Atopic Keratoconjunctivitis: Pathophysiology, Clinic, and Potential New Therapeutic Concepts. / Atopische Keratokonjunktivitis: Pathophysiologie, Klinik und potenzielle neue Therapiekonzepte.

Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease with a bipolar age distribution in childhood, adolescence and middle adulthood. Up to 50% of AD patients show ocular involvement, which can be potentially sight threatening. Clinically, the majority of cases present with atopic blepharo(kerato)conjunctivitis or atopic keratoconjunctivitis (AKC); other clinical variants from this group of inflammatory ocular surface diseases are keratoconjunctivitis vernalis in childhood and adolescence and allergic conjunctivitis. In addition to the aforementioned blepharitis, keratitis and conjunctivitis, AD is also associated with eyelid involvement with subsequent eyelid malposition, limbal insufficiency with the development of pseudopterygia, (chronic) cicatrizing conjunctivitis with symblephara formation and fornix shortening, as well as ocular surface malignancies such as conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma. In addition, an association with AD or AKC has been described for keratoconus. Whereas the therapy of AD in dermatology has made revolutionary advances in recent years through the use of biologicals, the primary use of these biologicals in ophthalmological complications is still very hesitant. Treatment here is often provided using topical steroids and calcineurin inhibitors. The following article summarises recent developments in basic and clinical dermatological research and discusses them in the context of current concepts for ophthalmological therapy.

Non-infectious and non-hereditary diseases of the corneal epithelium.

The corneal epithelium serves as a physical barrier and a refractive element. Therefore, diseases of the corneal epithelium can increase the risk for infection and causes vision loss. The corneal epithelium can be affected by a multitude of conditions, such as infections, hereditary diseases, depositions, trauma, autoimmune conditions, factitious disorders, and iatrogenic causes. Non-infectious and non-hereditary corneal epithelial diseases represent a collection of conditions with diverse etiologies and clinical presentations but similar patient symptoms. The differing therapeutic interventions for each condition make clinical distinction important. The clinical characteristics, disease course, pathophysiology and current treatments for non-infectious, non-hereditary corneal epithelial diseases are reviewed.

The spectrum of allergic ocular diseases.

OBJECTIVE: The purpose of this article is to review the pathophysiologic mechanisms, differential diagnosis, evaluation, and treatment of the various manifestations of ocular allergy, with an especial focus on immunoglobulin E (IgE)-mediated disease. DATA SOURCES: A PubMed search was performed to include articles, using the search terms ocular allergy and allergic conjunctivitis. STUDY SELECTIONS: Recent and relevant human studies in the English language pertaining to our topic of study were selected. Animal studies pertaining to pathophysiology of ocular allergy were also reviewed. We focused on clinical trials, practice guidelines, reviews, and systematic reviews. In addition, case reports were reviewed if they described rare clinical presentations, disease mechanisms, or novel therapies. RESULTS: Ocular allergy encompasses both IgE- and non-IgE-mediated disease, and the clinical severity may range from mild to sight-threatening inflammation. A comprehensive treatment regimen including education, lifestyle measures, topical therapies, and even systemic interventions may be necessary for the effective management of ocular allergies, tailored according to symptom severity. CONCLUSION: Ocular allergy is frequently encountered by allergists and eye-care specialists, and despite progressively increasing incidence, it often remains underdiagnosed and, hence, untreated.

Ocular surface pathogenesis associated with precocious eyelid opening and necrotic autologous tissue in mouse with disruption of Prickle 1 gene.

Ocular surface disease is one major type of eye diseases. Different etiologies trigger distinct pathological responses of the ocular surface. We previously reported that genetically engineered mice with ablation of Prickle 1 manifested precocious eyelid opening with ensuing cornea dysplasia. The current study aimed to characterize the molecular traits and the direct cause of ocular pathology associated with precocious eyelid opening in the Prickle 1 mutant mouse. Prickle 1 mutant mice exhibited a slew of ocular surface pathology including cell proliferation, cell fate transformation and inflammatory infiltration coinciding with the timing of the precocious eyelid opening. Forced eyelid opening in wild type mice did not induce cornea pathology comparable to that of the Prickle 1 mutants. Necrotic tissue debris was found associated with the lesioned cornea. RNAseq analysis of the mutant cornea revealed an expression profile shared by a range of dermatological diseases involving immune responses and cancer. Taken together, the data suggest that the necrotic eyelid debris plays an important role in ocular pathogenesis of the Prickle 1 mutant mouse, which may represent a type of non-infectious keratoconjunctivitis caused by damaged autologous tissues. Additionally, Prickle 1 mutant cornea pathogenesis may offer molecular insights into other types of epithelial pathogenesis.

Toxic Keratoconjunctivitis.

Toxic keratoconjunctivitis (TK) is an underrecognized complication of ophthalmic drug use and various environmental or occupational exposures. A detailed history and clinical examination are important to identify the offending agent(s). Common drug-related causes of TK include preservatives in ophthalmic medications, topical antimicrobials, and topical anesthetics. Alternatives to benzalkonium chloride as well as preservative-free formulations should be considered in patients requiring long-term topical medication. More advanced cases of TK may require preservative-free topical steroids and/or antibiotics, and occasionally surgical intervention. Early recognition and appropriate management of TK may help prevent permanent ocular and visual damage.

Atopic keratoconjunctivitis: A review.

Atopic keratoconjunctivitis is a chronic noninfectious inflammatory condition and is one of the most severe ophthalmic complications associated with atopic dermatitis. It requires prompt and effective treatment to prevent permanent vision loss. Complications of atopic keratoconjunctivitis include cataracts, keratoconus, infectious keratitis, blepharitis, tear dysfunction, and steroid-induced glaucoma. All treatment for atopic keratoconjunctivitis should be managed in conjunction with an ophthalmologist, and immediate referral is indicated when there is moderate to severe irritation, increased redness, discharge, or any visual symptoms. Treatment options include a combination of mast cell inhibitors, antihistamines, corticosteroids, and calcineurin inhibitors.

Corneal sensitivity may decrease in adenoviral epidemic keratoconjunctivitis--a confocal microscopic study.

OBJECTIVES: To report a new clinical finding, decreased corneal sensitivity, in epidemic keratoconjunctivitis and to evaluate this sign with corneal confocal microscopy. METHODS: Forty-one eyes of 28 patients who developed corneal infiltrates after an outbreak of epidemic keratoconjunctivitis were included in the study. Clinical and confocal microscopic findings are described. RESULTS: In this outbreak of 72 patients, 28 (38.9%) developed corneal infiltrates. The corneal involvement was unilateral in 15 patients (53.6%) and bilateral in 13 patients (46.4%). Corneal sensitivities were measured in 35 eyes of 24 patients and found to be decreased in 26 eyes (74.3%). Decreased corneal sensation was a feature of mainly stage 2 (7 eyes) and stage 3 (11 eyes) keratitis. Corneal sensitivity returned to normal levels in all eyes in a mean of 8.5 days. The main confocal microscopic features during the period of decreased corneal sensitivity were morphologic changes in the infected epithelial cells, extracellular bright microdeposits, infiltration with round inflammatory cells and dendritic cells, increased brightness in the extracellular matrix and the stroma surrounding the corneal nerves, and increased keratocyte activity. The intensity of the inflammatory reaction in the extracellular space and corneal stroma and the reflectivity of the corneal nerves had subsided by the second confocal measurements. CONCLUSION: There may be a transient decrease in the corneal sensitivity during the course of epidemic keratoconjunctivitis. Confocal microscopy can help to evaluate the changes in the cornea during this period. Future studies are needed to understand the nature of this clinical finding.

Conjunctival provocation with airborne allergen in patients with atopic keratoconjunctivitis.

BACKGROUND: Atopic keratoconjunctivitis (AKC) is a chronic eye disease with periods of exacerbations. Many patients experience no obvious seasonal variation, although a majority of patients are allergic to common airborne allergens. OBJECTIVE: To investigate the allergic reaction, to conjunctival provocation with airborne allergens, in patients with AKC. METHODS: Eleven patients with AKC and birch and/or grass pollen allergy participated in the study, which was performed outside the pollen season. Five patients with seasonal allergic conjunctivitis (SAC) and five healthy subjects were included for validation purposes. The challenge was performed in one eye with the allergen, to which the patient was reactive, and with dilution buffer in the other eye. Signs and symptoms from both eyes were graded at baseline and at 10 min, 8 and 48 h after provocation. Tear fluid was collected from both eyes for cytokine analyses at baseline and at 8 and 48 h. RESULTS: A significant change in clinical symptoms and signs, (redness and chemosis) was evident 10 min after provocation compared with baseline (P = 0.005) and compared with the unprovoked eye (P = 0.005) in AKC subjects. These parameters were normalized after 8 and 48 h. A significant increase for IFN-γ (P = 0.021) and IL-6 (P = 0.015), and a near significant increase for IL-10 (P = 0.066) were seen in the tear fluid of the challenged eye at 48 h after provocation vs. baseline and vs. the control eye for IFN-γ (P = 0.005), IL-6 (P = 0.028) and IL-10 (P = 0.008) in AKC subjects. CONCLUSION AND CLINICAL RELEVANCE: In this single dose allergen provocation study, AKC patients responded with a typical IgE-mediated allergic reaction. An increase in cytokines at 48 h after the challenge was demonstrated and might, with further studies, give us a better understanding of the nature of inflammation in AKC.

Eosinophil cationic protein as a marker for assessing the efficacy of tacrolimus ophthalmic solution in the treatment of atopic keratoconjunctivitis.

PURPOSE: To examine the clinical efficacy and anti-inflammatory effects of tacrolimus eye drops; we studied the changes in clinical ocular findings and measured tear eosinophil cationic protein (ECP) levels of atopic keratoconjunctivitis (AKC) patients before and after the treatment. METHODS: Nine eyes of 9 patients (8 males, 1 female; mean age: 16.9 ± 11.4 years; range: 6-44 years) diagnosed with moderate or severe AKC disease were enrolled in this prospective study and treated with tacrolimus. All patients received 0.1% tacrolimus eye drops 2 times a day for 1 month. Tear samples were taken before and after treatment and ECP concentrations were obtained. Corneal fluorescein staining and conjunctival injection, edema, and papillary formation were graded on the recruitment day and one month later. Analysis of pre- and post-treatment findings was done using the Wilcoxon signed test. The ECP concentrations were correlated with the clinical signs using Spearman correlation tests. RESULTS: Post-treatment tear ECP levels were significantly reduced compared to the pre-treatment level. Clinical corneal scores also improved significantly after one month treatment with tacrolimus eye-drops. The mean conjunctival injection and conjunctival edema scores were significantly (p<0.05) decreased after the drug therapy. Strong positive linear correlations between ECP values and clinical signs were observed. Patients did not present side effects during the treatment with tacrolimus. CONCLUSIONS: In this pilot study, tacrolimus eye drops were found to reduce signs of AKC. ECP proved to correlate well with clinical signs of AKC.

[Possible complications of orthokeratology in myopia correction].

Clinical cases representing complications (refractive, infectious and trophic) of orthokeratologic lenses (OKL) use are described. These clinical cases show that complications of OKL use can be both similar to those of routine contact correction and caused by features of mechanism of corneal refraction change as a result of OKL wear. In our opinion efficacy and safety of this option is directly depends on the correct lens fitting, patient's compliance and regular monitoring of corneal changes.

Evaluation of conjunctival inflammatory status by confocal scanning laser microscopy and conjunctival brush cytology in patients with atopic keratoconjunctivitis (AKC).

PURPOSE: To elucidate the status of the conjunctival inflammation in atopic keratoconjunctivitis (AKC) using laser scanning confocal microscopy and compare the relevant findings with conjunctival brush cytology in a prospective controlled study. METHODS: Twenty eyes from 20 AKC patients as well as 16 eyes from 16 age and sex matched normal subjects were studied. The subjects underwent tear film break-up time (BUT), fluorescein and Rose Bengal staining of the ocular surface, conjunctival confocal microscopy, Schirmer test, and brush cytology. Brush cytology specimens and in vivo confocal microscopy scans underwent evaluation for inflammatory cell densities. RESULTS: Brush cytology specimens and in vivo confocal microscopy scans from AKC patients revealed significantly higher numbers of inflammatory cells (p<0.05). Conjunctival inflammatory cell density showed a negative correlation with tear stability and a positive correlation with vital staining scores and conjunctival injection grades. The extent of conjunctival inflammation assessed by in vivo confocal microscopy showed a strong positive linear correlation with the inflammation status evaluated by brush cytology. The corneal inflammatory cell density assessed by in vivo confocal microscopy showed a significant negative correlation with tear stability and a positive linear correlation with corneal fluorescein staining. CONCLUSIONS: Confocal scanning laser microscopy is an efficient, noninvasive, and a promising tool for the quantitative assessment of conjunctival inflammation, a parameter of this new technology which correlated well with subjective and objective ocular surface clinical findings.

Topical Tacrolimus 0.03% for Maintenance Therapy in Steroid-Dependent, Recurrent Phlyctenular Keratoconjunctivitis.

PURPOSE: To evaluate the efficacy of topical tacrolimus 0.03% as steroid-free maintenance therapy in young patients with severe, recurrent phlyctenular keratoconjunctivitis (PKC). METHODS: The medical records of 6 eyes of 5 patients (4 children and 1 young adult) with recurrent, steroid-dependent PKC were reviewed. The patients were treated with combined application of topical steroids and tacrolimus 0.03% in the active phase and maintained on topical tacrolimus alone after remission. RESULTS: The clinical signs, symptoms, and visual acuities resolved in all patients after 25.2 ± 16.9 days of combined treatment with steroids and tacrolimus. After disease remission, the patients were maintained on topical tacrolimus 0.03% once daily alone for 8.4 ± 4.7 months, and no recurrence occurred during 10.6 ± 1.9 months of follow-up. Tacrolimus was successfully discontinued in 2 patients without further recurrence. There were no ocular side effects related to the use of topical tacrolimus. CONCLUSIONS: Topical tacrolimus 0.03% was effective in maintaining long-term remission in patients with recurrent, steroid-dependent PKC.

Potential Role of Oxidative Stress in Ocular Surface Inflammation and Dry Eye Disease.

Reactive oxygen species (ROS) are produced as a by-product during the mitochondrial respiration of the oxygen and potentially able to damage the tissues. Oxidative stress occurs as a result of the disruption of the balance between the anti-oxidant system and the pro-oxidant system found in cells. It has been accepted that overexpression of ROS can be induced in the ocular surface as a result of many acute and chronic diseases and even in normal aging. Recent studies demonstrated that oxidative stress damages the ocular surface and plays an important role in the mechanism of dry eye disease. There is a need to investigate the therapeutic modalities employing topical/systemic use of antioxidants in dry eye disease. This review will summarize the recent studies showing the important relationship between oxidative stress and dry eye disease.

Inflamed Obstructive Meibomian Gland Dysfunction Causes Ocular Surface Inflammation.

Meibomian gland dysfunction (MGD) is one of the primary causes of evaporative dry eye. Stagnation of meibum induces an unstable tear film, thus resulting in shortened tear film breakup time and superficial punctate keratopathy (SPK) in the lower cornea and punctate staining of lower bulbar conjunctiva. MGD is sometimes accompanied with inflammation (termed "meibomitis") via the proliferation of bacteria in the meibomian gland and eyelash area. Meibomitis is strongly related to ocular surface inflammation such as corneal cellular infiltrates and neovascularization, SPK, and conjunctivitis. It is difficult to differentiate SPK caused by dry eye from that caused by meibomitis. When clinicians are unaware of the existence of meibomitis, and only aware of SPK on the cornea, they often try to treat SPK as it is caused by dry eye using dry eye-specific eyedrops or even using punctual plugs when conservative therapy is ineffective. However, even when intensive dry eye therapy is applied, it may be unsuccessful until SPK caused by meibomitis is recognized and treated with systemic antimicrobial agents. Hence, the tear secreting glands, including the meibomian glands, and the ocular surface should be clinically considered as one unit (i.e., the meibomian gland and ocular surface [MOS]) when considering the pathophysiology and treatment of ocular surface inflammatory diseases (i.e., corneal epithelial damage). Following this clinical pathway, a treatment focusing on meibomian gland inflammation may be a more reasonable approach for meibomitis-related or associated keratoconjunctivitis to more effectively treat this ocular surface disease.

Ocular manifestations of systemic lupus erythematosus.

Ocular manifestations of lupus are fairly common, may be the presenting feature of the disease and can be sight-threatening. Almost any part of the eye and visual pathway can be affected by inflammatory or thrombotic processes. Ocular pain and visual impairment require urgent assessment by an ophthalmologist. Infection should be excluded. Optic neuritis and ischaemic optic neuropathy may be difficult to distinguish. Scleritis and severe retinopathy require systemic immunosuppression but episcleritis, anterior uveitis and dry eyes can usually be managed with local eye drops. Vaso-occlusive disease, particularly in the presence of antiphospholipid antibodies, requires treatment with anticoagulation and proliferative retinopathy is treated with laser therapy. Hydroxychloroquine rarely causes ocular toxicity at doses under 6.5 mg/kg/day. When this has occurred, it has been associated with more than 5 years of drug exposure.

Clinical grading of atopic keratoconjunctivitis.

PURPOSE OF REVIEW: Atopic keratoconjunctivitis (AKC), the most severe and chronic form of ocular surface allergy-related disorder, is the ocular surface complication that some atopic dermatitis patients can suffer. Its wide range of severity, from mild and occasional problems to persistent and intense inflammation, makes it difficult to appropriately select uniform patients for clinical studies. This article proposes a new classification system for AKC based on clinical severity. RECENT FINDINGS: Recent reports on AKC have contributed to a better understanding of the pathogenesis and clinical manifestations, and are offering new therapeutic candidates for AKC. No reports, however, have been found that address a classification of this disease. SUMMARY: A new definition and classification for AKC is presented by this review, based on clinical severity, grading the main symptoms and signs. It intends to serve as a first forum of discussion among clinicians and other scientists working in the field of ocular surface inflammation. The final intention is to have a common language helping develop efficient clinical trials leading to successful approval of new therapeutic compounds for this blinding ocular surface condition.

Immunopathogenesis of ocular allergy: a schematic approach to different clinical entities.

PURPOSE OF REVIEW: The immunopathogenesis of ocular allergic disorders is generally related to the specific immunoglobulin E-mediated mast cell activation and the following cascade of inflammatory mediators. Seasonal and perennial allergic conjunctivitis, however, are the only ocular diseases to involve solely type I hypersensitivity. The other main forms, vernal and atopic keratoconjunctivitis, have a more complex immunological basis and a chronic inflammatory component. Involvement of inflammatory cells, particularly eosinophils and T cells, cytokines and proteases can lead to more serious corneal damage with vision-threatening potential. RECENT FINDINGS: Experimental allergic conjunctival models and clinical research studies have shown that T helper type 2-related mechanisms are definitely involved in the sensitization phase of ocular allergy, however, both T helper type 1 and type 2 cytokines are overexpressed in the active disease, contributing to the development of ocular inflammation. SUMMARY: A review of the recent literature allows us to better understand the mechanisms involved in the development of ocular allergy and to guide us toward a more schematic approach, which could possibly be useful in forming a new classification, standardizing clinical phases and individuating new treatment targets.

Visual outcome and corneal changes in children with chronic blepharokeratoconjunctivitis.

OBJECTIVE: To describe the cause, management, and effect of chronic blepharokeratoconjunctivitis (BKC) on the cornea and visual function in children. DESIGN: Noncomparative, interventional, retrospective case series. PARTICIPANTS: Twenty-seven children with BKC. METHODS: Presenting age, best-corrected visual acuity (BCVA), refractive error, and any corneal or eyelid pathologic features were recorded. Treatment included modified lid hygiene, topical antibiotics, and steroids. Systemic therapy included oral antibiotics and, from 2003 onward, flaxseed oil as an alternative to long-term antibiotics. Amblyopia therapy included refractive correction, occlusion, or atropine therapy. MAIN OUTCOME MEASURES: Corneal and eyelid status, visual acuity (VA), and refractive error at final examination. RESULTS: Mean age at presentation was 6.9 years (range, 7 months-15.9 years), and mean follow-up was 2.3 years (range, 5 months-6.1 years). All patients had discomfort, conjunctival injection, and signs of posterior blepharitis at presentation. Photophobia was reported in 14 patients (52%), whereas anterior eyelid inflammation was noted in 6 (22%). Acne rosacea was confirmed in 3 patients (11%). Corneal involvement occurred in 44 eyes (81%), and a history of recurrent chalazia was seen in 18 patients (67%). Median monocular BCVAs in affected eyes were 0.28 logarithm of the minimum angle of resolution (logMAR) units (interquartile range [IqR], 0.02-0.40) at presentation and 0.02 logMAR units (IqR, 0.00-0.18) at last visit. Best-corrected VA improved in 70% of affected eyes and remained unchanged in 30%. Superimposed amblyopia was present and treated in 15 patients (48%). All 8 patients (20%) who failed to achieve VA of 0.2 logMAR units or better at the final examination had bilateral corneal involvement at presentation. One child experienced a systemic side effect from oral antibiotics. No child had significant side effects from topical treatment. Twelve patients (44%) received flaxseed oil as part of their tapering regimen. A 2-year lag between symptom onset and treatment resulted, on average, in a reduction of 0.06 logMAR units of VA (95% confidence interval, 0.00-0.12; P = 0.054). CONCLUSIONS: These findings suggest that visual loss may be significant in BKC and that delayed treatment may result in decreased final BCVA. Adequate management needs both topical and systemic treatment. Flaxseed oil may be an effective antiinflammatory nutritional therapy alternative to long-term antibiotics.

Long-term visual outcome of childhood blepharokeratoconjunctivitis.

PURPOSE: To assess the visual outcome of childhood blepharokeratoconjunctivitis. DESIGN: Retrospective noncomparative case series. METHODS: We reviewed visual acuity and corneal examination results for 23 patients (mean age 19 +/- 4 years, range, 11 to 26 years) who had healed more than three years previously (up to 15 years). RESULTS: The disease involved 29 eyes and was unilateral in 17 children. Corneal sequelae (neovascularization or scars) involved 18 eyes (62%) of 15 children (65%). Mean best-corrected visual acuity was 20/25 (range, 20/100 to 20/20). Best-corrected visual acuity was no more than 20/30 in seven eyes (24%) of seven children (30%). Fifteen eyes (52%) of 13 children (45%) had astigmatisms of at least 0.75 diopters attributable to corneal scars. CONCLUSIONS: Corneal and visual sequelae are frequent in childhood blepharokeratoconjunctivitis. Early diagnosis and specific treatment are mandatory.

Changes in Higher-Order Aberrations After Phototherapeutic Keratectomy for Subepithelial Corneal Infiltrates After Epidemic Keratoconjunctivitis.

PURPOSE: To investigate how corneal aberrations change after phototherapeutic keratectomy (PTK) for subepithelial infiltrates after adenoviral keratoconjunctivitis. METHODS: The records of patients who underwent transepithelial PTK for subepithelial infiltrates were retrospectively reviewed. Preoperative best-corrected visual acuity (VA) and the results of slit-lamp biomicroscopy examinations were recorded. The PTK procedure was performed under topical anesthesia with an Amaris excimer laser. Patients' manifest refraction values, topographical examination results, and corneal aberrations before and after surgery were analyzed. RESULTS: Twenty-four eyes of 16 women (84.3%) and 3 men (15.7%) were treated. The mean follow-up time was 6.0 ± 2.5 (range: 3-12) months, and the mean ablation depth was 82.3 ± 1.0 (range: 80-88) µm. Postoperative median best-corrected VA increased from 0.6 (range: 0.4-1.0) logarithm of the minimum angle of resolution to 0.2 (range: 0.1-0.5) logarithm of the minimum angle of resolution (P = 0.048), coma decreased from 0.56 (range: 0.29-0.37) to 0.44 (range: 0.07-0.74), secondary astigmatism decreased from 0.45 (range: 0.12-1.9) to 0.17 (range: 0.03-0.49), and total higher-order aberrations decreased from 1.24 (range: 0.61-6.74) to 0.9 (range: 0.33-1.64) (P = 0.008, 0.0032, and 0.018, respectively). CONCLUSIONS: PTK is an effective method for treating corneal opacity after epidemic keratoconjunctivitis, which yields significant improvements in both VA and visual quality.