Corneal sub-basal nerve plexus microneuromas in individuals with and without dry eye.

BACKGROUND/AIM: An objective marker is needed to detect when corneal nerve abnormalities underlie neuropathic corneal pain (NCP), as symptoms often overlap with those of dry eye (DE). This study evaluated microneuroma (MN) frequency in various populations and investigated relationships between MN presence and DE clinical features in individuals with DE symptoms but without a history of refractive surgery, in order to eliminate refractive surgery as a potential confounder of nerve abnormalities. METHODS: This was a retrospective study that included individuals with and without DE symptoms who underwent a clinical evaluation for DE (symptom surveys and ocular surface evaluation) and in vivo confocal microscopy imaging. DE clinical features (including those suggestive of neuropathic pain) were compared based on MN presence using t-tests, χ2 analyses and Pearson's correlation coefficients with 0.05 alpha level. RESULTS: MN frequencies did not significantly differ between individuals with DE symptoms (Dry Eye Questionnaire 5 score ≥6) and a history of refractive surgery (n=1/16, 6%), individuals with DE symptoms without a history of refractive surgery (n=26/119, 22%) and individuals without DE symptoms (n=2/18, 11%, p=0.22). Among individuals with DE symptoms without a history of refractive surgery, DE clinical features, including those indicative of NCP (burning sensation and sensitivity to light, wind and extreme temperatures), did not significantly differ based on MN presence (p>0.05). CONCLUSION: MN frequencies did not significantly differ between individuals with and without DE symptoms. Their presence alone could not distinguish between DE subtypes, including features of NCP in our study population.

Content, Readability, and Accountability of Freely Available Online Information for Patients Regarding Epiretinal Membranes.

PURPOSE: To assess content, readability, and accountability of online information for patients regarding epiretinal membranes (ERMs). METHODS: Cross-sectional study evaluating nine major medical websites on ERMs. Fifteen questions assessed patient-relevant content. Four indices estimated U.S. grade literacy level of the text. JAMA benchmarks (authorship, attribution, disclosure, currency) evaluated website accountability. RESULTS: Average content score was 36.78 (SD 13.91, 95% CI ±0.64) from a possible maximum of 60, with significant variability between websites (H = 22.68, p=0.004). Mean reading grade level was 12.29 (SD 2.30, 95% CI ±1.50). No website achieved all JAMA benchmarks; only one website fulfilled three of the four. Content score did not correlate with Google rank (order of listed websites, r = -0.23, p=0.55) or JAMA benchmarks (r = 0.19, p=0.62) but significantly correlated with mean reading grade (r = 0.67, p=0.05). CONCLUSION: Online information regarding ERMs varies significantly, may not adequately answer common patient questions, and is written at too complex a literacy level for the average patient.

Case-Control Study Examining the Composition of the Gut Microbiome in Individuals With and Without Immune-Mediated Dry Eye.

PURPOSE: Gut microbiome alterations have been associated with various autoimmune diseases. There are limited data, however, on relationships between gut dysbiosis and immune-related dry eye (DE). Our aim was to compare the gut microbiome composition of individuals with early and late markers of Sjögren syndrome (SS) with controls without DE. METHODS: We compared 20 individuals with positive early markers [antisalivary protein 1 (SP1), antiparotid secretory protein (PSP), anticarbonic anhydrase 6 (CA6) IgG, IgA, and IgM, n = 19)], or late markers (anti-Ro/SS-A and anti-La/SS-B, n = 1) of SS with no comorbid autoimmune diagnoses and 20 age-matched and sex-matched controls. Collected stool samples underwent deep RNA sequencing. The main outcomes measured included gut microbiome composition and diversity. RESULTS: A total of 20 cases [Dry Eye Questionnaire-5 15.2 ± 3.4, Ocular Surface Disease Index 55.1 ± 22.8, and Schirmer 7.1 ± 5.2 mm] were compared with 20 controls (Dry Eye Questionnaire-5 4.8 ± 3.8, Ocular Surface Disease Index 14.2 ± 12.3, and Schirmer 20.4 ± 9.2 mm). No differences were observed in α-diversity (P = 0.97) or overall community structure (P = 0.62). Between groups, 32 species were differentially abundant (P < 0.01). Among cases, 27 were relatively more abundant, including 10 Lactobacillus and 4 Bifidobacterium species. A relative depletion of 5 species was found in cases compared with controls, notably Fusobacterium varium and Prevotella stercorea. CONCLUSIONS: Differences in gut microbiome composition were found in individuals with mostly early markers of SS compared with controls. However, their clinical significance to DE manifestations remains unclear. Further studies are needed to elucidate the role of gut dysbiosis on immune dysregulation and disease activity in the various forms of immune-mediated DE.

Relationships between activated dendritic cells and dry eye symptoms and signs.

PURPOSE: To examine whether "activated" dendritic cells (aDCs) could serve as a biomarker of systemic immune disorders in individuals with dry eye (DE) symptoms. Secondarily, to examine the impact of a topical anti-inflammatory agent on aDC number. METHODS: Retrospective analysis was conducted to identify individuals with DE symptoms who had in-vivo confocal microscopy (IVCM) imaging between October 2018 and July 2020 at the Miami Veterans Hospital. aDCs were manually quantified based on morphology. Receiver operating curve (ROC) analysis examined relationships between aDC number and systemic immune disease status. Individuals were then grouped by aDC number (≥2 versus <2) and demographics and DE parameters were examined. Paired t-test was performed to evaluated aDC number pre-vs post-initiation of an anti-inflammatory agent. RESULTS: 128 individuals were included. Their mean age was 57.1 ± 15.0 years; 71.1% were male, 53.1% self-identified as White and 24.2% as Hispanic. The mean number of aDCs in the central cornea was 1.28 ± 2.16 cells/image. The presence of ≥2 aDCs had a sensitivity of 60% and specificity of 77% for the diagnosis of a systemic immune disorder. Individuals with ≥2 aDCs were more likely to self-identify as Black, have Secondary Sjögren's, and have higher nerve fiber area and fractal dimension. In 12 individuals, aDC number decreased from 2.69 ± 2.36 to 0.58 ± 0.73 cells/image after initiation of an anti-inflammatory agent, p = 0.01. CONCLUSIONS: The presence of ≥2 aDCs in the central cornea suggests a systemic immune disorder in individuals with DE symptoms. Topical anti-inflammatory therapy can reduce the number of aDCs in the central cornea.

Long-Term Trigeminal Nerve Stimulation as a Treatment for Ocular Pain.

OBJECTIVES: Ocular pain symptoms (e.g., hypersensitivity to light and wind, "burning" sensations) can be debilitating and difficult to treat. Neuromodulatory therapies targeting sensory trigeminal and central pain pathways may help treat chronic ocular pain refractory to traditional therapies. The current study evaluates the long-term effects of a trigeminal neurostimulator (TNS) on ocular pain. MATERIALS AND METHODS: Retrospective review of 18 individuals at the Miami Veterans Affairs Eye Clinic with chronic, severe ocular pain who were prescribed and used TNS at home for ≥3 months. The primary outcome measures were 1) ocular symptom intensity over a 24-hour recall period (dryness, pain, light sensitivity, wind sensitivity, burning; rated on 0-10 scales) captured pre-TNS and at monthly follow-up intervals and 2) side effects. The frequency and duration of TNS was a secondary outcome measure. RESULTS: The mean age of the population (n = 18) was 57.5 years (range, 34-85 years) with a male majority (67%). Two individuals discontinued use due to lack of efficacy and one due to confounding health issues. Initial mean weekly frequency of TNS use was 3.7 ± 1.9 sessions of 25.8 min at month 1 and 2.7 ± 2.3 sessions of 28.0 min at month 6. At six months, pain intensity (↓ 31.4%), light sensitivity (↓ 36.3%), wind sensitivity (↓ 32.6%), and burning sensation (↓ 53.9%) were all decreased compared to baseline (p < 0.01 for all); greater decreases in ocular pain were noted in individuals with migraine (n = 10) than those without migraine (n = 8). No significant change was noted in mean dryness scores. Fifteen subjects experienced sedation with TNS use, persisting throughout the follow-up visits. No other adverse effects were communicated by any subjects. CONCLUSION: Our study suggests TNS is a safe, adjunctive treatment option in individuals with severe, chronic ocular pain. Individuals demonstrated gradual, continual improvement in pain symptoms over time within a multimodal approach.

Can in vivo confocal microscopy differentiate between sub-types of dry eye disease? A review.

Many studies utilised in vivo confocal microscopy (IVCM) to associate variations in corneal structures with dry eye disease (DED). However, DED is an umbrella term that covers various aetiologies and presentations. This review analyses populations by DED aetiology to determine the relationships between IVCM parameters and specific DED sub-types. It focuses on the most commonly examined structures, sub-basal nerves and dendritic cells. Across the literature, most studies found individuals with immune-mediated DED had lower sub-basal nerve fibre number and density than controls, with smaller differences between non-immune DED and controls. However, wide ranges of values reported across studies demonstrate considerable overlap between DED sub-types and controls, rendering these metrics less helpful when diagnosing an individual patient. Dendritic cell density was considerably higher in individuals with immune-mediated DED than in non-immune DED or controls. As such, dendritic cell density may be a better indicator of DED associated with a systemic immune-mediated process.

Conjunctival Vessels in Diabetes Using Functional Slit Lamp Biomicroscopy.

PURPOSE: This study used functional slit lamp biomicroscopy (FSLB) to quantify conjunctival microvessel parameters in individuals with and without diabetes and examined whether these metrics could be used as surrogate markers of diabetes-related complications. METHODS: A cross-sectional study of 98 controls (C), 13 individuals with diabetes without complications (D-C), and 21 with diabetes and related complications (D+C), which included retinopathy, nephropathy, neuropathy, and cardiovascular-, peripheral vascular-, and cerebrovascular diseases, was performed. Bulbar conjunctival metrics (venule diameter, length, axial velocity [Va], cross-sectional velocity [Vs], flow [Q], and branching complexity) were measured using FSLB (digital camera mounted on traditional slit lamp). RESULTS: The mean age was 60 ± 11 years, and demographics were similar across the groups. Va and Vs significantly differed between groups. Va was 0.51 ± 0.17 mm/s, 0.62 ± 0.17 mm/s, and 0.45 ± 0.17 mm/s in the C, D-C, and D+C groups, respectively (P = 0.025). Similarly, Vs was 0.35 ± 01.12, 0.43 ± 0.13, and 0.32 ± 0.13 mm/s in the C, D-C, and D+C groups, respectively (P = 0.031). Black individuals had increased Va, Vs, and Q compared with White individuals (P < 0.05), but differences in velocities persisted after accounting for race. Among patients with diabetes, Va and Vs correlated with number of organ systems affected (Va: ρ = -0.42, P = 0.016; Vs: ρ = -0.41, P = 0.021). Va, Vs, and Q significantly (P ≤ 0.005) discriminated between diabetic patients with and without complications (area under the receiver operating curve for Va = 0.81, Vs = 0.79, Q = 0.81). CONCLUSIONS: Bulbar conjunctival blood flow metrics measured by FSLB differed between controls, diabetic patients without complications, and diabetic patients with complications. FSLB is a quick, easily accessible, and noninvasive alternative that might estimate the burden of vascular complications in diabetes.

Prevalence of Ocular Demodicosis in an Older Population and Its Association With Symptoms and Signs of Dry Eye.

PURPOSE: To evaluate associations between Demodex and its symptoms and ocular surface parameters in individuals with dry eye (DE). METHODS: A cross-sectional study of 119 individuals with DE symptoms or signs, grouped by the presence of ocular demodicosis, was performed. All individuals filled out questionnaires and underwent an ocular surface examination. Demographics, comorbidities, symptoms profiles, and ocular surface parameters were compared between the 2 groups. Multivariable regression analyses were used to determine which factors were associated with DE symptoms. Receiver operating curves analyses were performed to evaluate relationships between Demodex quantity and specific clinical phenotypes. RESULTS: Demodex was highly prevalent in our population (68.9%) with average counts of 4.2 ± 3.9. Individuals with and without Demodex had comparable demographics. Overall, symptoms profiles were similar between individuals with and without Demodex using the Dry Eye Questionnaire 5 and Ocular Surface Disease Index. Individuals with Demodex, however, were more likely to report itching (58.5% vs. 35.1%, P = 0.03), with increasing frequency in those with higher Demodex counts. Individuals with Demodex also had more severe eyelid abnormalities [cylindrical dandruff (CD) and lid vascularity] and a more unstable tear film but similar tear production and corneal staining when compared with individuals without Demodex. Neither Demodex nor ocular surface findings related to DE symptoms in multivariable analyses. Receiver operating curves analysis revealed Demodex counts ≥2 maximized sensitivity and specificity for both itching (64.7% and 59.0%, respectively) and CD (80.4% and 60.4%, respectively). CONCLUSIONS: Demodex is highly prevalent in an older population with DE. Symptom of itching and CD were the findings most specific for Demodex.

Utilization of Online Resources by Patients in an Ophthalmic Emergency Department.

Objective To describe the utilization of online resources by patients prior to presentation to an ophthalmic emergency department (ED) and to assess the accuracy of online resources for ophthalmic diagnoses. Methods This is a prospective survey of patients presenting to an ophthalmic ED for initial evaluation of ocular symptoms. Prior to evaluation, patients completed surveys assessing ocular symptoms, Internet usage, and presumed self-diagnoses. Demographics and characteristics of Internet usage were determined. Accuracy of self-diagnoses was compared between Internet users and nonusers. Diagnoses were classified as high or low acuity based on agreement between senior authors. Results A total of 144 patients completed surveys. Mean (standard deviation) age was 53.2 years (18.0). One-third of patients used the Internet for health-related searches prior to presentation. Internet users were younger compared with nonusers (48.2 years [16.5] vs. 55.5 years [18.3], p = 0.02). There were no differences in sex, ethnicity, or race. Overall, there was a threefold difference in proportion of patients correctly predicting their diagnoses, with Internet users correctly predicting their diagnoses more often than nonusers (41 vs. 13%, p < 0.001). When excluding cases of known trauma, the difference in proportion increased to fivefold (Internet users 40% vs. nonusers 8%, p < 0.001). Upon classification by acuity level, Internet users demonstrated greater accuracy than nonusers for both high- (42 vs. 17%, p = 0.03) and low (41 vs. 10%, p = 0.001)-acuity diagnoses. Greatest accuracy was in cases of external lid conditions such as chalazia and hordeola (100% [4/4] of Internet users vs. 40% (2/5) of nonusers), conjunctivitis (43% [3/7] of Internet users vs. 25% [2/8] of nonusers), and retinal traction or detachments (57% [4/7] of Internet users vs. 0% [0/4] of nonusers). The most frequently visited Web sites were Google (82%) and WebMD (40%). Patient accuracy did not change according to the number of Web sites visited, but patients who visited the Mayo Clinic Web site had greater accuracy compared with those who visited other Web sites (89 vs. 30%, p = 0.003). Conclusion Patients with ocular symptoms may seek medical information on the Internet before evaluation by a physician in an ophthalmic ED. Online resources may improve the accuracy of patient self-diagnosis for low- and high-acuity diagnoses.

Corneal Nerve Abnormalities in Ocular and Systemic Diseases.

The trigeminal nerve gives rise to the corneal subbasal nerve system, which plays a crucial role in sensations of touch, pain, and temperature and in ocular healing processes. Technological advancements in instruments, in particular in vivo confocal microscopy and aethesiometry, have allowed for the structural and functional evaluation of corneal nerves in health and disease. Through application of these technologies in humans and animal models, structural and functional abnormalities have been detected in several ocular and systemic disorders, including dry eye disease (DED), glaucoma, migraine, and fibromyalgia. However, studies across a number of conditions have found that structural abnormalities do not always relate to functional abnormalities. This review will discuss instruments used to evaluate corneal nerves and summarize data on nerve abnormalities in a number of ocular and systemic conditions. Furthermore, it will discuss potential treatments that can alleviate the main manifestations of nerve dysfunction, namely ocular surface pain and persistent epithelial defects.

Periorbital botulinum toxin A improves photophobia and sensations of dryness in patients without migraine: Case series of four patients.

PURPOSE: Individuals receiving botulinum toxin A (BoNT-A) injections in the head and neck for migraine treatment have reported decreases in photophobia and sensations of dryness, independent of ocular surface parameters. We hypothesized that patients without migraine but with similar ocular neuropathic-like symptoms would also experience symptomatic improvement with periocular BoNT-A injections, independent of ocular surface changes. OBSERVATIONS: We identified four individuals without a history of migraine but with neuropathic ocular pain (symptoms of dryness, burning, and photophobia that were out of proportion to ocular surface findings and unresponsive to ongoing dry eye (DE) therapies). Individuals underwent 1 session of periocular BoNT-A injections. Validated questionnaires (Visual Light Sensitivity Questionnaire-8, Dry Eye Questionnaire-5) assessed photophobia and DE symptoms pre- and 1-month post-injections. All four reported improvements in frequency and severity of photophobia and eye discomfort following BoNT-A injections. Tear film parameters (phenol red thread test, tear break-up time, corneal staining, and Schirmer test) and eyelid (palpebral fissure height and levator palpebrae superioris function) and eyebrow (position) anatomy were also evaluated before and after injections. Despite a unanimous improvement in symptoms, there were no consistent changes in ocular surface parameters with BoNT-A injections across individuals. CONCLUSIONS: Periocular BoNT-A shows promise in reducing photophobia and sensations of dryness in individuals with neuropathic-like DE symptoms without a history of migraine, independent of tear film, eyelid, or eyebrow parameters.

Photophobia and sensations of dryness in patients with migraine occur independent of baseline tear volume and improve following botulinum toxin A injections.

BACKGROUND: To evaluate the efficacy of botulinum toxin A (BoNT-A) in reducing photophobia and dry eye symptoms in individuals with chronic migraine. Additionally, we aimed to evaluate tear film volume as a potential contributor to symptoms in these patients. METHODS: Retrospective review of 76 patients who received BoNT-A for chronic migraine between 23 August 2017 and 13 December 2017 at the Miami Veterans Affairs Medical Center Neurotoxin Clinic. Demographic data and all comorbidities were queried via chart review. Standardised validated surveys were administered to assess symptoms prior to and after BoNT-A injection. Preinjection tear volumes were obtained using the phenol red thread (PRT) test. RESULTS: Preinjection migraine, photophobia and dry eye symptom scores were all significantly correlated, p<0.05, and none were associated with preinjection PRT results. After BoNT-A, improvements in migraine, photophobia and dry eye symptoms were also significantly correlated, p<0.05 and similarly did not associate with preinjection PRT results. Photophobia scores significantly improved following BoNT-A, while dry eye symptoms significantly improved in those with severe symptoms at baseline (DEQ-5 score ≥12), p=0.027. In logistic regression analysis of all individuals with dry eye symptoms (DEQ-5 ≥6), individuals with more severe dry eye symptoms were more likely improve, OR 1.27, 95% CI 1.06 to 1.51, p<0.01. CONCLUSIONS: BoNT-A significantly improved photophobia in patients being treated for migraine and also improved dry eye symptoms in patients with severe symptoms at baseline, independent of baseline tear film volume. These improvements may be due to modulation of shared trigeminal neural pathways.