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Cherfan DG, Melki SA. Corneal perforation by an astigmatic keratotomy performed with an optical coherence tomography-guided femtosecond laser. J Cataract Refract Surg 2014;40(7):1224-7.Abstract

UNLABELLED: We present a case of corneal perforation secondary to an intrastromal astigmatic keratotomy performed with an optical coherence tomography-guided femtosecond laser. The keratotomy was concomitant with cataract surgery and resulted in a flat anterior chamber prior to the start of lens extraction. Interrupted nylon sutures were placed to seal the keratotomy prior to phacoemulsification. Escape of cavitation bubbles into the anterior chamber or the liquid interface can alert the surgeon to the possibility of unintended perforation of the endothelium or the epithelium, respectively. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.

Chi M, Kim JH, Basham R, Yoon MK, Vagefi R, Kersten RC. Temporal Artery Calciphylaxis Presenting as Temporal Arteritis in a Case of Rhinoorbitocerebral Mucormycosis. Ophthal Plast Reconstr Surg 2015;31(5):e132-5.Abstract

Mucormycosis is a rare often fatal opportunistic fungal infection. It is typically described in patients with diabetes in ketoacidotic status and is rare in renal transplant recipients. Calciphylaxis is a rare and highly morbid disease of vascular calcification affecting patients with end-stage renal disease (ESRD). The first case of a renal transplant recipient who was inflicted with both rhinoorbitocerebral mucormycosis and calciphylaxis is reported. A 45-year-old man presented with 2-day history of left upper blepharoptosis, periorbital pain, left-sided headache, binocular diplopia, and left V2 numbness. He had undergone renal transplant for ESRD 7 months earlier with resultant immunosuppressive therapy. MRI and nasal biopsy confirmed rhinoorbitocerebral mucormycosis. Immunosuppressive therapy was stopped and antifungal therapy begun. He had orbital exenteration for progressive rhinoorbitocerebral mucormycosis. Two months later, the patient reported new-onset intermittent bitemporal headache and bilateral swollen, tender temporal arteries. Temporal artery biopsy revealed features consistent with calciphylaxis. Clinical presentation, treatment course, and follow up are discussed.

Chintalapudi SR, Maria D, Di Wang X, Bailey JCN, Bailey JCN, Bailey JCN, Hysi PG, Wiggs JL, Williams RW, Jablonski MM. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. Nat Commun 2017;8(1):1755.Abstract
Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.
Cho H, Pillai P, Nicholson L, Sobrin L. Inflammatory Papillitis in Uveitis: Response to Treatment and Use of Optic Nerve Optical Coherence Tomography for Monitoring. Ocul Immunol Inflamm 2016;24(2):194-206.Abstract

PURPOSE: To describe the clinical course of uveitis-associated inflammatory papillitis and evaluate the utility and reproducibility of optic nerve spectral domain optical coherence tomography (SD-OCT). METHODS: Data on 22 eyes of 14 patients with uveitis-related papillitis and optic nerve imaging were reviewed. SD-OCT measure reproducibility was determined and parameters were compared in active vs. inactive uveitis. RESULTS: Papillitis resolution lagged behind uveitis resolution in three patients. For SD-OCT measures, the intraclass correlation coefficients were 99.1-100% and 86.9-100% for intraobserver and interobserver reproducibility, respectively. All SD-OCT optic nerve measures except inferior and nasal peripapillary retinal thicknesses were significantly higher in active vs. inactive uveitis after correction for multiple hypotheses testing. Mean optic nerve central thickness decreased from 545.1 to 362.9 µm (p = 0.01). CONCLUSIONS: Resolution of inflammatory papillitis can lag behind resolution of uveitis. SD-OCT assessment of papillitis is reproducible and correlates with presence vs. resolution of uveitis.

Cho H, Shin YU, Siegel NH, Yu HG, Sobrin L, Patel A, Durand ML, Miller JW, Husain D. Endogenous Endophthalmitis in the American and Korean Population: An 8-year Retrospective Study. Ocul Immunol Inflamm 2016;:1-8.Abstract

PURPOSE: To study the clinical features of endogenous endophthalmitis (EE) in sample patient populations from the USA and South Korea over an 8-year period. METHODS: We reviewed data from 128 eyes of 60 American and 48 Korean patients diagnosed with EE and compared their clinical characteristics. RESULTS: Fungemia and liver abscess were the most common extraocular infection sources among American (26.7%) and Korean patients (33.3%), respectively. Klebsiella pneumoniae and Candida species were the most common pathogens of EE in the Korean and the American patients, respectively. Endophthalmitis caused by fungi had a better visual prognosis than that caused by bacteria (p = 0.001). Vitrectomy was beneficial for eyes with EE due to virulent bacteria presenting with worse than counting finger vision. CONCLUSIONS: The predisposing conditions and responsible organisms for EE vary in different regions of the world. The visual prognosis was strongly influenced by the underlying pathogen.

Choi CJ, Stagner AM, Freitag SK, Jakobiec FA, Lee NG. Atypical location of primary orbital conjunctival epithelial cysts: a case series. Clin Experiment Ophthalmol 2016;44(6):524-6.
Choi CJ, Jakobiec FA, Zakka FR, Foster SC, Chodosh J, Freitag SK. Conjunctival Squamous Cell Neoplasia Associated With Ocular Cicatricial Pemphigoid. Ophthal Plast Reconstr Surg 2017;33(6):e157-e160.Abstract
The purpose of this study was to describe a possible causal relationship between ocular cicatricial pemphigoid (OCP) and ocular surface squamous neoplasia. Two middle-aged female patients with already diagnosed OCP were studied in regard to the subsequent onset of conjunctival squamous neoplasia. Their clinical histories, ocular examinations, clinical photographs, and results of biopsies and any ancillary immunofluorescent laboratory evaluation studies were carefully reviewed. One patient had a preinvasive squamous dysplasia and the other an invasive squamous cell carcinoma, both in the unequivocal setting of OCP with bilateral conjunctivitis, symblephara, and forniceal foreshortening. The patients had been receiving intensive immunotherapy consisting of some combination of corticosteroids, rituximab, and interferon alpha. Both patients had a positive immunofluorescent study demonstrating immunoreactants at the level of the epithelial basement membrane. Each patient had 2 earlier negative immunofluorescent studies before a third was positive. While rare, there is 1 previous report of an association between OCP and conjunctival squamous neoplasia. The current report provides more data supporting the proposal that this conjunction is more than a random event. Repeat immunofluorescent studies after an initial negative result in a patient with strong clinical signs of OCP are imperative due to the frequency of false negative studies in the context of clinically persuasive disease.
Choi CJ, Stagner AM, Jakobiec FA, Chodosh J, Yoon MK. Eyelid Mass in Boston Keratoprosthesis Type 2. Ophthal Plast Reconstr Surg 2016;Abstract

Boston keratoprosthesis type 2 is used to treat severe corneal blindness secondary to cicatricial or autoimmune ocular surface disease. This case report describes an atypical eyelid mass in a 41-year-old woman with Stevens-Johnson syndrome who underwent placement of Boston keratoprosthesis type 2 in the left eye. The postoperative course was complicated by methicillin-sensitive Staphylococcus aureus keratitis and endophthalmitis requiring replacement of the keratoprosthesis. Three months thereafter, the patient presented with a progressively enlarging upper eyelid mass adjacent to the keratoprosthesis optic causing distortion of the eyelid. Excisional biopsy revealed an elongated cystic mass abutting the superior aspect of the optic. Pathologic examination was consistent with a conjunctival cyst with lipogranulomatous reaction. Removal of eyelid margins and conjunctiva, and placement of a full-thickness blepharotomy are standard steps in placement of Boston keratoprosthesis type 2, which can lead to conjunctival cysts and lipogranulomas that present as eyelid masses.

Choi CJ, Stagner AM, Jakobiec FA, Lee NG. Nonlimbal Squamous Cell Carcinoma of the Conjunctiva. Ophthalmology 2016;123(2):254.
Choi CJ, Peggy Chang H-Y, Lee NG. An Unusual Corneal Degeneration. JAMA Ophthalmol 2017;135(6):667-668.
Choi CJ, Chou JC, Lefebvre DR, Yoon MK. Margin Reflex Distance: Differences Based on Camera and Flash Positions. Ophthal Plast Reconstr Surg 2016;32(3):199-203.Abstract

PURPOSE: To evaluate the effect of camera flash position on the measurement of photographic margin reflex distances (MRD). METHODS: Subjects without any ophthalmic disease were prospectively enrolled after institutional review board approval. Clinical measurements of MRD1 and interpalpebral fissure were obtained. Photographs were then taken with a digital single lens reflex with built-in pop-up flash (dSLR-pop), a dSLR with lens-mounted ring flash (dSLR-ring), a point-and-shoot camera, and a smartphone, each in 4 positions: with the camera upright, rotated 90°, 180°, and 270°. The images were analyzed using ImageJ software to measure MRD1, interpalpebral fissure, horizontal white-to-white, and distance from nasal limbus to the corneal light reflex. RESULTS: Thirty-two eyes of 16 subjects were included (ages 27-65). When using the dSLR-ring, point-and-shoot, and smartphone, the difference between clinical and photographic MRD1 did not reach statistical significance. There was, however, a statistically significant difference in the upright position with dSLR-pop (mean difference 0.703 mm, σ = 0.984 mm, p = 0.0008). For dSLR-pop, photographic MRD1 in upright versus inverted position differed significantly (mean difference -0.562 mm, σ =0.348 mm, p < 0.0001). Photographic MRD1 between dSLR-pop and dSLR-ring showed significant difference in upright position (mean difference -0.572 mm, σ = 0.701 mm, p = 0.0002). There were no statistically significant differences between clinical and photographic interpalpebral fissure, and among white-to-white and nasal limbus to light reflex measurements in any position in all 4 cameras. CONCLUSIONS: When using photographs for measurement of MRD1, cameras with a near-coaxial light source and aperture have values that are most similar to clinical measurements.

Choi CJ, Bauza A, Yoon MK, Sobel RK, Freitag SK. Full-Thickness Skin Graft as an Independent or Adjunctive Technique for Repair of Cicatricial Lower Eyelid Ectropion Secondary to Actinic Skin Changes. Ophthal Plast Reconstr Surg 2015;31(6):474-7.Abstract

PURPOSE: To retrospectively review and describe full-thickness skin graft repair of lower eyelid cicatricial ectropion secondary to actinic skin. METHODS: A retrospective, noncomparative chart review of all patients who underwent lower eyelid ectropion repair with placement of a full-thickness skin graft between June 2004 and March 2014 was conducted with IRB approval. The etiology of lower eyelid ectropion, demographics including age, gender, ethnicity, laterality, graft donor site, additional surgical procedures, graft viability, surgical success rate, complications, and clinical exam findings were summarized. RESULTS: Twenty-nine eyelids in 24 patients underwent skin grafting for repair of cicatricial ectropion secondary to actinic skin changes. Ninety six percent of patients were male and 96% were Caucasian. Donor sites for skin grafts included upper eyelid (9, 31%), supraclavicular skin (9, 31%), postauricular skin (7, 24%), inner brachial skin (2, 7%), axilla (1, 3.5%), and preauricular skin (1, 3.5%). Twenty-four of 29 eyelids in the series underwent 1 or more additional procedures at the time of full-thickness skin grafting, including lateral tarsal strip (9 eyelids, 37.5%), punctoplasty (8, 33%), canthoplasty (7, 29%), excision of keratinized conjunctiva (2, 8%), transverse tarsotomy (1, 4%), ipsilateral external dacryocystorhinostomy (3, 12.5%), and lesion removal (1, 4%). There was 100% viability of the skin grafts. Overall surgical success rate was 76%, with asymptomatic recurrence rate of 17% and symptomatic recurrence rate of 7%. CONCLUSION: Repair of cicatricial lower eyelid ectropion secondary to actinic skin changes may be accomplished with full-thickness skin grafting, and is often performed in conjunction with additional procedures to fully address anatomic abnormalities.

Choi CJ, Lefebvre DR, Yoon MK. Validation of the facial assessment by computer evaluation (FACE) program for software-aided eyelid measurements. Orbit 2016;35(3):117-20.Abstract

The aim of this article is to validate the accuracy of Facial Assessment by Computer Evaluation (FACE) program in eyelid measurements. Sixteen subjects between the ages of 27 and 65 were included with IRB approval. Clinical measurements of upper eyelid margin reflex distance (MRD1) and inter-palpebral fissure (IPF) were obtained. Photographs were then taken with a digital single lens reflex camera with built-in pop-up flash (dSLR-pop) and a dSLR with lens-mounted ring flash (dSLR-ring) with the cameras upright, rotated 90, 180, and 270 degrees. The images were analyzed using both the FACE and ImageJ software to measure MRD1 and IPF.Thirty-two eyes of sixteen subjects were included. Comparison of clinical measurement of MRD1 and IPF with FACE measurements of photos in upright position showed no statistically significant differences for dSLR-pop (MRD1: p = 0.0912, IPF: p = 0.334) and for dSLR-ring (MRD1: p = 0.105, IPF: p = 0.538). One-to-one comparison of MRD1 and IPF measurements in four positions obtained with FACE versus ImageJ for dSLR-pop showed moderate to substantial agreement for MRD1 (intraclass correlation coefficient = 0.534 upright, 0.731 in 90 degree rotation, 0.627 in 180 degree rotation, 0.477 in 270 degree rotation) and substantial to excellent agreement in IPF (ICC = 0.740, 0.859, 0.849, 0.805). In photos taken with dSLR-ring, there was excellent agreement of all MRD1 (ICC = 0.916, 0.932, 0.845, 0.812) and IPF (ICC = 0.937, 0.938, 0.917, 0.888) values. The FACE program is a valid method for measuring margin reflex distance and inter-palpebral fissure.

Choi CJ, Jakobiec FA, Zakka FR, Sanchez AV, Lee NG. Ocular Surface Squamous Neoplasia in a Patient With Hepatitis C. JAMA Ophthalmol 2017;135(10):1121-1123.
Choi CJ, Oropesa S, Callahan AB, Glass LR, Teo L, Cestari DM, Kazim M, Freitag SK. Patterns of visual field changes in thyroid eye disease. Orbit 2017;36(4):201-207.Abstract
This article provides a systematic description of visual field changes in thyroid eye disease-compressive optic neuropathy (TED-CON). A retrospective, non-comparative chart review of patients with TED-CON and documented Humphrey Visual Field 24-2 or 30-2 testing was conducted with IRB approval. Ninety-six visual fields in 68 patients were classified into 7 broad categories (superior, inferior, diffuse, temporal, nasal, central/paracentral, enlarged blind spot) and 17 mutually exclusive patterns from the Ocular Hypertension Treatment Study (OHTS) or "other." Fifty-three of 96 visual fields (55%) showed an inferior defect using the broad categories, with the remaining 6 categories ranging from 2% to 14%. The five most common OHTS patterns were other (28%), partial arcuate (28%), partial peripheral rim (9%), arcuate (8%) and altitudinal (7%). Further sub-classification showed a predominance of inferior visual field defects, ranging from 33% to 93% of each category. Of the 78 visual fields in these five categories combined, 52 (67%) were inferior defects. Inferior defect is the most typical TED-CON-associated visual field change. While the OHTS categories are geared toward classification of glaucomatous patterns, the overall predominance of inferior field defects in TED-CON was clearly demonstrated. These "other" visual field changes showing central inferior defect up to but not crossing the horizontal meridian and not contiguous from blind spot to nasal meridian should be designated as "TED-CON pattern." The high proportion of visual fields falling under the "other" category, however, does demonstrate the need for a more specific and tailored visual field classification system for TED-CON.
Choi W, Byun YJ, Jung E, Noh H, Hajrasouliha AR, Sadrai Z, Chang EJ, Lee JH, Lee HK. Chemokine decoy receptor D6 mimicking trap (D6MT) prevents allosensitization and immune rejection in murine corneal allograft model. J Leukoc Biol 2015;97(2):413-24.Abstract

Although corneal allotransplantation is performed in the immune-privileged cornea, many grafts are still rejected after transplantation. This study examined the role of chemokine receptor D6 expression in a corneal allograft rejection, investigated the modulation of D6 expression in cells, and determined the effect of D6 on graft survival. Interestingly, D6 was highly expressed in CD45 -: cells and the corneal epithelium of accepted corneal allografts. From the mouse corneal allograft model, TGF-β was found to play a key role in D6 up-regulation, leading to reduced CCL2, CCL5, and CCL3. To modulate D6 chemokine binding, a D6MT was developed and showed effective chemokine trapping through SPR and FACS assays. By treating corneal allografts with D6MT, the allograft survival rate was improved, and (lymph) angiogenesis was reduced. Direct allosensitization and DC LN homing was drastically reduced in the mouse corneal allograft model. These findings suggest that TGF-β is a positive regulator of D6 expression, and it is a potential therapeutic target to enhance the survival of corneal allografts.

Choi HJ, Wang R, Jakobs TC. Single-Cell Dissociation and Characterization in the Murine Retina and Optic Nerve. Methods Mol Biol 2018;1695:311-334.Abstract
Recent technological advances have extended the range of analytic tools to very small samples. It is now possible to assay the transcriptome, and in some cases even the proteome, of single cells reliably. This allows addressing novel questions, such as the genotype/phenotype relationships of single neurons, heterogeneity within individual cells of the same type, or the basis of differential vulnerability to injury. An important prerequisite for these kinds of studies is the ability to isolate well-defined individual cells without contamination by adjacent tissue. In the retina and optic nerve, cells of different types and functions are closely intermingled, limiting the use of standard methods such as laser capture microdissection. Here, we describe a simple method to isolate morphologically intact cells from the retina and the optic nerve and discuss considerations in recognizing and isolating different cell types after dissociation.
Choi VW, Bigelow CE, McGee TL, Gujar AN, Li H, Hanks SM, Vrouvlianis J, Maker M, Leehy B, Zhang Y, Aranda J, Bounoutas G, Demirs JT, Yang J, Ornberg R, Wang Y, Martin W, Stout KR, Argentieri G, Grosenstein P, Diaz D, Turner O, Jaffee BD, Police SR, Dryja TP. AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice. Mol Ther Methods Clin Dev 2015;2:15022.Abstract

Recessive mutations in RLBP1 cause a form of retinitis pigmentosa in which the retina, before its degeneration leads to blindness, abnormally slowly recovers sensitivity after exposure to light. To develop a potential gene therapy for this condition, we tested multiple recombinant adeno-associated vectors (rAAVs) composed of different promoters, capsid serotypes, and genome conformations. We generated rAAVs in which sequences from the promoters of the human RLBP1, RPE65, or BEST1 genes drove the expression of a reporter gene (green fluorescent protein). A promoter derived from the RLBP1 gene mediated expression in the retinal pigment epithelium and Müller cells (the intended target cell types) at qualitatively higher levels than in other retinal cell types in wild-type mice and monkeys. With this promoter upstream of the coding sequence of the human RLBP1 gene, we compared the potencies of vectors with an AAV2 versus an AAV8 capsid in transducing mouse retinas, and we compared vectors with a self-complementary versus a single-stranded genome. The optimal vector (scAAV8-pRLBP1-hRLBP1) had serotype 8 capsid and a self-complementary genome. Subretinal injection of scAAV8-pRLBP1-hRLBP1 in Rlbp1 nullizygous mice improved the rate of dark adaptation based on scotopic (rod-plus-cone) and photopic (cone) electroretinograms (ERGs). The effect was still present after 1 year.

Choi HJ, Sun D, Jakobs TC. Astrocytes in the optic nerve head express putative mechanosensitive channels. Mol Vis 2015;21:749-66.Abstract

PURPOSE: To establish whether optic nerve head astrocytes express candidate molecules to sense tissue stretch. METHODS: We used conventional PCR, quantitative PCR, and single-cell reverse transcription PCR (RT-PCR) to assess the expression of various members of the transient receptor potential (TRP) channel family and of the recently characterized mechanosensitive channels Piezo1 and 2 in optic nerve head tissue and in single, isolated astrocytes. RESULTS: Most TRP subfamilies (TRPC, TRPM, TRPV, TRPA, and TRPP) and Piezo1 and 2 were expressed in the optic nerve head of the mouse. Quantitative real-time PCR analysis showed that TRPC1, TRPM7, TRPV2, TRPP2, and Piezo1 are the dominant isoforms in each subfamily. Single-cell RT-PCR revealed that many TRP isoforms, TRPC1-2, TRPC6, TRPV2, TRPV4, TRPM2, TRPM4, TRPM6-7, TRPP1-2, and Piezo1-2, are expressed in astrocytes of the optic nerve head, and that most astrocytes express TRPC1 and TRPP1-2. Comparisons of the TRPP and Piezo expression levels between different tissue regions showed that Piezo2 expression was higher in the optic nerve head and the optic nerve proper than in the brain and the corpus callosum. TRPP2 also showed higher expression in the optic nerve head. CONCLUSIONS: Astrocytes in the optic nerve head express multiple putative mechanosensitive channels, in particular the recently identified channels Piezo1 and 2. The expression of putative mechanosensitive channels in these cells may contribute to their responsiveness to traumatic or glaucomatous injury.

Choi CJ, Stagner AM, Jakobiec FA, Lee NG. Limbal Mantle Cell Lymphoma of the Conjunctiva. Ophthalmology 2016;123(2):377.

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