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.

Applications of topical immunomodulators enhance clinical signs of vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC): a meta-analysis.

PURPOSE: This meta-analysis aimed to review the safety and efficacy of topical cyclosporine A (CsA) and topical tacrolimus in allergic eye disease. METHODS: A systematic search identified thirteen studies and a total of 445 patients for inclusion, making this the largest meta-analysis published on the subject. The current review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Thirteen randomized control trials were included in the meta-analysis. Eleven studies used CsA as the treatment, and two used Tacrolimus. In total, 445 participants were included, of whom 76.6% were male. The mean age of participants across the included studies was 14 years. All studies reported clinical signs as evaluated by an examining clinician. Signs were usually assessed by anatomical region, with the most common regions being the conjunctiva and the cornea, and the most common signs assessed were hyperemia and papillae. Three studies accounted for more than 50% of the meta-analysis's weight. Effect size (d) ranged from - 2.37 to - 0.03, negative values favoring immunomodulators. Fixed Effect Meta-Analysis returned an SMD of - 0.81 (95% CI [- 0.98, - 0.65]). However, there was significant heterogeneity (I2 = 61%, Qw = 30.76) in the outcome measure (P = 0.0021); therefore, a random-effect meta-analysis was also completed in which the pooled SMD was - 0.98 (95% CI [- 1.26, - 0.69], τ2 = 0.16). CONCLUSIONS: This study affirms the current scientific community's stance that immunomodulators effectively treat clinical signs, including blepharitis, conjunctival hyperemia, edema, papillae, and corneal damage in severe ocular allergic disease.

Clinical spectrum in microbiologically proven Demodex blepharokeratoconjunctivitis: An observational study.

PURPOSE: To study the demographic, clinical, and microbiological profile of Demodex-related blepharokeratoconjunctivitis (BKC) at a tertiary eye care hospital. METHODS: This retrospective observational study was conducted from January 2016 to September 2022. It included 83 patients with microbiologically proven Demodex BKC who presented to the cornea department of our tertiary care eye center. The clinical, microbiological, and demographic data of the 83 cases were analyzed. RESULTS: Of the 83 cases, 57 (68.67%) were younger than 40 years, and 25 (30.12%) were below 20. Most patients presented with a good visual acuity of 20/40 or better (93 eyes; 84.55%). The disease was unilateral in 55 patients and bilateral in 28. Cylindrical dandruff was the predominant presentation noted in 61 eyes (54.95%), followed by corneal scarring in 47 eyes (42.34%) and corneal vascularization in 40 eyes (36.04%). On light microscopy, 87.95% of the positive samples were identified as Demodex folliculorum , 7.23% as Demodex brevis , and 6.02% remained unidentified. Tea tree oil and lid scrubs eradicated the disease in most patients clinically (75/83, 90.36%). CONCLUSION: The spectrum of BKC includes both lid signs and corneal involvement. It can be a cause of recurrent BKC and detection of the mite by microscopic evaluation of the lashes can confirm the diagnosis. In most cases, the tea tree oil can effectively manage this condition. However, low doses of topical steroids are needed to control the inflammation in patients with corneal involvement.

Amniotic membrane transplantation as part of a multimodal management approach to Streptococcus pyogenes necrotizing keratoconjunctivitis.

Streptococcus pyogenes (group A beta-hemolytic Streptococcus, GABHS) causes a range of human infections, including necrotizing fasciitis and toxic shock syndrome, because it produces exotoxins that damage host cells, facilitate immune evasion, and serve as T cell superantigens. GABHS conjunctivitis is rare. We report a case of membranous conjunctivitis in a 3-year-old child who was treated with a combination of targeted bactericidal antimicrobials, toxin-synthesis inhibition, and amniotic membrane transplantation.

[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.

Relation Between Corneal Dendritic Cell Density and Tear Film Stability in Patients with Epidemic Keratoconjunctivitis Associated Dry Eye.

PURPOSE: To clarify the ocular surface features of patients with recent history of epidemic keratoconjunctivitis (EKC) and the relation between corneal dendritic cells (DCs) and ocular discomfort. METHODS: Normal controls (NC) and dry eye (DE) patients without EKC were recruited. Patients with recent EKC history (onset >4 weeks, but <20 weeks) were recruited as EKC + DE group (with dry eye) or EKC-DE group (without dry eye). Ocular surface disease index (OSDI) questionnaire, tear film parameters including lipid layer thickness, first tear break-up time (fBUT), average tear break-up time (aBUT), tear meniscus height and Schirmer I test, meibomian gland parameters, and in vivo corneal confocal microscopy were evaluated. RESULTS: 50 subjects in the NC group, 83 patients in the DE group, 76 patients in the EKC + DE group, and 38 patients in the EKC-DE group were included. Compared with the NC, DE, and EKC-DE groups, the EKC + DE group represented higher OSDI, lid margin, and meibum score (p < 0.05). In the EKC + DE group, the tear volume (10.5 ± 3.7 mm) was significantly higher than in the DE group (8.1 ± 2.8 mm, p < 0.001). The DC density in the EKC + DE group (29.98 ± 15.38 cells/image) was significantly higher than in NC, DE, and EKC-DE groups (4.68 ± 4.05 cells/image) (p < 0.001). The DC density was positively correlated with OSDI, lid margin, and meibum score (all p < 0.01) while inversely correlated with fBUT, aBUT (all p < 0.001) in the EKC + DE group. CONCLUSIONS: Corneal DC density significantly correlates to ocular discomfort and tear film instability in patients with recent EKC history who suffer from DE without aqueous tear deficiency.

Definition and Diagnostic Criteria for Pediatric Blepharokeratoconjunctivitis.

Importance: Pediatric blepharokeratoconjunctivitis (PBKC) is a chronic, sight-threatening inflammatory ocular surface disease. Due to the lack of unified terminology and diagnostic criteria, nonspecific symptoms and signs, and the challenge of differentiation from similar ocular surface disorders, PBKC may be frequently unrecognized or diagnosed late. Objective: To establish a consensus on the nomenclature, definition, and diagnostic criteria of PBKC. Design, Setting, and Participants: This quality improvement study used expert panel and agreement applying the non-RAND modified Delphi method and open discussions to identify unified nomenclature, definition, and definitive diagnostic criteria for PBKC. The study was conducted between September 1, 2021, and August 14, 2022. Consensus activities were carried out through electronic surveys via email and online virtual meetings. Results: Of 16 expert international panelists (pediatric ophthalmologists or cornea and external diseases specialists) chosen by specific inclusion criteria, including their contribution to scientific leadership and research in PBKC, 14 (87.5%) participated in the consensus. The name proposed was "pediatric blepharokeratoconjunctivitis," and the agreed-on definition was "Pediatric blepharokeratoconjunctivitis is a frequently underdiagnosed, sight-threatening, chronic, and recurrent inflammatory eyelid margin disease associated with ocular surface involvement affecting children and adolescents. Its clinical spectrum includes chronic blepharitis, meibomitis, conjunctivitis, and corneal involvement ranging from superficial punctate keratitis to corneal infiltrates with vascularization and scarring." The diagnostic criteria included 1 or more suggestive symptoms accompanied by clinical signs from 3 anatomical regions: the eyelid margin, conjunctiva, and cornea. For PBKC suspect, the same criteria were included except for corneal involvement. Conclusions and Relevance: The agreements on the name, definition, and proposed diagnostic criteria of PBKC may help ophthalmologists avoid diagnostic confusion and recognize the disease early to establish adequate therapy and avoid sight-threatening complications. The diagnostic criteria rely on published evidence, analysis of simulated clinical cases, and the expert panel's clinical experience, requiring further validation with real patient data analysis.

Early detection of infectious bovine keratoconjunctivitis with artificial intelligence.

Artificial intelligence (AI) was developed to distinguish cattle by their muzzle patterns and identify early cases of disease, including infectious bovine keratoconjunctivitis (IBK). It was tested on 870 cattle in four locations, with 170 developing IBK. The AI identified 169 of the 170 cases prior to their identification by veterinarians, and another 17 cases that remained free of IBK signs (sensitivity = 99.4%, specificity = 97.6%). These results indicate the AI can detect emerging IBK cases by muzzle images very early in the disease process and be used as an intervention tool in the prevention of IBK outbreaks.

Metagenomic sequencing for investigation of a national keratoconjunctivitis outbreak, Israel, 2022.

BackgroundEpidemics of keratoconjunctivitis may involve various aetiological agents. Microsporidia are an uncommon difficult-to-diagnose cause of such outbreaks.AimDuring the third quarter of 2022, a keratoconjunctivitis outbreak was reported across Israel, related to common water exposure to the Sea of Galilee. We report a comprehensive diagnostic approach that identified Vittaforma corneae as the aetiology, serving as proof of concept for using real-time metagenomics for outbreak investigation.MethodsCorneal scraping samples from a clinical case were subjected to standard microbiological testing. Samples were tested by calcofluor white staining and metagenomic short-read sequencing. We analysed the metagenome for taxonomical assignment and isolation of metagenome-assembled genome (MAG). Targets for a novel PCR were identified, and the assay was applied to clinical and environmental samples and confirmed by long-read metagenomic sequencing.ResultsFluorescent microscopy was suggestive of microsporidiosis. The most abundant species (96.5%) on metagenomics analysis was V. corneae. Annotation of the MAG confirmed the species assignment. A unique PCR target in the microsporidian rRNA gene was identified and validated against the clinical sample. The assay and metagenomic sequencing confirmed V. corneae in an environmental sludge sample collected at the exposure site.ConclusionsThe real-time utilisation of metagenomics allowed species detection and development of diagnostic tools, which aided in outbreak source tracking and can be applied for future cases. Metagenomics allows a fully culture-independent investigation and is an important modality for public health microbiology.

Diagnostic criteria of chronic conjunctivitis: atopic keratoconjunctivitis and vernal keratoconjunctivitis.

PURPOSE OF REVIEW: Chronic ocular allergies, vernal (VKC) and atopic keratoconjunctivitis (AKC) are relatively rare conditions that require definite diagnostic criteria to the most appropriate therapeutical approach. RECENT FINDINGS: The diagnosis of both VKC and AKC is generally based on clinical history, signs and symptoms, and the results of allergic tests, which allow to identify the different diseases phenotypes. However, other subtypes of the two diseases and/or overlaps may occur making the diagnosis non always so clear, such as VKC and AKC overlaps or adult-like VKC disease. Each of these phenotypes may be sustained by different mechanisms which are still not well defined but not only related to a type 2 inflammation. The further challenges will be to correlate clinical or molecular biomarkers to a single subtype or disease severity. SUMMARY: Definite criteria of chronic allergies will further guide to more specific therapeutical approaches.

Rise in the incidence of severe pediatric blepharokeratoconjunctivitis during the COVID-19 pandemic.

Severe blepharokeratoconjunctivitis (BKC) is associated with vision loss and ocular morbidity; hence, early diagnosis and treatment are crucial. Retrospective data collection using electronic patient and billing database records of all patients <18 years of age with severe BKC between March 2010 and March 2022 was performed at the Eye Clinic at the Hospital for Sick Children in Toronto, Canada. Severe BKC was defined as including corneal inflammation, new vessel formation, scarring, thinning and lipid deposits. We excluded patients with mild or no corneal involvement, and those with other corneal pathologies. Over the study period, 257 patients were diagnosed with severe BKC (161 females), with an average age of 8 years. There was a statistically significant threefold increase in the diagnosis of severe BKC since the beginning of the COVID-19 pandemic in 2020 compared to the previous years. We speculate that the increased use of facial masks during the pandemic contributed to this significant increase.

Microsporidia-Associated Anterior Uveitis After Keratoconjunctivitis.

OBJECTIVE: The aim of this study was to describe the clinical features and management of uveitis associated with microsporidial keratoconjunctivitis (MKC). METHODS: The medical records of clinically diagnosed or microbiologically proven patients with MKC between July 2016 and August 2021 were reviewed. Patients with documented evidence of keratic precipitates (KPs) or anterior chamber cells were analyzed for their demography, clinical features, and treatment. Patients with microsporidial stromal keratitis and herpes simplex virus keratouveitis were excluded from the study. RESULTS: Of the 2212 patients reviewed within the study period 171 of 172 eyes (7.7%) had documented evidence of KPs and/or anterior chamber cells. The patients' mean age was 43.8 ± 13.8 years, and there were more men (n = 120). The mean duration of appearance of KPs was 6.9 ± 5.5 days, and 28% (n = 48 of 171) appeared on the day of presentation. Superficial punctate keratitis was central and diffuse in 48 and 49 patients, respectively. The treatment was either lubricant alone (45.3%; 78 eyes) or combined with topical steroids (54.7%; 94 eyes). The mean duration of the resolution was longer in the "corticosteroid" than "no corticosteroid" group: KPs: 15.3 ± 6.5 days versus 12.3 ± 5.8 days ( P = 0.007) and superficial punctate keratitises: 15.4 ± 9.4 days versus 11.7 ± 6.2 days ( P = 0.01). The presenting visual acuity with a pinhole was 0.26 ± 0.26 (logMAR) and it improved to 0.03 ± 0.07 on resolution ( P < 0.0001, paired t test). CONCLUSIONS: Uveitis after MKC is a self-limiting entity that often resolves without corticosteroid. One must exercise caution in using steroids in the presence of active corneal lesions.

Human MPox (Monkeypox) Virus Membranous Keratoconjunctivitis With Transient Corneal Hypoesthesia and Late Symblepharon Formation: A Novel Case and Clinical Implications.

PURPOSE: The aim of this study was to describe a case of corneal involvement as an early manifestation of ocular disease in the 2022 human mpox (monkeypox) virus outbreak. METHODS: This is a single case report with longitudinal care. RESULTS: A 47-year-old immunocompetent man presented with viral conjunctivitis before development of skin lesions or systemic symptoms. Subsequently, he developed membranous keratoconjunctivitis and a corneal epithelial defect. Orthopoxvirus-positive polymerase chain reaction test from his ocular surface was positive. The epithelial defect did not heal with conservative treatment but was successfully treated with amniotic membrane transplantation over 8 days. Reduced corneal sensation was noted after epithelial healing, and polymerase chain reaction from the ocular surface remained positive at 17 days from symptom onset, with slowly recovering conjunctivitis at 21 days. Continued membrane formation required repeated removal but significantly improved with topical corticosteroid treatment after epithelial healing by 29 days of symptom onset. Corneal sensation normalized by 87 days from symptom onset at which time symblepharon were noted but PCR testing from the ocular surface was negative. CONCLUSIONS: Early corneal involvement of human monkeypox virus is possible. Transient corneal hypoesthesia may be due to acute inflammation. Chronic inflammatory changes can result in symblepharon. These findings have potential implications in patient care and corneal donation.

Applying Metagenomic Analysis Using Nanopore Sequencer (MinION) for Precision Medicine in Bacterial Keratoconjunctivitis: Comprehensive Validation of Molecular Biological and Conventional Examinations.

Smear microscopic examination and culture of the corneal scrapings are the gold standards for the diagnosis of bacterial keratoconjunctivitis. High-sensitivity molecular biological examinations of the ocular surface specimens are used clinically. However, the results require careful interpretation to avoid the unintentional detection of indigenous bacteria. Results of conventional and state-of-the-art examinations require clinical verification for specificity and sensitivity. In this study, smear microscopic examination, culture, and nanopore sequencing using the MinION of ocular surface specimens from eight clinically diagnosed bacterial keratoconjunctivitis cases were performed and compared. Seven of the eight cases (87.5%) were smear positive and five (62.5%) were culture positive. The former showed the same genus in >60% of the classified reads as one specific bacterium inferred from the smear microscopy when sequenced by the MinION. In two of the three culture-negative cases, the smear-positive images were highly reminiscent of the species comprising most of the MinION sequences. Four of the five culture-positive cases were consistent with the most prevalent bacteria in the sequencing results. Probable contamination among specimens processed on the same day were observed. In conclusion, the microscopic examination of the corneal scraping specimens may be more sensitive and specific than the culture examination. Additionally, although metagenomic analysis using the MinION contributes to more precise medication for bacterial keratoconjunctivitis, contamination can affect the results.

Past, present, and prospects in microsporidial keratoconjunctivitis- A review.

Ocular microsporidiosis comprises two entirely different spectra of disease as keratoconjunctivitis and stromal keratitis. Microsporidial keratoconjunctivitis (MKC) has been increasingly reported in the past two decades, probably due to raised awareness, simpler diagnostic procedures, and a better understanding of the clinical presentation. It is characterized by the presence of raised, coarse, punctate, multifocal, round to oval, greyish-white corneal epithelial lesions which usually evolve into nummular scars before resolution. Conjunctivitis seen is non-purulent and of mild-moderate intensity, with mixed papillary-follicular reaction. The mode of transmission and pathogenesis is poorly understood. Despite lack of inflammatory response, uncommon associations reported were- endotheliitis, corneal edema, limbitis, uveitis, and sub-epithelial infiltrates. There has been no consensus on the management of MKC. It varies from the use of multiple antimicrobial agents to simple lubricants. The majority of the disease goes underdiagnosed or misdiagnosed and treated as adenoviral keratoconjunctivitis, with topical steroids or anti-virals empirically. Changing trends have been noticed in the pattern of infection, possibly with increasing evidence of Vittaforma corneae as causative organisms, previously reported to cause stromal keratitis. An elaborate review of the past and present literature on MKC is provided in this review article, along with gaps in knowledge, and future directions of research.

Keratoconjunctivitis as a Single Entity in X-linked Agammaglobulinemia?

PURPOSE: To report a case of a male patient with a severe corneal and conjunctival immunopathy likely caused by an X-linked agammaglobulinemia. METHODS: A clinical case report with observation results from 2001-2021. RESULTS: A severe corneal immunopathy of both eyes is reported in a retrospective long-term observation of nearly twenty years in a 32-year-old male patient with X-linked agammaglobulinemia (XLA). A chronic progressive corneal scarring with a loss of visual acuity and typical symptoms of a phlyctenular keratoconjunctivitis were observed. CONCLUSION: Whereas steroid eye drops like dexamethasone could control the symptoms and the corneal scarring progression as short time therapy options, ciclosporin A eye drops showed problems in therapy adherence in long-time use. Antibiotic eye drops supported the anti-inflammatory therapy effects, but no typical pathogen was detected. Antineovascular subconjunctival application did not show any relevant effect in one-time use. Artificial tears were needed as basic therapy.

Molecular, Epidemiological and Clinical Assessment of Adenoviral Keratoconjunctivitis in Egypt: Institutional Study.

PURPOSE: To evaluate the frequency of Human adenovirus (HAdV) and its serotypes in keratoconjunctivitis patients who attended the outpatient clinics of Mansoura Ophthalmic Center, Egypt. METHODS: Conjunctival secretions and corneal scrapings were collected from patients complaining of clinically diagnosed viral keratoconjunctivitis. The molecular method for HAdV detection was performed by polymerase chain reaction (PCR) followed by restriction enzymes (REA) determination of serotypes for hexone gene. RESULTS: HAdV infection was detected in 38% of samples. There were 4 serotypes of Human adenovirus species D (HAdV-D) isolated (4, 8, 37, 3), where HAdV-D8 was the most dominant. Contact with infected patient, follicular conjunctivitis and subepithelial corneal infiltrates are useful features for clinical diagnosis of adenoviral conjunctivitis. CONCLUSION: HAdV was significant etiological factor of acute follicular conjunctivitis. Accurate diagnosis of adenoviral conjunctivitis is essential for appropriate management, reducing permanent visual impairment and to limit the transmission of the virus within the community.

Topical cyclosporine A 1 mg/ml for atopic keratoconjunctivitis: Five-year case series of 99 children and young people.

PURPOSE: To explore the effects of cyclosporine A (CsA) in the management of atopic keratoconjunctivitis (AKC). METHODS: Open single-group interventional consecutive cohort study (case series) at a single eye care facility in the UK. We reviewed the electronic patient records of 99 children and young people (CYP) aged 3.4-18 years with AKC treated with topical CsA 1 mg/ml. Main outcome measures were number of prescriptions and hospital clinic visits over 12 months before and after the start of CsA and the proportion of CYP affected by adverse effects. RESULTS: The median number of inflammatory episodes requiring treatment with topical corticosteroids (tCS) fell from 3 (interquartile range IQR 1-4) during the 12 months prior to CsA to 1 (IQR 0-3) during the 12 months after, excluding tCS prescriptions with the first CsA prescription (Wilcoxon signed ranks test, 2 tailed, p < 0.01). In the 12-month period following initiation of CsA 1 mg/ml with concomitant prescription of tCS (n = 66), daily dosage of steroids was reduced in 62 CYP (93.9%), and they were discontinued in 43 (65.2%). The median number of hospital visits fell from 4 (IQR 3-6) to 3 (IQR 2-5; Wilcoxon p < 0.01). Adverse events leading to discontinuation of CsA were stinging (instillation site pain; 9/99, 9%) and a transient skin rash (1/99, 1%). CONCLUSIONS: Off-label use of commercial preparations of CsA 1 mg/ml significantly reduces the need for concomitant topical corticosteroids and hospital clinic visits in CYP with AKC. Stinging and skin rash can lead to discontinuation.

Risk factors for development of superior limbic keratoconjunctivitis in thyroid eye disease in Japanese.

PURPOSE: To analyse risk factors for the development of superior limbic keratoconjunctivitis (SLK) in thyroid eye disease (TED). METHODS: This prospective, observational study included 638 eyes/sides from 319 patients with TED. The eyes were classified into two groups, based on the presence and absence of SLK. Multivariate logistic regression analysis was performed to evaluate potential risk factors, including sex, patient age, past treatment history (steroid, orbital radiotherapy and radioiodine therapy), smoking, clinical activity score, margin reflex distance (MRD)-1 and -2, Graefe sign/lid lag, Hertel exophthalmometric results, Schirmer's test results, tear break-up time (TBUT) and tear meniscus height (TMH). RESULTS: SLK was found in 198 eyes (31.0%) from 121 patients. Young age (OR, 0.977; P = 0.006), smoker (OR, 1.785; P = 0.009), presence of Graefe sign (OR, 2.912; P < 0.001), absence of lid lag (OR, 0.485; P = 0.031), high Hertel exophthalmometric values (OR, 1.125; P = 0.002), shorter Schirmer's test results (OR, 0.962; P < 0.001), shorter TBUT (OR, 0.815; P = 0.002) and high upper TMH (OR, 1.003; P = 0.013) were associated with the development of SLK. A high MRD-1 measurement value also tended to be associated with a risk of SLK, with an OR of 1.187 (P = 0.056). CONCLUSION: The present study proposed several risk factors in relation to the development of SLK in TED.