Expert Consensus Recommendations for the Management of Ocular Surface Inflammation in Patients with Glaucoma.

PRECIS: We have developed via a consensus process 24 clinical recommendations for the comprehensive management of ocular surface inflammation in glaucoma patients, including diagnostic criteria, prevention measures, and treatment strategies according to ocular surface disease severity. PURPOSE: To obtain expert consensus on the diagnosis, prevention and management of ocular surface inflammation (OSI) in patients with glaucoma. METHODS: An international steering committee of glaucoma and/or ocular surface disease (OSD) experts and a wider faculty of members from the Educational Club of Ocular Surface and Glaucoma (ECOS-G) collaborated to develop clinical recommendations on best practice in the management of OSI in glaucoma patients using a non-anonymous interactive quasi-Delphi process. Clinical recommendations were formulated by the steering committee based on an analysis of the recent literature to determine unmet needs, together with a web-based interactive survey of faculty members' opinion in seven identified areas of OSI management in glaucoma. Topics included 1) diagnosis of OSD, 2) diagnosis of OSI, 3) causes of OSI, 4) impact of OSD/OSI, 5) prevention of OSI, 6) treatment of OSI, and 7) inflammation and the deep structures of the eye. Faculty members were invited to vote on the clinical recommendations, and the steering committee then determined whether consensus had been achieved. RESULTS: Consensus was obtained on 24 clinical recommendations by 80-100% of faculty members. There was consensus that OSI should be investigated in all glaucoma patients. The main prevention measure in glaucoma patients with pre-existing OSD was the elimination/minimisation of preserved medications, especially BAK-preserved eye drops. A subtractive treatment strategy rather than an additive strategy is recommended according to OSI/OSD severity to improve the ocular health and/or before glaucoma surgery. CONCLUSION: These recommendations for the management of OSI in glaucoma should be useful to guide decision-making in clinical practice.

How gut microbiota may impact ocular surface homeostasis and related disorders.

Changes in the bacterial flora in the gut, also described as gut microbiota, are readily acknowledged to be associated with several systemic diseases, especially those with an inflammatory, neuronal, psychological or hormonal factor involved in the pathogenesis and/or the perception of the disease. Maintaining ocular surface homeostasis is also based on all these four factors, and there is accumulating evidence in the literature on the relationship between gut microbiota and ocular surface diseases. The mechanisms involved are mostly interconnected due to the interaction of central and peripheral neuronal networks, inflammatory effectors and the hormonal system. A better understanding of the influence of the gut microbiota on the maintenance of ocular surface homeostasis, and on the onset or persistence of ocular surface disorders could bring new insights and help elucidate the epidemiology and pathology of ocular surface dynamics in health and disease. Revealing the exact nature of these associations could be of paramount importance for developing a holistic approach using highly promising new therapeutic strategies targeting ocular surface diseases.

[Current aspects of vernal and atopic keratoconjunctivitis]. / Aktuelles zur Keratoconjunctivitis vernalis und atopica.

BACKGROUND: Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are complex and rare diseases. Thus, their diagnosis and treatment are often a challenge. OBJECTIVE: Discussion on the epidemiology, new pathogenetic concepts, interesting clinical findings, diagnostic possibilities and new treatment options and their side effects in severe ocular allergies. Analysis of the presentation of VKC in the internet. MATERIAL AND METHODS: Evaluation of recent review articles, original publications, and case reports on the topics of VKC and AKC over the past 5 years. RESULTS: Ocular allergies have significantly increased over the last decades. Recent concepts discussed in the pathogenesis of VKC and AKC are the role of the local and gut microbiome as well as the influence of neuroinflammation. Keratoconus is significantly more common in patients with VKC and AKC compared to the normal population. It is associated with faster progression and a more severe course of disease. A conjunctival provocation test is only rarely necessary in the diagnosis of allergic conjunctivitis. Treatment of atopic dermatitis with dupilumab, an interleukin 4 receptor alpha (IL-4Ra) antagonist, can cause ocular side effects. Unfortunately, information available on the internet for patients and parents on the topic of VKC is sometimes dangerously incorrect. CONCLUSION: From the abovementioned new pathogenetic concepts, preventive and personalized treatment options could be developed in the future. Keratoconus in AKC/VKC must be recognized and treated early. Official guidelines are now available for a standardized conjunctival provocation test in the diagnosis of allergic conjunctivitis. The unwanted ocular side effects of dupilumab are often difficult to discriminate from the actual underlying AKC and respond well to anti-inflammatory treatment. Patients with VKC must be informed about the incorrect information on the internet regarding their disease.

[New and future treatment approaches for allergic conjunctivitis]. / Neue und zukünftige Therapieansätze in der Behandlung der allergischen Konjunktivitis.

BACKGROUND: In severe and recurrent ocular allergies conventional ophthalmic drugs can reach their limits, especially in chronic forms. The first novel immunomodulators and biologicals are already in clinical use and could provide relief. OBJECTIVE: Based on the immunopathophysiological mechanisms of ocular allergies, possible targets for innovative treatment approaches are presented. An overview of promising new and future immunomodulators and biologicals and their modes of action is also given. MATERIAL AND METHODS: Current reviews on ocular allergies and the treatment of systemic allergic diseases were screened. Case reports on the treatment of ocular allergy using immunomodulators and biologicals were analyzed. The clinical relevance and possible applications are presented. RESULTS: In chronic forms of ocular allergies, complex ocular surface inflammatory responses mediated via immunoglobulin E (IgE), mast cells, CD4-positive type 2 T­helper cells and eosinophilic granulocytes are predominant. Cyclosporine A 0.1% eyedrops have been approved in Europe since 2018 for children aged 4 years and older with severe vernal keratoconjunctivitis (VKC). In addition, case reports present promising data on the systemic off-label use of biologicals, such as dupilumab or omalizumab, in refractory VKC or atopic keratoconjunctivitis (AKC). CONCLUSION: A profound understanding of the immunopathophysiology of ocular allergies is necessary to detect further targets for future immunomodulators and biologicals. Currently, immunomodulatory therapy remains limited to cyclosporine A eyedrops. Other immunomodulatory agents, such as tacrolimus and biologicals can only be used off-label. Further studies on the controlled clinical use of these substances in the treatment of VKC or AKC are underway.

[Corneal disease in childhood-Hereditary, degenerative or infectious?] / Hornhauterkrankungen im Kindesalter ­ Hereditär, degenerativ oder infektiös?

BACKGROUND: Adequate visual acuity significantly contributes to the age-appropriate development of children's neurobehavior. Infantile corneal opacities are rare but implicate a high potential for amblyopia. OBJECTIVE: This review aims to provide an overview of the most common causes of infantile corneal opacities and highlights ophthalmopathological correlations. METHODS: The following review is based on an extensive literature search. RESULTS: If metabolic diseases, traumatic or infectious events can be excluded as a cause for an infantile corneal opacity, it is important to focus on the 3Ds, corneal dysgenesis, corneal dystrophy or corneal degeneration. DISCUSSION: If corneal opacities occur in childhood, early recognition, diagnosis, and initiation of treatment, including prophylaxis of amblyopia, are of utmost importance. In unexplained corneal opacities the histopathological work-up of the explanted cornea can contribute to the final diagnosis.

Refractive surgery and dry eye.

Refractive surgery is one of the most common elective surgeries performed worldwide. The incidence of dry eye disease (DED) after corneal refractive surgery varies among different studies. Pre-existing untreated DED has been identified as a risk factor for postsurgical dry eye symptoms. On the basis of both evidence and clinical experience, some recommendations for ocular surface and DED management pre- and post-refractive surgery are described. In aqueous deficiency Dry Eye Disease, preservative-free lubricating drops should be preferred, in addition to ointment and gel forms. Topical anti-inflammatory agents (Cyclosporine 0.1%, hydrocortisone phosphate, fluorometholone) should be used for 3-6 months in cases of ocular surface damage. The therapy of evaporative DED includes lifestyle modifications, lid hygiene (either performed by the patient or offered as professional lid hygiene by the physician), use of lubricating eye drops with lipid components, topical and/or systemic antibiotic treatment with anti-inflammatory properties and Intense Pulsed Light (IPL-) Treatment for meibomian gland dysfunction.

TFOS Lifestyle: Impact of elective medications and procedures on the ocular surface.

The word "elective" refers to medications and procedures undertaken by choice or with a lower grade of prioritization. Patients usually use elective medications or undergo elective procedures to treat pathologic conditions or for cosmetic enhancement, impacting their lifestyle positively and, thus, improving their quality of life. However, those interventions can affect the homeostasis of the tear film and ocular surface. Consequently, they generate signs and symptoms that could impair the patient's quality of life. This report describes the impact of elective topical and systemic medications and procedures on the ocular surface and the underlying mechanisms. Moreover, elective procedures performed for ocular diseases, cosmetic enhancement, and non-ophthalmic interventions, such as radiotherapy and bariatric surgery, are discussed. The report also evaluates significant anatomical and biological consequences of non-urgent interventions to the ocular surface, such as neuropathic and neurotrophic keratopathies. Besides that, it provides an overview of the prophylaxis and management of pathological conditions resulting from the studied interventions and suggests areas for future research. The report also contains a systematic review investigating the quality of life among people who have undergone small incision lenticule extraction (SMILE). Overall, SMILE refractive surgery seems to cause more vision disturbances than LASIK in the first month post-surgery, but less dry eye symptoms in long-term follow up.

Patient-reported burden and overall impact of dry eye disease across eight European countries: a cross-sectional web-based survey.

OBJECTIVE: Dry eye disease (DED) is a multifactorial disease involving the tears and ocular surface. It impacts a patient's quality of life (QoL) and ability to perform daily activities. This study assessed the burden of self-reported DED among adults in eight European countries. DESIGN: Online cross-sectional survey. SETTING: General population in France, Italy, Germany, Greece, the Netherlands, Portugal, Spain and Sweden. PARTICIPANTS: Adults aged ≥18 years with (n=6084) and without (n=6161) self-reported DED were recruited via emails and screened. MAIN OUTCOME MEASURES: All participants completed National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) and EuroQol-5 Dimension-5 Level Questionnaire (EQ-5D-5L). All DED participants completed the Eye Dryness Score (EDS) Visual Analogue Scale, and Ocular Comfort Index and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem questionnaires. In addition, half of the respondents with DED completed Survey A (Impact of Dry Eye on Everyday Life) and the other half completed Survey B (Standard Patient Evaluation of Eye Dryness Questionnaire) and Dry Eye Questionnaire-5. RESULTS: Participants with self-reported DED had lower functional vision and lower overall health status than participants without self-reported DED as measured by the NEI-VFQ and EQ-5D-5L, respectively.Increasing self-reported DED severity as measured by the EDS was shown to correspond with worse symptom severity/frequency, lower functional vision, higher impact on work productivity, daily activities and QoL. CONCLUSION: This study showed that patients' reported burden of self-reported DED was similar across the eight European countries. Those with self-reported DED reported lower health status and functional vision compared to those without self-reported DED and these parameters worsen with increasing disease severity.

Management of inflammation in dry eye disease: Recommendations from a European panel of experts.

INTRODUCTION: Early initiation of anti-inflammatory therapies is recommended for dry eye disease (DED) to break the vicious cycle of pathophysiology. However, there is limited guidance on how to implement topical ciclosporin (CsA) and corticosteroid treatment into clinical practice. This expert-led consensus provides practical guidance on the management of DED, including when and how to use topical CsA. METHODS: A steering committee (SC) of seven European DED experts developed a questionnaire to gain information on the unmet needs and management of DED in clinical practice. Consensus statements on four key areas (disease severity and progression; patient management; efficacy, safety and tolerability of CsA; and patient education) were generated based on the responses. The SC and an expanded expert panel of 22 members used a nine-point scale (1 = strongly disagree; 9 = strongly agree) to rate statements; a consensus was reached if ≥75% of experts scored a statement ≥7. RESULTS: A stepwise approach to DED management is required in patients presenting with moderate corneal staining. Early topical CsA initiation, alone or with corticosteroids, should be considered in patients with clinical risk factors for severe DED. Patient education is required before and during treatment to manage expectations regarding efficacy and tolerability in order to optimise adherence. Follow-up visits are required, ideally at Month 1 and every 3 months thereafter. Topical CsA may be continued indefinitely, especially when surgery is required. CONCLUSION: This consensus fills some of the knowledge gaps in previous recommendations regarding the use of topical corticosteroids and CsA in patients with DED.

Topical Omega-3 Polyunsaturated Fatty Acids for the Treatment of Dry Eye - Results from a Pilot Randomized Controlled Masked-Observer Study.

Purpose: To investigate the efficacy, safety and tolerability of topical omega-3 polyunsaturated fatty acids (PUFA) as an innovative treatment of dry eye disease (DED). Patients and Methods: In a pilot, multicenter, masked-observer, randomized, active-controlled, non-inferiority study in Germany, patients self-treated their eyes with daily instillations of eye drops containing either omega-3 PUFA or povidone as major components for three months. At four and twelve weeks, efficacy was among others evaluated based on Ocular Surface Disease Index (OSDI), ocular surface symptoms intensity, general clinical impression, tear break-up time (TBUT), corneal fluorescein staining using the Oxford grading scale, tear volume, and matrix metalloproteinase-9 (MMP-9) concentration in the tear film. Safety evaluation included visual acuity, intraocular pressure, and the incidence of adverse events. Co-primary endpoints were the mean percent changes from baseline of TBUT and OSDI after four weeks. Results: In total 80 patients were included, of whom 37 in the PUFA group and 39 in the povidone group were evaluable for the co-primary endpoints. Patients had a mean age of 52 years and >80% were women. Both co-primary endpoints (TBUT and OSDI) significantly improved from baseline in both treatment groups, at Week 4 and Week 12 and the statistical analysis demonstrated topical omega-3 PUFA to be non-inferior to 2% povidone for these two parameters. Both treatments resulted in a significant improvement of most secondary efficacy endpoints as well, often with a slight difference in favor of PUFA, not reaching statistical significance though. One non-severe, treatment-related local AE was reported in each group. Conclusion: Omega-3 PUFA-based eye drops proved to be non-inferior to povidone-containing eye drops in the treatment of signs and symptoms of dry eye. This treatment may thus be an additional tool for the management of DED.

Focus on Ophthalmopathology - Orbital Infections from Hordeolum to Necrotizing Fasciitis. / Schwerpunkt Ophthalmopathologie Orbitainfektion: vom Hordeolum bis zur nekrotisierenden Fasziitis.

(Peri)orbital infections comprise a multitude of diagnoses, ranging from common hordeolum to rare but life-threatening necrotizing fasciitis. However, these disease entities are rarely diagnosed by an ophthalmic pathologist because (peri)orbital infections are usually diagnosed clinically, with the help of imaging and microbiological techniques when indicated. In this review article, the role of ophthalmopathology in the diagnosis of (peri)orbital infections is illustrated on the basis of several exemple diagnoses. An infectious hordeolum must be distinguished from a noninfectious chalazion. A nodular thickening of the eyelid, which is diagnosed and treated as a chalazion, can hide a malignant neoplasia. The correct diagnosis and treatment of canaliculitis is often delayed. In this context the most common causative organism, Actinomyces, can be depicted histologically, as can lacrimal stones/dacryoliths. Necrotizing fasciitis is a rapidly worsening infection of the fascia, which can lead to necrosis, sepsis, and death. During the Sars-CoV2 pandemic, an increased incidence of mucormycosis cases was observed, especially in India. This superinfection was facilitated by the widespread use of steroids and immunosuppression. Histologically, it is possible to visualize infiltration of vessel walls by the fungus. Ophthalmopathology contributes to the diagnosis and to understanding the pathophysiology of these diseases.

Pathophysiology of dry eye disease and novel therapeutic targets.

The pathophysiology of Dry Eye Disease (DED) is complex, and therapy may be a challenge. Tear film instability, tear film hyperosmolarity, ocular surface damage and ocular surface inflammation are accepted key events in the pathogenesis of the disease. New anti-inflammatory targets have been identified and novel anti-inflammatory treatments may enrich our therapeutic armamentarium in the future. Neurosensory changes in DED secondary to neuroinflammation in the corneal nerves, the trigeminal ganglion, and the trigeminal brainstem sensitivity complex have recently been reported and may play an important role in the pathophysiology of DED. Receptor complexes on the axonal membranes of corneal nerves may be promising novel therapeutic targets. Recent studies have shown changes in the both the systemic and local (conjunctival) microbiomes with DED as well as an association of DED with laryngopharyngeal reflux. These new insights into DED suggest new treatment approaches. In hyperevaporative DED typically associated with meibomian gland dysfunction (MGD), hyperkeratinized and obstructed meibomian glands are important treatment targets, and novel techniques may be available soon to better manage patients with MGD. The observation of changes in brain function in patients with DED sheds a completely new light on the pathophysiology of the disease. Increased understanding of the pathogenetic events described above may define novel treatment targets, guide management and may allow customized treatment of DED in the future.

Epidemiological characteristics and clinical course of eyelid squamous cell carcinoma patients from a large tertiary centre between 2009 and 2020.

BACKGROUND/AIMS: To assess epidemiological tumour features, risk factors, clinical management and outcome of eyelid squamous cell carcinoma (SCC) and changes thereof. Furthermore, we searched for validating predictors of the American Joint Committee on Cancer (AJCC) 8 classification system. METHODS: We evaluated data of 117 patients with histologically proven eyelid SCC at a large tertiary German university centre between January 2009 and March 2020. This retrospective, monocentric analysis included descriptive statistics and non-parametric tests (p<0.05). RESULTS: Histologically controlled excision and follow-up was performed in 88 (75.2%) patients. In the remaining patients with higher T-category, individual adjuvant therapy combinations were initiated. We found higher numbers of nodal metastasis and recurrence for male patients and higher T-category (p=0.035, p=0.008 and p=0.001, p<0.001). Recurrence rates proved higher for patients with multiple lesions (p=0.008). Disease-specific survival (DSS) was 95.7% at 2 and 94.9% at 5 years of follow-up. Six patients (5.1%) died from eyelid SCC with nodal metastasis and higher T-category being negative prognostic factors (p<0.001 and p=0.009). Mortality was associated with tumour location in the medial upper eyelid, nodal metastasis being more frequent (p=0.001 and p=0.009) and tumour of the lower eyelid alone as positive predictor (p=0.012). T category differed in 34 (29.1%) patients when comparing AJCC 7 and 8 (p<0.001). Changes in T category as per the AJCC 8 classification resulted in better prediction of DSS (p=0.024). CONCLUSION: Special attention should be paid to male patients, tumour location in the upper medial eyelid and lymph node diagnostics. Prediction of DSS proved superior as per the AJCC 8 staging system.

The Enduring Experience in Dry Eye Diagnosis: A Non-Interventional Study Comparing the Experiences of Patients Living With and Without Sjögren's Syndrome.

INTRODUCTION: Previous studies have examined the patient experience regarding the diagnosis and management of dry eye disease (DED). The current study explored the ways in which the DED diagnostic pathway differs for those living with and without Sjögren's syndrome (SS), to identify aspects that influence the patient experience and associated quality of life (QoL). METHODS: An observational/descriptive, non-interventional, retrospective, self-reported online survey was conducted among adults living in France, Spain and Italy who were diagnosed with DED (with/without SS), were using topical DED treatments (≥ 6 months), and were not contact lens users. Recruitment was via an online database for non-SS participants and through local patient advocacy groups for SS respondents. RESULTS: The analysis included 827 respondents; 416 (50.3%) had SS and 82% were female. The mean age was 55 (SD 11; range 16-99) years. The mean age at diagnosis was 46 (SD 12; range 13-78) years and 50 (SD 10; range 21-73) years for SS and non-SS groups, respectively (p < 0.0001). The mean time to diagnosis was extended for SS participants [32 (SD 62) months] versus non-SS individuals [8.6 (SD 28) months (p < 0.0001)] and was associated with reduced QoL scores (r = 0.113; p = 0.0169). More SS participants (31%) consulted ≥ 4 healthcare professionals (HCPs) before DED diagnosis, versus non-SS individuals (6%) (p < 0.0001). Diagnosing clinician varied for SS respondents according to country, probably due to differences in healthcare systems/structures. More SS participants viewed their condition as a handicap than a discomfort, reporting greater QoL impact (p < 0.0001). CONCLUSIONS: Patient experiences in DED diagnosis vary substantially when comparing SS and non-SS individuals. Time to diagnosis significantly impacts QoL for SS patients, who see more HCPs ahead of DED diagnosis. The number of HCPs consulted before diagnosis and perceptions of DED are important for both groups. Country-specific variations highlight opportunities to improve consistency and efficiency across DED diagnostic pathways. These data should be considered alongside existing evidence from high-quality sources (e.g. clinical records).