Low-dose naltrexone is effective and well-tolerated for modulating symptoms in patients with neuropathic corneal pain

PurposeNeuropathic corneal pain (NCP) is caused by damage or disease of the somatosensory nervous system that innervates the cornea and presents with symptoms of pain or persistent unpleasant sensations, such as burning, dryness, or light sensitivity. This retrospective study aims to assess the efficacy and tolerability of low-dose naltrexone (LDN) in refractory NCP patients.MethodsFifty-nine NCP patients with a centralized component treated with oral LDN 4.5  mg at bedtime for at least four weeks were identified. Thirty out of 59 patients who had a baseline pain score ≥4 on the visual analogue scale had completed the ocular pain assessment survey (OPAS) and presented persistent pain, despite instillation of topical anesthetic drops, were included. Changes in pain scores, comorbidities, side effects, among others, were analyzed. Change in ocular pain scores (scale 0–10) and quality of life (QoL) scores (scale 0–100%) were the main endpoints.ResultsMean age (years ± SD) was 45.60 ± 19.30 with a white (80.00%) female (73.33%) predominance. Duration of LDN use was 14.87 ± 11.25 months, and the duration of NCP before treatment was 17.53 ± 17.29 months. Eight patients used LDN as a monotherapy, whereas the remaining used it as an adjunct therapy. LDN resulted in a 49.22% decrease in mean pain score from 6.13 ± 1.93 to 3.23 ± 2.60 (p < 0.001). Mean QoL scores by the OPAS were 5.84 ± 2.57 at the first visit and improved to 3.77 ± 2.91 at the last visit (p = 0.023). Common side effects were vivid dreams, headaches, and stomachache.ConclusionLDN was effective and well-tolerated for NCP treatment.     

Concurrent ocular pain in patients with neurotrophic keratopathy

PurposeTo illustrate that ocular pain may occur in patients with neurotrophic keratopathy (NK) that typically are thought to lack symptoms of discomfort, and that aa subset of these patients may also present with neuropathic corneal pain (NCP).MethodRetrospective Case series of 7 stage 1 NK patients who presented with concurrent ocular pain, as confirmed by clinical examination, proparacaine challenge test, and in vivo corneal confocal microscopy (IVCM). Records were assessed for results of ocular surface disease index (OSDI), pain on visual analog scale (VAS), ocular pain assessment survey (OPAS), best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS) score, and IVCM findings. IVCM findings were compared to that of 20 healthy reference controls.ResultsMean age of patients was 63.7 ± 11.6 (range 44–76) years and 56.9 ± 8.6 (range 42–74) years in reference controls (p = 0.11). At presentation, ocular discomfort was 8.0 ± 1.3 (range 7–10) on VAS and mean OSDI scores were 72.26 ± 6.81 (range 62.50–79.54). Mean BCVA was 20/40, and mean CFS scores were 3.43 ± 0.79 (range 2–4) on the Oxford scale. IVCM analysis showed significant decrease in mean total, main and branch nerve densities in ranges consistent with NK as compared to normal controls (p < 0.001 for all), increased dendritiform cell density in three patients (p < 0.001), and the presence of microneuromas in six of the patients.ConclusionPatients with NK are thought to present with hypoesthesia. However, nerve damage and inflammation, which play a role in the development of NK may result in the development of chronic ocular pain, such as NCP, resulting in potential underdiagnosis of either disease.     

Comparison of clinical characteristics of post-refractive surgery-related and post-herpetic neuropathic corneal pain

PurposeTo compare the clinical characteristics and in vivo confocal microscopy (IVCM) findings of patients with neuropathic corneal pain (NCP) due to refractive surgery (RS-NCP) and herpetic eye disease (H-NCP) to controls.MethodsSixteen patients with RS-NCP and 7 patients with H-NCP, and 37 healthy reference age- and sex-matched healthy controls were included to the study. The medical records were reviewed for demographic features, detailed disease history, ocular surface disease index (OSDI), ocular pain assessment survey (OPAS) scores. IVCM images of patients were analyzed and compared to reference controls by two masked observers.ResultsThe mean pain intensity score for the last 24 h (5.1 ± 2.4 vs. 3.9 ± 1.2; p = 0.27), last 2 weeks (6.1 ± 2.5 vs. 4.8 ± 2.3; p = 0.13) for RS-NCP vs. H-NCP respectively, and quality of life scores (p = 0.23) were similar in both groups. Quality of life, especially mood (p = 0.06) and enjoying life/relations to others (p = 0.10) were affected in both groups, but were not statistically significant between groups. The mean total nerve density was lower in RS-NCP (5,702.4 ± 4,599.0 μm/mm²) compared to their respective controls (26,422.8 ± 4,491.0; p < 0.001) and in the H-NCP group (2,149.5 ± 2,985.9) compared to their respective controls (22,948.8 ± 3,169.0; p < 0.001). Alterations in DC density were similar between all groups (38.3 ± 48.0 cells/mm² in RS-NCP, 61.0 ± 76.9 in H-NCP, p = 0.95).ConclusionNeuropathic corneal pain patients due to refractive surgery show similar clinical characteristics, pain levels, quality of life impact, and IVCM findings as patients with NCP due to herpetic eye disease.     

Ocular pain in ocular graft-versus-host disease patients with neurotrophic keratopathy

PurposeNeurotrophic keratopathy (NK) is a degenerative disorder of the cornea characterized by decreased sensory innervation, epitheliopathy, and impaired epithelial healing. In this study, we assessed ocular pain and quality-of-life-related parameters in ocular graft-versus-host disease (oGVHD) patients with and without NK.MethodsWe included 213 oGVHD patients in this retrospective study, including 29 patients with NK assessed by the Cochet-Bonnet esthesiometer. We evaluated their records for ocular pain assessment survey (OPAS) scores and clinical parameters, including corneal sensation, corneal fluorescein staining (CFS) score, Schirmer's test, tear break-up time (TBUT), and ocular surface disease index (OSDI) score.ResultsoGVHD patients with NK had lower corneal sensation (3.4 ± 1.4 vs. 5.9 ± 0.3; p < 0.0001), higher CFS scores (6.4 ± 4.2 vs. 4.7 ± 4.0; p = 0.01), and lower TBUT scores (1.2 ± 2.1 vs. 2.2 ± 3.1; p = 0.08) compared to oGVHD patients without NK and additionally had significantly higher ocular pain intensity scores (OPAS 24-h average eye pain intensity: 2.0 ± 2.8 vs. 1.1 ± 1.9; p = 0.03). Patients with NK more commonly reported burning (0.2 ± 0.3 vs. 0.3 ± 0.4; p = 0.021) and sensitivity to light (0.2 ± 0.3 vs. 0.3 ± 0.4; p = 0.049) as compared to patients without NK.ConclusionClinical signs of ocular surface disease are worse in oGVHD patients with NK compared to oGVHD patients without NK. These patients additionally experience higher intensity ocular pain and lower quality-of-life-related parameters.     

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.     

Phenotypic characterization of patients developing chronic dry eye and pain after refractive surgery: A cross-sectional study

PurposeTo describe the clinical characteristics of patients suffering from chronic dry eye (DE) and pain after refractive surgery (RS).MethodsCross-sectional, observational, single-visit study. DE-, pain- and psychological-related symptoms were evaluated with specific questionnaires. DE-related tests evaluated tear osmolarity, conjunctival hyperemia, Meibomian gland dysfunction, tear stability and production, and ocular surface staining. Corneal mechanical sensitivity (Cochet-Bonnet) was measured pre/post topical anesthesia, and symptomatic variation post-anesthesia (anesthetic challenge test) was recorded. When pain was present, it was further categorized as neuropathic or nociceptive based on published criteria.ResultsWe recruited 104 patients (39.5 ± 9.5 years). Most, 85.6%, had corneal RS as opposed to intraocular RS. Migraines, anxiety, depression (p < 0.0001), and central sensitization syndromes (p = 0.0214) were more frequent post-RS than pre-RS. Persistent DE-symptoms, severe in 86.5% patients, developed in a range of 0–204 months post-RS. Dryness and pain were the two most frequent symptoms. The only DE-related tests showing abnormal values were tear osmolarity (315.2 ± 17.1 mOsm/L; normal ≤308) and tear break-up time (4.1 ± 2.5 s; normal >7). Corneal sensitivity was 55.4 ± 7.0 mm, and decreased (p < 0.0001) after topical anesthesia, 6.0 ± 10.4 mm. However, it remained pathologically elevated, ≥10 mm in 61 (58.7%) patients. The normal symptomatic post-anesthesia improvement was absent in 58 (55.7%) patients. Ocular pain was present in 82 (78.8%) patients, and it was categorized as neuropathic in 66 (80.5%) of them, 63.5% of the entire cohort.ConclusionsChronic ocular pain and its neuropathic subtype were diagnosed in 78.8% and 63.5% respectively of patients seeking consultation for persistent symptomatic DE post-RS.     

A randomized,vehicle-controlled,Phase 2b study of two concentrations of the TRPM8 receptor agonist AR-15512 in the treatment of dry eye disease (COMET-1)

PurposeDry eye disease (DED) symptoms can negatively impact quality of life (QoL). AR-15512, a transient receptor potential melastatin 8 (TRPM8) agonist, was evaluated as a potential therapy for DED.MethodsIn a Phase 2b study, patients with DED were randomized 1:1:1 to 0.0014% AR-15512, 0.003% AR-15512, or vehicle twice daily for 12 weeks. Eligibility criteria included DED signs and symptoms of prespecified severity levels. Outcomes assessed were DED signs (Schirmer score ± anesthetic, ocular surface staining, hyperemia), symptoms (Ocular Discomfort [ODS-VAS], Symptoms Assessment iN Dry Eye [SANDE], Eye Dryness-VAS, Ocular Pain-VAS), QoL-VAS, and adverse events. Co-primary endpoints were changes from baseline in ODS-VAS and anesthetized Schirmer score at Day 28.Results0.003% AR-15512 (n = 122) was associated with early and sustained improvements in unanesthetized Schirmer score (Days 1 and 14, p < 0.0001), as well as improvements in ocular surface staining (Days 14 and 84, p ≤ 0.0365) and hyperemia (Day 84, p < 0.0215). Statistically significant improvements in symptoms were observed for the 0.003% concentration on SANDE (Days 14, 28, and 84, p ≤ 0.0254), ODS-VAS (Day 84, p = 0.0281), Eye Dryness-VAS (Day 84, p = 0.0302), and multiple QoL measures (Days 14, 28, and 84, p < 0.05). There were no significant differences between active and vehicle groups for the co-primary endpoints. The most common adverse events were burning and stinging upon instillation.ConclusionsAlthough predefined co-primary study endpoints were not met, AR-15512 demonstrated statistically significant improvements in DED signs, symptoms, and disease-related QoL.     

Pain sensitivity and autonomic nervous system parameters as predictors of dry eye symptoms after LASIK

PurposeDifferences in pain processing and autonomic function among patients have been implicated in the development of chronic pain after surgery. This study was designed to evaluate whether pain and autonomic metrics predict severity of chronic dry eye (DE) symptoms after LASIK, as there is increasing evidence that DE symptoms may be manifestations of persistent post-operative ocular pain.MethodsSecondary analysis of prospective randomized clinical trial. Patients were treated with either pregabalin or placebo. As no significant differences in DE symptoms were detected by treatment allocation at six months, all participants were grouped together for the present analyses. Subjects were evaluated pre-LASIK with regard to evoked pain sensitivity (utilizing quantitative sensory testing), autonomic metrics and DE and ocular pain symptoms (via validated questionnaires). Measures of DE and ocular pain were assessed post-LASIK, and the Dry Eye Questionnaire 5 (DEQ5) score 6-months after surgery was the primary outcome of interest.Results43 individuals were randomized to pregabalin (n = 21) or placebo (n = 22). 42 completed the 6-month visit. Several baseline autonomic metrics correlated with 6-month post-operative DEQ5 scores, including lower systolic (r −0.37, p = 0.02) and diastolic blood pressure (r −0.32, p = 0.04). Ocular pain at 6 months was also negatively correlated with blood pressure (r −0.31, p = 0.047). The presence of painful aftersensations was a significant predictor of chronic DE symptoms at 6 months (mean DEQ5 scores: 8.0 ± 1.9 versus 5.0 ± 5.0, p = 0.009).ConclusionsHeightened parasympathetic tone and prolonged pain sensitivity measured prior to surgery predicted greater DE symptom severity 6 months after LASIK.Trial registrationNCT02701764.     

Chronic ocular complications in lamotrigine vs. trimethoprim-sulfamethoxazole induced Stevens-Johnson syndrome/toxic epidermal necrolysis

PurposeThe purpose of this study is to compare the severity of chronic ocular complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by lamotrigine (LT) vs. trimethoprim-sulfamethoxazole (TS).MethodsThis retrospective cross-sectional study evaluated all SJS/TEN patients treated within our hospital network from 2008 to 2018. Inclusion criteria included patients with reactions identified as caused by either LT or TS, and patients with at least one ophthalmology follow up in the chronic phase (≥3 months from disease onset). Primary outcome measures included LogMAR best-corrected VA at most recent visit and the presence or absence of severe ocular complications (SOC). Secondary outcome measures included chronic ocular complication severity scores using a modified Sotozono scoring system.ResultsForty-eight eyes of 24 patients were included in the study. The mean duration of follow-up was 39.50 ± 35.62 vs. 48.17 ± 33.09 months, respectively (p = 0.482). The LT group had worse average VA at the most recent visit (LogMAR VA; 0.508 vs. 0.041, p < 0.0001) and had a higher prevalence of SOCs (66.7% vs. 8.3%, p = 0.0038). The LT group scored worse on Sotozono chronic complications scores for the cornea (1.875 vs. 0.5, p = 0.0018), eyelid margin (5.583 vs.3.083, p = 0.0010), and overall condition (8.500 vs. 4.833, p = 0.0015). Sub-analyses showed that a moderate or severe acute ocular severity score was a significant predictor of chronic outcomes.ConclusionsCompared to patients with TS-induced SJS/TEN, patients with LT-induced SJS/TEN developed worse chronic ocular complications on several parameters. Future prospective studies are warranted to provide additional insight into the drug type as a predictor of chronic ocular complications.     

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.     

The Role of Multisystem Disease in Composition of Autologous Serum tears and ocular surface symptom improvement

PurposeAutologous serum tears (AST) contain growth factors and vitamins similar to those in healthy tears and are an effective treatment option for ocular surface disease. This study determined the differences in composition of AST in patients with systemic diseases versus patients with localized ocular surface diseases and the effects on ocular surface symptom improvement.MethodAn observational study was performed on 53 patients with either systemic diseases (Group I) or localized ocular surface diseases (Group II) who were prescribed AST. Concentrations of epidermal growth factor (EGF), interleukin 8 (IL-8), fibronectin, vitamin A, and tumor necrosis factor-α (TNF-α) were determined through ELISA assays from patients in both groups. The Ocular Surface Disease Index (OSDI) scores were calculated prior to and 6 weeks after initiation of treatment with AST for new patients.ResultsThe average concentration of EGF in Group I (29.39 pg/ml ± 52.85 pg/ml) was significantly lower than in Group II (88.04 pg/ml ±113.75 pg/ml) (p < 0.05). Levels of fibronectin, IL-8, and vitamin A were similar in both groups. There was a 24% reduction in OSDI score 6 weeks after initiation in Group I compared to a 36% reduction reported in Group II (p = 0.065). The OSDI score was reduced significantly after the treatment in all subjects (p = 0.002).ConclusionSerum tears are a promising therapy for management of ocular surface disease and associated symptoms. The differences between levels of EGF in patients with localized ocular surface disease and systemic inflammatory disease may account for differences in therapeutic outcome.     

Meibomian gland dysfunction is the primary determinant of dry eye symptoms: Analysis of 2346 patients

PurposeTo determine relative contributions of various ocular surface clinical signs and predisposing factors to the magnitude of dry eye symptoms.MethodsClinical audit data were prospectively collected for newly referred dry eye patients. All 2346 patients had an initial visit evaluation of the Ocular Surface Disease Index (OSDI), and a detailed ophthalmic examination including tear breakup time (TBUT), ocular surface fluorescein staining, Schirmer's I test. Among the participants, 1414 had number of liquid meibum expressing glands (NLMEG) evaluated on standard force expression. Other variables collected included history of glaucoma or glaucoma surgery, and history of allergies.ResultsIn patients aged 46.2 ± 14.8 years, 77.4% were women and 87.1% Chinese. The mean ± SD OSDI was 35.2 ± 21.7. On univariate analysis, higher OSDI was associated with glaucoma diagnosis (p = 0.003), glaucoma surgery (p = 0.002), greater temporal corneal staining (p = 0.002), reduced NLMEG (p < 0.001), and higher inferior forniceal papillary grade (p < 0.001). OSDI was not significantly associated with gender, TBUT, Schirmer's I test values, or the use of cyclosporine eyedrops. On multivariate regression, higher OSDI scores were associated with fewer NLMEG (p = 0.002) and increased lower eyelid forniceal papillary grading (p = 0.002). Corneal staining, glaucoma status and glaucoma surgery were not significantly associated with OSDI. Logistic regression showed that severe symptoms (OSDI>32) was associated with <2 NLMEG [OR(95%CI): 1.34(1.08–1.66)], and presence of inferior eyelid forniceal papillae [1.50(1.17–1.91)].ConclusionsMeibomian gland dysfunction (MGD) and lower forniceal papillary reaction had significant contributions to the severity of symptoms, in contrast to traditional dry eye signs. MGD should be objectively assessed and treated to improve symptoms.     

Prevalence of neurotrophic keratopathy in patients with chronic ocular graft-versus-host disease

PurposeTo determine the prevalence, clinical characteristics, and risk factors associated with neurotrophic keratopathy (NK) in patients with chronic ocular graft-versus-host disease (oGVHD).DesignRetrospective cohort study.MethodsWe performed a chart review of patients diagnosed with chronic oGVHD between January 2015 and December 2018 at a single academic institution and recorded demographic data, systemic and ocular comorbidities, history of hematologic malignancy, transplant characteristics, oGVHD severity scores, and adnexal and ocular examination findings. We determined the prevalence of NK and clinical characteristics associated with NK in these patients. A multivariate logistic regression analysis was performed to determine the risk factors associated with NK in these patients.Main outcome measurePrevalence of NK in chronic oGVHD.ResultsWe identified 213 patients diagnosed with chronic oGVHD following hematopoietic stem cell or bone marrow transplantation from our electronic patient database, and the prevalence of NK was 14%. The mean age of oGVHD patients with NK was 62.6 ± 12.9 years; 48% were women, 19 had unilateral NK, and ten had bilateral NK. In the cohort, 56%, 20%, and 24% eyes of the patients had grades 1, 2, and 3 of NK, respectively. The mean time to diagnose NK after transplantation was 52.9 ± 45.4 months. oGVHD patients diagnosed with NK had a significantly higher NIH oGVHD severity score (p = 0.04) and a lower corneal sensation score (p = 0.0001) than those without NK. Our analyses showed a significantly higher CFS score (p = 0.01) and a trend toward lower Schirmer test scores (p = 0.16) and tear break-up times (p = 0.08) in oGVHD patients with NK. Additionally, we observed a significantly higher prevalence of persistent epithelial defect (p = 0.0001), corneal ulceration (p = 0.0001), and corneal perforation (p = 0.005) in oGVHD patients diagnosed with NK. A logistic regression analysis to determine factors associated with NK showed that a higher NIH oGVHD score (odds ratio [OR] = 2.03, p = 0.026) and history of cataract surgery (odds ratio [OR] = 5.03, p = 0.001) are significant risk factors for NK in oGVHD patients.ConclusionsThe prevalence of NK in chronic oGVHD patients was 14% during the study period. Our analysis shows that oGVHD patients with a higher NIH oGVHD severity score and previous history of cataract surgery are at a higher risk of developing NK and may develop severe sequelae such as persistent epithelial defect or corneal ulceration.     

Anterior segment optical coherence tomography angiography in the assessment of ocular surface lesions

PurposeDescribe the utility of anterior segment optical coherence tomography angiography (AS-OCTA) to assess ocular surface lesions.MethodsRetrospective, case-control study of 10 eyes of 9 patients with malignant lesions and 23 eyes of 22 patients with benign lesions. Lesions included 13 epithelial, 10 pigmented and 10 lymphoid lesions. Graders performed an average of 3 depth and diameter measurements of peri-lesional vessels entering each lesion on AS-OCTA. Statistical models to assess differences between groups accounted for bilateral eye inclusion and lesion thickness (on AS-OCT). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were performed for each parameter.ResultsIn the benign and malignant groups, age was 49.5 ± 22.4 and 64.3 ± 10.6 years (p = 0.145) with 45% males and 55% males (p = 0.458), in their respective groups. AS-OCTA showed greater peri-lesional vessel depth and diameter in malignant lesions (315.2 ± 73.0 μm, p < 0.001 and 76.4 ± 18.2 μm, p < 0.001; respectively) compared to benign lesions (199.4 ± 34.1 μm and 44.0 ± 9.4 μm, respectively). Malignant lesions showed deep and dilated peri-lesional vessels, which may represent feeder vessels. Vessel depth showed AUC = 0.980, 90.9% sensitivity and 100.0% specificity with a 236.5 μm cutoff. Vessel diameter showed AUC = 0.960, 100.0% sensitivity and 88.9% specificity with a 53.9 μm cutoff.ConclusionAS-OCTA shows greater peri-lesional vessel depth and diameter of malignant lesions compared to benign lesions. This imaging modality provides novel and non-invasive functional vascular parameters that can potentially aid the assessment of ocular surface lesions.     

Meibomian gland dropout is associated with immunodeficiency at HIV diagnosis: Implications for dry eye disease

AimTo characterize anterior eye health and tear film characteristics in individuals with human immunodeficiency virus (HIV) undergoing anti-retroviral therapy.MethodsThis cross-sectional study involved 35 adults, categorized as healthy controls (n = 18) or as HIV-positive patients (n = 17), with no history of opportunistic infection or current ocular fundus abnormalities. Participants underwent a comprehensive anterior eye assessment. Primary outcome measures were dry eye symptoms (Ocular Surface Disease Index survey), tear film osmolarity, and extent of meibomian gland dropout. Secondary outcomes measures were ocular redness, tear film stability, and ocular surface staining. Levels of 36 cytokines were assayed from basal tears using a multiplex bead array.ResultsThe HIV-positive group showed more extensive meibomian gland dropout relative to controls (mean ± SD, controls: 29.6 ± 5.8 versus 37.0 ± 13.9%, p = 0.045). The extent of meibomian gland dropout was negatively correlated with blood CD4 T-cell count (a marker of immunodeficiency) at diagnosis (r = −0.69, p = 0.006). All other tests of anterior ocular health, including dry eye symptom levels, were not significantly different between the groups. There were no significant inter-group differences for the 36 cytokines assayed in the tear film.ConclusionsWe find greater meibomian gland dropout in HIV-positive individuals that is related to disease severity at diagnosis. Given this feature predisposes to dry eye disease, it suggests the need for long-term studies of anterior eye health in people with HIV.     

Randomized trial of topical periocular castor oil treatment for blepharitis

PurposeTo evaluate the effects of topical castor oil application to the eyelids on ocular surface and tear film parameters in patients with blepharitis.MethodsTwenty-six participants (14 females, 12 males; mean ± SD age, 38 ± 21 years) with clinical signs of blepharitis were enrolled in a prospective, investigator-masked, randomized, paired-eye trial. A 100% cold pressed castor oil formulation (Lotus Garden Botanicals, Biddeford, ME, USA) was applied to the eyelids of one eye (randomized), twice daily for 4 weeks. Ocular surface characteristics, symptoms, and tear film parameters were assessed at baseline and day 28.ResultsBaseline measurements did not differ between treated and control eyes (all p > 0.05). A significant reduction in OSDI symptomology score was observed following the four-week treatment period (p = 0.001). Clinical improvements in eyelid margin thickening, telangiectasia, eyelash matting, madarosis, cylindrical dandruff, and lid wiper epitheliopathy were limited to treated eyes (all p < 0.01), while greater decreases in staphylococcal and seborrheic eyelash crusting were observed in treated than control eyes (both p < 0.05). No adverse events were reported during the treatment period.ConclusionTopical castor oil application effected significant improvements in ocular surface signs and symptoms in patients with blepharitis. The favourable therapeutic profile would suggest that castor oil demonstrates promise as a potential treatment for blepharitis, and support the conduct of further efficacy trials with longer follow up.Trial registration numberACTRN12618000856213.     

Optical coherence tomography angiography in the evaluation of vascular patterns of ocular surface squamous neoplasia during topical medical treatment

PurposeOptical coherence tomography angiography (OCTA) was utilized to examine changes in ocular surface squamous neoplasia (OSSN) vascular patterns over time in individuals treated with topical medical therapy.MethodsTen individuals with OSSN diagnosed by clinical examination and high resolution (HR)-optical coherence tomography (OCT) were recruited. All individuals received topical immuno- or chemotherapy. OCTA images were obtained and analyzed at three points: presentation, mid-treatment and tumor resolution. Tumor metrics including tumor area (TA), tumor volume (TV), tumor depth (TD), and total tumor density (TTD) were calculated. Vessel area density (VAD) was also quantified within the OSSN, the subepithelium under and adjacent to the OSSN and the subepithelium of the uninvolved, contralateral eye. Vascular network changes were also subjectively evaluated.ResultsTA, TV, TD and TTD all significantly decreased with time (p < 0.001). The mean VAD within the OSSN significantly decreased (p < 0.001) between visits (presentation: 26.52 ± 6.8%, mid-treatment: 7.19 ± 5.88%, tumor resolution: 0.11 ± 0.34%). The mean subepithelial VAD under the OSSN also decreased with time (23.22 ± 11.03%, 20.99 ± 5.99% and 19.58 ± 7.08%), and after resolution the sub-tumor VAD (19.58 ± 7.08%) was comparable to the subepithelial VAD in the contralateral eye (15.47 ± 4.37%, p > 0.05). The mean VAD in the subepithelium adjacent to the OSSN increased with treatment, then decreased significantly between mid-treatment and resolution (23.26 ± 4.54, 28.30 ± 7.43% and 21.68 ± 6.10%, p = 0.009). Qualitatively, the tumor subepithelial vascular network was complex and dense but with tumor resolution appeared less tortuous and similar to the uninvolved eye.ConclusionOCTA provided insight into the pathophysiology of tumor angiogenesis, showing decreased vascular density and normalization of vascular networks associated with tumor resolution.     

Effects of meibomian gland dysfunction and aqueous deficiency on friction-related disease

PurposeTo evaluate the effects of meibomian gland dysfunction (MGD) and aqueous deficiency (AD) on friction-related disease (FRD).MethodsCross-sectional comparative study. This study included 550 eyes (550 patients) with dry eye disease (DED). The DED subtype and dynamic tear-film parameters by automated assessments were investigated for the analysis of FRD (superior limbic keratoconjunctivitis, conjunctivochalasis, and lid wiper epitheliopathy).ResultsPatients with FRD had a higher proportion of moderate-to-severe MGD and AD (p < 0.001 and p < 0.001, respectively). The dropout rate of the meibomian gland was higher (30.5 ± 31.8 and 14.1 ± 25.0%, p < 0.001), tear meniscus height (TMH) was lower (227.8 ± 60.4 and 241.7 ± 55.6 μm, p = 0.008), and he first non-invasive keratographic tear break-up time (NIKBUT-1) was shorter (5.9 ± 3.5 and 7.3 ± 3.7 s, p < 0.001) in patients with FRD than in those without FRD. In the logistic regression analysis with clinical manifestation, both moderate-to-severe MGD and AD were associated with FRD (odds ratios [OR] 12.27, 95% confidence interval [CI] 7.72–19.50, and 2.31, 95% CI 1.43–3.71], p < 0.001 and p < 0.001, respectively). The dropout rate was positively associated with FRD (OR 1.017, 95% CI 1.010–1.023, p < 0.001). TMH and NIKBUT-1 were negatively associated with FRD (OR 0.995, 95% CI 0.991–0.999, and 0.90, 95% CI 0.85–0.95, p = 0.039 and p < 0.001, respectively).ConclusionsThis study showed that FRD was highly associated with MGD and meibomian gland dropout rate, suggesting that FRD may be mainly affected by lipid components. AD and TMH also had a good but relatively lower association with FRD, compared to MGD and meibomian gland dropout rate.     

A reliable animal model of corneal stromal opacity: Development and validation using in vivo imaging

PurposeTo validate an animal model of corneal stromal opacity by using objective vision-independent in vivo imaging metrics.MethodsThis was a prospective study, with two arms: (i) observational human arm which included 14 patients with healed unilateral ulcerative keratitis; and (ii) experimental rabbit arm, which included 6 New Zealand white rabbits. A 3-mm central wound was created in the left eye of the rabbits by manually removing 200–250 μm of the superficial stroma, followed by rotating-burr application. Both groups underwent photography, high-resolution anterior segment optical coherence tomography, and Scheimpflug imaging using similar diagnostic platforms and standardized image capturing protocols. Parameters studied were relative change in (i) corneal thickness; (ii) corneal epithelial: stromal (E:S) reflectivity ratio; (iii) corneal stromal light scattering using densitometry; and (iv) central corneal keratometry.ResultsIn the experimental arm, there was a significant decrease in corneal thickness (273 ± 51.3 vs. 407.3 ± 10.3 μm, p = 0.0038), E:S reflectivity ratio (0.71 ± 0.09 vs. 0.99 ± 0.06, p = 0.0018), and keratometry (40.4 ± 2.3 vs. 45.8 ± 0.9D, p = 0.0033) and increase in densitometry (54.2 ± 11.65 vs.18.7 ± 3.8 GSU, p = 0.0001) from baseline, which stabilized at 4 to 8-weeks post-wounding (p > 0.3632). At 8-weeks, the relative change from baseline in corneal thickness (28.4 ± 13.5% vs.22.4 ± 13%, p = 0.368), E:S reflectivity ratio (28.1 ± 11.5% vs. 30.6 ± 8.9%, p = 0.603), corneal densitometry (204.17 ± 97.3% vs. 304.9 ± 113.6%, p = 0.1113), and central corneal keratometry (13.6 ± 6.9% vs. 18.9 ± 7.4%, p = 0.1738) in rabbits was similar to human corneal scars.ConclusionThe animal model of corneal opacification was objectively comparable to human post-keratitis scars and can be valuable for in vivo evaluation of emerging therapies for corneal opacities.