R mutant. These research findings suggest a new regulatory mechanism by which enhanced association of Cx46 with CaM leads to the increase in hemichannel activity and dysregulation may lead to cataract development. In this review, we will first discuss the involvement of Ca/CaM in lens homeostasis and pathology, and follow by providing a general overview of Ca/CaM in the regulation of Cx46 gap junctions. We discuss the most recent studies concerning the molecular mechanism of Ca/CaM in regulating Cx46 hemichannels. Finally, we will offer perspectives of the impacts of Ca/CaM and dysregulation on Cx46 channels and vice versa.
Gilmore MS, Salamzade R, Selleck E, Bryan N, Mello SS, Manson AL, Earl AM. Genes Contributing to the Unique Biology and Intrinsic Antibiotic Resistance of Enterococcus faecalis. mBio 2020;11(6)Abstract
The enterococci, which are among the leading causes of multidrug-resistant (MDR) hospital infection, are notable for their environmental ruggedness, which extends to intrinsic antibiotic resistance. To identify genes that confer this unique property, we used Tn-seq to comprehensively explore the genome of MDR strain MMH594 for genes important for growth in nutrient-containing medium and with low-level antibiotic challenge. As expected, a large core of genes for DNA replication, expression, and central metabolism, shared with other bacteria, are intolerant to transposon disruption. However, genes were identified that are important to that are either absent from or unimportant for and fitness when similarly tested. Further, 217 genes were identified that when challenged by sub-MIC antibiotic levels exhibited reduced tolerance to transposon disruption, including those previously shown to contribute to intrinsic resistance, and others not previously ascribed this role. is one of the few Gram-positive bacteria experimentally shown to possess a functional Entner-Doudoroff pathway for carbon metabolism, a pathway that contributes to stress tolerance in other microbes. Through functional genomics and network analysis we defined the unusual structure of this pathway in and assessed its importance. These approaches also identified toxin-antitoxin and related systems that are unique and active in Finally, we identified genes that are absent in the closest nonenterococcal relatives, the vagococci, and that contribute importantly to fitness with and without antibiotic selection, advancing an understanding of the unique biology of enterococci. Enterococci are leading causes of antibiotic-resistant infection transmitted in hospitals. The intrinsic hardiness of these organisms allows them to survive disinfection practices and then proliferate in the gastrointestinal tracts of antibiotic-treated patients. The objective of this study was to identify the underlying genetic basis for its unusual hardiness. Using a functional genomic approach, we identified traits and pathways of general importance for enterococcal survival and growth that distinguish them from closely related pathogens as well as ancestrally related species. We further identified unique traits that enable them to survive antibiotic challenge, revealing a large set of genes that contribute to intrinsic antibiotic resistance and a smaller set of uniquely important genes that are rare outside enterococci.
Charles NC, Jakobiec FA, Sherwood P, Belinsky I. Multicameral Steatocystoma Simplex of the Caruncle. Ophthalmic Plast Reconstr Surg 2020;Abstract
A yellow cyst of the caruncle in a 68-year-old man displayed the characteristic sebaceous glands and sebocytes of steatocystoma within the cyst wall, with a unique configuration of multiple branching compartments. The cyst lining was of trichilemmal character, lacking a keratohyalin granular layer, and replicated the immunohistochemical characteristics of a previously reported caruncular steatocystoma with the exception of a positive trichilemmal marker, calretinin, in the present case. Four previous cases of caruncular steatocystoma have been described, only one of which incorporated immunohistochemical analysis. Steatocystoma develops from a sebaceous gland duct, which displayed in this case multiple chambers subdividing what is usually a single round lumen.
Lužnik Z, Anchouche S, Dana R, Yin J. Regulatory T Cells in Angiogenesis. J Immunol 2020;205(10):2557-2565.Abstract
Regulatory T cells (Tregs) are crucial mediators of immune homeostasis. They regulate immune response by suppressing inflammation and promoting self-tolerance. In addition to their immunoregulatory role, a growing body of evidence highlights the dynamic role of Tregs in angiogenesis, the process of forming new blood vessels. Although angiogenesis is critically important for normal tissue regeneration, it is also a hallmark of pathological processes, including malignancy and chronic inflammation. Interestingly, the role of Tregs in angiogenesis has been shown to be highly tissue- and context-specific and as a result can yield either pro- or antiangiogenic effects. For these reasons, there is considerable interest in determining the molecular underpinnings of Treg-mediated modulation of angiogenesis in different disease states. The present review summarizes the role of Tregs in angiogenesis and mechanisms by which Tregs regulate angiogenesis and discusses how these mechanisms differ in homeostatic and pathological settings.
Sohn EH, Mullins RF, Eliott D. Reply. Retina 2020;40(11):e68-e69.
Redler Y, Levy M. Rodent Models of Optic Neuritis. Front Neurol 2020;11:580951.Abstract
Optic neuritis (ON) is an inflammatory attack of the optic nerve that leads to visual disability. It is the most common optic neuropathy affecting healthy young adults, most commonly women aged 20-45 years. It can be idiopathic and monophasic or as part of a neurologic disease such as multiple sclerosis with recurrence and cumulative damage. Currently, there is no therapy to repair the damage from optic neuritis. Animal models are an essential tool for the understanding of the pathogenesis of optic neuritis and for the development of potential treatment strategies. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental rodent model for human autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). In this review, we discuss the latest rodent models regarding optic neuritis, focusing on EAE model, and on its recent achievements and developments.
Duarte D, Bauer CCC, Pinto CB, Saleh Velez FG, Estudillo-Guerra MA, Pacheco-Barrios K, Gunduz ME, Crandell D, Merabet L, Fregni F. Cortical plasticity in phantom limb pain: A fMRI study on the neural correlates of behavioral clinical manifestations. Psychiatry Res Neuroimaging 2020;304:111151.Abstract
The neural mechanism of phantom limb pain (PLP) is related to the intense brain reorganization process implicating plasticity after deafferentation mostly in sensorimotor system. There is a limited understanding of the association between the sensorimotor system and PLP. We used a novel task-based functional magnetic resonance imaging (fMRI) approach to (1) assess neural activation within a-priori selected regions-of-interested (motor cortex [M1], somatosensory cortex [S1], and visual cortex [V1]), (2) quantify the cortical representation shift in the affected M1, and (3) correlate these changes with baseline clinical characteristics. In a sample of 18 participants, we found a significantly increased activity in M1 and S1 as well as a shift in motor cortex representation that was not related to PLP intensity. In an exploratory analyses (not corrected for multiple comparisons), they were directly correlated with time since amputation; and there was an association between increased activity in M1 with a lack of itching sensation and V1 activation was negatively correlated with PLP. Longer periods of amputation lead to compensatory changes in sensory-motor areas; and itching seems to be a protective marker for less signal changes. We confirmed that PLP intensity is not associated with signal changes in M1 and S1 but in V1.
Venkatraman P, Mills-Henry I, Padmanabhan KR, Pascuzzi P, Hassan M, Zhang J, Zhang X, Ma P, Pang CP, Dowling JE, Zhang M, Leung YF. Rods Contribute to Visual Behavior in Larval Zebrafish. Invest Ophthalmol Vis Sci 2020;61(12):11.Abstract
Purpose: Although zebrafish rods begin to develop as early as 2 days postfertilization (dpf), they are not deemed anatomically mature and functional until 15 to 21 dpf. A recent study detected a small electroretinogram (ERG) from rods in a cone mutant called no optokinetic response f (nof) at 5 dpf, suggesting that young rods are functional. Whether they can mediate behavioral responses in larvae is unknown. Methods: We first confirmed rod function by measuring nof ERGs under photopic and scotopic illumination at 6 dpf. We evaluated the role of rods in visual behaviors using two different assays: the visual-motor response (VMR) and optokinetic response (OKR). We measured responses from wild-type (WT) larvae and nof mutants under photopic and scotopic illuminations at 6 dpf. Results: Nof mutants lacked a photopic ERG. However, after prolonged dark adaptation, they displayed scotopic ERGs. Compared with WT larvae, the nof mutants displayed reduced VMRs. The VMR difference during light onset gradually diminished with decreased illumination and became nearly identical at lower light intensities. Additionally, light-adapted nof mutants did not display an OKR, whereas dark-adapted nof mutants displayed scotopic OKRs. Conclusions: Because the nof mutants lacked a photopic ERG but displayed scotopic ERGs after dark adaptation, the mutants clearly had functional rods. WT larvae and the nof mutants displayed comparable scotopic light-On VMRs and scotopic OKRs after dark adaptation, suggesting that these responses were driven primarily by rods. Together, these observations indicate that rods contribute to zebrafish visual behaviors as early as 6 dpf.

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