PURPOSE: To investigate the longitudinal alterations of subbasal corneal nerves in patients with infectious keratitis (IK) during the acute phase, cessation of treatment, and the recovery phase by in vivo confocal microscopy (IVCM). DESIGN: Prospective, longitudinal, case-control, single-center study. PARTICIPANTS: Fifty-six eyes of 56 patients with the diagnosis of bacterial (n = 28), fungal (n = 15), or Acanthamoeba (n = 13) keratitis were included in the study. Thirty eyes of 30 normal volunteers constituted the control group. METHODS: Corneal sensation and serial IVCM of the central cornea were performed prospectively using the Heidelberg Retina Tomograph 3/Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany). The IVCM images were assessed at 3 time points: at the acute phase (first visit to the cornea service), at cessation of antimicrobial treatment, and up to 6 months after the resolution of infection. MAIN OUTCOME MEASURES: Total nerve number and length, main nerve trunks, branching, and corneal sensation were assessed during the follow-up period. RESULTS: Corneal nerves were reduced significantly during the acute phase in eyes with IK compared with controls across all subgroups, with total nerve length of 5.47±0.69 mm/mm(2) versus 20.59±1.06 mm/mm(2) (P <0.0001). At the cessation of treatment, corneal nerves in patients with IK had regenerated, including total nerve length (8.49±0.94 mm/mm(2); P = 0.02) and nerve branch length (4.80±0.37 mm/mm(2); P = 0.005). During the recovery phase, after resolution of infection, corneal nerves regenerated further, including total nerve length (12.13±1.97 mm/mm(2); P = 0.005), main nerve trunk length (5.80±1.00 mm/mm(2); P = 0.01), and nerve branch length (6.33±0.76 mm/mm(2); P = 0.003) as compared with the acute phase, but were still significantly lower when compared with controls (P < 0.05 for all parameters). Corneal degeneration and regeneration correlated with corneal sensation (r = 0.47; P = 0.0009). CONCLUSIONS: Patients with IK who sustain profound loss of corneal nerves during the acute phase of infection demonstrate increased corneal nerve density during the first 6 months after the resolution of infection. However, despite significant nerve regeneration, corneal nerve density does not recover fully and remains low compared to controls. By providing an objective methodology to monitor corneal re-innervation, IVCM adds potentially important findings that may have implications for clinical management and surgical planning.

PURPOSE: We examined agreement among experts in the assessment of corneal subbasal nerve tortuosity. METHODS: Images of corneal subbasal nerves were obtained from investigators at seven sites (Auckland, Boston, Linköping, Manchester, Oslo, Rostock, and Sydney) using laser-scanning in vivo confocal microscopy. A set of 30 images was assembled and ordered by increasing tortuosity by 10 expert graders from the seven sites. In a first experiment, graders assessed tortuosity without a specific definition and performed grading three times, with at least 1 week between sessions. In a second experiment, graders assessed the same image set using four focused tortuosity definitions. Intersession and intergrader repeatability for the experiments were determined using the Spearman rank correlation. RESULTS: Expert graders without a specific tortuosity definition had high intersession (Spearman correlation coefficient 0.80), but poor intergrader (0.62) repeatability. Specific definitions improved intergrader repeatability to 0.79. In particular, tortuosity defined by frequent small-amplitude directional changes (short range tortuosity) or by infrequent large-amplitude directional changes (long range tortuosity), indicated largely independent measures and resulted in improved repeatability across the graders. A further refinement, grading only the most tortuous nerve in a given image, improved the average correlation of a given grader's ordering of images with the group average to 0.86 to 0.90. CONCLUSIONS: Definitions of tortuosity specifying short or long-range tortuosity and considering only the most tortuous nerve in an image improved the agreement in tortuosity grading among a group of expert observers. These definitions could improve accuracy and consistency in quantifying subbasal nerve tortuosity in clinical studies.

PURPOSE: Idiopathic vitritis is a poorly understood complication after Boston keratoprosthesis surgery with unclear etiology. We sought to determine whether an association exists between periprosthetic corneal tissue loss and the development of idiopathic vitritis in keratoprosthesis recipients. METHODS: Thirteen Boston type I keratoprosthesis recipient eyes with a history of idiopathic vitritis and 34 type I keratoprosthesis recipient eyes with no history of idiopathic vitritis underwent anterior segment optical coherence tomography (AS-OCT) at a median time postoperatively of 2.4 years versus 1.9 years (range, 0.5-14.2 vs. 0.1-13.6 years), respectively. Areas of corneal graft tissue loss ("gaps") around the keratoprosthesis stem were identified and analyzed by 2 masked observers. The difference in the presence, number, and size of gaps was compared between cases and controls. RESULTS: A periprosthetic gap was identified more commonly in idiopathic vitritis cases than in controls on AS-OCT (11/13, 86% vs. 11/34, 33.3%, P < 0.001). The number of gaps between cases and controls was also significantly different (2.6 ± 1.6 vs. 0.5 ± 0.8, P < 0.001), but not the estimated gap area (0.056 ± 0.049 mm vs. 0.039 ± 0.025 mm, P = 0.22). CONCLUSIONS: A significantly higher proportion of keratoprosthesis recipient eyes with idiopathic vitritis had corneal tissue loss around the keratoprosthesis stem than did controls. Tissue loss could serve as an entry point for debris or bacterial components, triggering idiopathic vitritis. Our study underscores the utility of AS-OCT imaging in the postoperative management of keratoprosthesis patients.

PURPOSE: To report bilateral corneal endothelial cell density (ECD), as well as its correlation with subbasal nerve changes, in patients with unilateral herpes simplex keratitis (HSK). METHODS: Thirty-six eyes of 36 patients with corneal scarring caused by HSK, as well as their respective contralateral clinically unaffected eyes, were prospectively studied and compared with 26 eyes of 26 healthy volunteers. In vivo confocal microscopy and corneal sensation of the central cornea were performed bilaterally in all patients and in one random eye of controls. The ECD and subbasal corneal nerve density, including the lengths of total nerves, main trunks, and branches were evaluated and correlated to central corneal sensation. RESULTS: The ECD was significantly lower in eyes affected with HSK than in controls (2304 ± 578 vs. 2940 ± 370 cells/mm2, P < 0.0001). Surprisingly, lower ECD was also detected in contralateral clinically unaffected eyes (2548 ± 423), compared to controls (P = 0.02). Both affected and contralateral eyes showed decrease in total nerve length, compared to controls (10.0 ± 6.3 vs. 17.6 ± 6.3 vs. 21.9 ± 4.3 mm/mm2, respectively; P < 0.05 for all). The ECD correlated positively with total nerve length (r = 0.39, P = 0.0009) and with corneal sensation (r = 0.31, P = 0.009). CONCLUSIONS: In vivo confocal microscopy findings demonstrated alterations in corneal ECD in both affected and clinically unaffected contralateral eyes of patients with unilateral HSK. Moreover, the positive significant correlation between the ECD and the subbasal nerve density may suggest a potential link between corneal innervation and corneal endothelial cell homeostasis.

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.

PURPOSE: Each year, over 8,000 corneal transplantation surgeries are performed in China. Unlike developed countries, which have established standard requirements for operative experience for corneal specialists, little information exists on surgical training for keratoplasty in China. The aim of this study was to assess the keratoplasty experience of Chinese corneal specialists and to characterize their surgical patterns. METHODS: One hundred and twenty-one corneal specialists in 16 provinces (65 cities) in China were invited to complete an anonymous survey at the 2014 Chinese Corneal Society annual meeting, which consisted of questions with single or multiple-choice answers. Demographics, the number and type of keratoplasties performed, and the perceived limiting factors for performing keratoplasties were analyzed. RESULTS: An overwhelming 89% response rate was achieved. Of the 108 respondents, 76% worked in tertiary centers, and only 23% held a medical doctorate degree. Furthermore, 69% of the participants had received corneal fellowship training of less than one year. Only 71% were capable of keratoplasties. Among those doing keratoplasty, 68% performed less than 50 keratoplasties each year. Of the same group of keratoplasty surgeons, 88% of corneal specialists capable of keratoplasties had performed penetrating keratoplasties, 87% had performed lamellar keratoplasties, 12% had performed deep anterior lamellar keratoplasties, and 5% had performed Descemet's stripping endothelial keratoplasties. When questioned on the reasons for the low number of keratoplasties performed in China, the respondents deemed the following factors most important: lack of surgical training (71%), a shortage of donor supply (52%), and a lack of curricula (42%). A multivariate logistic regression analysis showed that corneal transplantation capabilities are significantly associated with responders' education levels and training time. CONCLUSION: Keratoplasty surgery experience is suboptimal for Chinese corneal specialists. Penetrating and lamellar keratoplasties are the preferred surgical patterns. Our findings raise concerns about the adequacy of keratoplasty training in China.

PURPOSE: To illustrate that corneal neuralgia may be the basis for refractory dry eye syndrome after laser-assisted in situ keratomileusis (LASIK). METHODS: The methodology used is that of a retrospective medical record review of a small case series. RESULTS: Three male patients, aged 30 to 48 years, referred in 2012 for dry eye syndrome refractory to treatment within 1 year of LASIK or LASIK enhancement are reported. Each patient gave history of eye pain, light sensitivity, and difficulty with visual activities beginning within 2 months of LASIK or LASIK enhancement. Best-corrected visual acuity was 20/15 or 20/20 in each of the six eyes. Tear-centered models and metrics did not explain persistent symptoms, which was consistent with inadequate response to standard dry eye treatments used before referral and reported here. In vivo confocal microscopy was abnormal at presentation in each case and was followed over time. Treatments undertaken subsequent to referral included autologous serum tears (three cases), PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem) treatment (two cases), and systemic agents for pain, anxiety, or depression (three cases). By the end of 2013, at a mean of 23 months after LASIK or LASIK enhancement, symptoms improved in all three patients. CONCLUSIONS: Patients with persistent dry eye symptoms out of proportion to clinical signs after LASIK have a syndrome that may best be classified as corneal neuralgia. In vivo confocal microscopy can be informative as to the neuropathic basis of this condition. In keeping with current understanding of complex regional pain syndrome, early multimodal treatment directed toward reducing peripheral nociceptive signaling is warranted to avoid subsequent centralization and persistence of pain. Distinguishing this syndrome from typical post-LASIK dry eye remains a challenge.

PURPOSE: To describe the clinical and histopathologic features distinguishing an extensive complex choristoma of the epibulbar surface and to address the management of such lesions. METHODS: Clinical history, diagnostic imaging studies, and histopathologic sections stained with hematoxylin and eosin were reviewed from a 2-year-old girl with a congenital conjunctival lesion of the right eye that was surgically excised. RESULTS: The patient clinically displayed an extensive, vascularized amelanotic conjunctival lesion located superotemporally with extension onto the cornea. Her visual acuity was reduced to 20/670. The clinical diagnosis was a large lacrimal gland choristoma with corneal involvement and resulting deprivation amblyopia. The patient underwent an excision of the lesion including the corneal portion, and the ocular surface was reconstructed with amniotic membrane. Histopathologic evaluation disclosed lobules of lacrimal tissue and cartilage plaques, smooth muscle, and nerves consistent with a complex choristoma. Six weeks postoperatively, the visual acuity had improved to 20/180. The patient returned to her local ophthalmologist for amblyopia management. CONCLUSIONS: We emphasize the importance of recognizing lesion-induced amblyopia and the timely performance of appropriate surgery for complex epibulbar choristomas. A differential diagnosis of other congenital epibulbar lesions is provided.

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.

Impaired corneal wound healing that occurs with ocular surface disease, trauma, systemic disease, or surgical intervention can lead to persistent corneal epithelial defects (PCED), which result in corneal scarring, ulceration, opacification, corneal neovascularization, and, ultimately, visual compromise and vision loss. The current standard of care can include lubricants, ointments, bandage lenses, amniotic membranes, autologous serum eye drops, and corneal transplants. Various inherent problems exist with application and administration of these treatments, which often may not result in a completely healed surface. A topically applicable compound capable of promoting corneal epithelial cell proliferation and/or migration would be ideal to accelerate healing. We hypothesize that human growth hormone (HGH) is such a compound. In a recent study, HGH was shown to activate signal transducer and activators of transcription-5 (STAT5) signaling and promote corneal wound healing by enhancing corneal epithelial migration in a co-culture system of corneal epithelial cells and fibroblasts. These effects require an intact communication between corneal epithelia and fibroblasts. Further, HGH promotes corneal wound healing in a rabbit debridement model, thus demonstrating the effectiveness of HGH in vivo as well. In conclusion, HGH may represent an exciting and effective topical therapeutic to promote corneal wound healing.

OBJECTIVE: Patients suffering from corneal neuropathy may present with photoallodynia; i.e., increased light sensitivity, frequently with a normal slit-lamp examination. This study aimed to evaluate the efficacy of autologous serum tears (AST) for treatment of severe photoallodynia in corneal neuropathy and to correlate clinical findings with corneal subbasal nerve alterations by in vivo confocal microscopy (IVCM). METHODS: Retrospective case control study with 16 patients with neuropathy-induced severe photoallodynia compared to 16 normal controls. Symptom severity, clinical examination and bilateral corneal IVCM scans were recorded. RESULTS: All patients suffered from extreme photoallodynia (8.8±1.1) with no concurrent ocular surface disease. Subbasal nerves were significantly decreased at baseline in patients compared to controls; total nerve length (9208±1264 vs 24714±1056 μm/mm(2); P<.0001) and total nerve number (9.6±1.4 vs 28.6±2.0; P<.0001), respectively. Morphologically, significantly increased reflectivity (2.9±0.2 vs 1.8±0.1; P<.0001), beading (in 93.7%), and neuromas (in 62.5%) were seen. AST (3.6±2.1 months) resulted in significantly decreased symptom severity (1.6±1.7; P=.02). IVCM demonstrated significantly improved nerve parameters (P<.005), total nerve length (15451±1595 μm/mm(2)), number (13.9±2.1), and reflectivity (1.9±0.1). Beading and neuromas were seen in only 56.2% and 7.6% of patients. CONCLUSION: Patients with corneal neuropathy-induced photoallodynia show profound alterations in corneal nerves. AST restores nerve topography through nerve regeneration, and this correlated with improvement in patient-reported photoallodynia. The data support the notion that corneal nerve damage results in alterations in afferent trigeminal pathways to produce photoallodynia.

PurposeThe utility of in vivo confocal microscopy (IVCM) in the investigation of palpebral conjunctival and corneal inflammation in patients with meibomian gland dysfunction (MGD)-associated refractory dry eye symptoms following gland expression, despite objective clinical improvement.MethodsA retrospective, observational pilot study was conducted evaluating five patients with MGD-associated refractory dry eye symptoms and three control groups: symptomatic untreated MGD patients (n=3), treatment-responsive MGD patients with improved symptoms (n=3) and asymptomatic healthy normals (n=11). Ocular surface disease index (OSDI) scores, tear break-up time (TBUT), the number of meibomian glands yielding liquid secretion (MGYLS), palpebral conjunctival epithelial and substantia propria immune cell (EIC, SIC), and corneal dendritic cell (DC) densities were measured.ResultsDespite clinical improvement (TBUT: 6.4±1.2 s to 10.1±2.1 s, P=0.03; MGYLS: 3.5±0.8 glands to 7.0±1.1 glands, P=0.13) and a normal clinical examination post treatment, MGD patients remained symptomatic. IVCM revealed increased immune cells in the palpebral conjunctiva (refractory MGD EIC=592.6±110.1 cells/mm(2); untreated MGD EIC=522.6±104.7 cells/mm(2), P=0.69; responsive MGD EIC=194.9±119.4 cells/mm(2), P<0.01; normals EIC=123.7±19.2 cells/mm(2), P< 0.001), but not the cornea (refractory MGD DC=60.9±28.3 cells/mm(2); normals DC=25.9±6.3 cells/mm(2); P=0.43). EIC did not correlate with TBUT (Rs=-0.26, P=0.33). OSDI scores correlated with both EIC (Rs=0.76, P<0.001) and TBUT (Rs=-0.69, P<0.01) but not SIC. Intraglandular immune cells were also seen.ConclusionMGD-associated refractory symptoms and the symptom-sign disparity may be explained by clinically non-apparent, active inflammation of the palpebral conjunctiva as detected by IVCM. These patients may benefit from anti-inflammatory therapy.

PURPOSE: Amino-amide or amino-ester local anesthetics, which are currently used for topical ocular anesthesia, are short acting and may delay corneal healing with long-term use. In contrast, site 1 sodium channel blockers (S1SCBs) are potent local anesthetics with minimal adverse tissue reaction. In this study, we examined topical local anesthesia with two S1SCBs, tetrodotoxin (TTX) or saxitoxin (STX) individually or in combination with α2-adrenergic receptor agonists (dexmedetomidine or clonidine), and compared them with the amino-ester ocular anesthetic proparacaine. The effect of test solutions on corneal healing was also studied. METHODS: Solutions of TTX ± dexmedetomidine, TTX ± clonidine, STX ± dexmedetomidine, dexmedetomidine, or proparacaine were applied to the rat cornea. Tactile sensitivity was measured by recording the blink response to probing of the cornea with a Cochet-Bonnet esthesiometer. The duration of corneal anesthesia was calculated. Cytotoxicity from anesthetic solutions was measured in vitro. The effect on corneal healing was measured in vivo after corneal debridement followed by repeated drug administration. RESULTS: Addition of dexmedetomidine to TTX or STX significantly prolonged corneal anesthesia beyond that of either drug alone, whereas clonidine did not. Tetrodotoxin or STX coadministered with dexmedetomidine resulted in two to three times longer corneal anesthesia than did proparacaine. S1SCB-dexmedetomidine formulations were not cytotoxic. Corneal healing was not delayed significantly by any of the test solutions. CONCLUSIONS: Coadministration of S1SCBs with dexmedetomidine provided prolonged corneal anesthesia without delaying corneal wound healing. Such formulations may be useful for the management of acute surgical and nonsurgical corneal pain.

PURPOSE: To establish the efficacy of topical N-acetylcysteine (NAC) as a treatment to reduce protein deposition on the contact lens surface. METHODS: In this prospective, nonrandomized clinical trial, a total of 10 eyes (9 patients) were enrolled from a single center. All patients had a prior ocular history of either a Boston Keratoprosthesis type I or trichiasis from Stevens-Johnson syndrome, which necessitated full-time contact lens wear. Four visits were required to complete the study. During visit 1, a new contact lens was inserted and a baseline examination was performed. Visit 2 served as the control month, whereas visits 3 and 4 were month 1 and 2 on treatment with 20% NAC. At the end of each visit the contact lens was replaced. The lenses from visit 2 (control month-without NAC) and from visit 3 (treatment month-with NAC) were collected for proteomic analysis. The main outcome measures were to quantify protein deposition, as well as to assess the visual acuity and ocular surface symptoms before and after treatment. RESULTS: Topical NAC resulted in a 20% decrease in protein deposition. This correlated with a trend for improvement in visual acuity and increased subjective improvement in vision at month 1 (P=0.0153) and 2 (P=0.0016). CONCLUSIONS: NAC reduced protein deposition, decreased ocular surface symptoms, and improved contact lens transparency, thereby providing increased optical clarity.

PURPOSE: The contribution of lymphangiogenesis (LA) to allergy has received considerable attention and therapeutic inhibition of this process via targeting VEGF has been considered. Likewise, certain inflammatory settings affecting the ocular mucosa can trigger pathogenic LA in the naturally avascular cornea. Chronic inflammation in allergic eye disease (AED) impacts the conjunctiva and cornea, leading to sight threatening conditions. However, whether corneal LA is involved is completely unknown. We addressed this using a validated mouse model of AED. METHODS: Allergic eye disease was induced by ovalbumin (OVA) immunization and chronic OVA exposure. Confocal microscopy of LYVE-1-stained cornea allowed evaluation of corneal LA, and qRT-PCR was used to evaluate expression of VEGF-C, -D, and -R3 in these mice. Administration of VEGF receptor (R) inhibitor was incorporated to inhibit corneal LA in AED. Immune responses were evaluated by in vitro OVA recall responses of T cells, and IgE levels in the serum. RESULTS: Confocal microscopy of LYVE-1-stained cornea revealed the distinct presence of corneal LA in AED, and corroborated by increased corneal expression of VEGF-C, -D, and -R3. Importantly, prevention of corneal LA in AED via VEGFR inhibition was associated with decreased T helper two responses and IgE production. Furthermore, VEGFR inhibition led a significant reduction in clinical signs of AED. CONCLUSIONS: Collectively, these data reveal that there is a distinct involvement of corneal LA in AED. Furthermore, VEGFR inhibition prevents corneal LA and consequent immune responses in AED.

PURPOSE: To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). DESIGN: Prospective study. PARTICIPANTS: Eighty-four patients diagnosed with chronic ocular GVHD. METHODS: We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. MAIN OUTCOME MEASURES: We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. RESULTS: The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5±17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with the exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P < 0.001), SANDE (R = -0.56, P < 0.001), CFS (R = -0.36, P = 0.001), and BCVA (R = -0.30, P = 0.004). CONCLUSIONS: Patients with ocular GVHD experience measurable impairment of vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition.

OBJECTIVE: In angiogenesis, circulating mononuclear cells are recruited to vascular lesions; however, the underlying mechanisms are poorly understood. APPROACH AND RESULTS: Here, we characterize the functional role of protein tyrosine kinase 7 (PTK7)-expressing CD11b(+) mononuclear cells in vitro and in vivo using a mouse model of angiogenesis. Although the frequencies of PTK7(+)CD11b(+) cells in the bone marrow remained similar after vascular endothelial growth factor-A-induced neovascularization, we observed an 11-fold increase in the cornea. Importantly, vascular endothelial growth factor-A-induced chemotaxis of PTK7(+) cells was mediated by vascular endothelial growth factor receptor 2. In a coculture with endothelial cells, PTK7(+)CD11b(+) cells stabilized the vascular network for 2 weeks by expressing high levels of angiopoietin-1. The enhanced vascular stability was abolished by knockdown of angiopoietin-1 in PTK7(+)CD11b(+) cells and could be restored by angiopoietin-1 treatment. CONCLUSIONS: We conclude that PTK7 expression in perivascular mononuclear cells induces vascular endothelial growth factor receptor 2 and angiopoietin-1 expression and thus contributes to vascular stabilization in angiogenesis.

The cornea functions as the major refractive interface for vision and protects the internal eye from insult. Current understanding of innate immune responses to corneal infection derives from a synthesis of in vitro and in vivo analyses. However, monolayer cell cultures and mouse models do not accurately duplicate all aspects of innate immunity in human patients. Here, we describe a three-dimensional culture system that incorporates human cells and extracellular matrix to more completely simulate the human cornea for studies of infection. Human corneal stromal fibroblasts were mixed with type I collagen in 3-μm pore size transwell inserts, and overlayed with Matrigel to simulate a human corneal stroma and epithelial basement membrane. These were then infected with a cornea-tropic adenovirus, and exposed on their inferior side to leukocytes derived from human peripheral blood. Subsequent analyses were performed with histology, confocal microscopy, ELISA, and fluorescence-activated cell sorting (FACS). CXCL8, a neutrophil chemokine shown previously as the first cytokine induced in infection of human corneal cells, increased upon adenovirus infection of facsimiles in a dose-responsive fashion. Myeloperoxidase-positive cells infiltrated infected corneal facsimiles in a sub-Matrigel location, possibly due to CXCL8 colocalization with heparan sulfate, a Matrigel constituent. Cellular infiltration was significantly inhibited by treatment with chemical inhibitors of p38 MAPK and Src kinase, both constituents of a signaling cascade previously suggested to regulate inflammation after adenovirus infection. FACS analysis determined that both virus and corneal fibroblasts were necessary for the induction of leukocyte migration into the facsimiles. The corneal facsimile, literally a cornea in a test tube, permits mechanistic studies on human tissue in a highly tractable system.

AIM: To characterise the emergence pattern of cavitation bubbles into the anterior chamber (AC) following femtosecond laser-assisted in situ keratomileusis (LASIK)-flap creation METHODS: Retrospective review of patients undergoing femtosecond LASIK surgery at Boston Laser, a private refractive surgery practice in Boston, Massachusetts, between December 2008 and February 2014. Patient charts were reviewed to identify all cases with gas bubble migration into the AC. Surgical videos were examined and the location of bubble entry was recorded separately for right and left eyes. RESULTS: Five thousand one hundred and fifty-eight patients underwent femtosecond LASIK surgery. Air bubble migration into the AC, presumably via the Schlemm's canal and trabecular meshwork, occurred in 1% of cases. Patients with AC bubbles had an average age of 33±8 years with a measured LASIK flap thickness of 96±21 μm. The occurrence of gas bubbles impaired iris registration in 64% of cases. Gas bubbles appeared preferentially in the nasal or inferior quadrants for right (92% of cases) and left (100% of cases) eyes. This bubble emergence pattern is significantly different from that expected with a random distribution (p<0.0001) and did not seem associated with decentration of the femtosecond laser docking system. CONCLUSIONS: The migration of gas bubbles into the AC is a rare occurrence during femtosecond laser flap creation. The preferential emergence of gas bubbles into the nasal and inferior quadrants of the AC may indicate a distinctive anatomy of the nasal Schlemm's canal.

PURPOSE: To compare the postoperative measurements of intraocular pressure (IOP) using the Corvis ST Tonometer (CST), ocular response analyzer (ORA), and Goldmann applanation tonometry (GAT) in eyes undergoing laser in situ keratomileusis (LASIK), as well as to analyze the relationship between the corneal biomechanical parameters of the CST and the ORA. METHODS: Fifty participants who had undergone LASIK to treat myopia in the previous 3 months were enrolled. Postoperative IOP measurements of these participants were obtained using the CST, ORA (corneal-compensated IOP [IOPcc], Goldmann-correlated IOP [IOPg]), and GAT. Device agreement was calculated by Bland-Altman analysis. The metrics of corneal biomechanical properties were recorded using the ORA and the CST. Corneal biomechanical parameters were compared. RESULTS: The Bland-Altman analysis revealed a significant bias between CST and GAT, between CST and IOPcc, and between CST and IOPg of 3.4, 1.0, and 3.8, mm Hg, respectively, with 95% limits of agreement of -0.7 to 7.5 mm Hg, -2.1 to 4.2 mm Hg, and -0.4 to 8.0 mm Hg. The ORA-derived IOP measurements, CST-derived IOP, and GAT IOP values showed good correlation with each other. The CST IOP and IOPcc were higher than the GAT IOP (all p < 0.05), whereas IOPg did not differ from the GAT IOP readings. Ocular response analyzer-derived corneal biomechanical parameters (corneal hysteresis and the corneal resistance factor) showed significant correlations with CST-derived parameters, including the maximum deformation amplitude at the corneal apex and the time from start until the first applanation. CONCLUSIONS: The CST offers an alternative method for measuring postoperative IOP in LASIK patients, and it appears to obtain higher IOP values than other tonometry techniques. The technique may facilitate the investigation of corneal biomechanical property changes in LASIK-treated eyes.

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.

PURPOSE: The aim of this study was to compare patient-reported symptoms of dry eye disease (DED) as assessed by the Ocular Surface Disease Index (OSDI), a 12-item symptom frequency-based questionnaire, and the Symptom Assessment iN Dry Eye (SANDE), a 2-item frequency- and severity-based visual analog scale. DESIGN: Clinic-based evaluation of a diagnostic test. PARTICIPANTS: A total of 114 patients with DED. METHODS: Patients were administered the OSDI and SANDE questionnaires at baseline and follow-up visits to evaluate DED-related symptoms. The correlations between both questionnaires' scores were evaluated using the Spearman coefficient, and their clinical differences were assessed using Bland-Altman analysis. MAIN OUTCOME MEASURES: Baseline and follow-up visit OSDI and SANDE dry eye symptom scores. RESULTS: At the baseline visit, the OSDI and SANDE questionnaire scores were significantly correlated (R = 0.64; P < 0.001). Moreover, a significant correlation was found between changes in the OSDI and SANDE scores from baseline to follow-up visits (R = 0.47; P < 0.001). A Bland-Altman analysis, after score normalization, revealed a difference (bias) of less than 2 centesimal units between the scores of the 2 questionnaires. CONCLUSIONS: Data collected from the SANDE questionnaire showed a significant correlation and negligible score differences with those from the OSDI, suggesting that the SANDE visual analog scale-based questionnaire has the potential to provide clinicians with a short, quick, and reliable measure for DED symptoms.

PURPOSE: To evaluate the safety and efficacy of topical loteprednol etabonate (LE) 0.5% compared with cyclosporine A (CsA) 0.05% for the prophylaxis and treatment of dry eye syndrome (DES) after hematopoietic stem cell transplantation (HSCT). METHODS: Seventy-five patients were randomized to LE (n = 76 eyes of 38 patients) or CsA (n = 74 eyes of 37 patients) pre-HSCT. Lissamine green and fluorescein staining, tear break-up time, tear osmolarity (Osm), Schirmer score (Sch), intraocular pressure, visual acuity, and Ocular Surface Disease Index were assessed pre-HSCT, 3, 6, 9, and 12 months post-HSCT. RESULTS: There were no differences in DES incidence (P = 0.22; log-rank test) or progression (P = 0.41; log-rank test) between the 2 treatment arms during the course of the study. Among eyes with no DES at enrollment, the Kaplan-Meier analysis yielded a 90% rate of DES development in cyclosporine-treated eyes and a 79% rate of DES development in LE-treated eyes by 12 months post-HSCT. The Kaplan-Meier analysis of eyes with DES at enrollment demonstrated a 38% rate of disease progression among cyclosporine-treated eyes and a 26% rate of disease progression among loteprednol-treated eyes by 12 months. No patient in either group had an elevation of 10 mm Hg or greater from baseline at any study visit, and no patients had their treatment discontinued for elevation in intraocular pressure. CONCLUSIONS: Pre-HSCT initiation of LE 0.5% appears to be safe and may be as effective as CsA 0.5% for the treatment and prophylaxis of DES following HSCT.

BACKGROUND: Graft failure because of immune rejection remains a significant problem in organ transplantation, and lymphatic and blood vessels are important components of the afferent and efferent arms of the host alloimmune response, respectively. We compare the effect of antihemangiogenic and antilymphangiogenic therapies on alloimmunity and graft survival in a murine model of high-risk corneal transplantation. METHODS: Orthotopic corneal transplantation was performed in hemevascularized and lymph-vascularized high-risk host beds, and graft recipients received subconjunctival vascular endothelial growth factor (VEGF)-trap, anti-VEGF-C, sVEGFR-3, or no treatment, beginning at the time of surgery. Fourteen days after transplantation, graft hemeangiogenesis and lymphangiogenesis were evaluated by immunohistochemistry. The frequencies of Th1 cells in regional lymphoid tissue and graft-infiltrating immune cells were evaluated by flow cytometry. Long-term allograft survival was compared using Kaplan-Meier curves. RESULTS: VEGF-trap significantly decreased graft hemangiogenesis as compared to the control group and was most effective in reducing the frequency of graft-infiltrating immune cells. Anti-VEGF-C and sVEGFR3 significantly decreased graft lymphangiogenesis and lymphoid Th1 cell frequencies as compared to control. VEGF-trap (72%), anti-VEGF-C (25%), and sVEGFR-3 (11%) all significantly improved in the 8-week graft survival compared to control (0%), although VEGF-trap was significantly more effective than both anti-VEGF-C (P < 0.05) and sVEGFR-3 (P < 0.05). CONCLUSION: In a clinically relevant model of high-risk corneal transplantation in which blood and lymphatic vessels are present and treatment begins at the time of transplantation, VEGF-trap is significantly more effective in improving long-term graft survival as compared to anti-VEGF-C and sVEGFR-3, but all approaches improve survival when compared to untreated control.