Genome Wide Association Study of Neuropathic Ocular Pain.

Purpose: To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development. Design: Prospective study of individuals with NOP. Participants: Three hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic. Methods: The Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of P < 5 × 10-8. A gene-based analysis was performed using the multimarker analysis of genomic annotation software (in the functional mapping and annotation of GWAS online platform). The 13 865 778 single nucleotide polymorphisms (SNPs) from our GWAS analysis were mapped to 10 834 protein coding genes, and significant genes were run through gene set enrichment analysis. Main Outcome Measures: Identification of SNPs and protein products that may be associated with the development of NOP. Results: One hundred seventy-one SNPs reached a threshold of P < 10-5, of which 10 SNPs reached the suggestive level of significance of P < 5 × 10-7 and 1 SNP met our genome-wide significance threshold of P < 5 × 10-8. This lead SNP, rs140293404 (P = 1.23 × 10-8), is an intronic variant found within gene ENSG00000287251 coding for transcript ENST00000662732.1. Rs140293404 is in linkage disequilibrium with exon variant rs7926353 (r2 > 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 (MMP19) (P = 1.12 × 10-5), zinc finger RNA-binding motif and serine/arginine rich-1 (ZRSR1) (P = 1.48 × 10-4), CTC-487M23.8 (P = 1.79 × 10-4), receptor expression-enhancing protein-5 (REEP5) (P = 2.36 × 10-4), and signal recognition particle-19 (SRP19) (P = 2.56 × 10-4). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 × 10-3) and olfactory signaling (false discovery rate = 1.63 × 10-2) pathways were enriched with the most significant genes. Conclusions: Our GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better understanding of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

FL-41 Tint Reduces Activation of Neural Pathways of Photophobia in Patients with Chronic Ocular Pain.

PURPOSE: To assess the therapeutic effect of tinted lenses (FL-41) on photophobia and light-evoked brain activity using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular surface pain. DESIGN: Prospective case series. METHODS: 25 subjects from the Miami veterans affairs (VA) eye clinic were recruited based on the presence of chronic ocular pain, dry eye symptoms, and photophobia. Using a 3T MRI scanner, subjects underwent 2 fMRI scans using an event-related design based on light stimuli: one scan while wearing FL-41 lenses and one without. Unpleasantness ratings evoked by the light stimuli were collected after each scan. RESULTS: With FL-41 lenses, subjects reported decreased (n = 19), maintained (n = 2), or increased (n = 4) light-evoked unpleasantness ratings. Group analysis at baseline (no lens) revealed significant light evoked responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral insula, bilateral frontal pole, visual, precuneus, paracingulate, and anterior cingulate cortices (ACC) as well as cerebellar vermis, bilateral cerebellar hemispheric lobule VI, and bilateral cerebellar crus I and II. With FL-41 lenses, light-evoked responses were significantly decreased in bilateral S1, bilateral S2, bilateral insular, right temporal pole, precuneus, ACC, and paracingulate cortices as well as bilateral cerebellar hemispheric lobule VI. CONCLUSION: FL-41 lenses modulated photophobia symptoms in some individuals with chronic ocular pain. In conjunction, FL-41 lenses decreased activation in cortical areas involved in processing affective and sensory-discriminative dimensions of pain. Further research into these relationships will advance the ability to provide precision therapy for individuals with ocular pain.

Disentangling the neurological basis of chronic ocular pain using clinical, self-report, and brain imaging data: use of K-means clustering to explore patient phenotypes.

Introduction: The factors that mediate the expression of ocular pain and the mechanisms that promote chronic ocular pain symptoms are poorly understood. Central nervous system involvement has been postulated based on observations of pain out of proportion to nociceptive stimuli in some individuals. This investigation focused on understanding functional connectivity between brain regions implicated in chronic pain in persons reporting ocular pain symptoms. Methods: We recruited a total of 53 persons divided into two cohorts: persons who reported no ocular pain, and persons who reported chronic ocular pain, irrespective of ocular surface findings. We performed a resting state fMRI investigation that was focused on subcortical brain structures including the trigeminal nucleus and performed a brief battery of ophthalmological examinations. Results: Persons in the pain cohort reported higher levels of pain symptoms relating to neuropathic pain and ocular surface disease, as well as more abnormal tear metrics (stability and tear production). Functional connectivity analysis between groups evinced multiple connections exemplifying both increases and decreases in connectivity including regions such as the trigeminal nucleus, amygdala, and sub-regions of the thalamus. Exploratory analysis of the pain cohort integrating clinical and brain function metrics highlighted subpopulations that showed unique phenotypes providing insight into pain mechanisms. Discussion: Study findings support centralized involvement in those reporting ocular-based pain and allude to mechanisms through which pain treatment services may be directed in future research.

It Is All About the Angle: A Clinical and Optical Coherence Tomography Comparison of Corneal Ocular Surface Squamous Neoplasia and Corneal Pannus.

PURPOSE: The aim of this study was to compare clinical characteristics and high-resolution optical coherence tomography (HR-OCT) findings between corneal ocular surface squamous neoplasia (OSSN) and corneal pannus. METHODS: Retrospective study of 9 individuals, 3 with lesions histologically confirmed to be OSSN, 3 with lesions histologically confirmed to be pannus, 1 with lesions histologically confirmed to be OSSN followed by pannus, and 2 with long-standing, nonchanging lesions clinically diagnosed as pannus. All individuals presented to the Miami Veterans Affairs Medical Center eye clinic or Bascom Palmer Eye Institute between 2015 and 2023. Clinical characteristics and HR-OCT findings were evaluated and compared. RESULTS: Mean age of the population was 72.8 ± 5.1 years, 100% self-identified as male, 100% as White, and 11.1% as Hispanic. Clinically, all lesions appeared as whitish, opalescent, variably vascularized opacities extending from the limbus. None of the OSSN cases had vessels that extended to the border, whereas 4 cases of pannus (67%) had at least 1 vessel that reached the border. On HR-OCT, epithelial hyperreflectivity was observed in all cases of OSSN and pannus. Epithelial thickening was observed in all cases of OSSN, but in none of the cases of pannus. An important distinction between the 2 groups was the transition between normal and abnormal epithelium. All cases of OSSN had a vertical transition, whereas all cases of pannus had an angled transition. CONCLUSIONS: Corneal OSSN and corneal pannus can both present with clinical findings of an opalescent lesion and may have overlapping findings on HR-OCT. Although both entities may show epithelial hyperreflectivity on HR-OCT, OSSN demonstrates an abrupt transition at a vertical, 90 degrees angle perpendicular to the Bowman layer, whereas pannus appears as an angled transition around 45 degrees. Therefore, the angle of transition between normal and abnormal epithelium can be useful in distinguishing between the 2 entities.

Individuals with Diabetes Mellitus Have a Dry Eye Phenotype Driven by Low Symptom Burden and Anatomic Abnormalities.

Dry eye disease is an umbrella term that includes a variety of symptoms and signs. A link between diabetes mellitus and dry eye disease exists, but the associated phenotype needs further examination. Thus, our aim was to determine how diabetes mellitus relates to the dry eye disease phenotype. A prospective, cross-sectional study was conducted at the Miami Veteran Affairs Medical Center ophthalmology clinic between October 2013 and September 2019. Participants included a volunteer sample of 366 South Florida veterans with one or more symptoms or signs of dry eye disease [Dry Eye Questionnaire-5 ≥ 6 OR tear break-up time ≤ 5 OR Schirmer's test score ≤ 5 OR corneal fluorescein staining ≥ 2]. Participants were divided into three groups: (1) individuals without diabetes mellitus (controls); (2) individuals with diabetes mellitus but without end-organ complications; and (3) individuals with diabetes mellitus and end-organ complications. Dry eye metrics were compared across groups. The main outcome measures included ocular symptom questionnaires [e.g., 5-item Dry Eye Questionnaire, Ocular Surface Disease Index, and ocular pain assessment] and clinical parameters obtained from an ocular surface evaluation. A total of 366 individuals were included (mean age 59 ± 6 years; 89% males; 39% White; 11% diabetes mellitus and end-organ complications; 15% diabetes mellitus but without end-organ complications). Individuals with diabetes mellitus and end-organ complications had lower symptom scores on the dry eye disease and pain-specific questionnaires compared to individuals with diabetes mellitus but without end-organ complications and controls (Ocular Surface Disease Index: 42.1 ± 24.5 vs. 38.9 ± 25.1 vs. 23.6 ± 16.2; p < 0.001; numerical rating scale of ocular pain intensity: 4.9 ± 3.2 vs. 4.3 ± 2.7 vs. 3.5 ± 2.7; p = 0.02). Eyelid laxity was also more severe in the group with diabetes mellitus and end-organ complications (0.69 ± 0.64 vs. 0.73 ± 0.72 vs. 1.08 ± 0.77; p = 0.004) compared to the two other groups. The diabetic dry eye disease phenotype is driven by signs more so than by symptoms, with anatomic eyelid abnormalities being more frequent in individuals with diabetes mellitus and end-organ complications. Given this, ocular surface abnormalities in individuals with DM may be missed if screened by symptoms alone. As such, individuals with DM should undergo a slit lamp examination for signs of ocular surface disease, including anatomic abnormalities.

Face and Content Validity of an Artificial Eye Model for Secondary Intraocular Lens Fixation via Yamane Technique.

Purpose: To assess the face and content validity of an artificial eye model for secondary intraocular lens (IOL) fixation via the Yamane technique. Methods: Ophthalmologists and residents participated in a 90-minute simulation session on secondary IOL fixation via the Yamane technique. Hands-on practice of this technique was performed on an artificial eye, the Bioniko Okulo BR8. After, all ophthalmologists answered an 18-question survey assessing the face and content validity of the model. Survey responses were recorded on a 5-point double-headed Likert scale, ranging from strongly agree (1)-to-strongly disagree (5) (Figure 1). Results: Twenty-three surveys were completed. Respondents rated the survey with a median response of 1 (strongly agree)-to-3 (neutral). Highest ratings for the model were received for "usefulness for training residents", and "easier to set up and clean-up compared to a cadaver". Lowest ratings were received for realism of the model compared to cadaveric eyes. Statistical analysis revealed no significant difference among identified groups. Ratings for face and content validity were viewed favorably, both with an overall median response of 2.00 (agree). Conclusion: The Bioniko Okulo BR8 shows promise as a valid tool for practicing secondary IOL fixation via the Yamane technique. Considering recent guidelines in competency-based ophthalmology education programs, this model may be a valuable tool over traditional techniques for teaching and improving surgical skill amongst trainees.

Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia.

Introduction: To examine the effect of botulinum toxin A (BoNT-A) on neural mechanisms underlying pain and photophobia using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular pain. Methods: Twelve subjects with chronic ocular pain and light sensitivity were recruited from the Miami Veterans Affairs eye clinic. Inclusion criteria were: (1) chronic ocular pain; (2) presence of ocular pain over 1 week recall; and (3) presence of photophobia. All individuals underwent an ocular surface examination to capture tear parameters before and 4-6 weeks after BoNT-A injections. Using an event-related fMRI design, subjects were presented with light stimuli during two fMRI scans, once before and 4-6 weeks after BoNT-A injection. Light evoked unpleasantness ratings were reported by subjects after each scan. Whole brain blood oxygen level dependent (BOLD) responses to light stimuli were analyzed. Results: At baseline, all subjects reported unpleasantness with light stimulation (average: 70.8 ± 32.0). Four to six weeks after BoNT-A injection, unpleasantness scores decreased (48.1 ± 33.6), but the change was not significant. On an individual level, 50% of subjects had decreased unpleasantness ratings in response to light stimulation compared to baseline ("responders," n = 6), while 50% had equivalent (n = 3) or increased (n = 3) unpleasantness ("non-responders"). At baseline, several differences were noted between responders and non-responders; responders had higher baseline unpleasantness ratings to light, higher symptoms of depression, and more frequent use of antidepressants and anxiolytics, compared to non-responders. Group analysis at baseline displayed light-evoked BOLD responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral anterior insula, paracingulate gyrus, midcingulate cortex (MCC), bilateral frontal pole, bilateral cerebellar hemispheric lobule VI, vermis, bilateral cerebellar crus I and II, and visual cortices. BoNT-A injections significantly decreased light evoked BOLD responses in bilateral S1, S2 cortices, cerebellar hemispheric lobule VI, cerebellar crus I, and left cerebellar crus II. BoNT-A responders displayed activation of the spinal trigeminal nucleus at baseline where non-responders did not. Discussion: BoNT-A injections modulate light-evoked activation of pain-related brain systems and photophobia symptoms in some individuals with chronic ocular pain. These effects are associated with decreased activation in areas responsible for processing the sensory-discriminative, affective, dimensions, and motor responses to pain.

Comparison of 3D heads-up display system with conventional surgical microscopy for minimally invasive glaucoma surgery on an artificial eye model.

OBJECTIVE: To survey ophthalmic surgeons' opinions comparing a novel three-dimensional (3D) heads-up display system with a conventional surgical microscopy for minimally invasive glaucoma surgery (MIGS) on an artificial eye model. MATERIALS AND METHODS: Twenty-one ophthalmologists at the 2021 Canadian Ophthalmological Society Annual Meeting in Halifax, Nova Scotia, underwent a 90-minute skills-transfer course on MIGS. Using an artificial eye model (SimulEYE iTrack Model; InsEYE LLC, Westlake Village, Calif.), participants engaged in hands-on practice of MIGS via both a 3D heads-up display system (3D HUDS) (Zeiss Artevo 800; Carl Zeiss Meditec, Jena, Germany) and a conventional surgical microscope. Following completion, participants and instructors answered a 16-question survey comparing the 2 systems (3D HUDS vs conventional surgical microscope). Survey responses were recorded on a 9-point double-headed Likert scale ranging from strongly favour 3D HUDS (1) to strongly favour conventional surgical microscopy (9). Mann-Whitney U nonparametric analysis was used to compare instructor versus participants and experts versus nonexperts. RESULTS: Survey ratings favoured the 3D HUDS over the conventional surgical microscopy, with respondent ratings for all survey questions ranging from a response of 1 (strongly favour 3D HUDS) to 5 (equal). Mann-Whitney U statistical analysis revealed no significant difference between instructor versus participant as well as between expert versus nonexpert. Most ratings for the 3D HUDS were received for ergonomic setup of the surgical modality, depth of field (or) field of view, and usefulness in training residents for MIGS. Equal ratings for the 3D HUDS and conventional surgical microscope were received for system malfunctions and lag during surgery. CONCLUSIONS: The 3D HUDS was favoured over conventional microscopy for the performance of simulated MIGS by ophthalmologists with varying levels of experience. The survey results suggest that the 3D HUDS in an artificial eye model is useful for teaching minimally invasive glaucoma surgery, particularly with the advent of competency-based ophthalmology education programs.

Pyridostigmine Bromide Pills and Pesticides Exposure as Risk Factors for Eye Disease in Gulf War Veterans.

To examine associations between the pyridostigmine bromide (PB) pill and/or pesticide exposure during the 1990-1991 Gulf War (GW) and eye findings years after deployment. A cross-sectional study of South Florida veterans who were deployed on active duty during the GW Era (GWE). Information on GW exposures and ocular surface symptoms were collected via standardized questionnaires and an ocular surface examination was performed. Participants underwent spectral domain-ocular coherence tomography (SD-OCT) imaging that included retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and macular maps. We examined for differences in eye findings between individuals exposed versus not exposed to PB pills or pesticides during service. A total of 40.7% (n = 44) of individuals reported exposure to PB pills and 41.7% (n = 45) to pesticides; additionally, 24 reported exposure to both in the GW arena. Demographics were comparable across groups. Individuals exposed to PB pills reported higher dry eye (DE) symptoms scores (the 5-Item Dry Eye Questionnaire, DEQ-5: 9.3 ± 5.3 vs. 7.3 ± 4.7, p = 0.04) and more intense ocular pain (average over the last week: 2.4 ± 2.6 vs. 1.5 ± 1.8, p = 0.03; Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-E): 18.2 ± 20.0 vs. 10.8 ± 13.8, p = 0.03) compared to their non-exposed counterparts. DE signs were comparable between the groups. Individuals exposed to PB pills also had thicker OCT measurements, with the largest difference in the outer temporal segment of the macula (268.5 ± 22.2 µm vs. 260.6 ± 14.5 µm, p = 0.03) compared to non-exposed individuals. These differences remained significant when examined in multivariable models that included demographics and deployment history. Individuals exposed to pesticides had higher neuropathic ocular pain scores (NPSI-E: 17.1 ± 21.1 vs. 11.6 ± 12.9, p = 0.049), but this difference did not remain significant in a multivariable model. Individuals exposed to PB pills during the GWE reported more severe ocular surface symptoms and had thicker OCT measures years after deployment compared to their non-exposed counterparts.

Comparing Impact and Concussion Risk in Leatherhead and Modern Football and Hockey Helmets.

BACKGROUND: Improvements in the modern helmet have demonstrated beneficial effects in reducing concussion risk in football players. However, previous studies yield conflicting results regarding the protective quality of leatherhead football helmets. There is limited research comparing the modern football helmet and the modern hockey helmet, with one previous study demonstrating the football helmet as providing a lower risk of concussion. OBJECTIVE: To compare the head acceleration produced in a leatherhead football helmet vs a modern football helmet vs a modified modern football helmet with softer padding vs a modern hockey helmet in helmet-to-helmet strikes. METHODS: Accelerometers were placed on the frontal, apex, and parietal regions of a Century Body Opponent Bag manikin. Each type of helmet was placed on the manikin and struck by a swinging modern football helmet. The G-force acceleration was determined in three-dimensional axes of 100 total helmet-to-helmet impacts. RESULTS: The leatherhead football helmet was the least protective in reducing G-forces. The modified modern football helmet did not provide a significant difference compared with the modern football helmet. Significantly greater G-forces were produced in a collision between 2 modern football helmets in comparison with 2 modern hockey helmets. CONCLUSION: The leatherhead football helmet was the least protective, and the hockey helmet was the most protective, with the football helmet being intermediate. This study provides additional insight into the inconclusive evidence regarding the safety of leatherhead football helmets and into the design of football and hockey helmets in the future.

Conjunctival Nevus.

Purpose of Review: To provide an up-to-date review of the epidemiology, presentation, diagnosis, and treatment options for conjunctival nevi (CN). Recent Findings: Around 17.2%-42% of all conjunctival tumors have been found to be CN, which most frequently present in White individuals between the first to early third decade of life, with equal distribution between males and females. CN commonly occur in the interpalpebral bulbar conjunctiva with pigmentation ranging from amelanotic to dark. Diagnosis is typically made through slit lamp examination, visualized by a well circumscribed, variably elevated, variably pigmented, solitary lesion with clear cysts distributed throughout the pigment. In ambiguous cases, anterior segment optical coherence tomography (AS-OCT) can highlight the presence of sub-clinical cysts, whose presence points to a diagnosis of nevus. However, excisional biopsy with histopathology examination is the gold standard for identifying CN. Summary: CN are benign, variably pigmented lesions. They are the most common of the conjunctival melanocytic tumors. Due to the extremely low risk of transformation to malignant melanoma (MM), CN are usually managed with routine observation and photo documentation.