Lopez MJ, Seyed-Razavi Y, Jamali A, Harris DL, Hamrah P. The Chemokine Receptor CXCR4 Mediates Recruitment of CD11c+ Conventional Dendritic Cells Into the Inflamed Murine Cornea. Invest Ophthalmol Vis Sci 2018;59(13):5671-5681.Abstract
Purpose: The cornea contains distinct populations of antigen-presenting cells (APCs), including conventional dendritic cells (cDCs). Little is known about the molecular mechanisms involved in cDCs homing and recruitment into the naïve and inflamed cornea. The purpose of this study was to investigate the presence of CXCR4 and its ligand CXCL12 in the murine cornea and its role in cDC migration during corneal inflammation. Methods: The expression of CXCR4 and CXCL12 in naïve and suture-inflamed murine corneas was assessed by whole-mount staining, flow cytometry, and quantitative PCR. The role of CXCR4 in recruitment into inflamed corneas was investigated using adoptive transfer of cDCs blocked with neutralizing antibody against CXCR4. Results: We show the chemokine receptor CXCR4 to be expressed on 51.7% and 64.8% of total corneal CD11c+ cDCs, equating to 98.6 ± 12.5 cells/mm2 in the peripheral and 64.7 ± 10.6 cells/mm2 in the central naïve cornea, respectively. Along with a 4.5-fold increase in CXCL12 expression during inflammation (P < 0.05), infiltrating cDCs also expressed CXCR4 in both the peripheral (222.6 ± 33.3 cells/mm2; P < 0.001) and central cornea (161.9 ± 23.8 cells/mm2; P = 0.001), representing a decrease to 31.0% and 37.3% in the cornea, respectively. Further, ex vivo blockade (390.1 ± 40.1 vs. 612.1 ± 78.3; P = 0.008) and local blockade (263.5 ± 27.1 vs. 807.5 ± 179.5, P < 0.001) with anti-CXCR4 neutralizing antibody resulted in a decrease in cDCs homing into the cornea compared with cells pretreated with isotype controls. Conclusions: Our results demonstrate that corneal CXCL12 plays a direct role in CXCR4+ cDC recruitment into the cornea. The CXCR4/CXCL12 axis is therefore a potential target to modulate corneal inflammatory responses.
Ibrahim AS, Elmasry K, Wan M, Abdulmoneim S, Still A, Khan F, Khalil A, Saul A, Hoda MN, Al-Shabrawey M. A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse. Invest Ophthalmol Vis Sci 2018;59(13):5548-5557.Abstract
Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON. Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions. Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare. Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.
Fortin E, Cestari DM, Weinberg DH. Ocular myasthenia gravis: an update on diagnosis and treatment. Curr Opin Ophthalmol 2018;29(6):477-484.Abstract
PURPOSE OF REVIEW: Myasthenia gravis is an autoimmune disease that commonly affects the palpebral and extraocular muscles. Ocular myasthenia gravis (OMG) is a variant of the disease that is confined to the ocular muscles but frequently becomes generalized over time. The diagnosis of OMG is often challenging but both clinical and laboratory findings are helpful in confirming the clinical suspicion. This review provides an update on the diagnostic approach and therapeutic options for OMG. RECENT FINDINGS: Antimuscle-specific tyrosine kinase and LDL-related receptor-related protein 4 are newly available serologic testing for myasthenia gravis that can help in increasing the diagnostic sensitivity of OMG. They should be included to the diagnostic algorithm of OMG in appropriate clinical situations. SUMMARY: OMG remains a primarily clinical diagnosis, but recent advances in laboratory testing can improve the diagnostic accuracy and should be used in appropriate clinical settings. The mainstay of treatment for OMG has not significantly changed over the past years, but the increasing availability of steroid-sparing agents improved the disease control while minimizing steroid-induced complications.
Chwalisz BK, Stone JH. Neuro-ophthalmic complications of IgG4-related disease. Curr Opin Ophthalmol 2018;29(6):485-494.Abstract
PURPOSE OF REVIEW: IgG4-related disease (IgG4-RD) is increasingly recognized as a fibroinflammatory disease with a plethora of organ-specific manifestations but a particular predilection for head and neck tissues, including the nervous system. This review discusses general features and organ-specific presentations of IgG4-RD as well as treatment considerations, particularly emphasizing features of neuro-ophthalmic interest. RECENT FINDINGS: IgG4-RD is emerging as a common cause of several fibroinflammatory disorders in the head and neck that were previously considered idiopathic, such as sclerosing orbital pseudotumor, orbital myositis, hypophysitis, and hypertrophic pachymeningitis. New and unusual presentations continue to be described, including a number of vascular manifestations. Substantial progress has been made in elucidating the cell types involved in IgG4-RD, and new pathogenic models are being proposed. Although clinicopathologic correlation remains the cornerstone of diagnosis, ancillary tests such as flow cytometry for circulating plasmablasts and PET-computed tomography have high sensitivity, and certain radiologic features are recognized to be particularly suggestive, such as infraorbital nerve enlargement in IgG4-RD orbitopathy. IgG4-RD often responds to steroids but incomplete responses and relapses are common. Rituximab is emerging as a promising new therapy. SUMMARY: The current review summarizes manifestations of IgG4RD that are of particular relevance to neuro-ophthalmic practice.
Koo EB, VanderVeen DK, Lambert SR. Global Practice Patterns in the Management of Infantile Cataracts. Eye Contact Lens 2018;44 Suppl 2:S292-S296.Abstract
OBJECTIVES: Surveys are an important tool to assess the impact of research on physicians' approach to patient care. This survey was conducted to assess current practice patterns in the management of infantile cataracts in light of the findings of the Infant Aphakia Treatment Study. METHODS: Pediatric ophthalmologists were emailed a link to the survey using newsletters from American Association of Pediatric Ophthalmology and Strabismus, World Society of Pediatric Ophthalmology and Strabismus, and the Pediatric Listserv. The 17-question survey was anonymous and active during July to August 2016. RESULTS: One hundred twenty-five respondents (North America, 65%; Asia, 12%; Europe, 9%; and other, 14%) reported operating on pediatric cataracts. Most practice in a university setting (55%). There was a strong consensus that unilateral cataract surgery should be performed between ages 4 to 6 weeks and aphakic contact lenses should be used to optically correct their eyes, particularly in children ≤6 months of age. For bilateral cataracts, there was a trend for surgeons to perform cataract surgery at an older age than unilateral cataract surgery. Surgeons who performed less than 5 versus greater than 20 pediatric cataract surgeries/year were more likely to use aphakic contact lenses in children undergoing cataract surgery more than 6 months of age (62% vs. 35%, P=0.04). Most respondents (73%) indicated that the Infant Aphakia Treatment Study had changed how they manage unilateral congenital cataracts. CONCLUSION: Most pediatric cataract surgeons perform congenital cataract surgery between ages 4 to 6 weeks and use aphakic contact lenses for initial optical correction in infants less than 6 months. Surgeons have equal preference for intraocular lenses and contact lenses in infants more than 6 months of age.
Dobyns WB, Aldinger KA, Ishak GE, Mirzaa GM, Timms AE, Grout ME, Dremmen MHG, Schot R, Vandervore L, van Slegtenhorst MA, Wilke M, Kasteleijn E, Lee AS, Barry BJ, Chao KR, Szczałuba K, Kobori J, Hanson-Kahn A, Bernstein JA, Carr L, D'Arco F, Miyana K, Okazaki T, Saito Y, Sasaki M, Das S, Wheeler MM, Bamshad MJ, Nickerson DA, of for Genomics UWCM, for at the of and Harvard CMGBIMIT, Engle EC, Verheijen FW, Doherty D, Mancini GMS. MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet 2018;103(6):1009-1021.Abstract
To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.
Chun BY, Cestari DM. Myelin oligodendrocyte glycoprotein-IgG-associated optic neuritis. Curr Opin Ophthalmol 2018;29(6):508-513.Abstract
PURPOSE OF REVIEW: Myelin oligodendrocyte glycoprotein (MOG)-IgG-associated optic neuritis has been established as a new entity of optic neuropathy. We will review recent advances in pathophysiology, diagnosis, and clinical manifestations of MOG-IgG-associated optic neuritis to better understand its distinctive characteristics. RECENT FINDINGS: MOG is expressed on the surface of myelin sheaths and oligodendrocytes. MOG is highly immunogenic and is a potential target of inflammatory demyelinating disease. MOG-IgG activate immune responses and cause demyelination without astrocytopathy. MOG-IgG are measured by cell-based assays, which have higher sensitivity and specificity than ELISA. Patients with MOG-IgG-associated optic neuritis present with initially severe vision loss, are more likely to have optic disc edema, but have favorable visual outcomes. Furthermore, patients with MOG-IgG-associated optic neuritis have higher rates of recurrence compared with MOG-IgG seronegative patients. MOG-IgG-associated optic neuritis responds well to steroid treatment, however, close monitoring for signs of relapse and long-term immunosuppression may be necessary. SUMMARY: MOG-IgG associated optic neuritis demonstrates distinctive pathophysiological and clinical characteristics from optic neuritis in aquaporin4-IgG seropositive or multiple sclerosis patients. Measurements of MOG-IgG titers by cell-based assays will be helpful for the diagnosis and treatment of optic neuritis.
Jurkunas UV. Fuchs Endothelial Corneal Dystrophy Through the Prism of Oxidative Stress. Cornea 2018;37 Suppl 1:S50-S54.Abstract
The corneal endothelium (CE) is vital for maintaining the water balance and clarity of the cornea. The CE is a cell layer that is particularly susceptible to aging because of its postmitotic arrest, high metabolic activity involving pumping of ions, and lifelong exposure to ultraviolet light. Despite gradual age-related cell loss, a sufficient number of CE cells are preserved during the lifespan of an individual. However, in conditions such as Fuchs endothelial corneal dystrophy (FECD), permanent loss of CE cells leads to corneal edema and loss of vision requiring corneal transplantation. FECD is a genetic and oxidative stress disorder manifested by abnormal cell-matrix interactions and expedited cellular aging culminating in cellular death. Because the endothelium has minimal replicative capacity in vivo and an inability to replace its genome, it is particularly prone to cumulative DNA damage acquired throughout life. In FECD, the underlying genetic defects make the CE genome even more vulnerable to this damage, to the point of causing mitochondrial dysfunction, mitochondrial membrane potential loss, and excessive mitophagy activation. Endogenous and exogenous intracellular stressors alter the synthetic footprint of CE cells, leading to endothelial-mesenchymal transition and secretion of aberrant extracellular matrix (in the form of guttae), resembling scar formation in other organs. In turn, the guttae or endothelial scars contribute to a vicious cycle of FECD pathogenesis and, by further inducing endothelial-mesenchymal transition and oxidant-antioxidant imbalance, perpetuate the molecular changes of the degenerating endothelium.
Galli J, Ambrosi C, Micheletti S, Merabet LB, Pinardi C, Gasparotti R, Fazzi E. White matter changes associated with cognitive visual dysfunctions in children with cerebral palsy: A diffusion tensor imaging study. J Neurosci Res 2018;96(11):1766-1774.Abstract
Children with cerebral palsy often present with cognitive-visual dysfunctions characterized by visuo-perceptual and/or visuo-spatial deficits associated with a malfunctioning of visual-associative areas. The neurofunctional model of this condition remains poorly understood due to the lack of a clear correlation between cognitive-visual deficit and morphological brain anomalies. The aim of our study was to quantify the pattern of white matter abnormalities within the whole brain in children with cerebral palsy, and to identify white matter tracts sub-serving cognitive-visual functions, in order to better understand the basis of cognitive-visual processing. Nine subjects (three males, mean age 8 years 9 months) with cerebral palsy underwent a visual and cognitive-visual evaluation. Conventional brain MRI and diffusion tensor imaging were performed. The fractional anisotropy maps were calculated for every child and compared with data from 13 (four males, mean age 10 years 7 months) healthy children. Children with cerebral palsy showed decreased fractional anisotropy (a marker of white matter integrity) in corticospinal tract bilaterally, left superior longitudinal fasciculus and bilateral hippocampus. Focusing on the superior longitudinal fasciculus, the mean fractional anisotropy values were significantly lower in children affected by cerebral palsy with cognitive-visual deficits than in those without cognitive-visual deficits. Our findings reveal an association between cognitive-visual profile and the superior longitudinal fasciculus integrity in children with cerebral palsy, supporting the hypothesis that visuo-associative deficits are related to changes in fibers connecting the occipital cortex with the parietal-frontal cortices. Decreased fractional anisotropy within the superior longitudinal fasciculus could be considered a biomarker for cognitive-visual dysfunctions.
Lammer J, Karst SG, Lin MM, Cheney M, Silva PS, Burns SA, Aiello LP, Sun JK. Association of Microaneurysms on Adaptive Optics Scanning Laser Ophthalmoscopy With Surrounding Neuroretinal Pathology and Visual Function in Diabetes. Invest Ophthalmol Vis Sci 2018;59(13):5633-5640.Abstract
Purpose: We evaluate diabetic microaneurysm (MA) features on high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and their correlations with visual acuity (VA) and local retinal pathology on spectral domain optical coherence tomography (SDOCT). Methods: Diabetic participants underwent VA testing and AOSLO and SDOCT imaging of MAs. AOSLO images were graded for MA dimension, wall hyperreflectivity (WH), intraluminal hyperreflectivity (IH), and perfusion pattern. SDOCTs centered on each MA were graded for disorganization of the retinal inner layers (DRIL) and other neuroretinal pathology. Results: We imaged 109 MAs (30 eyes). Multivariate modeling, including statistically significant covariates from bivariate analyses, associated WH with greater MA size (P = 0.001) and DRIL (P = 0.04). IH was associated with perfusion (P = 0.003) and MA visibility on photographs (P = 0.0001), and larger MA size with partial perfusion (P = 0.03), MA ring signs (P = 0.0002), and photographic visibility (P = 0.01). Multivariate modeling revealed an association of WH and VA with DRIL. Conclusions: AOSLO imaging demonstrates associations of hyperreflective MA walls with MA size and adjacent DRIL, as well as the presence of DRIL with lower VA. This study identifies a correlation between vascular and neural pathology associated with VA decline. Further studies of MA structure and neuroretinal disorganization may enable novel approaches to assess anatomic and functional outcomes in the diabetic eye.
Hark LA, Myers JS, Rahmatnejad K, Wang Q, Zhan T, Hegarty SE, Leiby BE, Udyaver S, Waisbourd M, Leite S, Henderer JD, Pasquale LR, Lee PP, Haller JA, Katz JL. Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Analysis of Unreadable Fundus Images. J Glaucoma 2018;27(11):999-1008.Abstract
PURPOSE: The purpose of this study was to ascertain determinants of unreadable fundus images for participants enrolled in the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study. METHODS: Individuals were screened for glaucoma at 7 primary care practices and 4 Federally Qualified Health Centers using telemedicine. Screening (visit 1) included fundus photography, assessing family history of glaucoma, and intraocular pressure (IOP) measurements. Participants with an unreadable image in at least one eye were deemed unreadable and invited to return for a confirmatory eye examination (visit 2). RESULTS: A total of 906 participants completed the visit 1 eye screening and 17.1% (n=155/906) were "unreadable." In the multivariable logistic regression analysis, older age, male sex, smoking, and worse visual acuity were significantly associated with an unreadable fundus image finding at the eye screening (P<0.05). Of the 89 participants who were invited for the confirmatory eye examination solely for unreadable images and attended visit 2, 58 (65.2%) were diagnosed with at least one ocular pathology. The most frequent diagnoses were cataracts (n=71; 15 visually significant, 56 nonvisually significant), glaucoma suspects (n=27), and anatomical narrow angle (n=10). CONCLUSIONS: Understanding the causes of unreadable fundus images will foster improvements in telemedicine techniques to optimize the predictive accuracy, efficiency, and cost in ophthalmology. A high proportion of participants with unreadable images (65.2%) in our study were diagnosed with some ocular pathology, indicating that the finding of an unreadable fundus image warrants a referral for a comprehensive follow-up eye examination.
de Boer IH, Zelnick LR, Lin J, Schaumberg D, Wang L, Ruzinski J, Friedenberg G, Duszlak J, Bubes VY, Hoofnagle AN, Thadhani R, Glynn RJ, Buring JE, Sesso HD, Manson JAE. Vitamin D and omega-3 trial to prevent and treat diabetic kidney disease: Rationale, design, and baseline characteristics. Contemp Clin Trials 2018;74:11-17.Abstract
Diabetic kidney disease (DKD), defined as reduced glomerular filtration rate (GFR), elevated urine albumin excretion, or both that is clinically attributable to diabetes, is a common and morbid diabetes complication. Animal-experimental data, observational human studies, and short-term clinical trials suggest that vitamin D and omega-3 fatty acid supplements may be safe and inexpensive interventions to reduce the incidence and progression of DKD. The Vitamin D and Omega-3 Trial to Prevent and Treat DKD (VITAL-DKD) was designed as an ancillary study to the VITAL trial of 25,871 US adults. In a 2 × 2 factorial design, VITAL participants were randomly assigned to vitamin D (cholecalciferol, 2000 IU daily) or placebo and to marine omega-3 fatty acids (eicospentaenoic acid and docosahexaenoic acid, 1 g/d) or placebo. VITAL-DKD enrolled a subset of 1326 VITAL participants with type 2 diabetes at baseline to test the effects of vitamin D and omega-3 fatty acids on changes in estimated GFR and urine albumin excretion. Over five years of follow-up, VITAL-DKD collected blood and urine samples to quantify changes in estimated GFR (the primary study outcome) and urine albumin excretion. At baseline, mean age of VITAL-DKD participants was 67.6 years, 46% were women, 30% were of racial or ethnic minority, and the prevalence of DKD (estimated GFR <60 mL/min/1.73m or urine albumin-creatinine ratio ≥ 30 mg/g) was 17%. In this type 2 diabetes population, VITAL-DKD will test the hypotheses that vitamin D and omega-3 fatty acids help prevent the development and progression of DKD.
Tatematsu Y, Khan Q, Blanco T, Bair JA, Hodges RR, Masli S, Dartt DA. Thrombospondin-1 Is Necessary for the Development and Repair of Corneal Nerves. Int J Mol Sci 2018;19(10)Abstract
Thrombospondin-1-deficient (TSP-1) mice are used as an animal model of Sjögren's Syndrome because they exhibit many of the symptoms associated with the autoimmune type of dry eye found in primary Sjögren's Syndrome. This type of dry eye is linked to the inflammation of the lacrimal gland, conjunctiva, and cornea, and is thought to involve dysfunction of the complex neuronal reflex arc that mediates tear production in response to noxious stimuli on the ocular surface. This study characterizes the structural and functional changes to the corneal nerves that are the afferent arm of this arc in young and older TSP-1 and wild type (WT) mice. The structure and subtype of nerves were characterized by immunohistochemistry, in vivo confocal microscopy, and confocal microscopy. Cytokine expression analysis was determined by Q-PCR and the number of monocytes was measured by immunohistochemistry. We found that only the pro-inflammatory cytokine MIP-2 increased in young corneas of TSP-1 compared to WT mice, but tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) all increased in older TSP-1 mouse corneas. In contrast, CD11b+ pro-inflammatory monocytes did not increase even in older mouse corneas. Calcitonin gene-related peptide (CGRP)-, but not Substance P (SubP)-containing corneal nerves decreased in older, but not younger TSP-1 compared to WT mouse corneas. We conclude that CGRP-containing corneal sensory nerves exhibit distinct structural deficiencies as disease progresses in TSP-1 mice, suggesting that: (1) TSP-1 is needed for the development or repair of these nerves and (2) impaired afferent corneal nerve structure and hence function may contribute to ocular surface dysfunction that develops as TSP-1 mice age.
Grant EP, Im K, Ahtam B, Laurentys CT, Chan W-M, Brainard M, Chew S, Drottar M, Robson CD, Drmic I, Engle EC. Altered White Matter Organization in the TUBB3 E410K Syndrome. Cereb Cortex 2018;Abstract
Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.