Chao W, Belmonte C, Benitez Del Castillo J, Bron A, Dua H, Nichols K, Novack G, Schrader S, Willcox M, Wolffsohn J, Sullivan DA. Report of the Inaugural Meeting of the TFOS i2 = initiating innovation Series: Targeting the Unmet Need for Dry Eye Treatment (London, United Kingdom, March 21, 2015). Ocul Surf 2016;Abstract

In March 2015, a meeting was held in London, United Kingdom, to address the progress in targeting the unmet need for dry eye disease (DED) treatment. The meeting, which launched the i(2) = initiating innovation series, was sponsored by the Tear Film & Ocular Surface Society (TFOS; and supported by Dompé. The TFOS i(2) meeting was designed to review advances in the understanding of DED since publication of the 2007 TFOS International Dry Eye WorkShop (DEWS) report, and to help launch the highly anticipated sequel, DEWS II. The meeting was structured to discuss the scope of the DED problem, to review the clinical challenges of DED, and to consider the treatment challenges of DED. This article provides a synopsis of the presentations of this TFOS i(2) meeting.

Kheirkhah A, Saboo US, Marmalidou A, Dana R. Overestimation of Corneal Endothelial Cell Density in Smaller Frame Sizes in In Vivo Confocal Microscopy. Cornea 2016;35(3):363-9.Abstract

PURPOSE: To evaluate the effect of frame size on the calculated corneal endothelial cell density (CECD) in images of laser scanning in vivo confocal microscopy (IVCM). METHODS: Forty-nine corneal endothelial images acquired by laser scanning IVCM (Heidelberg Retina Tomograph 3 with Rostock Corneal Module) with different endothelial cell densities were analyzed. In each image (160,000 μm), the CECD was calculated using the fixed-frame method by counting cells in the following frame sizes: 80,000 μm, 40,000 μm, 20,000 μm, 10,000 μm, 5000 μm, and 2500 μm. The calculated CECD was then compared with that of the variable-frame method as the reference value. RESULTS: There was no significant difference in the calculated CECD between the variable-frame method (2004 ± 832 cells/mm), and the fixed-frame method using a 40,000-μm frame (2023 ± 810 cells/mm). On the other hand, the calculated CECD showed significant overestimations in frame sizes of 20,000 μm (2066 ± 820 cells/mm), 10,000 μm (2156 ± 785 cells/mm), 5000 μm (2352 ± 783 cells/mm), and 2500 μm (2715 ± 754 cells/mm), with P < 0.001 in all. This resulted in overestimations of 4.8 ± 9.8%, 11.9 ± 16.2%, 24.9 ± 23.1%, and 49.1 ± 38.8% for these frame sizes, respectively. Images with lower CECD demonstrated higher overestimations of cell density in smaller frame sizes. CONCLUSIONS: In laser scanning IVCM images, there is significant overestimation of CECD if the cells are counted in frames smaller than 25% of the image. Similar frame sizes should be used when monitoring CECD over time.

Lienert JP, Tarko L, Uchino M, Christen WG, Schaumberg DA. Long-term Natural History of Dry Eye Disease from the Patient's Perspective. Ophthalmology 2016;123(2):425-33.Abstract

PURPOSE: To describe the natural history of dry eye disease (DED), which chronically affects millions of people in the United States. DESIGN: This study is based on the Women's Health Study and Physicians' Health Studies, and uses questionnaires and medical records. PARTICIPANTS: A total of 398 men and 386 women who reported a diagnosis of DED and responded to a questionnaire about change in disease since diagnosis. METHODS: Three subscales were developed using factor analysis of questionnaire responses: ocular surface symptoms, vision-related symptoms, and social impact. We examined correlates of worsening on each subscale, obtained medical records from a subset of 261 study participants, and examined changes in clinical signs of DED over time. MAIN OUTCOME MEASURES: Worsening in ocular surface symptoms, vision-related symptoms, and social impact plus clinical signs. RESULTS: The average duration of DED of 10.5 years (standard deviation, 9.5 years). Worsening was reported by 24% for ocular surface symptoms, 29% for vision-related symptoms, and 10% for social impact. Factors associated with worsening on at least 2 of 3 subscales included a previous report of severe DED symptoms (odds ratio [OR], 2.17 for ocular surface symptoms; OR, 2.35 for vision-related symptoms), spending >$20 per month on DED treatments (OR, 1.80 for ocular surface symptoms; OR, 1.99 for vision-related symptoms), history of blepharitis or meibomian gland dysfunction (MGD) (OR, 1.57 for vision-related symptoms; OR, 2.12 for social impact), and use of systemic beta-blockers (OR, 1.62 for ocular surface symptoms; OR, 1.84 for vision-related symptoms; OR, 1.86 for the social impact of DED). Presence of corneal staining based on review of medical records was associated with use of level 2 or higher DED treatments (OR, 1.54; confidence interval [CI], 1.01-2.36), a previous report of severe DED symptoms (OR, 1.79; CI, 1.07-3.00), having a tear break-up test performed (OR, 2.73; CI, 1.72-4.36), and having blepharitis or MGD (OR, 0.59; CI, 0.35-0.98). CONCLUSIONS: A proportion of patients with DED experience worsening over time, tending to report with more severe symptoms earlier in the disease. Forthcoming data on the natural history of DED from prospective studies should help clarify some of the limitations of this retrospective study.

Rudnisky CJ, Belin MW, Guo R, Ciolino JB, Group BTKS1. Visual Acuity Outcomes of the Boston Keratoprosthesis Type 1: Multicenter Study Results. Am J Ophthalmol 2016;162:89-98.e1.Abstract

PURPOSE: To report logarithm of the minimal angle of resolution (logMAR) visual outcomes of the Boston keratoprosthesis type 1. DESIGN: Prospective cohort study. METHODS: Preoperative, intraoperative, and postoperative parameters of 300 eyes of 300 patients who underwent implantation of a Boston keratoprosthesis type 1 device between January 2003 and July 2008 by 1 of 19 surgeons at 18 medical centers were collected. RESULTS: After an average of 17.1 ± 14.8 months, visual acuity improved significantly (P < .0001) to a mean final value of 0.89 ± 0.64 (20/150). There were also significantly fewer eyes with light perception (6.7%; n = 19; P < .0001), although 3.1% (n = 9) progressed to no light perception. There was no association between age (P = .08), sex (P = .959), operative side (P = .167), or failure (P = .494) and final visual acuity. The median time to achieve 20/200 visual acuity was 1 month (95% confidence interval 1.0-6.0) and it was retained for an average of 47.8 months. Multivariate analysis, controlling for preoperative visual acuity, demonstrated 2 factors associated with final visual outcome: chemical injury was associated with better final vision (P = .007), whereas age-related macular degeneration was associated with poorer vision (P < .0001). CONCLUSIONS: The Boston keratoprosthesis type 1 is an effective device for rehabilitation in advanced ocular surface disease, resulting in a significant improvement in visual acuity. Eyes achieved a mean value of 20/150 (0.89 ± 0.64 logMAR units) after 6 months and this was relatively stable thereafter. The best visual prognosis is observed in chemical injury eyes, whereas the worst prognosis is in aniridia, although the latter has limited visual potential.

Sarker-Nag A, Hutcheon AEK, Karamichos D. Mitochondrial Profile and Responses to TGF-β Ligands in Keratoconus. Curr Eye Res 2016;41(7):900-7.Abstract

PURPOSE: Keratoconus (KC) is a complex corneal dystrophy with multifactorial etiology. Previous studies have shown evidence of mitochondrial abnormalities in KC; however, the exact cause of these abnormalities remains unknown. The aim of this study was to identify if transforming growth factor-β (TGF-β) isoforms play a role in the regulation of mitochondrial proteins in human KC cells (HKC). MATERIALS AND METHODS: Human corneal fibroblasts (HCF) and HKC were isolated and cultured for 4 weeks in three different conditions: (a) CONTROL: MEM + 10%FBS, (b) MEM + 10%FBS + TGF-β1 and (c) MEM + 10%FBS + TGF-β3. All samples were processed for mitochondrial damage analysis using real-time PCR. RESULTS: We quantified and analyzed 84 mitochondrial and five housekeeping genes in HCFs and HKCs. Our data showed that when TGF-β1 and/or TGF-β3 were compared with control in HCFs, nine genes were significantly different; however, no genes were significantly regulated by the TGF-β isoforms in HKCs. Significant differences were also seen in seven genes when HFCs were compared with HKCs, in all three conditions. CONCLUSIONS: Overall, our data support the growing consensus that mitochondrial dysfunction is a key player in KC disease. These in vitro data show clear links between mitochondrial function and TGF-β isoforms, with TGF-β1 severely disrupting KC-mitochondrial function, while TGF-β3 maintained it, thus suggesting that TGF-β may play a role in KC-disease treatment.

Ma KN, Thanos A, Chodosh J, Shah AS, Mantagos IS. A Novel Technique for Amniotic Membrane Transplantation in Patients with Acute Stevens-Johnson Syndrome. Ocul Surf 2016;14(1):31-6.Abstract

Cryopreserved amniotic membrane (AM) transplantation is an emerging technique that is becoming the gold standard for the management of acute Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN). We describe a novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring, which facilitates AM placement. Our technique is easy to use and minimizes suturing and manipulation of ocular tissues, resulting in decreased operative time. This technique may be applied in the management of multiple ocular surface disease processes, including chemical or thermal burns, severe ocular graft versus host disease (GVHD), and other autoimmune diseases.

DeLoss KS, Le H-G, Gire A, Chiu GB, Jacobs DS, Carrasquillo KG. PROSE Treatment for Ocular Chronic Graft-Versus-Host Disease as a Clinical Network Expands. Eye Contact Lens 2016;42(4):262-6.Abstract

BACKGROUND: Keratoconjunctivitis sicca occurs in 40% to 90% of patients with ocular chronic graft-versus-host disease (cGVHD). Ocular symptoms can have profound effects in both the visual function and quality of life of patients with GVHD. We report the impact of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment in patients with cGVHD as a clinical network expands. METHODS: We queried the BostonSight PROSE manufacturing database from January 2002 to December 2011. Patients treated for ocular cGVHD were reported by age, gender, year, and network site where the treatment was undertaken. The baseline and six-month follow-up scores of visual function using a standardized validated instrument, the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), were evaluated for a period in 2006 and again in 2010 after network expansion had occurred. RESULTS: A total of 407 patients with a male:female ratio of 226:181, mean age was 51 years with ocular cGVHD underwent PROSE treatment from January 2002 to December 2011. By 2011, 67% of all cases were treated at network clinics. Baseline characteristics of patients treated throughout the network in 2010 were similar to that of 2006 and 2010 cohorts from the main center. There was a significant improvement of 41 points (P<0.001) in composite NEI VFQ score among patients treated across the network in 2010, similar to the improvement of 30 points (P<0.001) seen among the patients treated at the main center in 2010. There was a trend toward lower baseline self-reported general health status (SRGHS) and VFQ scores among patients treated at network clinics, suggesting that expansion of the network allows treatment of sicker patients (lower general health status) or those more severely affected by ocular cGVHD. CONCLUSIONS: PROSE treatment of ocular cGVHD has increased in the last decade with the establishment of BostonSight network clinics across the United States. Patients treated at network clinics showed similar levels of baseline visual function and SRGHS, and achieved a similar high level of improvement in visual function as those treated at the main center. Patient-reported measures of functional status are useful in evaluating treatment options for patients with cGVHD. PROSE treatment has significant positive impact on the visual function of patients with ocular cGVHD regardless of whether the patient is treated at the main center or at a network site.

Contreras-Ruiz L, Mir FA, Turpie B, Krauss AH, Masli S. Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090. Exp Eye Res 2016;143:1-8.Abstract

Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues - cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1β compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjögren's syndrome.

Kammerdiener LL, Speiser JL, Aquavella JV, Harissi-Dagher M, Dohlman CH, Chodosh J, Ciolino JB. Protective effect of soft contact lenses after Boston keratoprosthesis. Br J Ophthalmol 2016;100(4):549-52.Abstract

PURPOSE: To evaluate associations between preoperative diagnosis, soft contact lens (SCL) retention and complications. METHODS: A retrospective chart review was conducted of 92 adult patients (103 eyes) who received a Boston keratoprosthesis type I at the Massachusetts's Eye and Ear Infirmary or the Flaum Eye Institute. Records were reviewed for preoperative diagnosis, SCL retention and subsequent complications. Preoperative categories included 16 autoimmune (Stevens-Johnson syndrome, ocular cicatricial pemphigoid, rheumatoid arthritis and uveitis), 9 chemical injury and 67 'other' (aniridia, postoperative infection, dystrophies, keratopathies) patients. RESULTS: 50% of the lenses had been lost the first time after about a year. A subset (n=17) experienced more than 2 SCL losses per year; this group is comprised of 1 patient with autoimmune diseases, 2 patients with chemical injuries and 14 patients with 'other' diseases. The preoperative diagnosis was not predictive of contact lens retention. However, multivariate analysis demonstrated that the absence of a contact lens was an independent risk factor for postoperative complications, such as corneal melts with or without aqueous humour leak/extrusion and infections. CONCLUSIONS: Presence of a contact lens after Boston keratoprosthesis implantation decreases the risk of postoperative complications; this has been clinically experienced by ophthalmologists, but never before has the benefit of contact lens use in this patient population been statistically documented.

García-Posadas L, Hodges RR, Li D, Shatos MA, Storr-Paulsen T, Diebold Y, Dartt DA. Interaction of IFN-γ with cholinergic agonists to modulate rat and human goblet cell function. Mucosal Immunol 2016;9(1):206-17.Abstract

Goblet cells populate wet-surfaced mucosa including the conjunctiva of the eye, intestine, and nose, among others. These cells function as part of the innate immune system by secreting high molecular weight mucins that interact with environmental constituents including pathogens, allergens, and particulate pollutants. Herein, we determined whether interferon gamma (IFN-γ), a Th1 cytokine increased in dry eye, alters goblet cell function. Goblet cells from rat and human conjunctiva were cultured. Changes in intracellular [Ca(2+)] ([Ca(2+)]i), high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with IFN-γ with or without the cholinergic agonist carbachol. IFN-γ itself increased [Ca(2+)]i in rat and human goblet cells and prevented the increase in [Ca(2+)]i caused by carbachol. Carbachol prevented IFN-γ-mediated increase in [Ca(2+)]i. This cross-talk between IFN-γ and muscarinic receptors may be partially due to use of the same Ca(2+)i reservoirs, but also from interaction of signaling pathways proximal to the increase in [Ca(2+)]i. IFN-γ blocked carbachol-induced high molecular weight glycoconjugate secretion and reduced goblet cell proliferation. We conclude that increased levels of IFN-γ in dry eye disease could explain the lack of goblet cells and mucin deficiency typically found in this pathology. IFN-γ could also function similarly in respiratory and gastrointestinal tracts.

Davies EC, Pavan-Langston D, Chodosh J. Herpes zoster ophthalmicus: declining age at presentation. Br J Ophthalmol 2016;100(3):312-4.Abstract

OBJECTIVE: To investigate changes in the age of occurrence of herpes zoster ophthalmicus (HZO) in patients presenting to the Massachusetts Eye and Ear Infirmary (MEEI) from 2007 through 2013. DESIGN: Retrospective chart review. SETTING: Academic tertiary referral centre for ophthalmic conditions. PARTICIPANTS: 913 patients with acute HZO. METHODS: A total of 1283 potential cases were identified by searching the MEEI electronic medical record for patient charts with International Classification of Diseases 9 codes for herpes zoster, shingles and varicella from 2007 through 2013. The cases were reviewed to confirm diagnosis of acute HZO, requiring documentation of a skin rash or pain in the V1 distribution, resulting in inclusion of 913 cases. MAIN OUTCOME MEASURES: Number of HZO cases each year, mean age of HZO cases each year, number of HZO cases with an immunodeficiency state. RESULTS: The number of patients with HZO presenting to MEEI increased from 71 cases in 2007 to 195 cases in 2013. The mean age of patients with acute HZO reduced significantly from 61.2 years in 2007 to 55.8 years in 2013 (p=0.0119). The number of patients with acute HZO in the setting of an immunodeficiency state did not change significantly over the study period. CONCLUSIONS: Ever since the introduction of varicella vaccination in children, there has been debate regarding its effect on zoster epidemiology, particularly regarding the potential to reduce population exposure and limit repeated immunological boosts against varicella zoster virus in adults. Patients presenting to MEEI with HZO were younger on average in 2013 than in 2007. Although a population-based study is necessary to test the hypothesis, our study suggests that varicella vaccination of children remains a possible explanation for the increased number of cases and reduction in mean age of newly diagnosed patients.

Saeed H, Mantagos IS, Chodosh J. Complications of Stevens-Johnson syndrome beyond the eye and skin. Burns 2016;42(1):20-7.Abstract

INTRODUCTION: Ocular and cutaneous disease are common chronic sequelae of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and have been well described in the literature. Long-term complications affecting other organ systems have not been so well described. The purpose of this review article is to highlight non-ocular and non-cutaneous chronic complications of SJS/TEN. METHODS: The PubMed database was searched for the keywords "Stevens-Johnson syndrome" and "toxic epidermal necrolysis" through September 1, 2014. Relevant articles were then reviewed in full. RESULTS: 138 articles in the English language were found that described chronic sequelae of SJS/TEN. Our search revealed six affected organ systems other than the eyes and integument, with chronic sequelae from SJS/TEN: respiratory, gastrointestinal/hepatic, oral, otorhinolaryngologic, gynecologic/genitourinary, and renal. Complications involving these organs systems appeared likely to reduce the quality of life for SJS/TEN survivors. DISCUSSION: SJS/TEN is a multi-organ disease requiring multidisciplinary care from a variety of specialists. Affected patients have complex hospital stays, and their quality of life may be severely impacted by multiple long-term complications. We believe that preventative care in the acute setting might limit the development and progression of many of the sequelae described above.

Katikireddy KR, Jurkunas UV. Limbal Stromal Tissue Specific Stem Cells and Their Differentiation Potential to Corneal Epithelial Cells. Methods Mol Biol 2016;1341:437-44.Abstract

From the derivation of the first human embryonic stem (hES) cell line to the development of induced pluripotent stem (iPS) cells; it has become evident that tissue specific stem cells are able to differentiate into a specific somatic cell types. The understanding of key processes such as the signaling pathways and the role of the microenvironment in epidermal/epithelial development has provided important clues for the derivation of specific epithelial cell types.Various differentiation protocols/methods were used to attain specific epithelial cell types. Here, we describe in detail the procedure to follow for isolation of tissue specific stem cells, mimicking their microenvironment to attain stem cell characteristics, and their potential differentiation to corneal epithelial cells.

Kheirkhah A, Rahimi Darabad R, Cruzat A, Hajrasouliha AR, Witkin D, Wong N, Dana R, Hamrah P. Corneal Epithelial Immune Dendritic Cell Alterations in Subtypes of Dry Eye Disease: A Pilot In Vivo Confocal Microscopic Study. Invest Ophthalmol Vis Sci 2015;56(12):7179-85.Abstract

PURPOSE: To evaluate density and morphology of corneal epithelial immune dendritic cells (DCs) in different subtypes of dry eye disease (DED) using in vivo confocal microscopy (IVCM). METHODS: This retrospective study included 59 eyes of 37 patients with DED and 40 eyes of 20 age-matched healthy controls. Based on clinical tests, eyes with DED were categorized into two subtypes: aqueous-deficient (n = 35) and evaporative (n = 24). For all subjects, images of laser scanning in vivo confocal microscopy (IVCM) of the central cornea were analyzed for DC density and DC morphology (DC size, number of dendrites, and DC field). These DC parameters were compared among all dry eye and control groups. RESULTS: Compared with the controls, patients with DED had significantly higher DC density, larger DC size, higher number of dendrites, and larger DC field (all P < 0.001). Comparison between aqueous-deficient and evaporative subtypes demonstrated that DC density was significantly higher in aqueous-deficient subtype (189.8 ± 36.9 vs. 58.9 ± 9.4 cells/mm2, P = 0.001). However, there were no significant differences in morphologic parameters between DED subtypes. When aqueous-deficient DED with underlying systemic immune disease (Sjögren's syndrome and graft versus host disease) were compared with nonimmune conditions, the immunologic subgroup showed significantly higher DC density, DC size, and number of dendrites (all P < 0.05). CONCLUSIONS: Corneal IVCM demonstrated differential changes in DC density and morphologic DC parameters between subtypes of DED. These changes, which reflect the degree of immune activation and inflammation in DED, can be used for clinical practice and endpoints in clinical trials.

White ML, Chodosh J, Jang J, Dohlman C. Incidence of Stevens-Johnson Syndrome and Chemical Burns to the Eye. Cornea 2015;34(12):1527-33.Abstract

PURPOSE: This population-based observational study was designed to estimate the incidence and distribution of SJS-spectrum (Stevens-Johnson syndrome, toxic epidermal necrolysis, and toxic epidermal Necrolysis/Stevens-Johnson syndrome overlap) and chemical burns (alkali or acid burn of the cornea/conjunctiva) in the United States and extrapolate these numbers to the world. METHODS: All patients evaluated in 961 hospital-based US emergency departments between July 1, 2010, and June 30, 2012 were identified retrospectively using the Nationwide Emergency Department Sample (NEDS) from the Agency for Healthcare Research and Quality. SJS-spectrum and chemical burn cases were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. RESULTS: A mean of 3834 new SJS-spectrum cases per year were identified in the United States, resulting in an incidence rate of 12.35 new cases per million per year. Similarly, a mean of 15,865 new chemical burn cases per year were identified, resulting in an incidence rate of 51.10 new cases per million per year. CONCLUSIONS: If the incidence of SJS-spectrum is approximately uniform the world-over, extrapolation from the US figure would amount to approximately 86,500 new cases per year in the world. Extrapolation of ocular chemical burns to the world is difficult because the incidence and severity are anticipated to be higher in the developing world than in the United States. Still, using a US incidence rate, a minimum of 357,710 burn accidents would be expected to occur worldwide every year; there are presently too few data available to calculate the degree of severity and bilaterality.