ITPR1: The missing gene in miosis-ataxia syndrome?

The association of early-onset non-progressive ataxia and miosis is an extremely rare phenotypic entity occasionally reported in the literature. To date, only one family (two siblings and their mother) has benefited from a genetic diagnosis by the identification of a missense heterozygous variant (p.Arg36Cys) in the ITPR1 gene. This gene encodes the inositol 1,4,5-trisphosphate receptor type 1, an intracellular channel that mediates calcium release from the endoplasmic reticulum. Deleterious variants in this gene are known to be associated with two types of spinocerebellar ataxia, SCA15 and SCA29, and with Gillespie syndrome that is associated with ataxia, partial iris hypoplasia, and intellectual disability. In this work, we describe a novel individual carrying a heterozygous missense variant (p.Arg36Pro) at the same position in the N-terminal suppressor domain of ITPR1 as the family previously reported, with the same phenotype associating early-onset non-progressive ataxia and miosis. This second report confirms the implication of ITPR1 in the miosis-ataxia syndrome and therefore broadens the clinical spectrum of the gene. Moreover, the high specificity of the phenotype makes it a recognizable syndrome of genetic origin.

The Reinforced Treat-and-Extend Protocol for Exudative Age-Related Macular Degeneration: Retrospective Assessment of 24-Month Real-World Outcomes in France.

INTRODUCTION: The aim of this work is to evaluate the real-world outcomes of the reinforced treat-and-extend (RTE) protocol for the treatment of exudative age-related macular degeneration with intravitreal injections of aflibercept or ranibizumab (anti-vascular endothelial growth factor therapies). METHODS: This was a retrospective review of patients from two tertiary ophthalmology centers in France initiating the RTE protocol between February 2018 and June 2021. The primary outcome was change in best-corrected visual acuity (BCVA) after 24 months. Secondary outcomes were change in central retinal thickness (CRT), recurrence, and management-related factors (injection interval, number of injections/consultations). Outcomes were additionally evaluated after protocol changes (strict versus modified RTE protocol groups). RESULTS: Sixty-eight patients (72 eyes) were included (68% females; mean age 82.2 ± 7.8 years). After 24 months, mean BCVA significantly improved (65.22 ± 14 vs. 71.96 ± 13 Early Treatment Diabetic Retinopathy Study letters; p < 0.001) and CRT significantly decreased (388.6 ± 104 vs. 278.8 ± 51 µM; p < 0.001) with 21% of eyes showing signs of exudation. Over the 24 months, a mean total of 14.9 ± 4.0 injections and 8.6 ± 1.4 consultations were performed. Mean 24-month injection interval was 7.9 ± 2.3 weeks. Initial and 24-month ophthalmic outcomes for eyes in the strict (47%) versus modified (53%) groups were not significantly different, but mean time interval to first recurrence of disease activity was significantly shorter for the modified group (7.3 ± 2.4 vs. 9.9 ± 2.5 weeks; p < 0.001). Patients in the strict RTE group received significantly less injections (13.9 ± 3.6 vs. 16.5 ± 3.9; p = 0.006) and mean 24-month injection interval was significantly longer (9.5 ± 2.7 vs. 6.5 ± 2.1 weeks; p < 0.001). Consultation number was similar (8.5 ± 1.9 vs. 8.8 ± 1.6; p = 0.93). Treatment with aflibercept versus ranibizumab did not influence ophthalmic or management outcomes. CONCLUSIONS: The RTE protocol, even when modified, reduced consultations but improved ophthalmic outcomes. The RTE protocol could reduce hospital visits and overall burden while also encouraging better patient compliance. Video Abstract available for this article. VIDEO ABSTRACT: Vincent Soler and François-Philippe Roubelat summarize the Reinforced Treat-and-Extend Protocol and main results (MP4 225022 KB).

Conventional Epithelial-Off Corneal Crosslinking in Patients With Progressive Keratoconus: 10-Year Outcomes.

PURPOSE: Corneal crosslinking (CXL) is the standard treatment of progressive keratoconus (KC). We evaluated the safety and 10-year outcomes of conventional "epithelial-off" CXL for progressive KC for the first time in a cohort in France. METHODS: We conducted a retrospective review of patients undergoing conventional CXL (Dresden protocol) in our tertiary ophthalmology department from 2006 to 2011 with 10-year follow-up. The primary outcome was change in preoperative versus postoperative keratometry measured by maximum keratometry (Kmax), steep keratometry (K2), flat keratometry (K1), mean keratometry (Km), and topographic cylinder. Secondary outcomes were changes in visual and refractive outcomes. We report postoperative complications and adverse events. RESULTS: Eighty-nine eyes from 76 patients (67% male patients, mean age 22.7 ± 7.6 years) were included. Mean Kmax (-2.31 ± 2.98 diopters (D); P < 0.00001), K2 (-2.07 ± 3.15 D; P < 0.00001), K1 (-1.00 ± 2.29 D; P = 0.00008), Km (-1.53 ± 2.47 D; P < 0.00001), and topographic cylinder (-1.15 ± 2.53 D; P = 0.00004) significantly decreased 10 years after CXL compared with preoperative baseline. Significant decreases were still observed between 5 and 10 years after for mean Kmax, mean K2, mean K1, and mean Km. Mean distance best spectacle-corrected visual acuity and mean manifest refraction spherical equivalent were significantly improved after 10 years versus before CXL. The 10-year rate of repeat CXL was n = 3/76 patients (4%) (all younger than 18 years at first CXL) and of loss of >3 lines in best spectacle-corrected visual acuity was n = 1/76 patients (1%). CONCLUSIONS: Progressive KC was effectively stabilized with a prolonged flattening and maintenance of functional vision improvements after 10 years. Repeat CXL was rare and only required among younger patients.

Neuro-ophthalmological changes in healthy females exposed to a 5-day dry immersion: a pilot study.

After exposure to microgravity, astronauts undergo microgravity-induced thoraco-cephalic fluid shift, which may lead to ocular changes called "spaceflight associated neuro-ocular syndrome" (SANS). The onset of SANS may be multifactorial, including a potential elevation in intracranial pressure. Moreover, little is known about the impact of spaceflight on SANS in women due to the fact that fewer female astronauts have spent time in long-term missions. The objective is to determine whether similar ophthalmological changes occur in healthy women after short-term exposure to microgravity. The auto-refractometer was used to determine objective refraction. The best corrected distance visual acuity was assessed with a Monoyer chart. The ocular axial length was assessed using optical biometry. The applanation tonometry was used to determine intraocular pressure. Peripapillary retinal nerve fibre layer thickness (pRNFLT), macular total retinal thickness, and ganglion cell complex (GCC) were measured using optical coherence tomography. Ocular axial length is reduced after DI. pRNFL is thickest after DI specifically in the temporal, temporal-inferior, and nasal-inferior quadrants. Macular total retinal at the inferior quadrant of the 6-mm ring is thickest after DI. Global GCC is thinnest after DI. In this study, 5 days of DI induces slight but significant ophthalmological changes in women. However, these subtle changes do not correspond to criteria defined in SANS.

Amniotic membrane grafting for a case of bilateral giant full-thickness macular hole in Alport syndrome after cataract surgery.

PURPOSE: To describe the surgical management of bilateral giant full-thickness macular hole with sudden onset two months after cataract surgery in a patient with Alport syndrome. METHODS: Observational, single-case report. RESULTS: A 54-year-old female with a history of Alport syndrome presented with severe bilateral visual loss two months after cataract surgery. The diagnosis of bilateral giant full-thickness macular hole was made. We found the absence of the internal limiting membrane and the inability to lift and peel a continuous posterior hyaloid sheet during surgical management with 25-gauge pars plana vitrectomy (left eye). Amniotic membrane grafting followed by gas tamponade were performed for hole closure. The hole remained closed but vision was poorly restored two months after. CONCLUSION: Cataract surgery in patients with Alport syndrome could promote early development of giant full-thickness macular hole. Collagen defects could underlie internal limiting membrane absence and the inability to properly peel the posterior hyaloid.

Keratoconus and the Impact of Treatment on Patients' Quality of Life: A Qualitative Study.

INTRODUCTION: Keratoconus has a significant impact on patients' quality of life (QoL), from diagnosis to the advanced stages of the disease. The aim of this research was to identify domains of QoL affected by this disease and its treatment. METHODS: Phone interviews were conducted using a semi-structured interview guide, with patients with keratoconus stratified according to their current treatment. A board of keratoconus experts helped identify the guide's main themes. RESULTS: Thirty-five patients (rigid contact lenses, n = 9; cross-linking, n = 9; corneal ring implants, n = 8; and corneal transplantation, n = 9) were interviewed by qualitative researchers. Phone interviews revealed several QoL domains affected by the disease and its treatments: "psychological", "social life", "professional life", "financial costs" and "student life". All domains were impacted, independently of the treatment history. Few differences were found between treatment regimens and keratoconus stages. Qualitative analysis enabled the development of a conceptual framework based on Wilson and Cleary's model for patient outcomes common to all patients. This conceptual model describes the relationship between patients' characteristics, their symptoms, their environment, their functional visual impairment and the impact on their QoL. CONCLUSIONS: These qualitative findings supported the generation of a questionnaire to evaluate the impact of keratoconus and its treatment on patients' QoL. Cognitive debriefings confirmed its content validity. The questionnaire is applicable for all stages of keratoconus and treatments and may help tracking change over time in regular clinical settings. Psychometric validation is yet to be performed before its use in research and clinical practices.

Identifying predictive factors for long-term visual recovery after corneal endothelial keratoplasty in Fuchs' dystrophy: Potential interaction between the corneal dysfunction and retinal status.

Introduction: Descemet membrane endothelial keratoplasty (DMEK) is the main treatment for Fuchs' dystrophy (FECD). The outcomes are excellent, but the final visual recovery may vary from patient to patient with sometimes no obvious reason of such a spread. Methods: We conducted a clinical prospective multicentric study to identify the predictive factors for the visual result 1 year after surgery. Eighty three patients (83 eyes) were included. Results: Postoperative BCVA after 1 year was 0.20 ± 0.18 logMAR. Logistic regression revealed that good visual recovery correlated negatively with preoperative central macular thickness (p < 0.001) and the need for rebubbling (p = 0.05), and positively with preoperative visual acuity (p = 0.009). Multivariate formula to predict the 1-year BCVA has been suggested. Discussion: Preoperative retinal status seems to be the main predictive factor for long-term visual result after DMEK. Our predictive multivariate model could assist in better informing the patient about the prognosis of the surgery, and in adjusting the therapeutic strategy also, further highlighting the essential collaboration between both cornea and retina subspecialists.

First-line management of necrotizing herpetic retinitis by prioritizing the investigation of immune status and prognostic factors for poor visual outcomes.

PURPOSE: To review management, treatment, and outcomes of patients with necrotizing herpetic retinitis (NHR) to propose an algorithm for first-line management of NHR. METHODS: Retrospective evaluation of a series of patients with NHR at our tertiary center between 2012 and 2021 using demographic, clinical, ophthalmologic, virological, therapeutic, and prognostic characteristics was performed. Patients were classified by NHR type: acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), cytomegalovirus (CMV) retinitis. RESULTS: Forty-one patients with NHR were included: 59% with ARN, 7% with PORN, and 34% with CMV retinitis. All patients with CMV retinitis and PORN were immunocompromised versus 21% of patients with ARN. CMV infection was found in 14 (34%) patients, varicella zoster virus infection in 14 (34%) patients, herpes simplex virus type 2 infection in 8 (20%) and type 1 infection in 5 (12%) patients. Intravenous antiviral therapy was received by 98% of patients and intravitreal antiviral injections by 90% of patients. The overall complication rate during follow-up was 83% of eyes. Most frequent complications were retinal detachment (33% eyes) and retinal break (29% eyes). Prognostic factors for poor visual outcomes were pre-existing monocular vision loss in contralateral eye among 17% of patients, bilateral NHR in 17% of patients, posterior pole involvement in 46% of eyes, and involvement > 2 retinal quadrants in 46% of eyes. CONCLUSIONS: The visual prognosis of patients with NHR remains poor. Prompt investigation of immune status and presence of factors justifying intravitreal antiviral injections must be prioritized to initiate and adapt management while awaiting causative virus confirmation.

New Keratoconus Risk Factors: A Cross-Sectional Case-Control Study.

Purpose: To evaluate risk factors associated with keratoconus in a monocentric cross-sectional case-control study. Methods: This observational study occurred from June 2019 to February 2021 in a university hospital (France). The case group consisted of 195 patients with keratoconus in at least one eye who were followed up by a corneal specialist. The control group consisted of 195 patients without any evidence of keratoconus on slit-lamp examination and corneal topography, who were matched 1 : 1 to controls by age and sex. Data were collected by a self-completed paper questionnaire before the consultation, and a multivariate logistic regression was performed. Results: Multivariate analysis revealed significant associations of keratoconus with family history (odds ratio [OR] = 22.2, p < 0.001), rubbing eyes (OR = 10.9, p < 0.001), allergy (any kind) (OR = 3.80, p < 0.001), smoking exposure (OR = 2.08, p=0.017), and dry eyes (OR = 1.77, p=0.045f). The worst eye was associated with the more rubbed eye (p < 0.001) and the more pressed eye during the night according to sleeping position (p < 0.041). Conclusion: This study confirmed the association between keratoconus and eye rubbing, family history, and allergy. It highlighted the role of pressure on the eyes during sleep. Other less known risk factors such as dry eyes and smoking exposure should be explored in future studies.

Corneal epithelium in keratoconus underexpresses active NRF2 and a subset of oxidative stress-related genes.

Keratoconus (KC) is a multifactorial progressive ectatic disorder characterized by local thinning of the cornea, leading to decreased visual acuity due to irregular astigmatism and opacities. Despite the evolution of advanced imaging methods, the exact etiology of KC remains unknown. Our aim was to investigate the involvement of corneal epithelium in the pathophysiology of the disease. Corneal epithelial samples were collected from 23 controls and from 2 cohorts of patients with KC: 22 undergoing corneal crosslinking (early KC) and 6 patients before penetrating keratoplasty (advanced KC). The expression of genes involved in the epidermal terminal differentiation program and of the oxidative stress pathway was assessed by real time PCR analysis. Presence of some of the differentially expressed transcripts was confirmed at protein level using immunofluorescence on controls and advanced KC additional corneal samples. We found statistically significant under-expression in early KC samples of some genes known to be involved in the mechanical resistance of the epidermis (KRT16, KRT14, SPRR1A, SPRR2A, SPRR3, TGM1 and TGM5) and in oxidative stress pathways (NRF2, HMOX1 and HMOX2), as compared to controls. In advanced KC samples, expression of SPRR2A and HMOX1 was reduced. Decreased expression of keratin (KRT)16 and KRT14 proteins was observed. Moreover, differential localization was noted for involucrin, another protein involved in the epidermis mechanical properties. Finally, we observed an immunofluorescence staining for the active form of NRF2 in control epithelia that was reduced in KC epithelia. These results suggest a defect in the mechanical resistance and the oxidative stress defense possibly mediated via the NRF2 pathway in the corneal keratoconic epithelium.

Ocular Inflammation Induced by Immune Checkpoint Inhibitors.

Ocular immunotherapy-related adverse events (IRAEs), although rare, can be sight-threatening. Our objective was to analyze ocular IRAEs diagnosed in France from the marketing of immune checkpoint inhibitors (ICPIs) until June 2021 and to review the literature. We collected the cases of 28 patients (36 ocular IRAEs), occurring after an average of 17 weeks (±19). Forty-six percent of patients were treated for metastatic melanoma. Anti-PD1 agents were responsible for 57% of the IRAEs. Anterior uveitis was the most common (44%), followed by panuveitis (28%). Of 25 uveitis cases, 80% were bilateral and 60% were granulomatous. We found one case with complete Vogt-Koyanagi-Harada syndrome and one case of birdshot retinochoroidopathy. The other IRAEs were eight ocular surface disorders, one optic neuropathy, and one inflammatory orbitopathy. Seventy percent of the IRAEs were grade 3 according to the common terminology of AEs. ICPIs were discontinued in 60% of patients and 50% received local corticosteroids alone. The literature review included 230 uveitis cases, of which 7% were granulomatous. The distributions of ICPIs, cancer, and type of uveitis were similar to our cohort. Ocular IRAEs appeared to be easily controlled by local or systemic corticosteroids and did not require routine discontinuation of ICPIs. Further work is still warranted to define the optimal management of ocular IRAEs.

Evaluation of the Effects of Vitrectomy with Primary Epiretinal Membrane Peel on Optical Quality Using Double-Pass Aberrometry.

INTRODUCTION: We performed a prospective, single-center, cohort study in order to evaluate the effects of vitrectomy with epiretinal membrane (ERM) peel on optical quality in patients with primary ERM. METHODS: Thirty patients treated for primary ERM by vitrectomy with ERM peel were included from our tertiary university hospital ophthalmology department. The main study outcome was a variation in optical quality parameters measured using the HD Analyzer™ between preoperative and 2-month postoperative evaluations in operated eyes. Optical quality parameters comprised point spread function (PSF) width at 10% and 50%, objective scatter index (OSI), and modulation transfer function (MTF) cutoff. Contralateral non-operated eyes were used as an internal control for measurement reproducibility. RESULTS: Mean PSF width at 10% (42.22 vs. 27.37 arc/min; p = 0.0002) and mean OSI (3.32 vs. 2.32; p = 0.0003) were significantly improved between pre- versus postoperative evaluations. Mean PSF width at 50% and mean MTF cutoff showed no changes. Subgroup analysis according to crystalline lens status gave similar results, demonstrating that improvements in mean PSF width at 10% and OSI were not lens-related. Non-operated eyes showed no changes in any of the parameters analyzed. CONCLUSION: Reduced light scattering measured by OSI indicates improved optical quality following vitrectomy with ERM peel among patients with primary ERM. OSI measurement could thus be a new parameter of interest in the preoperative assessment of primary ERM and other pre-vitrectomy assessments.

Dupilumab-Associated Adverse Events During Treatment of Allergic Diseases.

Among the new biological therapies for atopic diseases, dupilumab is a fully human monoclonal antibody directed against IL-4Rα, the common chain of interleukin-4 and interleukin-13 receptors. Dupilumab showed clinical improvements in patients with atopic dermatitis, asthma, and chronic rhinosinusitis and is currently under development for other indications. While dupilumab is considered to be well tolerated, a number of recent publications have reported various adverse events. This review aims to summarize the current knowledge about these adverse events, which may help clinicians to improve the follow-up of patients on dupilumab. Injection-site reactions are the most common reported adverse event. However, dupilumab has also been shown to cause ophthalmic complications (e.g., dry eyes, conjunctivitis, blepharitis, keratitis, and ocular pruritus), head and neck dermatitis, onset of psoriatic lesions, progression of cutaneous T-cell lymphoma exacerbation, alopecia areata, hypereosinophilia, and arthritis. Most are managed during dupilumab treatment continuation, but some (e.g., severe conjunctivitis) may result in a discontinuation of treatment. Their molecular origin is unclear and requires further investigations. Among other hypothesis, it has been suggested that T helper (Th)2-mediated pathway inhibition may worsen Th1/Th17-dependent immune responses. An ophthalmological examination for the presence of potential predictive indicators of ophthalmic adverse events is recommended before initiation of dupilumab therapy.

New polynomial regression formula to improve second-eye refractive outcomes in sequential bilateral cataract surgery.

PURPOSE: To assess a new polynomial regression formula integrating the refractive prediction error of the first-operated eye to improve the intraocular lens power calculation of the second eye in cataract surgery. SETTING: Centre Hospitalier Universitaire, Toulouse, France. DESIGN: Retrospective multicentric dataset study. METHODS: A polynomial regression formula, WeOptimeye2nd (WO2nd), was developed using a machine-learning algorithm trained on a dataset of 534 patients who underwent sequential bilateral cataract surgery. A separate multicentric dataset was used to retrospectively calculate predicted refraction with WO2nd, SRK/T and Barrett Universal II formulas, and 3 other methods of constant factors (CFs) second-eye refinement (CF0.38, CF0.35, and CF0.5). Mean absolute errors (MAEs) and percentage of eyes within ±0.25, ±0.5, and ±1.0 diopter (D) from predicted spherical equivalent were compared between formulas. RESULTS: The study comprised data on 722 patients. In the overall population, WO2nd had the lowest MAE: 0.339 vs 0.347 (P = .137), 0.340 (P = .956), 0.350 (P = .066), 0.399 (P < .001), and 0.410 (P < .001), with CF0.38, CF0.5, and CF0.35, Barrett II, and SRK/T, respectively. WO2nd had the highest percentage of eyes within ±0.5 D of the predicted refraction, and the difference was statistically significant vs SRK/T and Barrett II formulas but not vs CF0.38, CF0.5, and CF0.35. WO2nd performed the best in axial length (AL) < 22 mm with the lowest MAE and a statistically significant difference vs any other formula. CONCLUSIONS: WO2nd improved the refractive outcome of the second-operated eye and performed well in extreme AL and mean keratometry subgroups.

Use of the heads-up NGENUITY 3D Visualization System for vitreoretinal surgery: a retrospective evaluation of outcomes in a French tertiary center.

Heads-up three-dimensional (3D) surgical visualization systems allow ophthalmic surgeons to replace surgical microscope eyepieces with high-resolution stereoscopic cameras transmitting an image to a screen. We investigated the effectiveness and safety of the heads-up NGENUITY 3D Visualization System in a retrospective evaluation of 241 consecutive vitreoretinal surgeries performed by the same surgeon using conventional microscopy (CM group) over a 1-year period versus the NGENUITY System (3D group) over a consecutive 1-year period. We included for study vitreoretinal surgeries for treatment of retinal detachment (RD) (98 surgeries), macular hole (MH) (48 surgeries), or epiretinal membrane (ERM) (95 surgeries). A total of 138 and 103 eyes were divided into 3D and CM groups, respectively. We found no differences in 3-month postoperative rates of recurrence of RD (10% versus 18%, p = 0.42), MH closure (82% versus 88%, p = 0.69), or decrease in central macular thickness of ERMs (134 ± 188 µm versus 115 ± 105 µm, p = 0.57) between the 3D and CM groups, respectively. Surgery durations and visual prognosis were also similar between both groups. We consolidate that the NGENUITY System is comparable in terms of visual and anatomical outcomes, giving it perspectives for integration into future robotized intervention.

Transepithelial Corneal Cross-linking With Supplemental Oxygen in Keratoconus: 1-Year Clinical Results.

PURPOSE: To evaluate the efficacy and safety of transepithelial corneal cross-linking (CXL) with supplemental oxygen. METHODS: This was a prospective, non-comparative, pilot cohort study conducted at the National Reference Center for Keratoconus (Toulouse, France) on patients with progressive keratoconus. Transepithelial, pulsed, accelerated CXL was performed in an oxygen-rich atmosphere. Oxygen goggles were applied to the eyes to maintain a high level of oxygen during treatment. The main efficacy outcome was the mean change from baseline in maximum keratometry (Kmax) and the secondary outcomes were the mean changes in flat keratometry (K1), steep keratometry (K2), mean keratometry (Km), corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), and demarcation line depth. The safety outcomes were the incidence of adverse events, the mean change in pachymetry, and endothelial cell count. RESULTS: Thirty-four eyes of 34 patients were included. At 12 months postoperatively, the Kmax decreased by 1.56 ± 1.71 diopters (D) (P < .0001) and CDVA improved by 0.093 ± 0.193 logMAR (P < .02). The K2 and Km decreased by 0.51 ± 1.03 D (P < .02) and 0.40 ± 0.78 D (P < .01), respectively. There was no change in K1 and UDVA. The most frequent adverse event was corneal haze (64.78%). There were neither cases of infectious keratitis or loss of more than two lines in CDVA nor changes in pachymetry or endothelial cell count. CONCLUSIONS: Transepithelial CXL performed in an oxygen-rich atmosphere results in improved Kmax and CDVA with good safety. These promising findings suggest that this procedure could be safe and capable of halting the progression of keratoconus. [J Refract Surg. 2021;37(1):42-48.].

Keratoconus Prevalence in Families: A French Study.

PURPOSE: To assess the keratoconus (KC) prevalence among first-degree relatives of affected subjects. METHODS: We performed large epidemiological, prospective, and observational cohort, which took place in the French KC National Reference Centre, in Bordeaux. We studied data from 94 unrelated patients with KC and at least 2 first-degree relatives assessable. Each subject had a thorough ocular examination including visual acuity, refraction, slitlamp biomicroscopy, indirect ophthalmoscopy, keratometry, corneal topography and tomographer (Topographic Modeling System; Tomey Corporation, Japan; and Galilei G4, Ziemer, Switzerland, respectively), pachymetry, and biomechanical properties of cornea (Ocular Response Analyzer; Reichert, Depew, NY). Additional data were collected about atopy, smoking, and eye-rubbing habits. KC prevalence, multivariate analysis, and familial correlation analysis have been studied. RESULTS: Of the 221 relatives, 9.05% (n = 20) had clinically manifest KC, and 15.4% (n = 31) had subclinical KC. The prevalence of KC was estimated equal to 0.14 [95% confidence interval (CI), 0.07-0.22] among parents, 0.03 (95% CI, 0-0.10) among offspring, and 0.10 (95% CI, 0.04-0.20) among siblings. In multivariable analysis, age and eye-rubbing were associated with an increased risk of KC. The familial correlation of KC among probands' first-degree relatives was estimated at 0.55 among parents, 0.29 among offspring, and 0.49 among siblings. CONCLUSIONS: Being a first-degree relative of a subject with KC remains a risk factor for developing KC. This should be taken into account especially when screening for KC in pediatric patients, for refractive surgery candidates, and for patients being evaluated for cataract surgery.

BMP-1 disrupts cell adhesion and enhances TGF-ß activation through cleavage of the matricellular protein thrombospondin-1.

Bone morphogenetic protein 1 (BMP-1) is an important metalloproteinase that synchronizes growth factor activation with extracellular matrix assembly during morphogenesis and tissue repair. The mechanisms by which BMP-1 exerts these effects are highly context dependent. Because BMP-1 overexpression induces marked phenotypic changes in two human cell lines (HT1080 and 293-EBNA cells), we investigated how BMP-1 simultaneously affects cell-matrix interactions and growth factor activity in these cells. Increasing BMP-1 led to a loss of cell adhesion that depended on the matricellular glycoprotein thrombospondin-1 (TSP-1). BMP-1 cleaved TSP-1 between the VWFC/procollagen-like domain and the type 1 repeats that mediate several key TSP-1 functions. This cleavage induced the release of TSP-1 C-terminal domains from the extracellular matrix and abolished its previously described multisite cooperative interactions with heparan sulfate proteoglycans and CD36 on HT1080 cells. In addition, BMP-1-dependent proteolysis potentiated the TSP-1-mediated activation of latent transforming growth factor-ß (TGF-ß), leading to increased signaling through the canonical SMAD pathway. In primary human corneal stromal cells (keratocytes), endogenous BMP-1 cleaved TSP-1, and the addition of exogenous BMP-1 enhanced cleavage, but this had no substantial effect on cell adhesion. Instead, processed TSP-1 promoted the differentiation of keratocytes into myofibroblasts and stimulated production of the myofibroblast marker α-SMA, consistent with the presence of processed TSP-1 in human corneal scars. Our results indicate that BMP-1 can both trigger the disruption of cell adhesion and stimulate TGF-ß signaling in TSP-1-rich microenvironments, which has important potential consequences for wound healing and tumor progression.

Clinical Characteristics and Outcomes of Ocular Cicatricial Pemphigoid: A Cohort Study and Literature Review.

PURPOSE: Ocular cicatricial pemphigoid (OCP) is a rare systemic autoimmune disease and a potentially blinding subepithelial blistering disorder. The purpose of this study was to describe the clinical spectrum of the disease and to assess the efficacy and safety of immunosuppressive agents in a cohort of patients with OCP. METHODS: We conducted a monocentric retrospective cross-sectional cohort study of all unselected consecutive patients diagnosed with progressive OCP. Ocular and extra ophthalmological involvement as well as histological findings were gathered. Other outcomes were exposures to immunosuppressive agents defined by the use of a particular treatment. For each exposure, success in controlling ocular inflammation was graded as a complete response, response, or failure. Relapses and adverse events (AE) were also recorded. RESULTS: Seventeen patients (34 affected eyes), 35% of whom were women, were included, with an age at diagnosis of 75 ± 11 years. Corneal involvement was diagnosed in 30 of 34 eyes, and 22 of 34 eyes had progressive fibrosing conjunctival involvement. Sixty-two exposures to immunosuppressive agents or biologics were recorded: dapsone, n = 26; mycophenolate mofetil, n = 6; azathioprine, n = 4; cyclophosphamide, n = 10; rituximab, n = 14; and intravenous immunoglobulin, n = 2. Rates of response and of complete response achievement during the first 3 months were 84% and 45%, respectively. Response rates were 100%, 100%, 86%, 85%, and 80% for intravenous immunoglobulin, mycophenolate mofetil, rituximab, dapsone, and cyclophosphamide, respectively. Thirteen percent of those drugs were discontinued because of an adverse event in 4 patients. CONCLUSIONS: This study describes the efficacy of immunosuppressants or biologics with an acceptable safety profile for OCP.

Transepithelial photorefractive intrastromal corneal crosslinking versus photorefractive keratectomy in low myopia.

PURPOSE: To compare the outcomes of transepithelial photorefractive intrastromal corneal crosslinking (CXL) and photorefractive keratectomy (PRK) in eyes with low myopia. SETTING: Purpan Hospital, Toulouse, France. DESIGN: Prospective case series. METHODS: Myopic patients with a manifest refraction spherical equivalent (MRSE) of -1.00 to -2.50 diopters (D) and a cylindrical component of plano to -0.75 D were included. The dominant eye had PRK (PRK eyes). The nondominant eye had transepithelial photorefractive intrastromal CXL with riboflavin (ParaCel Part 1 and 2), 30 mW/cm2 pulsed ultraviolet-A irradiation centered on the pupil (Mosaic System) for 16 minutes and 40 seconds, and a supplemental oxygen delivery mask (CXL eyes). The primary outcome measure was the change in the MRSE. Other outcome measures were the uncorrected (UDVA) and corrected (CDVA) distance visual acuities, mean keratometry, and endothelial cell count (ECC) over a 6-month follow-up. Adverse events were assessed. RESULTS: Nineteen patients were included. By 6 months, the mean MRSE had decreased by 0.72 D ± 0.42 (SD) in CXL eyes and by 1.35 ± 0.46 D in PRK eyes (P < .001). The mean change in UDVA was -0.35 ± 0.21 logarithm of the minimum angle of resolution (logMAR) in CXL eyes and -0.66 ± 0.19 logMAR in PRK eyes (P < .001). No complications were reported. The change in the ECC and CDVA was not statistically significant. CONCLUSIONS: Photorefractive keratectomy provided better visual and refractive outcomes than transepithelial photorefractive intrastromal CXL. Transepithelial photorefractive intrastromal CXL, however, showed the potential refractive effect of CXL but with a limited magnitude of myopic correction.