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Differential Diagnosis for Dry Eye

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 61149

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Prof. Georgi Georgiev

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Biointerfaces and Biomaterials Laboratory, Department of Optics and Spectroscopy, School of Optometry, Faculty of Physics, St. Kliment Ohridski University of Sofia 5 James Bourchier Blvd., 1164 Sofia, Bulgaria
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Dr. Norihiko Yokoi

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Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Interests: dry eye; tear film dynamics; tear film oriented diagnosis and therapy; biophysics; surgery of eyelid and ocular surface
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Dry eye disease (DED), characterized with tear film (TF) instability and ocular discomfort and/or visual impairment, is one of the most prevalent public health ophthalmic diseases affecting the quality of life of 10–30% of the human population worldwide. Caused by aging, general and eye diseases and their medications, and exposure to everyday influences (contact lens, air conditioners, computer screens, medicines etc.), it has gross socioeconomic impact on modern society. DED is a multifactorial disease which may involve (i) insufficiency in any of the TF layers, lipid and/or mucoacueous, or in the ocular surface epithelium and (ii) inflammation either by immunologic or neuropathic component. Therefore in order the best personalized therapy to be delivered to the patient, a differential diagnosis able to identify the root cause(s) of the disease is necessary. Multiple efforts were devoted on this involving (i) the assessment of the TF physical properties: evaluation of TF breakup, osmolarity, viscosity, ocular friction, tear ferning patterns etc. and (ii) the omics quest for DED specific biomarkers: inflammatory molecules, lipid and protein alterations in health and disease etc. The accumulation and the critical appreciation of such results is essential for breakthrough that results in personalized diagnosis and therapy of DED. In this special issue, we are looking for reviews and research results including new findings in the above fields. The aim is to broaden the understanding for the mechanisms involved in TF instability and DED pathology and to facilitate the possibilities for differential diagnostics of DED. We are looking forward to and will be welcoming your invaluable work in this issue

Prof. Georgi Georgiev
Prof. Norihiko Yokoi
Guest Editors

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Keywords

Dry eye syndrome
Differential diagnostics of dry eye
Tear film properties, dynamics and (in)stability
Dry eye mechanisms
Biomarkers

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Published Papers (13 papers)

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Editorial

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3 pages, 153 KiB

Open AccessEditorial

Editorial of Special Issue “Differential Diagnosis for Dry Eye”

by Georgi As. Georgiev and Norihiko Yokoi

Diagnostics 2021, 11(5), 910; https://doi.org/10.3390/diagnostics11050910 - 20 May 2021

Viewed by 2818

Abstract

This editorial aims to summarize the scientific papers that contributed to the Special Issue “Differential Diagnosis for Dry Eye” [...] Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

Research

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24 pages, 5529 KiB

Open AccessArticle

The Influence of Work Environment Factors on the Ocular Surface in a One-Year Follow-Up Prospective Clinical Study

by Edyta Chlasta-Twardzik, Aleksandra Górecka-Nitoń, Anna Nowińska and Edward Wylęgała

Diagnostics 2021, 11(3), 392; https://doi.org/10.3390/diagnostics11030392 - 25 Feb 2021

Cited by 29 | Viewed by 2751

Abstract

The purpose of this study was to assess the effect of environmental working conditions on the symptoms and signs of dry eye disease and to examine whether and how those conditions impact the ocular surface. Methods: This single-center, prospective clinical study with a 1-year follow-up included 150 patients. The following parameters were evaluated: non-invasive keratograph break-up time (NIKBUT), tear meniscus height (TMH), and conjunctival and limbal hyperemia. We also performed staining of the surface of the eye for simulated fluorescein images, Schirmer’s test I, assessment of Meibomian gland dysfunction (MGD), and an Ocular Surface Disease Index (OSDI) questionnaire. Results: In the OW (office workers) group, in people working >4 h at the computer, the NIKBUT before work and the Schirmer test results were statistically significantly lower than in people working <4 h. The conjunctival hyperemia result before work was statistically significantly higher for people working >4 h at a computer in both groups and after work in the MW (medical workers) group. Low relative air humidity in the building and air-conditioned rooms negatively affects the tear film, causing the symptoms of dry eye disease. At the 1-year follow-up, there was a statistically significant reduction in conjunctival and limbal hyperemia in the OW group as well as a statistically significant reduction in TMH at the first examination before and after work, and in the second examination after 1 year in both groups. Conclusions: Environmental factors such as reduced relative air humidity, increased air temperature, and decreased illumination have a negative impact on the ocular surface. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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11 pages, 1750 KiB

Open AccessArticle

Clinical Implication of Patchy Pattern Corneal Staining in Dry Eye Disease

by Seitaro Komai, Norihiko Yokoi, Hiroaki Kato, Aoi Komuro, Yukiko Sonomura, Shigeru Kinoshita and Chie Sotozono

Diagnostics 2021, 11(2), 232; https://doi.org/10.3390/diagnostics11020232 - 3 Feb 2021

Cited by 4 | Viewed by 9148

Abstract

Corneal fluorescein staining in a form that is commonly called a “patchy pattern (PP)” is sometimes seen with or without superficial punctate keratopathy (SPK) in dry-eye diseases (DEDs). Here, we investigated the differences in the clinical features of DED patients with and without PP corneal staining (PPCS). This study involved 35 DEDs with PPCS (PPCS group) and 30 DEDs with SPK and without PPCS (non-PPCS group). The tear meniscus radius (TMR, mm), spread grade (SG) of the tear-film lipid layer (i.e., SG 1–5, 1 being best), noninvasive breakup time (NIBUT, seconds), fluorescein breakup time (FBUT, seconds), corneal epithelial damage (CED, 15 points maximum), conjunctival epithelial damage (CjED, six points maximum), the Schirmer’s 1 test (ST1, mm), and the prevalence of Sjögren’s syndrome (SS) were examined, and then compared between the two groups. Our findings revealed that between the groups (PPCS vs. non-PPCS), there was a statistically significant difference (p < 0.05) in CjED (3.1 ± 1.9 vs. 1.3 ± 1.6), ST1 (5.6 ± 7.4 vs. 14.8 ± 11.4), and the prevalence of SS (60.0% vs. 16.7%). Our findings suggest that DEDs and dry-eye patients with PPCS may indicate not only SS itself, but also the ophthalmological characteristics compatible with SS. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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9 pages, 2010 KiB

Open AccessArticle

The Relationship between Subjective Symptoms and Quality of Life in Conjunctivochalasis Patients

by Aoi Komuro, Norihiko Yokoi, Hiroaki Kato, Yukiko Sonomura, Chie Sotozono and Shigeru Kinoshita

Diagnostics 2021, 11(2), 179; https://doi.org/10.3390/diagnostics11020179 - 27 Jan 2021

Cited by 4 | Viewed by 4766

Abstract

The purpose of this study was to evaluate the differences in subjective symptoms between patients with conjunctivochalasis (CCh) and dry eye (DE), and examine the relationship between subjective symptoms and quality of life (QOL). In 75 eyes of 75 CCh patients and 122 eyes of 122 DE patients, 12 subjective symptoms classified into four groups depending on the mechanisms associated with symptoms (ITF: instability of tear film, IF: increased friction, R: reflex, and DTC: delayed tear clearance) were evaluated by use of a visual analogue scale (VAS). Fifteen items related to DE symptoms and their influence on daily life were evaluated by use of the dry eye-related quality-of-life score (DEQS) questionnaire, with overall degree of QOL impairment calculated as a QOL score. The correlation between the Total VAS score and QOL score were evaluated. Between the CCh and DE patients, significant differences in subjective symptoms were found in eye dryness, pain, tearing sensitivity to light, and heavy eyelids, while tearing was higher in CCh. A significant strong correlation was found between QOL score and Total VAS score, ITF, and IF in CCh patients. The QOL of CCh patients is strongly determined by decreased tear-film stability and increased friction during blinking. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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12 pages, 1484 KiB

Open AccessArticle

Evaluation of Eye-Pain Severity between Dry-Eye Subtypes

by Yamato Yoshikawa, Norihiko Yokoi, Hiroaki Kato, Rieko Sakai, Aoi Komuro, Yukiko Sonomura, Tsunehiko Ikeda and Chie Sotozono

Diagnostics 2021, 11(2), 166; https://doi.org/10.3390/diagnostics11020166 - 25 Jan 2021

Cited by 6 | Viewed by 3138

Abstract

The aim of this study was to assess eye pain between dry eye (DE) subtypes using questionnaires and the PainVision^® (Osachi) apparatus. This study involved 52 eyes of 52 DE patients with eye pain (43 females and 9 males; mean age: 64.2 ± 13.2 (mean ± SD) years) who were classified into three DE subtypes (aqueous deficient DE (ADDE); decreased wettability DE (DWDE); and increased evaporation DE (IEDE)) based on fluorescein breakup pattern. In all subjects, severity of eye pain was evaluated using PainVision^®, the DE-symptom-questionnaire visual analog scale (DSQ-VAS), and the Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2). The severity of eye pain was compared between the three DE subtypes. PainVision^® findings revealed greater severity of eye pain in ADDE and DWDE than in IEDE (p < 0.05, respectively), despite no difference being found in each questionnaire. A significant correlation was found between eye pain in DSQ-VAS and continuous pain, intermittent pain, neuropathic pain, and total pain in SF-MPQ-2 (R = 0.50, 0.49, 0.47, and 0.56, respectively) (all: p < 0.001). Greater severity of eye pain was found in ADDE and DWDE than in IEDE, and PainVision^® was found useful for the objective assessment of eye pain. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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6 pages, 707 KiB

Open AccessCommunication

Short-Term Reproducibility of MUC5AC Measurement in Human Tear Fluid

by Ashley M. Woodward, Michelle Senchyna and Pablo Argüeso

Diagnostics 2021, 11(1), 57; https://doi.org/10.3390/diagnostics11010057 - 2 Jan 2021

Cited by 4 | Viewed by 2101

Abstract

The assessment of tear fluid components is a common and valuable approach to understanding ocular surface disease and testing the efficacy of novel therapeutic strategies. However, the interpretation and utility of the findings can be limited by changes in the composition of the tear film, particularly in studies requiring repetitive patient sampling. Here, tear samples were collected twice within a one-hour interval to evaluate the short-term reproducibility of an immunoassay aimed to measure the amount of MUC5AC mucin. We found no statistical difference in total protein or MUC5AC content between the two consecutive collections of tear fluid, although the inter-individual variability in each group was high, with coefficients of variation exceeding 30% and 50%, respectively. Scatterplots showed a significant correlation in both protein and MUC5AC following collection within a one-hour interval. These data indicate that, regardless of the high inter-individual variability, repeated collection of tear fluid within an hour interval produces reproducible intra-individual data in terms of MUC5AC mucin content, and suggest that the normal mucin composition of the tear fluid can be re-established within an hour of the initial collection. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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9 pages, 1498 KiB

Open AccessArticle

Tear Film Osmolarity Measurement in Japanese Dry Eye Patients Using a Handheld Osmolarity System

by Jun Shimazaki, Miki Sakata, Seika Den, Miki Iwasaki and Ikuko Toda

Diagnostics 2020, 10(10), 789; https://doi.org/10.3390/diagnostics10100789 - 5 Oct 2020

Cited by 10 | Viewed by 2950

Abstract

We studied the efficacy and safety of a handheld osmolarity measurement system (I-PEN) in Japanese patients with dry eye disease (DED) and non-DED subjects. In this prospective, multicenter study, tear osmolarity was examined using the I-PEN in a total of 122 eyes divided into DED (n = 71) and non-DED (n = 51) groups. Subjective symptoms were assessed using the Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire. Ocular surface condition was evaluated in terms of fluorescein tear breakup time (FBUT) and tear breakup pattern (TBUP), and by fluorescein staining and Schirmer’s test. The I-PEN measurements were performed safely in the majority of cases. There was no statistically significant difference in mean tear film osmolarity between the DED and non-DED groups (294.76 ± 16.39 vs. 297.76 ± 16.72 mOsms/L, respectively, p = 0.32). No significant correlations were observed between osmolarity values and DEQS score, FBUT, or the Schirmer score. Osmolarity did not differ among TBUP subgroups. This prospective clinical study found no correlations between the tear film osmolarity values obtained with the I-PEN system and any subjective or objective parameters of DED. Further studies are required to determine the utility of the I-PEN system in other settings. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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11 pages, 843 KiB

Open AccessArticle

Characteristics and Utility of Fluorescein Breakup Patterns among Dry Eyes in Clinic-Based Settings

by Chika Shigeyasu, Masakazu Yamada, Norihiko Yokoi, Motoko Kawashima, Kazuhisa Suwaki, Miki Uchino, Yoshimune Hiratsuka, Kazuo Tsubota and on behalf of the DECS-J Study Group

Diagnostics 2020, 10(9), 711; https://doi.org/10.3390/diagnostics10090711 - 17 Sep 2020

Cited by 9 | Viewed by 8057

Abstract

(1) Background: To evaluate the characteristics of fluorescein breakup patterns (FBUPs) among patients with dry eye disease (DED) and efficacy of FBUPs as a diagnostic test for DED subgroups. (2) Methods: The study enrolled 449 patients with DED. FBUPs were categorized as follows: area break (AB), line break (LB), spot break (SB), dimple break (DB), and random break (RB). Schirmer value, fluorescein breakup time (FBUT), keratoconjunctival score, DED subgroups and subjective symptoms were examined. (3) Results: LB patients presented with short FBUT and high keratoconjunctival score. AB patients presented with short FBUT, high cornea and keratoconjunctival scores. SB patients were young with short FBUT. DB patients exhibited low keratoconjunctival score. RB patients were young, with long FBUT and low keratoconjunctival scores. Among DED subgroups, LB and AB constituted 74.7% of aqueous-deficiency dry eye (ADDE). SB and DB constituted 42.4% of short FBUT dry eye (short FBUT-DE). Post-test probabilities and positive likelihood ratios for ADDE were 58.7% and 1.63, respectively; those for short FBUT-DE were 46.3% and 2.02, respectively. Patients with SB and AB exhibited significantly severe subjective symptoms than other FBUPs. (4) Conclusions: FBUPs are associated with both objective findings and symptoms of DED and may be a clinical tool for identification of DED subgroups. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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14 pages, 6868 KiB

Open AccessArticle

Correlation between Blood Flow and Temperature of the Ocular Anterior Segment in Normal Subjects

by Takashi Itokawa, Takashi Suzuki, Yukinobu Okajima, Tatsuhiko Kobayashi, Hiroko Iwashita, Satoshi Gotoda, Koji Kakisu, Yuto Tei and Yuichi Hori

Diagnostics 2020, 10(9), 695; https://doi.org/10.3390/diagnostics10090695 - 15 Sep 2020

Cited by 11 | Viewed by 3431

Abstract

Purpose: To determine a correlation between temperature and blood flow in the ocular anterior segment, and their effects on corneal temperature. Methods: In experiment 1, we recruited 40 eyes and measured the temperature and blood flow in the ocular anterior-segment (upper/lower eyelid skin, palpebral and bulbar conjunctiva, and cornea) before and after application of warm compresses. In experiment 2, we recruited 20 eyes and measured the same tissues before and during stimulation using water and capsaicin solution in the oral cavity. Results: In experiment 1, the temperatures of the upper/lower eyelid skin and cornea increased significantly until 15 min after the application of the warm compress; the temperatures of the palpebral and bulbar conjunctiva increased significantly until 10 min. The blood flow in the upper/lower eyelid skin and bulbar conjunctiva increased significantly until 10 min, and that of the palpebral conjunctiva increased significantly until 15 min. In experiment 2, the temperatures were correlated significantly with the blood flow in the upper and lower eyelid skin and palpebral and bulbar conjunctiva. The temperature of all locations and palpebral conjunctival blood flow contributed independently to the corneal temperature. Conclusions: In the ocular anterior segment, the temperature and blood flow were correlated significantly, and contributed to the corneal temperature. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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16 pages, 2464 KiB

Open AccessArticle

Prevalence and Risk Factors of Severe Dry Eye in Bangladesh-Based Factory Garment Workers

by Mamunur AKM Rashid, Calesta Hui Yi Teo, Sumaiya Mamun, Hon Shing Ong and Louis Tong

Diagnostics 2020, 10(9), 634; https://doi.org/10.3390/diagnostics10090634 - 26 Aug 2020

Cited by 5 | Viewed by 3757

Abstract

This study sought to evaluate the prevalence of dry eye and meibomian gland dysfunction (MGD) and the associated factors of severe dry eye symptoms (SDES) among garments worker of Gazipur, Bangladesh. We prospectively collected cross-sectional data for 1050 garments workers of a factory (70% response). All participants had an evaluation of the Ocular Surface Disease Index (OSDI), and a detailed ophthalmic examination including tear breakup time (TBUT), ocular surface fluorescein staining, and Schirmer’s I test. MGD grading was based on the viscosity/color and ease of manual expression of meibum. Mean age of participants was 35.5 ± 12.1 years; 53.8% were women. The prevalence of dry eye (OSDI > 12) was 64.2% (95% CI 61.2–67.1%). OSDI was not significantly different between sex or age-groups but associated with increasing MGD grade (p < 0.001), reduced TBUT (<5 s) [p < 0.001], and reduced Schirmer’s test (<5 mm) [p < 0.001]. Thirty-five percent had SDES (OSDI > 32). Using univariate logistic regressions, SDES was associated with older age (Odds Ratio (OR) 1.01, 95% Confidence Interval [1.005–1.03] per year increase) and male sex (OR 1.76, 95% CI: 1.36–2.27). When adjusted for age and sex, SDES were strongly associated with increase in MGD severity grading (OR 188, 95% CI: 91–390). However, in multivariate regression, TBUT, but not MGD severity, became the only significant determinant of SDES (OR 13.0, 95% CI: 6.3–27.0, for every 1 s decrease in TBUT). MGD is common in garments workers, contributing to dry eye symptoms in addition to other tear parameters. Reduced tear stability is associated with SDES. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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8 pages, 224 KiB

Open AccessArticle

Age Is a Determining Factor of Dry Eye-Related Signs and Symptoms

by Masahiko Ayaki, Kazuno Negishi, Motoko Kawashima, Miki Uchino, Minako Kaido and Kazuo Tsubota

Diagnostics 2020, 10(4), 193; https://doi.org/10.3390/diagnostics10040193 - 31 Mar 2020

Cited by 17 | Viewed by 3063

Abstract

Purpose: The reported signs and symptoms of dry eye (DE) have been discordant. This study evaluated risk factors of DE-related symptoms and signs to explore their association with patient demographics, focusing on the age factor. Methods: The study enrolled 704 consecutive patients visiting general eye clinics who complained of ocular discomfort, but had normal vision. The patients were asked about the presence of six common symptoms related to DE and, tear break-up time (TBUT). The severity of patients’ keratopathy was also examined, and patients underwent Schirmer’s test. Results: Logistic regression analysis demonstrated that younger age (≤29 years) was associated with non-visual symptoms and keratopathy, while older age (≥60 years) was associated with short TBUT and low values on Schirmer’s test. Middle age was associated with both severe symptoms and signs. Conclusions: Discrepancies in the signs and symptoms of DE may depend, in part, on age, with younger subjects showing severe non-visual symptoms with apparently normal tear function and severe keratopathy, and older subjects showing fewer symptoms and less severe keratopathy despite worse tear function. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

Review

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25 pages, 1834 KiB

Open AccessReview

Tear Osmolarity in the Diagnosis of Systemic Dehydration and Dry Eye Disease

by Anthony J. Bron and Catherine Willshire

Diagnostics 2021, 11(3), 387; https://doi.org/10.3390/diagnostics11030387 - 25 Feb 2021

Cited by 20 | Viewed by 10015

Abstract

Systemic dehydration due to inadequate water intake or excessive water loss, is common in the elderly and results in a high morbidity and significant mortality. Diagnosis is often overlooked and there is a need for a simple, bedside diagnostic test in at-risk populations. Body hydration is highly regulated with plasma osmolality (pOsm) being tightly controlled over a wide range of physiological conditions. By contrast, normal tear osmolarity (tOsm) is more variable since the tear film is exposed to evaporation from the open eye. While plasma hyperosmolality is a diagnostic feature of systemic dehydration, tear hyperosmolality, with other clinical features, is diagnostic of dry eye. Studies in young adults subjected to exercise and water-deprivation, have shown that tOsm may provide an index of pOsm, with the inference that it may provide a simple measure to diagnose systemic dehydration. However, since the prevalence of both dry eye and systemic dehydration increases with age, the finding of a raised tOsm in the elderly could imply the presence of either condition. This diagnostic difficulty can be overcome by measuring tear osmolality after a period of evaporative suppression (e.g., a 45 min period of lid closure) which drives tOsm osmolality down to a basal level, close to that of the pOsm. The arguments supporting the use of this basal tear osmolarity (BTO) in the diagnosis of systemic dehydration are reviewed here. Further studies are needed to confirm that the BTO can act as a surrogate for pOsm in both normally hydrated subjects and in patients with systemic dehydration and to determine the minimum period of lid closure required for a simple, “point-of-care” test. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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8 pages, 693 KiB

Open AccessCase Report

Atypical Granulomatosis with Polyangiitis Presenting with Meibomitis, Scleritis, Uveitis and Papillary Bladder Tumor: A Case Report and Literature Review

by Takashi Kojima, Murat Dogru, Eisuke Shimizu, Hiroyuki Yazu, Aya Takahashi and Jun Shimazaki

Diagnostics 2021, 11(4), 680; https://doi.org/10.3390/diagnostics11040680 - 9 Apr 2021

Cited by 3 | Viewed by 2805

Abstract

Granulomatosis with polyangiitis (GPA) presents with a variety of systemic findings, sometimes with ocular findings initially, but is often difficult to diagnose at an early stage. An 85-year-old male had complaints of ocular dryness and redness and was diagnosed with meibomian gland dysfunction with meibomitis. Despite an initial treatment with topical steroid and antibiotics, the meibomitis did not improve and the left eye developed scleritis and iridocyclitis. The patient was administered topical mydriatics and oral steroids. During follow-up, the patient developed left hearing difficulty and reported a darker urine. Urinalysis revealed microscopic hematuria. A blood test showed an elevated erythrocyte sedimentation rate, positivity for perinuclear anti-neutorophil cytoplasmic antibody, and elevations in blood urea nitrogen and serum creatinine. Nasal mucosal biopsy showed a non-necrotizing granulomatous inflammation. Renal biopsy revealed focal glomerulosclerosis. Cystoscopy and bladder wash followed by a planned transurethral resection revealed atypical cells and apical papillary tumors which were resected. Iridocyclitis and scleritis responded well to oral prednisolone with 0.1% topical betamethasone and prednisolone ointment. The patient is tumor free with no recurrences 24 months after resection. GPA may present atypically with meibomian gland dysfunction without showing representative clinical findings. Early detection and treatment are essential for visual recovery. Full article

(This article belongs to the Special Issue Differential Diagnosis for Dry Eye)

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