Habib LA, Wolkow N, Freitag SK, Yoon MK. Advances in Immunotherapy and Periocular Malignancy. Semin Ophthalmol 2019;:1-7.Abstract
Immunotherapy has significantly advanced the field of oncology in recent decades. Understanding normal immunosurveillance, as well as the ways in which tumor cells have evolved to evade it, has provided the knowledge for development of drugs that allow one's own immune system to target and destroy malignant cells (immunotherapy). Cutaneous malignancies are particularly sensitive to this class of drugs. In a very sensitive anatomic region such as the periocular tissue, where surgical excision may come with significant morbidity, this technology has had a strong impact in the successful treatment of historically challenging tumors.
Frints SGM, Hennig F, Colombo R, Jacquemont S, Terhal P, Zimmerman HH, Hunt D, Mendelsohn BA, Kordaß U, Webster R, Sinnema M, Abdul-Rahman O, Suckow V, Fernández-Jaén A, van Roozendaal K, Stevens SJC, Macville MVE, Al-Nasiry S, van Gassen K, Utzig N, Koudijs SM, McGregor L, Maas SM, Baralle D, Dixit A, Wieacker P, Lee M, Lee AS, Engle EC, Houge G, Gradek GA, Douglas AGL, Longman C, Joss S, Velasco D, Hennekam RC, Hirata H, Kalscheuer VM. Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita. Hum Mutat 2019;40(12):2270-2285.Abstract
Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.
Charles NC, Jakobiec FA, Ma L, Belinsky I. Angiofibroma of the Eyelid: A Rare Clinical and Histologic Variant. Ophthalmic Plast Reconstr Surg 2019;35(4):e199-e102.Abstract
A flesh-colored, supraciliary lesion of the left upper eyelid in a 47-year-old man was excised for cosmetic reasons. Histopathology and immunohistochemistry demonstrated CD34-positive benign spindle cells, factor XIIIa-positive dendritic cells, and CD163-positive histiocytes, all dispersed within a diffuse collagenous background. Prominent loose perivascular cuffs of fibroblastic cells and collagen surrounded small blood vessels. Interpreted as an angiofibroma, the histopathology bore resemblance to that of a single previously-reported forearm lesion termed a "dermal fibroma with a distinctive perivascular cell arrangement." The lesion represents the first eyelid example of an unusual variant of angiofibroma.
Ung C, Miller JB. Intraoperative Optical Coherence Tomography in Vitreoretinal Surgery. Semin Ophthalmol 2019;:1-6.Abstract
Intraoperative OCT (OCT) is an emerging modality capable of displaying real-time OCT images to the surgeon during surgery. The use of iOCT during vitreoretinal surgery improves our understanding of the tissue alterations that occur during surgical manipulations, which may impact surgical decision-making. We review the current OCT modalities and clinical applications of OCT.
Liu C-H, Wang Z, Huang S, Sun Y, Chen J. MicroRNA-145 Regulates Pathological Retinal Angiogenesis by Suppression of TMOD3. Mol Ther Nucleic Acids 2019;16:335-347.Abstract
Pathological angiogenesis is a hallmark of various vascular diseases, including vascular eye disorders. Dysregulation of microRNAs (miRNAs), a group of small regulatory RNAs, has been implicated in the regulation of ocular neovascularization. This study investigated the specific role of microRNA-145 (miR-145) in regulating vascular endothelial cell (EC) function and pathological ocular angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). Expression of miR-145 was significantly upregulated in OIR mouse retinas compared with room air controls. Treatment with synthetic miR-145 inhibitors drastically decreased levels of pathological neovascularization in OIR, without substantially affecting normal developmental angiogenesis. In cultured human retinal ECs, treatment with miR-145 mimics significantly increased the EC angiogenic function, including proliferation, migration, and tubular formation, whereas miR-145 inhibitors attenuated in vitro angiogenesis. Tropomodulin3 (TMOD3), an actin-capping protein, is a direct miR-145 target and is downregulated in OIR retinas. Treatment with miR-145 mimic led to TMOD3 inhibition, altered actin cytoskeletal architecture, and elongation of ECs. Moreover, inhibition of TMOD3 promoted EC angiogenic function and pathological neovascularization in OIR and abolished the vascular effects of miR-145 inhibitors in vitro and in vivo. Overall, our findings indicate that miR-145 is a novel regulator of TMOD3-dependent cytoskeletal architecture and pathological angiogenesis and a potential target for development of treatments for neovascular eye disorders.
Gise R, Gaier ED, Heidary G. Diagnosis and Imaging of Optic Nerve Head Drusen. Semin Ophthalmol 2019;:1-8.Abstract
The presence of optic nerve swelling in pediatric patients is a frequent cause for referral to pediatric ophthalmologists and neuro-ophthalmologists because this finding can be the harbinger of serious neurologic disease including brain tumor, demyelinating disease, infiltrative disease of the optic nerve, or idiopathic intracranial hypertension. Optic nerve head drusen (ONHD) are common and can be particularly difficult to distinguish from true optic nerve swelling in pediatric patients because the ONHD are typically buried beneath the substance of the optic nerve. Correct identification of ONHD is relevant because of the visual morbidity associated with this condition and because of the need to distinguish pseudopapilledema secondary to ONHD from true optic nerve swelling. A variety of imaging modalities may be employed to evaluate for the presence of ONHD, including ultrasound, optical coherence tomography (OCT), enhanced depth imaging-OCT, fluorescein angiography, fundus autofluorescence, and optical coherence tomography angiography. To date, there is no consensus as to which of these techniques is most accurate and which should be part of a standardized evaluation for children suspected of ONHD. This review examines the recent literature analyzing these diagnostic tools and summarizes data regarding best practices for identifying ONHD.
Foulsham W, Dohlman TH, Mittal SK, Taketani Y, Singh RB, Masli S, Dana R. Thrombospondin-1 in ocular surface health and disease. Ocul Surf 2019;Abstract
Thrombospondin 1 (TSP-1) is an extracellular matrix protein that interacts with a wide array of ligands including cell receptors, growth factors, cytokines and proteases to regulate various physiological and pathological processes. Constitutively expressed by certain ocular surface tissues (e.g. corneal and conjunctival epithelium), TSP-1 expression is modulated during ocular surface inflammation. TSP-1 is an important activator of latent TGF-β, serving to promote the immunomodulatory and wound healing functions of TGF-β. Mounting research has deepened our understanding of how TSP-1 expression (and lack thereof) contributes to ocular surface homeostasis and disease. Here, we review current knowledge of the function of TSP-1 in dry eye disease, ocular allergy, angiogenesis/lymphangiogenesis, corneal transplantation, corneal wound healing and infectious keratitis.
Somsen D, Heidary G. Rapid onset of orbital cellulitis after uncomplicated strabismus surgery. J AAPOS 2019;Abstract
Orbital cellulitis is extremely uncommon following strabismus surgery. When it occurs, the infection has been reported to present from day 1 to within 1 week following surgery and has the potential for significant morbidity postoperatively. We report the case of a 6-year-old boy presenting with unilateral orbital cellulitis growing group A Streptococcus pyogenes on postoperative day 1, after uncomplicated bilateral medial rectus recessions. The patient had two contacts with streptococcal pharyngitis at the time of surgery but was completely asymptomatic himself. We hypothesize that these contacts may have led to the rapid onset of his orbital cellulitis.
Lambert SR, Aakalu VK, Hutchinson AK, Pineles SL, Galvin JA, Heidary G, Binenbaum G, VanderVeen DK. Intraocular Lens Implantation during Early Childhood: A Report by the American Academy of Ophthalmology. Ophthalmology 2019;126(10):1454-1461.Abstract
PURPOSE: To compare the visual outcomes and adverse events associated with optical correction using an intraocular lens (IOL), contact lenses, or spectacles after cataract surgery in children 2 years of age or younger. METHODS: Literature searches were conducted in PubMed, the Cochrane Library, and the databases of clinical trials in February 2019, without date or language restrictions. The search resulted in 194 potentially relevant citations, and 34 were selected for full-text review. Fourteen studies were determined to be relevant to the assessment criteria and were selected for inclusion in this assessment. The panel methodologist then assigned a level of evidence rating to these studies. RESULTS: Intraocular lenses were associated with visual outcomes similar to outcomes for contact lenses or spectacles for children who had both bilateral and unilateral cataracts. Intraocular lenses were also associated with an increased risk of visual axis opacities. All treatments were associated with a similar incidence of glaucoma. Although ocular growth was similar for all treatments, infants younger than 6 months who underwent IOL implantation had large myopic shifts that often resulted in high myopia or severe anisometropia later in childhood. Corneal endothelial cell counts were lower in eyes that underwent IOL implantation. The incidence of strabismus was similar with all treatments. CONCLUSIONS: Intraocular lens implantation is not recommended for children 6 months of age or younger because there is a higher incidence of visual axis opacities with this treatment compared with aphakia. The best available evidence suggests that IOL implantation can be done safely with acceptable side effects in children older than 6 months of age. However, the unpredictability of ocular growth means that these children will often have large refractive errors later in childhood that may necessitate an IOL exchange or wearing spectacles or contact lenses with a large refractive correction. In addition, the training and experience of the surgeon as well as ocular and systemic comorbidities should be taken into consideration when deciding whether IOL implantation would be appropriate.
Silva RNE, Shen LQ, Chiou CA, Shanbhag SS, Paschalis EI, Pasquale LR, Colby KA, Dohlman CH, Chodosh J, Alves MR. Glaucoma Management in Patients with Aniridia and Boston Type 1 Keratoprosthesis. Am J Ophthalmol 2019;Abstract
PURPOSE: To assess outcomes and glaucoma management in eyes with aniridia following Boston type 1 Keratoprosthesis (KPro) implantation. DESIGN: Retrospective, interventional comparative case series. METHODS: POPULATION: Patients with aniridia and patients with other preoperative diagnoses (excluding Stevens-Johnson syndrome, mucous membrane pemphigoid, and congenital disorders) who underwent KPro implantation at Massachusetts Eye and Ear with at least 2 years of follow-up. One eye per patient was selected based on the longer follow-up time. MAIN OUTCOME: Intermediate and long-term outcomes related to glaucoma. RESULTS: The aniridia (n=22) and comparison (n=61) groups had similar preoperative visual acuity (VA, mean ± standard deviation, 1.86±0.52 LogMAR, p=0.33) and follow-up time (65.6±26.3 months, p=0.25). Prior to KPro implantation, eyes with aniridia had more glaucoma (76.2%) and glaucoma surgery (57.1%) than comparison eyes (51.8%, p=0.053; 23.2%, p=0.005, respectively). More Ahmed valves were co-implanted with KPro in aniridia (47.6%) versus comparison eyes (17.9%, p=0.008). At final follow-up, more aniridia eyes had glaucoma (90.5%) than comparison eyes (64.3%, p=0.02), but the two groups had similar percentages of eyes with cup-to-disc ratio (CDR) >0.8 (23.8% vs. 30.4%, p=0.57) or CDR progression of ≥0.2 (42.9% vs. 44.6%, p=0.89, respectively). None of the eyes with prophylactic tube implantation developed glaucoma. Eyes with and without aniridia did not differ in post-KPro VA improvement (72.7%, 72.1%, p=0.96), and final VA (1.28±0.79 LogMAR, 1.23±0.98 LogMAR, p=0.51). CONCLUSION: Despite a higher glaucoma prevalence, eyes with aniridia achieved similar VA as comparison eyes with more than 5 years of mean follow-up time. Boston KPro offers satisfactory visual rehabilitation in aniridia when glaucoma is managed aggressively.
Werner AC, Shen LQ. A Review of OCT Angiography in Glaucoma. Semin Ophthalmol 2019;:1-8.Abstract
There is growing evidence that vascular dysfunction plays a role in the pathogenesis of glaucoma. The details of this relationship have remained elusive partially due to limitations in our ability to assess blood flow in the optic nerve. Optical coherence tomography angiography (OCTA) has emerged as a promising new technology well positioned to become the first clinically suitable test of optic nerve perfusion. OCTA uses the motion of red blood cells as an intrinsic contrast agent to create reproducible images of microvascular networks rapidly and non-invasively. A significant body of research regarding the use of OCTA in glaucoma has emerged in recent years. This review aims to provide an overview of the basic principles underlying OCTA technology, summarize the current literature regarding the application of OCTA in the management of glaucoma, and address the role of OCTA in explicating the vascular pathogenesis of glaucoma.
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, Tsai L-H. Single-cell transcriptomic analysis of Alzheimer's disease. Nature 2019;570(7761):332-337.Abstract
Alzheimer's disease is a pervasive neurodegenerative disorder, the molecular complexity of which remains poorly understood. Here, we analysed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimer's disease pathology. Across six major brain cell types, we identified transcriptionally distinct subpopulations, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, whereas genes upregulated at late stages were common across cell types and primarily involved in the global stress response. Notably, we found that female cells were overrepresented in disease-associated subpopulations, and that transcriptional responses were substantially different between sexes in several cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting that myelination has a key role in Alzheimer's disease pathophysiology. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimer's disease.