Mental burden of ocular surface discomfort.

Dry eye disease (DED) is a common chronic condition with multifactorial etiologies that is increasing in prevalence worldwide, up to 20% in the elderly. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable. Chronic ocular pain is the most common symptom of DED and there is currently no topical ocular analgesic therapy available to treat this debilitating disease. Eye pain can be perceived as itch, irritation, dryness, grittiness, burning, aching, and light sensitivity. Ocular pain is triggered by corneal nociceptors (cornea being the most sensory innervated tissue of the body). It was clearly established that repeated direct damage to ocular surface and per se corneal nerves can cause peripheral and central sensitization mechanisms explaining the ocular pain in some patients with DED. However, the brain regions and the neuronal pathways associated with ocular pain are still unclear. Thus, a better characterization of chronic ocular pain and an understanding of the peripheral and central molecular and cellular mechanisms involved are crucial issues for developing effective management and therapeutic strategy to alleviate ocular pain. In this review, we first describe the nociceptive corneal nerve pathways and the classification and the neurochemistry of primary afferents innervating the cornea. Then, an update of the fundamental and clinical studies related to the inflammatory processes linked to ocular pain is detailed. The last part of the review presents the diagnostic tools used in clinic for evaluating corneal sensitivity and corneal inflammation.

Pain, Prostheses, and Prophylaxis

This thesis explores the development of an evaporative dry eye (EDE) animal model based on Meibomian gland cauterisation, aiming to replicate the tear film alteration caused by Meibomian gland dysfunction (MGD), a major driver of EDE. Dry eye disease (DED), which causes ocular surface inflammation, pain, and discomfort, is a multifactorial condition with significant impact on quality of life. EDE is the most common subtype, linked to MGD, which impairs lipid secretion from Meibomian glands, increasing the tear evaporation rate. The cauterisation method, as suggested by existing literature, faced challenges: technique variability and unclear guidelines on how many glands to cauterise or whether both eyelids should be involved. These inconsistencies can compromise the model’s reliability, indicating the need for further optimisation to ensure reproducibility and consistency in experimental outcomes. This thesis also presents a novel multiplex electrochemiluminescence immunoassay (ECLIA) for detecting key biomarkers in rat tear samples, critical for DED research. Biomarkers such as interleukin-17 (IL-17), matrix metalloproteinase-9 (MMP-9), and intercellular adhesion molecule-1 (ICAM-1) were targeted. The assay was validated with promising results, showing that the detection ranges for these biomarkers met the required parameters, though precision was identified as a limiting factor. Variations were mainly due to human error, such as pipetting inconsistencies and evaporation during incubation. Suggestions for improving precision include standardising operator expertise, minimising reagent variability, and controlling incubation conditions. These improvements would increase reliability and broaden the assay's detection range. Additionally, the thesis investigates the role of oxidative stress and ferroptosis in DED. Ferroptosis, a form of iron-dependent cell death linked to lipid peroxidation, is thought to contribute to DED pathogenesis. In vitro studies with the ferroptosis inhibitor UAMC-3203 suggested potential in reducing oxidative stress. However, clear evidence for ferroptosis in DED models was not found. In vivo tests showed that UAMC-3203 could restore GPX4 gene expression closer to the control group, hinting at potential benefits of ferroptosis inhibition. Finally, the thesis proposes optimising the EDE model with inflammation-triggering agents like LFA-1 and ICAM-1 inhibitors, or toll-like receptor agonists, to enhance chronicity and inflammation. The use of advanced 3D cell culture models for better simulation of the ocular surface is also discussed, highlighting their potential for testing new therapies. Further research is needed to address the multifactorial causes of DED and improve treatments for this widespread condition.

The aim of this real-world registry study was to evaluate the quality-of-life (QoL) impact of dry eye disease (DED). The specific objectives were to determine factors affecting QoL in DED, and to evaluate the psychometric properties of the Ocular Surface Disease Index (OSDI), Ocular Comfort Index (OCI), and Patient Health Questionnaire (PHQ) in a real-world DED population using modern psychometric methods. This descriptive cross-sectional study included 368 DED patients (mean 54.7±16.6 years; 80.2% female) who completed one or more of the three questionnaires (OSDI, OCI and PHQ). Psychometric analysis of the QoL data was carried out with Andrich's Rating Scale Model of Rasch analysis. The original OSDI and OCI had disordered categories. The Rasch-optimised final QoL scales (OSDI - Overall, OSDI - Symptoms [SY], OSDI - Activity limitation [AL], OSDI - Environmental trigger [EN], OCI Overall, OCI - Frequency [FR], OCI - Intensity [IN], and PHQ) had satisfactory psychometric properties. Patients diagnosed with a mixed aqueous/evaporative DED subtype had worse mean OSDI-Overall and OSDI-AL scores than individuals with evaporative DED (p=0.012 and 0.001 respectively). Patients with corneal neuropathic pain had worse QoL scores (OSDI-Overall, OSDI-AL, OSDI-SY, OSDI-EN, OCI-Overall, OCI-FR, OCI-IN, and PHQ; all p<0.05) than those without. Patients who reported undergoing prior treatment or procedure for DED had worse QoL scores than those who did not (all p<0.05 except for PHQ). The associations between DED signs (tear breakup time and staining) and symptoms were weak or not significant. In this real-world setting, diagnoses of mixed DED, corneal neuropathic pain, and history of DED treatment/procedures were associated with worse dry eye symptoms, activity limitation, and/or QoL.

It is well-known that diabetes is one of the major causes of dry eye disease (DED). As DED can lead to serious ocular surface complications such as punctate keratitis, corneal erosion, corneal scarring, corneal perforation and visual loss, research is ongoing to investigate ways of improving the diagnosis of DED in patients with diabetes. This thesis investigated the role of inflammatory cytokines and metabolic proteins in tear fluid as a non-invasive, objective measure of inflammation in the diagnosis of type 2 diabetes (T2D)-related DED. In this thesis, a number of studies were performed to investigate potential tear fluid biomarkers and comparing them to the established clinical and laboratory measures used in DED diagnosis. It was important to evaluate the clinical behaviours of eye care professionals, such as ophthalmologists and optometrists with respect to the diagnosis and management of diabetes-related DED (Chapter 3). Thus, the online survey was conducted among 194 eye care professionals who work in the UK and Mongolia, to evaluate and compare their preferences for specific clinical procedures used to diagnose the presence of DED in diabetes. For example, how these may differ, depending on the practitioners' profession (ophthalmologist and optometrist) and the countries they work in. This study is the first time that the awareness of eye care professionals in the diagnosis and the management of diabetes-related DED in different regions of the world has been investigated. The results of the survey showed that eye care professionals in both countries have similar practice behaviours for diagnosing and treating diabetes-related DED. That is, ophthalmologists in the UK and in Mongolia have similar practice behaviours in diagnosing diabetes-related DED, and its severity, as for optometrists in the UK. Before commencing the studies to analyse protein biomarkers in tear fluids, it was important to establish the best possible means of sampling and storing tear samples, along with the optimal method of analysing them (Chapter 4). Therefore, a study was conducted to investigate the methodology of tear sampling, storage, analysis, sample centrifugation duration and speed. For tear biomarker assessment, a pilot study investigating the detectability of metabolic proteins in 1 μl tears was conducted (Chapter 5). This study is the first time that metabolic proteins such as Leptin, Insulin, C-peptide, GIP and active Ghrelin, have been shown to be detected in human tears collected from “healthy” individuals using Luminex Xmap technology. The results of this study showed that Leptin could be used in the future as a potential diagnostic biomarker of ocular surface disorders and, possibly, in determining the effects of metabolic disorders, as it has a low intra-subject confidence interval (CI) and a high intra-class correlation coefficient (ICC). A pilot study investigating the correlation between the presence of tear fluid inflammatory cytokines and tear fluid stability (assessed using tear evaporation rate [TER]; and non-invasive tear break-up time [NITBUT]) in healthy subjects was carried out (Chapter 6). This study also investigated the effect of time of day on TER and NITBUT values, and its possible correlation with tear cytokine concentrations in healthy subjects. The results revealed that the NITBUT and TER values had no significant variability over a day, or on different days, in healthy subjects, when the humidity and temperature of the examination room were constant. However, some tear fluid cytokine concentrations did show inter- and intra-day variability, without any consistent correlation with TER diurnal variation. Before commencing the study in a large cohort, a pilot study investigating the detectability of inflammatory cytokines and metabolic proteins in 1 μl tears collected from patients with type 2 diabetes (T2D; with and without DED) and DED-only (without T2D) was conducted (Chapter 7). The concentrations of 14 inflammatory cytokines, six metabolic proteins, ocular surface parameters, DED-related symptoms and quality of life (QoL) were evaluated and compared in a total of 122 subjects divided into four study groups as: T2D with DED, T2D-only (without DED), DED-only (without T2D) and healthy controls (Chapter 8). Overall, the results of this study showed that the ocular surface parameters and DED-related symptoms were similar for patients in the T2D+DED group and the DED-only group. In addition, patients in the T2D-only group had similar ocular surface parameters to healthy controls. Tear fluid Interleukin (IL)-6 and IL-8 concentrations were significantly higher in the T2D+DED group than the T2D-only group, DED-only group and healthy controls, which suggests that IL-6 and IL-8 could potentially be diagnostic biomarkers of T2D-related DED. These studies show that tear fluid biomarker analysis is feasible and it can be utilised in the objective diagnosis of T2D-related DED. This research helps to improve the understanding of the inflammatory mechanisms and markers of DED in T2D. However this complex process will require further research to identify the most appropriate biomarkers.

The Ocular Pain Assessment Survey (OPAS) has been used to quantify chronic ocular pain and quality of life (QOL). We aim to investigate the psychometric properties of individual OPAS items with the Rasch analysis in an Asian population of dry eye disease and neuropathic corneal pain (NCP). Question responses were obtained from 196 patients; 138 with dry eye disease (DED) and 58 with NCP, at the Singapore National Eye Centre. Item hierarchy, item fit statistics, item separation, reliability indices, and Yen's Q3 values were calculated. Individual dimensions that quantify eye pain levels in the past 24hours and QOL showed good discriminative ability according to their person separation index values. However, individual dimensions that measured eye pain in the past 2weeks, non-eye pain, as well as aggravating and associated factors showed suboptimal person separation index values. Significant correlations were found between the individual item pairs of the aggravating factors dimension as well as between some of the items in the QOL and associated factors dimensions. Two dimensions of the OPAS questionnaire were validated with the Rasch analysis. Based on these findings, we shorten the number of questions in some dimensions to improve the performance of the tool in similar Asian populations. Our study provides insights to improve the existing OPAS for real-world clinical applications and clinical trials.

Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This disorder may also involve neuroplasticity in response to neuronal injury. This review will emphasize the key characteristics of dry eye pain and its pathologic mechanisms, making the argument that a subset of dry eye represents a neuropathic pain disorder of the eye, more appropriately called "burning eye syndrome." A literature review was conducted using a PubMed search focusing on dry eye, corneal nociception, and neuropathic pain. Articles were reviewed and those discussing clinical course, pathophysiology, and neuronal regulation of chronic ocular pain as related to dry eye were summarized. We found that there is a discordance between ocular pain and dryness on the ocular surface. Although tear dysfunction may be one of the initial insults, its persistence may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic pain transition associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain. Dry eye is becoming a major health concern due to its increasing incidence, significant morbidity, and economic burden. Recent evidence suggests that a subset of dry eye may be better represented as a chronic neuropathic pain disorder due to its features of dysesthesia, spontaneous pain, allodynia, and hyperalgesia. Future therapies targeted at the underlying neuroplasticity may yield improved efficacy for patients with this subset of dry eye, which we term "burning eye syndrome."

Dry eye disease (DED) is a multifactorial, chronic, and often relapsing condition with a significant impact on patient quality of life (QoL). Symptoms such as ocular discomfort and visual disturbances are diverse and frequently misaligned with objective clinical signs, complicating diagnosis and management. DED not only interferes with daily activities like reading, driving, and computer use but also imposes a substantial economic burden due to direct healthcare costs and reduced work productivity. Beyond its ocular manifestations, DED has been associated with higher prevalence rates of depression and anxiety, with a complex bidirectional relationship. Patients with DED may experience psychological distress that exacerbates symptoms, leading to a vicious cycle that further impairs QoL. This underscores the importance of integrating mental health screening into the management of DED, particularly for high-risk populations. Optimizing the care of DED patients requires empathy, effective communication, and the establishment of a therapeutic alliance that acknowledges patient experiences and involves them in personalized treatment plans. Such an approach can improve patient satisfaction, enhance treatment adherence, and address both ocular and psychological dimensions of the disease. This paper highlights current evidence on the impact of DED symptoms and its association with mental health and recommends strategies to improve clinical management through a patient-centered approach.

Recent evidence suggests that dry eye (DE) may be comorbid with other chronic pain conditions. To evaluate DE as a comorbid condition in the U.S. veteran population. Retrospective review of veterans seen in the Veterans Administration Healthcare System (Veteran Affairs) between January 1, 2010, and December 31, 2014. Dry eye and nonocular pain disorders were ascertained by International Classification of Diseases, Ninth Revision (ICD-9) codes. Dry eye was further separated into ICD-9 codes representing tear film dysfunction or ocular pain. χ2 and logistic regression analyses were used to examine frequency and risk of DE, ocular pain, and tear film dysfunction by pain disorders. Of 3,265,894 veterans, 959,881 had a DE diagnosis (29.4%). Dry eye frequency increased with the number of pain conditions reported (P < 0.0005). Ocular pain was most strongly associated with headache (odds ratio [OR] 2.98; 95% confidence interval [CI] 2.95-3.01), tension headache (OR 2.64; 95% CI 2.58-2.71), migraine (OR 2.58; 95% CI 2.54-2.61), temporomandibular joint dysfunction (OR 2.39; 95% CI 2.34-2.44), pelvic pain (OR 2.30; 95% CI 2.24-2.37), central pain syndrome (OR 2.24; 95% CI 1.94-2.60), and fibromyalgia/muscle pain (OR 2.23; 95% CI 2.20-2.26), all P < 0.0005. Tear film dysfunction was most closely associated with osteoarthritis (OR 1.97; 95% CI 1.96-1.98) and postherpetic neuralgia (OR 1.95; 95% CI 1.90-2.00), both P < 0.0005. Dry eye, including both ocular pain and tear film dysfunction, is comorbid with pain conditions in this nationwide population, implying common mechanisms.

PurposePatients with dry eye disease (DED) sometimes complain of ocular pain. DED-related ocular pain has many similarities with neuropathic pain. Mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, is approved for treating neuropathic pain in Japan. This study aimed to investigate the effect of mirogabalin on hyperalgesia and chronic ocular pain in a rat DED model.MethodsDED was induced in female Sprague Dawley rats by unilaterally excising the external lacrimal gland (ELG) and Harderian gland (HG). After 4 weeks of ELG and HG removal, tear production (pH threads) and corneal epithelial damage (fluorescein staining) were evaluated. Corneal hyperalgesia and chronic pain were analyzed, respectively, by measuring capsaicin-induced eye-wiping behavior and c-Fos expression in the trigeminal nucleus. Mirogabalin (10 or 3 mg/kg) was evaluated for effects on DED-induced hyperalgesia and chronic ocular pain.ResultsTear production was significantly lower in DED-induced eyes than in control eyes. Corneal damage was significantly higher in DED eyes than in control eyes. Hyperalgesia and chronic ocular pain were detected 4 weeks after ELG and HG removal. Five days of mirogabalin administration significantly suppressed capsaicin-induced eye-wiping behavior, which indicated the suppression of ocular hyperalgesia. Administration of 10 mg/kg mirogabalin significantly reduced c-Fos expression in the trigeminal nucleus, which indicated the amelioration of chronic ocular pain.ConclusionsMirogabalin suppressed DED-induced hyperalgesia and chronic ocular pain in a rat DED model. Our findings suggested that mirogabalin might effectively alleviate chronic ocular pain in patients with DED.

PurposeTo evaluate the safety and efficacy of topical TOP1630, a novel nonsystemic kinase inhibitor, in dry eye disease (DED).Patients and methodsA randomized, double-masked, parallel-group trial of 0.1% TOP1630 ophthalmic solution TID or placebo (vehicle without active drug) was conducted in DED subjects (n=61). Key eligibility criteria consistent with enrolling a moderate to severe DED population included >6 months DED history; OSDI© score ≥18; Schirmer’s test score ≤10 and ≥1 mm/5 minutes; tear film break-up time >1 and <7 seconds; and dry eye exacerbation in corneal staining and ocular discomfort in a Controlled Adverse Environment (CAE®). After a 7-day run-in period with placebo TID, eligible subjects were randomized to TOP1630 or placebo for 28 days. No supplemental artificial tears or rescue medication were allowed.ResultsTOP1630 was safe, well-tolerated, and efficacious in treating DED symptoms and signs. No serious adverse events (AEs) or withdrawals due to treatment emergent AEs occurred. Drop comfort scores showed TOP1630 to be comfortable and comparable with placebo. Significant symptom improvements were seen for TOP1630 vs placebo for ocular discomfort (P=0.02 post-CAE), grittiness/foreign body sensation (on four independent assessment scales, each P<0.05), worst DED symptom (diary, P=0.06), and ocular pain (VAS, P=0.03). Sign improvements were seen for total ocular surface (all regions), corneal sum, and conjunctival sum staining with TOP1630 compared with placebo (each P<0.05).ConclusionTOP1630 had placebo-like tolerability and produced improvements in multiple symptom and sign endpoints in both environmental and challenge settings. The emergent TOP1630 benefit–risk profile for DED treatment is highly favorable and supports further development.

Background/Objectives: Post-coronavirus syndrome (long-COVID) refers to a multi-systemic range of symptoms that follows acute SARS-CoV-3 infection. Long-COVID has been linked with autonomic neuropathy as well as dry-eye disease (DED), an umbrella term that includes a variety of ocular symptoms and signs. Despite these associations, little is known about the co-occurrence of DED and dysautonomia symptoms in individuals with long-COVID. This study aims to examine relationships between dysautonomia and ocular symptoms in a long-COVID patient population. Methods: Cross-sectional study of 162 veterans with long-COVID. The Composite Autonomic Symptom Score-31 (COMPASS-31) assessed dysautonomia symptoms, and the NASA lean test and heart-rate variability metrics captured dysautonomia signs. Dry-eye disease (DED) symptoms were measured with the 5-Item Dry-Eye Questionnaire (DEQ5) and the Ocular Surface Disease Index (OSDI), while ocular pain intensity and neuropathic pain descriptors were evaluated using a Numerical Rating Scale (NRS) and select questions from the Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-Eye), respectively. Results: Most participants (78%) reported DED symptoms (DEQ5 ≥ 6). Nearly all COMPASS-31 domains were associated with DED symptoms, with the strongest correlation observed between the OSDI and pupillomotor scores (r = 0.67, p < 0.001). Among the autonomic signs, the strongest associations were observed between the change in systolic and diastolic blood pressure from baseline to 8 min and ocular pain triggered by temperature (r = -0.44 and r = -0.48, respectively, p < 0.01 for both). On linear regression analyses, pupillomotor and secretomotor symptoms remained positively associated with DED symptoms, while autonomic signs were most closely related to ocular pain metrics, with fluctuating blood pressure changes during orthostasis relating to neuropathic symptoms. Conclusions: DED symptoms, including ocular pain intensity, relate to autonomic symptoms in a long-COVID cohort. While associations with autonomic signs were less consistent, these data suggest that subtle autonomic variability relates to ocular pain in the long-COVID setting.

Background and Objectives: Dry eye disease (DED) is a multifactorial condition that affects quality of life (QoL). Symptoms like discomfort, blurred vision, and light sensitivity can negatively impact work efficiency, productivity, and psychological well-being. This study aimed to examine the relationship between DED and QoL, identify risk factors, and estimate DED prevalence in Saudi Arabia. Materials and Methods: This cross-sectional study included 1062 participants from Saudi Arabia, recruited via convenience sampling. Data were collected using an online questionnaire with three sections: sociodemographic information, the ocular surface disease index (OSDI) to assess DED severity, and the Arabic WHOQOL-BREF questionnaire to evaluate QoL. Results: Among participants, 77% suffered from DED. Males (β = −9.18, p < 0.001), postgraduate degree holders (β = −13.86, p = 0.001), and individuals with income >15,000 SR (β = −5.10, p = 0.023) had lower OSDI scores compared to reference groups (females, those with high school education or lower, and those with income <5000 SR, respectively), indicating a lower DED risk. Employed individuals, students (employed: β = 10.78, p < 0.020; students: β = 10.60, p < 0.016), divorced/widowed individuals (β = 18.70, p < 0.003), and those with diabetes, hypertension, and thyroid disorders showed higher OSDI scores. Higher OSDI scores correlated with lower QoL scores across all domains (physical: β = −0.26, p < 0.001; psychological: β = −0.22, p < 0.001; social: β = −0.25, p < 0.001; environmental: β = −0.20, p < 0.001). Conclusions: DED significantly affects all QoL domains. Risk factors include occupation, diabetes, hypertension, and thyroid disorders. Awareness and prevention efforts should be prioritized by institutions, while physicians should screen for DED in patients with chronic conditions. Further research is needed on the long-term effects of these risk factors and to improve management strategies.

Dry eye disease (DED) is a clinically significant multifactorial disorder of the ocular surface and tear film as it results in ocular discomfort and visual impairment and predisposes the cornea to infections. It is important for the quality of life and tends to be a chronic disease. It is also common, as the prevalence is estimated between 5 % to 30 % and this increases with age. Therefore, it is recognised as a growing public health problem that requires correct diagnosis and appropriate treatment. There are two main categories of DED: the deficiency of tear production (hyposecretive), which includes Sjögren syndrome, idiopathic or secondary to connective tissue diseases (e.g. rheumatoid arthritis), and non-Sjögren syndrome (e.g. age-related); and the tear evaporation category, where tears evaporate from the ocular surface too rapidly due to intrinsic causes (e.g. meibomian gland disease or eyelid aperture disorders) or extrinsic causes (e.g. vitamin A deficiency, contact lenses wear, ocular allergies). Management of the disease aims to enhance the corneal healing and reduce patient’s discomfort. This is based on improving the balance of tear production and evaporation by increasing the tear film volume (lubrication drops) and improving quality of tear film (ex omega-3 supplements, lid hygiene, tetracyclines), reducing the tear film evaporation (paraffin ointments, therapeutic contact lenses), reducing tear’s drainage (punctal plugs, cautery) and finally by settling down the ocular surface inflammation (steroids, cyclosporine, autologous serous), as appropriate. In this article we will review the clinical presentation, differential diagnosis and treatment options for DED.

Dry eye disease (DED) is a multifactorial disease affecting approximately 5-50% of individuals in various populations. Contributors to DED include, but are not limited to, lacrimal gland hypofunction, meibomian gland dysfunction (MGD), ocular surface inflammation, and corneal nerve dysfunction. Current DED treatments target some facets of the disease, such as ocular surface inflammation, but not all individuals experience adequate symptom relief. As such, this review focuses on alternative and adjunct approaches that are being explored to target underlying contributors to DED. Neuromodulation, stem cell treatments, and oral royal jelly have all been studied in individuals with DED and lacrimal gland hypofunction, with promising results. In individuals with MGD, devices that provide eyelid warming or intense pulsed light therapy may reduce DED symptoms and signs, as may topical Manuka honey. For those with ocular surface inflammation, naturally derived anti-inflammatory agents may be helpful, with the compound trehalose being farthest along in the process of investigation. Nerve growth factor, blood-derived products, corneal neurotization, and to a lesser degree, fatty acids have been studied in individuals with DED and neurotrophic keratitis (i.e. corneal nerve hyposensitivity). Various adjuvant therapies have been investigated in individuals with DED with neuropathic pain (i.e. corneal nerve hypersensitivity) including nerve blocks, neurostimulation, botulinum toxin, and acupuncture, although study numbers and design are generally weaker than for the other DED sub-types. Several alternatives and adjunct DED therapies are being investigated that target various aspects of disease. For many, more robust studies are required to assess their sustainability and applicability.