Publications

2019

Jonas R, Ung L, Rajaiya J, Chodosh J. Mystery Eye: Human Adenovirus and the Enigma of Epidemic Keratoconjunctivitis. Prog Retin Eye Res. 2019;:100826.
Known to occur in widespread outbreaks, epidemic keratoconjunctivitis (EKC) is a severe ocular surface infection with a strong historical association with human adenovirus (HAdV). While the conjunctival manifestations can vary from mild follicular conjunctivitis to hyper-acute, exudative conjunctivitis with formation of conjunctival membranes, EKC is distinct as the only form of adenovirus conjunctivitis in which the cornea is also involved, likely due to specific corneal epithelial tropism of its causative viral agents. The initial development of a punctate or geographic epithelial keratitis may herald the later formation of stromal keratitis, and manifest as subepithelial infiltrates which often persist or recur for months to years after the acute infection has resolved. The chronic keratitis in EKC is associated with foreign body sensation, photophobia, glare, and reduced vision. However, over a century since the first clinical descriptions of EKC, and over 60 years since the first causative agent, human adenovirus type 8, was identified, our understanding of this disorder remains limited. This is underscored by a current lack of effective diagnostic tools and treatments. In part, stasis in our knowledge base has been encouraged by the continued acceptance, and indeed propagation of, inaccurate paradigms pertaining to disease etiology and pathogenesis, particularly with regard to mechanisms of innate and adaptive immunity within the cornea. Owing to its often persistent and medically refractory visual sequelae, reconsideration of key aspects of EKC disease biology is warranted to identify new treatment targets to curb its worldwide socioeconomic burden.
Brydon E, Bronstein R, Buskin A, Lako M, Pierce E, Fernandez-Godino R. AAV-Mediated Gene Augmentation Therapy Restores Critical Functions in Mutant PRPF31 iPSC-Derived RPE Cells. Mol Ther Methods Clin Dev. 2019;15:392–402.
Retinitis pigmentosa (RP) is the most common form of inherited vision loss and is characterized by degeneration of retinal photoreceptor cells and the retinal pigment epithelium (RPE). Mutations in pre-mRNA processing factor 31 () cause dominant RP via haploinsufficiency with incomplete penetrance. There is good evidence that the diverse severity of this disease is a result of differing levels of expression of the wild-type allele among patients. Thus, we hypothesize that -related RP will be amenable to treatment by adeno-associated virus (AAV)-mediated gene augmentation therapy. To test this hypothesis, we used induced pluripotent stem cells (iPSCs) with mutations in and differentiated them into RPE cells. The mutant iPSC-RPE cells recapitulate the cellular phenotype associated with the PRPF31 pathology, including defective cell structure, diminished phagocytic function, defects in ciliogenesis, and compromised barrier function. Treatment of the mutant iPSC-RPE cells with AAV- restored normal phagocytosis and cilia formation, and it partially restored structure and barrier function. These results suggest that AAV-based gene therapy targeting RPE cells holds therapeutic promise for patients with -related RP.
Ung L, Bispo P, Bryan N, Andre C, Chodosh J, Gilmore M. The Best of All Worlds: Conjunctivitis through the Lens of Community Ecology and Microbial Biogeography. Microorganisms. 2019;8(1).
The study of the forces which govern the geographical distributions of life is known as biogeography, a subject which has fascinated zoologists, botanists and ecologists for centuries. Advances in our understanding of community ecology and biogeography-supported by rapid improvements in next generation sequencing technology-have now made it possible to identify and explain where and why life exists as it does, including within the microbial world. In this review, we highlight how a unified model of microbial biogeography, one which incorporates the classic ecological principles of selection, diversification, dispersion and ecological drift, can be used to explain community dynamics in the settings of both health and disease. These concepts operate on a multiplicity of temporal and spatial scales, and together form a powerful lens through which to study microbial population structures even at the finest anatomical resolutions. When applied specifically to curious strains of conjunctivitis-causing, nonencapsulated , we show how this conceptual framework can be used to explain the possible evolutionary and disease-causing mechanisms which allowed these lineages to colonize and invade a separate biogeography. An intimate knowledge of this radical bifurcation in phylogeny, still the only known niche subspecialization for to date, is critical to understanding the pathogenesis of ocular surface infections, nature of host-pathogen interactions, and developing strategies to curb disease transmission.
Reshef E, Habib L, Rao R, Modjtahedi B, Eliott D, Freitag S, Reinshagen K, Lee N. Clinical and radiographic features of hydrolyzed MIRAgel scleral buckles: A comparative analysis. Clin Imaging. 2019;60(1):10–15.
The MIRAgel (hydrogel) scleral buckle, introduced in the 1980s, was a novel material to repair retinal detachments. It was later discontinued due to the frequency of long-term complications related to buckle hydrolysis and expansion. These complications included pain, limited extraocular motility, and more serious complications such as infection or scleral perforation, which ultimately necessitated surgical extraction as late as 20-30 years after placement. Prompt and proper diagnosis and treatment is often delayed as these buckle-associated complications frequently mimic other orbital pathologies such as tumors or infections. The hydrolyzed MIRAgel buckle exhibits distinct radiographic features that are helpful in arriving at the correct diagnosis, particularly in cases of ambiguous clinical presentation or history. Here, we expand on the previously described radiographic features of hydrolyzed MIRAgel and compare them to features of common, mimicking orbital pathology.
Elhusseiny A, Huynh E, Dagi L. Evaluation and Management of V pattern Strabismus in Craniosynostosis. J Binocul Vis Ocul Motil. 2019;:1–6.
V pattern strabismus is the most common ocular motor disorder reported in patients with craniosynostosis. Strabismus management may prove challenging, and few studies provide perspective on surgical approach. The purpose of this review is to discuss evaluation and surgical options for treating V pattern strabismus in patients with craniosynostosis. We provide a step-by-step approach to facilitate surgical planning.
Gaier E, Heidary G. Pediatric Idiopathic Intracranial Hypertension. Semin Neurol. 2019;39(6):704–710.
The presentation of idiopathic intracranial hypertension (IIH) in pediatric populations has several important distinctions from that in adults, especially among prepubertal patients, in which there is no apparent association with gender or obesity. Pediatric patients are more likely to be asymptomatic or present with atypical symptoms than their adult counterparts, posing a diagnostic challenge in some cases. It is important to be aware of the ways in which diagnostic criteria for IIH are modified from that of adults. Ideal treatment practices and the natural history of pediatric IIH remain unclear. Acetazolamide is the mainstay of medical treatment, but some patients with significant visual loss may require surgical intervention. Multicenter studies to accrue a large number of cases and future prospective studies will help to better define pediatric IIH and to formulate consensus guidelines for treatment and management of these patients.
Bakaeva T, Mallery R, Prasad S. Emerging Treatments for Leber’s Hereditary Optic Neuropathy and Other Genetic Causes of Visual Loss. Semin Neurol. 2019;39(6):732–738.
Leber's hereditary optic neuropathy (LHON) and other genetic causes of visual loss are important clinical entities that can cause profound visual loss. To date, therapeutic options have been quite limited, but insights into the genetic basis of these diseases and advances in the ability to deliver effective and safe gene therapy have opened the door for new therapeutics that may revolutionize the approach to treating these conditions. This article reviews emerging gene therapies of LHON and other inherited ophthalmological diseases, addressing the technical, clinical, and ethical challenges that researchers and clinicians will encounter as new treatments become available for these conditions.
Espinosa-Medina I, Garcia-Marques J, Cepko C, Lee T. High-throughput dense reconstruction of cell lineages. Open Biol. 2019;9(12):190229.
The first meeting exclusively dedicated to the 'High-throughput dense reconstruction of cell lineages' took place at Janelia Research Campus (Howard Hughes Medical Institute) from 14 to 18 April 2019. Organized by Tzumin Lee, Connie Cepko, Jorge Garcia-Marques and Isabel Espinosa-Medina, this meeting echoed the recent eruption of new tools that allow the reconstruction of lineages based on the phylogenetic analysis of DNA mutations induced during development. Combined with single-cell RNA sequencing, these tools promise to solve the lineage of complex model organisms at single-cell resolution. Here, we compile the conference consensus on the technological and computational challenges emerging from the use of the new strategies, as well as potential solutions.
Pistilli M, Joffe M, Gangaputra S, Pujari S, Jabs D, Levy-Clarke G, Nussenblatt R, Rosenbaum J, Sen N, Suhler E, Thorne J, Bhatt N, Foster S, Begum H, Fitzgerald T, Dreger K, Altaweel M, Holbrook J, Kempen J, Group SITED (SITE) R. Visual Acuity Outcome over Time in Non-Infectious Uveitis. Ocul Immunol Inflamm. 2019;:1–8.
: We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population.: Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up.: Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels.: Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA.