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.     

Benzalkonium chloride,a common ophthalmic preservative,compromises rat corneal cold sensitive nerve activity

PurposeCorneal nerves comprise the densest sensory network in the body. Dysfunction of the corneal cold sensitive neurons (CSN) is implicated in ophthalmic disorders, including Dry Eye Disease, the most common ocular surface disorder. The preservative Benzalkonium chloride (BAK) and the mydriatic agent Phenylephrine hydrochloride (PHE) are considered to be inactive at the level of the CSNs. The purpose of this study is to test the impacts of continuous exposures to BAK or PHE at their clinically used concentrations on corneal nerve structure and function.MethodsIn vivo extracellular electrophysiology of the rat trigeminal ganglion was used to monitor CSN functional response to stimuli mimicking physiological states and stressors of the cornea. Corneal nerve structure was evaluated by immunostaining.ResultsAmong the tested stimuli, cold probe receptive field stimulation and hyperosmolar stress were the most sensitive methods of detecting activity changes. CSN activity was attenuated after 30 min exposure to either PHE or BAK. After an hour-long washout period, BAK-treated neurons failed to recover activity while PHE-treated neurons showed signs of functional recovery. Intraepithelial nerve density was reduced and nerve fragmentation was increased in BAK-treated corneas, while PHE exposure left corneal nerves structurally intact.ConclusionsOur study suggests that prolonged ocular instillations of BAK or PHE alter CSN activity through two different processes — irreversible neuronal damage in the case of BAK vs. reversible attenuation in the case of PHE.     

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.     

Cytomorphological assessment of the lid margin in relation to symptoms,contact lens wear and lid wiper epitheliopathy

Purpose: Lid wiper epitheliopathy (LWE) is insufficiently understood from a cytological perspective. This study explored the relationship between lid margin cytomorphology, LWE, contact lens wear, and lens-related symptoms.Methods: Habitual, symptomatic (n = 20) and asymptomatic (n = 20) soft, rigid gas permeable (n = 18) and non-contact lens wearers (n = 19) were enrolled. LWE was graded using lissamine green and the Korb scale. Subjective symptoms were assessed using the Ocular Surface Disease Index and the Contact Lens Dryness Evaluation Questionnaire. Impression cytology samples obtained from the central upper and lower lid margins of both eyes stained histologically to highlight keratinization and imaged using high-resolution microscopy. A masked investigator digitally delimited and measured the average sagittal width of the lid wiper conjunctiva and mucocutaneous junction using ImageJ. Results:The upper lid wiper conjunctiva measured 424 ± 171 μm, 404 ± 75, 667 ± 219 and 266 ± 64 in asymptomatic soft, symptomatic soft, rigid and non-contact lens wearers, respectively. The corresponding lower lid wiper conjunctivae measured 141 ± 57 μm, 232 ± 150, 519 ± 212 and 225 ± 102, which was significantly narrower than that of the upper eyelid in most cases (p < 0.05). Symptoms were not associated with lid margin changes; however, rigid lens wear and clinical LWE were associated with histologically enlarged lid wiper conjunctival areas and increased keratinization.Conclusion: A novel, exploratory account of histological measures of LWE and cytomorphological change associated with contact lens wear suggests mechanical or frictional cellular insult is occurring at the lid wiper conjunctiva.     

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.     

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.     

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.     

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.     

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.     

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.     

DryEyeRhythm: A reliable and valid smartphone application for the diagnosis assistance of dry eye

PurposeUndiagnosed or inadequately treated dry eye disease (DED) decreases the quality of life. We aimed to investigate the reliability, validity, and feasibility of the DryEyeRhythm smartphone application (app) for the diagnosis assistance of DED.MethodsThis prospective, cross-sectional, observational, single-center study recruited 82 participants (42 with DED) aged ≥20 years (July 2020–May 2021). Patients with a history of eyelid disorder, ptosis, mental disease, Parkinson's disease, or any other disease affecting blinking were excluded. Participants underwent DED examinations, including the Japanese version of the Ocular Surface Disease Index (J-OSDI) and maximum blink interval (MBI). We analyzed their app-based J-OSDI and MBI results. Internal consistency reliability and concurrent validity were evaluated using Cronbach's alpha coefficients and Pearson's test, respectively. The discriminant validity of the app-based DED diagnosis was assessed by comparing the results of the clinical-based J-OSDI and MBI. The app feasibility and screening performance were evaluated using the precision rate and receiver operating characteristic curve analysis.ResultsThe app-based J-OSDI showed good internal consistency (Cronbach's α = 0.874). The app-based J-OSDI and MBI were positively correlated with their clinical-based counterparts (r = 0.891 and r = 0.329, respectively). Discriminant validity of the app-based J-OSDI and MBI yielded significantly higher total scores for the DED cohort (8.6 ± 9.3 vs. 28.4 ± 14.9, P < 0.001; 19.0 ± 11.1 vs. 13.2 ± 9.3, P < 0.001). The app's positive and negative predictive values were 91.3% and 69.1%, respectively. The area under the curve (95% confidence interval) was 0.910 (0.846–0.973) with concurrent use of the app-based J-OSDI and MBI.ConclusionsDryEyeRhythm app is a novel, non-invasive, reliable, and valid instrument for assessing DED.     

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.     

Homeopathic Agents or Vitamins in Reducing Ecchymosis after Oculofacial Surgery: A Report by the American Academy of Ophthalmology

PurposeTo review the published literature to determine the efficacy and safety of homeopathic agents or vitamins in reducing ecchymosis after oculofacial surgery or laser surgery.MethodsA literature search was conducted in the PubMed database initially in December 2019 and updated in March 2020 to identify all studies in the English language literature on the use of homeopathic agents or vitamins in oculofacial procedures, including laser surgery. The search yielded 124 citations, and 11 articles met all inclusion criteria for this assessment. A panel methodologist then assigned a level of evidence rating for each study. Eleven studies met inclusion criteria; 9 were rated level I, and 2 were rated level III.ResultsThe agents studied in the articles identified included oral or topical Arnica montana (AM), oral Melilotus extract, topical vitamin K oxide, and topical AM combined with Rhododendron tomentosum. Metrics to describe ecchymosis varied. In 7 controlled studies, perioperative AM provided no or negligible benefit versus placebo. In 2 studies, vitamin K cream was equivalent to placebo. One study of oral Melilotus extract had less ecchymosis compared with controls in paranasal and eyelid ecchymosis at postoperative day (POD) 7, but not at PODs 1 and 4. A lone cohort study of combined topical AM and R. tomentosum lacked objective metrics and adequate controls. No serious side effects from administration of homeopathic agents or vitamins were identified.ConclusionsThe current literature does not support the use of AM, vitamin K oxide, R. tomentosum, or Melilotus extract for reducing ecchymosis after oculofacial surgery or pulsed dye laser surgery.     

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.     

Membrane-associated mucins of the ocular surface: New genes,new protein functions and new biological roles in human and mouse

The mucosal glycocalyx of the ocular surface constitutes the point of interaction between the tear film and the apical epithelial cells. Membrane-associated mucins (MAMs) are the defining molecules of the glycocalyx in all mucosal epithelia. Long recognized for their biophysical properties of hydration, lubrication, anti-adhesion and repulsion, MAMs maintain the wet ocular surface, lubricate the blink, stabilize the tear film and create a physical barrier to the outside world. However, it is increasingly appreciated that MAMs also function as cell surface receptors that transduce information from the outside to the inside of the cell. A number of excellent review articles have provided perspective on the field as it has progressed since 1987, when molecular cloning of the first MAM was reported. The current article provides an update for the ocular surface, placing it into the broad context of findings made in other organ systems, and including new genes, new protein functions and new biological roles. We discuss the epithelial tissue-equivalent with mucosal differentiation, the key model system making these advances possible. In addition, we make the first systematic comparison of MAMs in human and mouse, establishing the basis for using knockout mice for investigations with the complexity of an in vivo system. Lastly, we discuss findings from human genetics/genomics, which are providing clues to new MAM roles previously unimagined. Taken together, this information allows us to generate hypotheses for the next stage of investigation to expand our knowledge of MAM function in intracellular signaling and roles unique to the ocular surface.     

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.     

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.     

Drug induced cicatrizing conjunctivitis: A case series with review of etiopathogenesis,diagnosis and management

Drug induced cicatrizing conjunctivitis (DICC) is defined as a disease in which conjunctival cicatrization develops as a response to the chronic use of inciting topical and, rarely, systemic medications. DICC accounts for up to one third of cases of pseudopemphigoid, a large group of cicatrizing conjunctival diseases sharing similar clinical features to those of mucous membrane pemphigoid (MMP) but generally without the morbidity of progressive scarring or the need for systemic immunosuppression. The preservatives in topical anti-glaucoma medications (AGM) are the most frequently implicated inciting causes of DICC although topical antivirals, vasoconstrictors and mydriatics and some systemic drugs have been implicated. The literature review summarizes the classification, epidemiology, etiopathogenesis, histopathology, clinical presentation, diagnosis, management, and treatment outcomes of DICC in the context of a case series of 23 patients (42 eyes) with AGM induced DICC, from India and the UK. In this series all subjects reacted to preserved AGM with one exception, who also reacted to non-preserved AGM. At diagnosis >70% of eyes showed punctal scarring, inflammation, and forniceal shortening. Pemphigoid studies were negative in the 19/23 patients in whom they were carried out. DICC can be classified as non-progressive, progressive with positive pemphigoid immunopathology or progressive with negative pemphigoid immunopathology. It is unclear whether progressive DICC is a stand-alone disease, or concurrent (or drug induced) ocular MMP. Progressive cases should currently be treated as ocular MMP. The diagnosis can be made clinically when there is rapid resolution of symptoms and inflammation, usually within 1–16 weeks, after withdrawal of suspected inciting medications, ideally by temporary substitution of oral carbonic anhydrase inhibitors. If the response to withdrawal is uncertain, or the progression of inflammation and scarring continues then patients must be evaluated to exclude concurrent (or drug induced) MMP, and other potential causes of CC, for which the treatment and prognosis is different. Management, in addition to withdrawing inciting medications, may require short-term treatment of conjunctival inflammation with steroids, treatment of associated corneal disease with contact lenses or surface reconstructive surgery, control of intra-ocular pressure with non-preserved AGM and, in some, surgery for glaucoma or for trichiasis and entropion.     

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.