TFOS DEWS III: Diagnostic Methodology.

Seeing through tears: Understanding and managing dry eye disease.

This report describes the development of an artificial intelligence system for automated assessment of tear film stability and the classification of tear breakup patterns (BUPs), supporting precise dry eye (DE) diagnosis and personalised treatment under the framework of tear film-oriented diagnosis. A dataset of 143 eyes (98 with dry eye, 45 healthy) was analysed. Participants were evaluated using the Ocular Surface Disease Index, Keratograph 5M assessments (tear meniscus height, non-invasive tear breakup time, lipid layer thickness grade and meiboscore) and the Schirmer I test. Tear film breakup with fluorescein was video recorded and processed via a mask region-based convolutional neural network for tear film segmentation and a temporal segment network for temporal feature extraction. The proposed system performed automated evaluation of DE and identified four representative BUPs, including line break, dimple break, spot break and random break. Model performance was assessed using key metrics, including accuracy, precision, recall and F1 score. The diagnostic model achieved 91.8% accuracy in detecting tear film breakup and 98% accuracy in identifying DE. The classification model reached 88% accuracy, with high precision and recall for line and spot break. Gradient-weighted class activation mapping indicated effective capture of morphological features. Significant differences in ocular surface parameters were observed between DE and healthy eyes, as well as among BUP groups, confirming the system's clinical relevance. This artificial intelligence system offers an objective, non-invasive approach to supporting DE diagnosis and classifying BUPs, reducing interobserver variability and extensive training. By accurately detecting tear film instability and deficiency patterns, it supports targeted tear film-oriented therapy and advances personalised treatment strategies.

Background: Dry eye is a disease (DED) of the tear film and ocular surface, leading to ocular discomforts and pain. The pathophysiology of DED includes tear film instability and ocular surface inflammation. Vitamin D refers to a group of fat-soluble secosteroids responsible for enhancing intestinal absorption of calcium, iron, magnesium, phosphate, and zinc. It is not strictly a vitamin, and may be considered a hormone as its synthesis and activity occur in different locations. Objective: Thisstudy aimed to investigate tear film function in patients with vitamin D deficiency. Patient and methods: A case-control study included 75 eyes of 39 patients who were referred to the Ophthalmologic Clinic, Menoufia University during the period from March 2020 to December 2020. Patients of dry eye underwent tear break up time, Schirmer I test without anesthesia and special tests as well as measurement of serum vitamin D level were assessed. Results: 25-hydroxy vitamin D level of the studied group ranged from 6-18.50 ng/ml with mean value of 8.22 ± 4.814 ng/ml. Also, majority of studied sample (92.3%) had bilateral affected eyes, followed by Gelinya (30%). Schirmer's test, tear film breakup time (TFBUT) and ocular surface disease index (OSDI) were increased significantly when compared the values at baseline and after treatment to be after 10 weeks (P < 0.001). Conclusion: Vitamin D replacement appears to improve ocular surface health in patients with vitamin D deficiency. However, further clinical trials with a large sample size and control group are warranted to define the role of vitamin D. Vitamin D supplementation is an effective and useful treatment for patients with dry eye syndrome (DES) that is refractory to conventional treatment.

Dry eye disease (DED) is a chronic ocular surface condition that affects millions of people and has a worldwide prevalence of over 50%. Morbidities associated with DED include pain, discomfort, and blurring of vision. DED has evolved into a pressing public health concern due to the economic and psychosocial burden it imparts on affected individuals. A multitude of etiological or risk factors has been identified, ranging from aging, surgery, and malnutrition to occupational environment. These factors contribute to ocular surface inflammation, epitheliopathy, hyperosmolarity, tear film instability, and neurosensory abnormalities that culminate in the presentation of signs and symptoms of DED. Aberrant and chronic ocular surface inflammation emerged as a key modifiable contributor in DED pathobiology due to its direct association with signs and symptoms of DED, and resolution of disease following the use of anti-inflammatory agents. Despite being one of the most successful therapeutic strategies in DED management, there is a substantial number of patients who are refractory to anti-inflammatory regimen and other current forms of treatment. In addition, complexity in the management of DED increases with the presence of discordance between signs and symptoms in some patients. Hence, there is an urgent and constant need to identify additional disease mechanisms and contributors that can be targeted to resolve the morbidities associated with DED. The current special issue DED is designed to report and highlight the various translational investigations that have been directed towards improving DED management in clinical practice. These include (i) disease-specific and biomarker-based stratification of patients for personalized treatment and prevention of disease progression; (ii) newer therapeutic strategies that include both pharmacological and non-pharmacological (such as thermal pulsation therapy) approaches; (iii) novel molecular factors and mechanisms including novel proteins, interferon imbalance and ionic imbalances; (iv) physiological variations, such as hormonal and nutritional changes; (iv) newer disease models, including animal models that can be used to understand newer mechanisms and to test emerging and novel therapeutic agents. In summary, the contributors to this special issue have provided critical additions to the DED knowledgebase, with reference to both pathological mechanisms and clinical management. About the AuthorDr. Rohit Shetty Dr. Rohit Shetty is the Vice Chairman of Narayana Nethralaya, Bangalore, a cornea-refractive surgeon and a clinician scientist with a keen interest in keratoconus, corneal ectatic disorders and dry eye disease. He has been practicing high volume refractive surgery for 15 years now. Dr Shetty obtained his FRCS Glasgow in 2006 and is currently an FRCS examiner. He is the Chief Mentor for the Dual Academic Program (PhD & Clinical Fellowship) at Narayana Nethralaya Eye Institute, Bangalore and Maastricht University. He was recently awarded the Fellowship of the American College of Surgeons. Dr Shetty has close to 350 publications in peer-reviewed journals and is a reviewer for many indexed journals in the specialty. He is also on the editorial board of the Journal of Refractive Surgery. With a keen interest in imaging, some of his research includes, waveform analysis of deformation and deflection amplitude in keratoconus, influence of ocular spherical aberration on near and intermediate visual acuity in presbyopic eyes, biomechanics of LASIK Flap and SMILE Cap and corneal tomography in post-refractive surgery ectasia. In the 2015 annual conference of the All India Ophthalmological Society, Dr Shetty won the prestigious Col. Rangachari Award for his work on "Is Inflammation Driving Keratoconus? A Holistic Study of Molecular Pathways". The American Academy of Ophthalmology recently conferred the Achievement Award to Dr Rohit Shetty for distinguished services rendered over the years to the programs of the society. Besides being conferred the Casebeer Award for outstanding contribution to refractive surgery, he was recently awarded the Achievement Award by the Asia-Pacific Academy of Ophthalmology.

Background: Shushkakshipaka is Sarvakshigata and Sadhya Netra Roga and can be correlated with Dry Eye Disease (DED) because of similarities in the clinical features. Dry Eye Disease is “A multi-factorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neuro-sensory abnormalities play an etiological role”. Materials and Methods:The subject with the clinical features of Shushkakshipaka (DED) was approached the out patient section of Shalakya Tantra and was treated with Jeevaniya Panchamoola Ghrita Netra Tarpana. Result: Significant changes in schirmer’s test and TBUT are noted. Conclusion:Netra Tarpana with Jeevaniya Panchamoola Ghrita is effective in the management of Shushkakshipka.

The aim of this review is to summarize the results of a consensus meeting held by a group of experts in dry eye disease (DED) to discuss the importance of tear substitutes in the treatment of DED. The meeting focused especially on the main characteristics of lacrimal substitutes, the development of in vitro models to investigate DED pathophysiology and treatment, the importance of conducting rigorous clinical trials, the requirements of the upcoming European Legislation on medical devices, the advances in the formulation of safer preservatives, the peculiarities of treatment in younger subjects, and the importance of an updated terminology for lacrimal substitutes. A literature search was conducted using MEDLINE, with different combinations of pertinent keywords, depending on the subject under discussion, such as "dry eye disease"; "tear substitutes"; "in vitro models"; "ocular surface"; "clinical trials"; "European Regulation"; "preservatives" "younger patients". Also, each author included in the discussion selected articles from their personal library. Using a consensus-based method called nominal group technique to reach a conclusion and proposal for a new classification of eye drops used to improve the tear film and ocular surface epithelia, the experts also conducted a round table meeting. The new terms proposed by the authors are "wetting agents", "multiple-action tear substitutes" or "ocular surface modulators". The new classification is needed to distinguish eye drops used to improve the tear film and ocular surface epithelia, in line with the new definition of DED, which recognizes the loss of ocular homeostasis, and the creation of a vicious circle of chronic inflammation and ocular damage as fundamental aspects of DED pathophysiology. Although tear substitutes have been historically used to provide eye lubrication to the ocular surface, recent advances in the pathophysiology of dry eye disease (DED) clarified that treatment should not just focus on tear film quality or quantity, but address the loss of homeostasis of the ocular surface, blocking the vicious circle of chronic inflammation and ocular damage. Given the scant comparative evidence on tear substitutes currently on the market, further studies should focus on developing new agents, considering the advantages provided by in vitro models, importance of conducting rigorous clinical trials, availability of less harmful preservatives and obligations related to the new European legislation on medical devices. Based on the discussion of these topics, a group of experts held a consensus meeting to identify new and more appropriate terms for different tear substitutes. The proposed terms are wetting agents, multiple-action tear substitutes and ocular surface modulators. Regardless of the agent used, it is important to note that tear substitutes represent one of many options for DED treatment, which should not overlook the psychological aspects of the disease and the peculiarities of younger subjects, who seem to have a higher risk for DED, possibly related to digital devices excessive use.

The aim of the study is to investigate the applicability of a newly developed corneal topographer in assessing tear film stability in Indian subjects. A prospective comparative study of 25 Indian subjects with dry eyes attending a tertiary eye care clinic in South India and 25 normal control subjects was conducted. The diagnosis of dry eye was made based on ocular surface disease index questionnaire. Non-invasive tear film break-up time (NI-TBUT) was measured using a new method based on a corneal topographer equipped with modified scan software. The correlations between the NI-TBUT and the traditional fluorescein tear film break-up time (F-TBUT), Schirmer I test values were determined. A total of 50 patients (100 eyes) were included. The values of NI-TBUT were significantly lower than the values of F-TBUT in both the cases (NI-TBUT 5.78±0.8s and F-TBUT 7.56±0.5s; p<0.02) and controls (NI-TBUT 11.66±1s and F-TBUT 12.92±1.2s; p<0.01). NI-TBUT values were significantly lower than the corresponding F-TBUT values in the varying grades of dry eyes. The mean NI-TBUT values in mild dry eyes was 6.42±0.2s, moderate dry eyes was 4.70±0.3s and in severe dry eyes was 2.32±1.2s. There was a significant difference in the NI-TBUT values for cases and controls (p<0.001). There was a good correlation seen between the NI-TBUT values and the F-TBUT values, Schirmer I values and the ODSI scores. NI-TBUT was found to have a sensitivity of 86.1% and a specificity of 81.1% when the cut-off value was kept at 6.2s. We investigated the performance of a non-invasive technique for measuring tear film stability to aid in the diagnosis of dry eye disease. It is a useful non-invasive objective method for the detection of dry eye, and its varying grades and may be useful in monitoring the efficacy of therapies for dry eye.

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 is a chronic disease of the ocular surface characterized by abnormal tear film composition, tear film instability, and ocular surface inflammation, affecting 5% to 50% of the population worldwide. Autoimmune rheumatic diseases (ARDs) are systemic disorders with multi-organ involvement, including the eye, and play a significant role in dry eye. To date, most studies have focused on Sjögren's syndrome (one of the ARDs) since it manifests as two of the most common symptoms-dry eyes and a dry mouth-and attracts physicians to explore the relationship between dry eye and ARDs. Many patients complained of dry eye related symptoms before they were diagnosed with ARDs, and ocular surface malaise is a sensitive indicator of the severity of ARDs. In addition, ARD related dry eye is also associated with some retinal diseases directly or indirectly, which are described in this review. This review also summarizes the incidence, epidemiological characteristics, pathogenesis, and accompanying ocular lesions of ARD's related dry eye, emphasizing the potential role of dry eye in recognition and monitoring among ARDs patients.

Strip Meniscometry (SM): A New and Simple Method of Tear Meniscus Evaluation

Dry eye disease (DED), primarily classified as multifactorial ocular surface disorder, afflicts tens of millions of individuals worldwide, adversely impacting their quality of life. Extensive research has been conducted on tear film analysis over the past decades, offering a range of tests to evaluate its volume, health, and integrity. Yet, early diagnosis and effective treatment for DED continue to pose significant challenges in clinical settings. Nevertheless, by recognizing key phenomena in DED such as ocular surface inflammation, hyperosmolarity, and tear film instability, this article provides a comprehensive overview of both traditional and recently developed methods for diagnosing and monitoring DED. The information serves as a valuable resource not only for clinical diagnosis but also for further research into DED.

Challenges of wearing face masks in ophthalmology during the COVID-19 pandemic.

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.

Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making.

Innumerable individuals suffer from tear film dysfunctions, which are collectively diagnosed as dry eye disease (DED). In the United States alone DED afflicts tens of millions of people, especially women, and is one of the most frequent causes of patient visits to eye care practitioners. DED is characterized by a vicious cycle of tear film hyperosmolarity and instability and ocular surface stress, leading to increased friction, inflammation and damage to the eye. DED is caused primarily by meibomian gland dysfunction, and is associated with significant pain, decreased vitality and poorer general health. Because of diminished worker productivity, the burden of DED for the United States is estimated to be over $55.4 billion. There is no safe and effective global treatment for DED, and its therapy remains a profound unmet need throughout the world. A virtual kaleidoscope of new therapeutic approaches have been proposed to treat the mucin, aqueous and/or lipid tear film deficiencies, as well as the ocular surface damage, associated with DED. My presentation will highlight these approaches, and also address the significant clinical endpoint challenges that serve as barriers to the successful development of potential treatments for DED. Commercial interest