Aftermarket effects of cenegermin for neurotrophic keratopathy in pediatric patients

PurposeNeurotrophic keratopathy (NK) is a rare condition characterized by poor corneal sensation and healing. Cenegermin (topical recombinant nerve growth factor) has gained traction as a medical therapy for NK in recent years, and is FDA-approved for patients over two years old. However, no major trials have demonstrated the drug's efficacy in children. This study reviews the outcomes of cenegermin therapy in a pediatric patient population.MethodsRetrospective case series of patients from three tertiary referral institutions who 1) initiated an 8-week course of cenegermin therapy, and 2) were 18 years or less at time of treatment initiation.ResultsEight pediatric patients, with a total of nine affected eyes, underwent cenegermin therapy. All eight patients had previously trialed other NK-specific treatments, none of which had been entirely successful. Five patients (63%) completed the full eight-week therapy course. Five patients (63%) experienced clinical improvement not attributed to another treatment, through improved corneal ulcer stage (n = 5) and best-corrected visual acuity (n = 2). Clinical improvements persisted through a mean recurrence-free period of 10 months. Adverse effects reported during therapy included ocular pain, difficulty sleeping, and continued corneal thinning.ConclusionThe results provide modest support for the use of cenegermin in pediatric patients with neurotrophic keratopathy. The primary benefit was an improvement in corneal epithelial stability. Clinicians should be aware that pre-existing corneal scarring in NK may significantly limit the ability of cenegermin alone to improve visual acuity, and should closely monitor the corneal epithelial status during therapy in pediatric patients.     

Visualization of microneuromas by using in vivo confocal microscopy: An objective biomarker for the diagnosis of neuropathic corneal pain?

PurposeThe diagnosis of neuropathic corneal pain (NCP) is challenging, as it is often difficult to differentiate it from conventional dry eye disease (DED). In addition to eye pain, NCP can present with similar signs and symptoms of DED. The purpose of this study is to find an objective diagnostic sign to identify patients with NCP, using in vivo confocal microscopy (IVCM).MethodsThis was a comparative, retrospective, case-control study. Patients with clinical diagnosis of NCP (n = 25), DED (n = 30), and age- and sex-matched healthy controls (n = 16), who underwent corneal imaging with IVCM (HRT3/RCM) were included. Central corneal IVCM scans were analyzed by 2 masked observers for nerve density and number, presence of microneuromas (terminal enlargements of subbasal corneal nerve) and/or nerve beading (bead-like formation along the nerves), and dendritiform cell (DC) density.ResultsThere was a decrease in total nerve density in both NCP (14.14 ± 1.03 mm/mm²) and DED patients (12.86 ± 1.04 mm/mm²), as compared to normal controls (23.90 ± 0.92 mm/mm²; p < 0.001). However, total nerve density was not statistically different between NCP and DED patients (p = 0.63). Presence of nerve beading was not significantly different between patients and normal controls (p = 0.15). Interestingly, microneuromas were observed in all patients with NCP, while they were not present in any of the patients with conventional DED (sensitivity and specificity of 100%). DC density was significantly increased in both NCP (71.89 ± 16.91 cells/mm²) and DED patients (111.5 ± 23.86 cells/mm²), as compared to normal controls (24.81 ± 4.48 cells/mm² (p < 0.05). However, there was no significant difference in DC density between DED and NCP patients (p = 0.31).ConclusionIVCM may be used as an adjunct diagnostic tool for the diagnosis of NCP in the presence of neuropathic symptoms. Microneuromas may serve as a sensitive and specific biomarker for the diagnosis of NCP.     

A multicenter report of the use of plasma rich in growth factors (PRGF) for the treatment of patients with ocular surface diseases in North America

PurposeTo investigate the efficacy and safety of plasma rich in growth factors (PRGF) eyedrops in the management of patients with ocular surface diseases in North America.MethodsMulticenter interventional case series of patients using PRGF eyedrops for the first time. A cohort of patients was analyzed for corneal staining score at initial visit and at 3 months of therapy with PRGF. Another cohort responded to a 10-item questionnaire that evaluated patients' satisfaction and safety, which included the symptom assessment questionnaire in dry eye (SANDE) score, after 6 months of PRGF treatment.ResultsA total of 153 patients were analyzed. Of these, 102 were reviewed for corneal epitheliopathy and 99 patients responded to the questionnaire. The mean (±SD) age of the population was 63.7 ± 17 years and 72.5% were female. The clinical indications for PRGF usage were dry eye (60%), neurotrophic keratopathy (15%), dormant corneal ulcers (12%), limbal stem cell deficiency (10%), and cicatrizing conjunctivitis (4%). At the final visit, 74.3% of patients showed an improvement of their corneal staining. Those who had punctate epithelial erosions or epithelial defects were reduced from 76.5% to 47% and 23.5% to 7.8% respectively (p < 0.0001). Symptoms, measured via SANDE score, significantly decreased from a median of 90 to 34.6 out of 100 points on follow-up (p < 0.0001). Only one patient (0.98%) complained of ocular burning sensation as a side effect.ConclusionsThis multicentric study demonstrates the safety and efficacy of the use of PRGF for treating signs and symptoms in patients with significant ocular surface diseases.     

Long-term outcomes of cultivated cell sheet transplantation for treating total limbal stem cell deficiency

PurposeThis study was conducted to determine the long-term outcomes of cultivated cell sheet transplantation (CCST), and to clarify risk factors that affected the outcomes.MethodsWe retrospectively analyzed the medical charts and photographs of 246 consecutive surgeries (162 eyes from 139 patients) that used CCST for treating total limbal stem cell deficiency. Deficiency types included Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (SJS/TEN; n = 80), ocular surface burns (Burn; n = 75), ocular cicatricial pemphigoid (OCP) or pseudo-OCP (n = 58), and others (n = 33). The methods of CCST included 103 cultivated limbal epithelial transplantations (28 autologous, 62 allogeneic, and 13 living-related relatives), and 143 cultivated oral mucosal epithelial transplantations. We analyzed the rate of successful ocular surface reconstruction, clear corneas, and best-corrected visual acuity equal to or better than 20/200.ResultsWith a mean observation period of 357 weeks, successful ocular surface reconstruction and clear corneas at last visit were achieved in 65.1% of the patients. Corrected visual acuity equal to or better than 20/200 was achieved in 19.0% of the patients. Eyes with SJS/TEN exhibited worse outcomes compared with the Burn group. Postoperative complications included corneal ulcerations or perforations (18.3%), glaucoma (13.8%), and infections (8.5%). Multivariate analyses using the logistic mixed-effects model indicated that the presence of preoperative corneal epithelial defects was a significant risk factor for postoperative failure.ConclusionsIn this series, the success rate of CCST after a mean observation period of 357 weeks was 65.1%, and preoperative epithelial defect was the most relevant risk factor.     

Alterations in corneal nerves in different subtypes of dry eye disease: An in vivo confocal microscopy study

PurposeTo evaluate corneal subbasal nerve alterations in evaporative and aqueous-deficient dry eye disease (DED) as compared to controls.MethodsIn this retrospective, cross-sectional, controlled study, eyes with a tear break-up time of less than 10 s were classified as DED. Those with an anesthetized Schirmer's strip of less than 5 mm were classified as aqueous-deficient DED. Three representative in vivo confocal microscopy images were graded for each subject for total, main, and branch nerve density and numbers.ResultsCompared to 42 healthy subjects (42 eyes), the 70 patients with DED (139 eyes) showed lower total (18,579.0 ± 687.7 μm/mm² vs. 21,014.7 ± 706.5, p = 0.026) and main (7,718.9 ± 273.9 vs. 9,561.4 ± 369.8, p < 0.001) nerve density, as well as lower total (15.5 ± 0.7/frame vs. 20.5 ± 1.3, p = 0.001), main (3.0 ± 0.1 vs. 3.8 ± 0.2, p = 0.001) and branch (12.5 ± 0.7 vs. 16.5 ± 1.2, p = 0.004) nerve numbers. Compared to the evaporative DED group, the aqueous-deficient DED group showed reduced total nerve density (19,969.9 ± 830.7 vs. 15,942.2 ± 1,135.7, p = 0.006), branch nerve density (11,964.9 ± 749.8 vs. 8,765.9 ± 798.5, p = 0.006), total nerves number (16.9 ± 0.8/frame vs. 13.0 ± 1.2, p = 0.002), and branch nerve number (13.8 ± 0.8 vs. 10.2 ± 1.1, p = 0.002).ConclusionsPatients with DED demonstrate compromised corneal subbasal nerves, which is more pronounced in aqueous-deficient DED. This suggests a role for neurosensory abnormalities in the pathophysiology of DED.     

Dry eye signs and symptoms in aromatase inhibitor treatment and the relationship with pain

PurposeAromatase inhibitors (AIs) limit the synthesis of oestrogen in peripheral tissues thus lowering levels of oestrogen. The primary aim was to evaluate whether women treated with AIs have altered dry eye symptoms and signs. A sub-aim was to investigate whether symptoms of dry eye in postmenopausal women were associated with symptoms of non-eye pain, ocular pain and self-rated pain perception.MethodsThis cross-sectional, observational, single visit study recruited 56 postmenopausal women (mean age 64.1 + 7.9 years) and 52 undergoing AI treatment (mean age 66.6 + 9.0). Ocular symptoms (OSDI, MGD14) and pain questionnaires (PSQ, OPAS) were administered and signs of dry eye and meibomian gland dysfunction were evaluated.ResultsAlmost half of each group reported dry eye symptoms, defined as OSDI>12 (48% control, 46% AI). The PSQ score was significantly higher in the AI group (p = 0.04). Neither frequency or severity of dry eye (or MGD) symptoms scores were significantly different between groups. In the AI group, meibomian gland expressibility score was worse (p = 0.003); there were no differences in any other signs. Higher OSDI scores were associated with higher OPAS eye-pain scores (r = 0.49, p < 0.001), but not OPAS non-eye pain (r = 0.09, p = 0.35). Pain perception (PSQ) showed a moderate positive association with OPAS eye-pain (r = 0.30, p = 0.003).ConclusionsIn this study elevated ocular symptoms were observed in both the AI treated and the untreated groups, with no difference between the groups. Women undergoing AI treatment for early stage breast cancer had worse meibum expressibility score and increased pain perception compared to an untreated group of women.     

Neurotrophic keratitis: Frequency,etiologies, clinical management and outcomes

PurposeTo determine neurotrophic keratitis (NK) frequency, etiologies and prognostic factors, and evaluate the outcome of its management.MethodsIn this retrospective epidemiologic study, we reviewed the electronic records of all patients consulting our tertiary referral eye hospital between November 2009 and October 2017. NK was defined as corneal hypoesthesia or anesthesia associated with epithelial irregularities.ResultsAmong the 305,351 patients’ files screened for eligibility, 335 (354 eyes) were included, yielding an NK frequency of 11/10,000 (0.11%). Their mean ± SD age was 63.1 ± 21.0 years. Eyes were equally divided among the Mackie classification 3 stages. The most frequent etiology was herpetic eye disease (114 eyes; 32.2%). A multifactorial cause was found for 121 (34.2%) eyes. Surgery required for 118 eyes (33.3%). Respective success rates for amniotic membrane transplantation (AMT) or matrix-regeneration of stages 2 and 3, and autologous serum of stage 1 were 57.2%, 63.6% and 21.7%, with mean healing times of 15.0, 16.3 and 85 days. The overall healing rate was 79.5%, with a mean of 44.8 days to healing. Advanced initial stage, diminished corrected-distance visual acuity (CDVA) and advanced age correlated with worse final CDVA.ConclusionsNK was more frequent than previously reported in the literature. Delayed diagnoses indicated we must increase ophthalmologists’ awareness of this disease for patients with decreased corneal sensitivity and abnormal epithelium. To improve prognosis and final CDVA, NK-specific treatment should be initiated as soon as the diagnosis is suspected. Patient-centered combinations of different therapeutic components and close monitoring achieved promising results.     

The Dry Eye Assessment and Management (DREAM) extension study – A randomized clinical trial of withdrawal of supplementation with omega-3 fatty acid in patients with dry eye disease

PurposeTo determine effects of continued or discontinued use of omega-3 (ω3) fatty acid supplements through a randomized withdrawal trial among patients assigned to ω3 supplements in the first year of the DREAM study.MethodsPatients who were initially assigned to ω3 (3000 mg) for 12 months in the primary trial were randomized 1:1 to ω3 active supplements or placebos (refined olive oil) for 12 more months. The primary outcome was change in the Ocular Surface Disease Index (OSDI) score. Secondary outcomes included change in conjunctival staining, corneal staining, tear break-up time, Schirmer test, and adverse events.ResultsAmong 22 patients assigned to ω3 and 21 to placebo supplements, the mean change in OSDI score between month 12 and 24 was similar between treatment groups (mean difference in change −0.6 points, 95% confidence interval [CI], (−10.7, 9.5), p = 0.91). There were no significant differences between groups in mean change in conjunctival staining (difference in mean change −0.5 points; 95% CI (−1.2, 0.3)), corneal staining (−0.3 points; 95% CI (−1.2, 0.3)), tear break-up time (−0.8 s; 95% CI (−2.6, 0.9)) and Schirmer test (0.6 mm, 95% CI (−2.0, 3.2)). Rates of adverse events were similar in both groups.ConclusionAmong patients who received ω3 supplements for 12 months in the primary trial, those discontinuing use of ω3 for an additional 12 months did not have significantly worse outcomes compared to those who continued use of ω3.ClinicalTrials.gov number NCT02128763.     

Infrared meibography allows detection of dimensional changes in meibomian glands following intranasal neurostimulation

PurposePatients with dry eye disease (DED) may suffer from decreased tear break-up time due to meibomian gland (MG) dysfunction. Infrared meibography (IR Meibography) uses infrared wavelength light to visualize meibomian glands in vivo. We aimed to explore the feasibility of using serial IR Meibography imaging to assess morphological changes in MGs as an indirect measure of functionality, following intranasal neurostimulation (ITN).MethodsFifteen DED subjects were prospectively enrolled in a single-center, single-arm study. Changes in MGs were captured using IR meibography (RTVUE-XR, Optovue, Inc. Fremont, CA, USA) on the lower eyelids before and after 3 min of ITN (TrueTear®, Allergan, Dublin, Ireland) use that delivers a microcurrent to sensory neurons of the nasal cavity. The same MGs were selected pre- and post-stimulation, and MG area and perimeter were analyzed by two masked observers.ResultsMean (±SD) pre- and post-stimulation MG areas were 2,187.60 ± 635.88 μm² and 1,933.20 ± 538.55 μm², respectively. The mean change in area, 254.49 μm², representing an 11.6% reduction following ITN use, was statistically significant (p = 0.001). Mean (±SD) pre- and post-stimulation MG perimeters were 235.9 ± 51.38 μm and 222.2 ± 47.72 μm, respectively. The mean change in perimeter, 13.7 μm, representing a 5.81% reduction following ITN use, was statistically significant (p = 0.012).ConclusionsOur study shows that IR meibography can be used to detect immediate changes in gland area and perimeter, an indirect measure of MG activity following intervention by ITN.     

Physical inactivity,prolonged sedentary behaviors,and use of visual display terminals as potential risk factors for dry eye disease: JPHC-NEXT study

PurposeThis population-based, cross-sectional study was performed to assess the influence of life-style modalities, including physical activity, sedentary behaviors, and visual display terminal (VDT) use, on the prevalence of dry eye disease (DED).MethodsThe study included a total of 102,582 participants aged 40–74 years, from the Japan Public Health Center-based Prospective Study for the Next Generation, a large nationwide prospective ongoing Japanese cohort study. Logistic regression analyses were used to investigate the relationship of total and leisure-time physical activity, duration of sedentary behaviors, and VDT use (hours/day) with DED.ResultsAmong 47,346 men and 55,236 women, 25,234 (8315 males and 16,919 females) cases of DED were documented. Total physical activity was significantly related to decreased DED in both sexes; for the highest vs. lowest total physical activity quartiles, the multivariable-adjusted odds ratios (ORs) for DED were 0.90 (95% confidence interval [CI], 0.84–0.97; P_trend<0.03) and 0.91 (95% CI, 0.86–0.95; P_trend<0.001) for men and women, respectively. Conversely, prolonged sedentary behaviors and VDT use had significantly higher prevalence of DED in both sexes (P_trend<0.001). Notably, the favorable effect of total physical activity on decreased DED in women was more prevalent with prolonged VDT use (≥2 h/day) (P_interaction<0.01). In men, the duration of VDT use or sitting was a significant modifier of the inverse relationship between leisure-time physical activity and DED (P_interaction<0.05).ConclusionsPhysical inactivity, prolonged sedentary behaviors, and use of VDT were related to increased susceptibility to DED among middle-aged to older Japanese adults.     

The natural history of untreated ocular hypertension and glaucoma

Glaucoma is a chronic, progressive disease leading to irreversible blindness if left untreated; however, since reducing intraocular pressure has proven to be successful in slowing disease progression, little is known about the natural history of untreated glaucoma. This knowledge can be valuable in guiding management decisions in the era of personalized medicine. A systematic search was performed in Medline (PubMed), Embase, and Web of Science in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRIMSA) guidelines. The rate of structural and/or functional progression and conversion to glaucoma or to a more advanced stage of glaucoma are discussed for ocular hypertension and different types of open-angle glaucoma. Forty-three studies were included. Different rates of progression were found both among and within the different diagnostic groups that belong to the open-angle glaucoma spectrum. The highest rate was found in pseudoexfoliation glaucoma, followed by high tension glaucoma, normal tension glaucoma, and ocular hypertension, in decreasing order. The lowest rate was observed in glaucoma suspects. The known rates of progression provide valuable prognostic information for ophthalmologists and patients. Nonetheless, due to high variability among patients, individual progression cannot be accurately predicted and repeated follow-up examinations are required to estimate individual progression.     

Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling

X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 gene mutations on the X-chromosome. XLRS causes bilateral reduced acuities from young age, and on clinical exam and by ocular coherence tomography (OCT) the neurosensory retina shows foveo-macular cystic schisis cavities in the outer plexiform (OPL) and inner nuclear layers (INL). XLRS manifests between infancy and school-age with variable phenotypic presentation and without reliable genotype-phenotype correlations. INL disorganization disrupts synaptic signal transmission from photoreceptors to ON-bipolar cells, and this reduces the electroretinogram (ERG) bipolar b-wave disproportionately to photoreceptor a-wave changes. RS1 gene expression is localized mainly to photoreceptors and INL bipolar neurons, and RS1 protein is thought to play a critical cell adhesion role during normal retinal development and later for maintenance of retinal structure. Several independent XLRS mouse models with mutant RS1 were created that recapitulate features of human XLRS disease, with OPL-INL schisis cavities, early onset and variable phenotype across mutant models, and reduced ERG b-wave to a-wave amplitude ratio. The faithful phenotype of the XLRS mouse has assisted in delineating the disease pathophysiology. Delivery to XLRS mouse retina of an AAV8-RS1 construct under control of the RS1 promoter restores the retinal structure and synaptic function (with increase of b-wave amplitude). It also ameliorates the schisis-induced inflammatory microglia phenotype toward a state of immune quiescence. The results imply that XLRS gene therapy could yield therapeutic benefit to preserve morphological and functional retina particularly when intervention is conducted at earlier ages before retinal degeneration becomes irreversible. A phase I/IIa single-center, open-label, three-dose-escalation clinical trial reported a suitable safety and tolerability profile of intravitreally administered AAV8-RS1 gene replacement therapy for XLRS participants. Dose-related ocular inflammation occurred after dosing, but this resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in dose-dependent fashion, but no antibodies were observed against the RS1 protein. Retinal cavities closed transiently in one participant. Technological innovations in methods of gene delivery and strategies to further reduce immune responses are expected to enhance the therapeutic efficacy of the vector and ultimate success of a gene therapy approach.     

Capsaicin-induced pain sensitivity in short tear break-up time dry eye

PurposeTo evaluate transient receptor potential vanilloid 1 (TRPV1)-mediated pain sensitivity in patients with short tear break-up time (TBUT) dry eye (DE) by using the capsaicin stimulus test.MethodsThis prospective cross-sectional comparative study included 22 eyes of 22 patients with short TBUT DE and 11 eyes of 11 non-DE control subjects. Patients were divided into two groups based on response to standard DE treatments: 10 non-responders (intractable DE) and 12 responders (responsive DE). Mechanical touch (M-touch) and mechanical pain (M-pain) were measured using a Cochet-Bonnet esthesiometer. Capsaicin-induced pain (C-pain) and C-pain duration (C-pain DT) were measured using a capsaicin stimulus test. Psychological distress was also assessed.ResultsM-touch sensitivity was similar among all three groups. M-pain sensitivity was higher in the responsive DE group than in the intractable DE and control groups (P < .001). C-pain sensitivity was lower (P < .001) in the intractable DE group than in the responsive DE and control groups, and C-pain DT was shorter (P = .006) in the intractable DE group than in the responsive DE group. Psychological distress was higher in the intractable DE group than in the control group (P < .001).ConclusionsPatients with intractable short TBUT DE were less sensitive to the effects of capsaicin than patients with responsive short TBUT DE and controls. Altered neural activation may contribute to the development of DE symptoms in the short TBUT DE subjects. The capsaicin stimulus test may be used to better understand pain sensitivity in short TBUT DE patients.     

Pollen shells and soluble factors play non-redundant roles in the development of allergic conjunctivitis in mice

PurposeWe aimed to clarify the role of particulate allergen exposure to the conjunctiva in the development of allergic conjunctivitis.MethodsWe administered ragweed pollen suspension, pollen extract, pollen shell, particulate air pollutants, and their combinations to the mouse conjunctiva five days a week without prior sensitization. Clinical signs were scored. Histological changes, cellular infiltrations, mRNA expressions, lymph node cell recall responses, and serum immunoglobulin levels were assessed. Immune cell-depleting antibodies and ST2 knockout mice were used to investigate the cellular and molecular requirements.ResultsPollen suspension, but not the extract or shell alone, induced robust eosinophilic conjunctivitis, accompanied by a proliferative response of epithelial cells. A combination of pollen extract and shell completely restored eosinophil accumulation. In addition, eosinophilic conjunctivitis was induced by a mixture of particulate air pollutants and pollen extract. Mechanistically, eosinophil accumulation was ameliorated by deficiency of the IL-33 receptor ST2 and abolished by depleting CD4⁺ T cells. Pollen shells, but not the extract, induced IL-33 release from conjunctival epithelial cells in vivo.ConclusionsOur results indicate the non-redundant roles for the allergens’ particulate properties and soluble factors in the development of allergic conjunctivitis.     

Investigation of factors associated with ABCB5-positive limbal stem cell isolation yields from human donors

PurposeTo identify factors associated with isolation yields of ATP-binding cassette (ABC) superfamily member B5 (ABCB5)-positive limbal stem cells (LSCs) from human cadaveric donor eyes.MethodsWhole eye globes were obtained from the Saving Sight eye bank, Kansas City, MO and the CorneaGen eye bank, Seattle, WA. ABCB5-positive LSCs were sorted by flow cytometry upon anti-ABCB5 monoclonal antibody staining within one week after donor death. The yields of live limbal epithelial cells in their entirety and of isolated pure ABCB5-positive LSC subsets were correlated with variables contained in the eye donors’ medical information.ResultsThe mean isolation yield of live limbal epithelial cells and ABCB5-positive LSCs per donor eye was (340,000 ± 160,000 and 2,608 ± 1,842 respectively, mean ± SD). Stepwise regression analysis showed that cardiac disease-related death was the strongest negative predictor of the ABCB5-positive LSC isolation yield (p = 0.01). While we observed a trend for an age-related decline in the yield of ABCB5-positive LSCs, a statistically significant association could not be established (2% decrease/year, p = 0.11). Additionally, despite a trend for decreased isolation yields of total live limbal epithelial cells isolated from single donors with a longer time between death and tissue processing (p = 0.04), this did not affect the yields of purified ABCB5-positive LSC, which was independent of increasing time between death and tissue processing (p = 0.50).ConclusionsOur study identifies cardiac disease-related death as a donor variable significantly associated with lower ABCB5-positive LSC isolation yields.     

Meibum sphingolipid composition is altered in individuals with meibomian gland dysfunction-a side by side comparison of Meibum and Tear Sphingolipids

PurposeSphingolipids (SPL) play a role in cell signaling, inflammation, and apoptosis. The purpose of this study was to examine meibum and tear SPL composition in individuals with poor versus good meibum quality.MethodsIndividuals were grouped by meibum quality (n = 25 with poor quality, case group and n = 25 with good quality, control group). Meibum and tears were analyzed with liquid chromatography-mass spectrometry (LC-MS) to quantify SPL classes. Semiquantitative and relative composition (mole percent) of SPL and major classes, Ceramide (Cer), Hexosyl-Ceramide (Hex-Cer), Sphingomyelin (SM), Sphingosine (Sph), and sphingosine 1-phosphate (S1P) were compared between groups.ResultsDemographic characteristics were similar between the two groups. Overall, individuals with poor meibum quality had more SPL pmole in meibum and tears than controls. Relative composition analysis revealed that individuals with poor meibum quality had SPL composed of less Cer, Hex-Cer, and Sph and more SM compared to individuals with good quality meibum. This pattern was not reproduced in tears as individuals with poor meibum quality had SPL composed of a similar amount of Cer, but more Hex-Cer, Sph and SM compared to controls. In meibum, SPL pmole and relative composition most strongly correlated with MG metrics while in tears, SPL pmole and relative composition most strongly correlated with tear production. SPL in both compartments, specifically Cer pmole in meibum and S1P% in tears, correlated with DE symptoms.ConclusionSPL composition differs in meibum and tears in patients with poor vs good meibum quality. These findings may be translated into therapeutic targets for disease.     

Update on pediatric corneal diseases and keratoplasty

Managing pediatric corneal disorders is challenging as the prognosis of pediatric keratoplasty depends on several factors. Advancements in the genetic basis of congenital corneal diseases and investigations in congenital corneal conditions provide a better understanding of pediatric corneal conditions. Surgeons performing keratoplasty in children now have a choice of various techniques. Evolving surgical techniques of anterior lamellar and endothelial keratoplasties have expanded the management interventions in these pediatric corneal morbidity conditions; however, considerable concerns still exist in association with corneal transplantation in infants and children. Outcomes in pediatric keratoplasty depend upon the preoperative indications, the timing of surgical intervention, intraoperative and postoperative factors including the patient/care givers’ compliance. Factors such as low scleral rigidity, higher rate of graft failure, need for frequent examinations under anesthesia, and difficulty in optimal visual acuity assessment still remain a considerable challenge in pediatric scenarios. In children, deprivation amblyopia as a result of the corneal opacification can adversely affect visual development, causing dense amblyopia. Outcomes to surgical interventions for management of corneal opacification in children are further compromised by the preexisting amblyopia apart from the concerns of refractive outcome of the graft. Graft rejection, graft infection, amblyopia, and glaucoma continue to be serious concerns. In recent years both anterior and posterior lamellar keratoplasty techniques are being increasingly performed in pediatric eyes, which offer advantages in the form of lower risk of graft rejection. The timing of surgery, careful case selection, cautious intraoperative approach, and optimal postoperative management can improve the anatomical and functional outcome in difficult cases.     

Advances in the management of Acanthamoeba keratitis: A review of the literature and synthesized algorithmic approach

Acanthamoeba keratitis (AK) is a severe cause of infectious keratitis and represents a significant clinical challenge. Recent literature regarding AK epidemiology, diagnosis, treatment modalities, and prognosis is reviewed and synthesized to propose an algorithmic protocol for AK management. Globally, AK outbreaks in developed countries are ongoing, and AK rates have increased. Moreover, current outbreaks may carry a worse prognosis than prior outbreaks. Despite identification of contact lens solutions implicated in AK outbreaks and the consequent market recall of these products, outbreaks persist. Acanthamoeba keratitis afflicts not only refractive soft contact lens users but also cosmetic contact lens users and gas permeable (especially orthokeratology) lens users. Innovations in in vivo confocal microscopy and PCR assays have increased the role for these adjuvant tests alongside corneal smear and culture in a multimodal diagnostic approach to suspected AK. Biguanides (such as chlorhexidine and polyhexamethylene biguanide) and diamidines (propamidine isethionate and hexamidine) remain cornerstones of AK management, and evidence for other treatment modalities continues to evolve. Voriconazole in topical and systemic forms may be useful as adjuvant therapy. The anti-leishmaniasis drug miltefosine, recently given orphan drug status by the United States Food and Drug Administration, has increasing evidence supporting a role in patients with severe/refractory disease. Prior topical corticosteroids have been consistently shown to be associated with worse outcomes in AK. Although not historically thought of as a treatment modality, benzalkonium chloride preservative may be leveraged for its anti-Acanthamoebal properties. The role of Rose-Bengal photodynamic antimicrobial therapy is evolving in selected cases of AK.