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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 (30 June 2020) | Viewed by 46684

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Dr. Murat Dogru

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1. Department of Ophthalmology, Keio University School of Medicine, Shi-nanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan
2. Visiting Senior Fellow, UNSW School of Optometry and Vision Science, Sydney, NSW 2052, Australia
Interests: dry eye; oxidative stress; diagnostic imaging; biomarkers; ocular allergy; contact lens
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Dr. Takashi Kojima

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Department of Ophthalmology, School of Medicine, Keio University, Tokyo 160-8582, Japan
Interests: dry eye; neuropathic pain; refractive surgery; oxidative stress; behavior science
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

In recent years, dry eye has been widely investigated in many studies, including epidemiological, basic, and clinical, and some of the recent achievements in the field are remarkable. Dry eye is a disease in which tear film stability decreases. The mechanism is associated with inflammation, friction with eyelids, changes in tear osmolarity, amount of tear secretion, wettability of ocular surface, tear evaporation, etc., which are involved in a complex way to form a pathological condition. In addition, the differences between subjective symptoms and ocular findings in dry eye disease have been pointed out. Recently, research has been conducted in several aspects, including involvement of the nervous system, and it has become clear that dry eye also contains elements of neuropathic pain. With regard to treatment, treatments targeting tear stability, inflammation, and friction are being performed. Moreover, in recent years, secretagogue of water and mucin components have been widely used in Asian countries. However, understanding of dry eye pathology, diagnosis, and treatment is still inadequate. New insights and breakthroughs will be needed to overcome these problems in the future. In this Special Issue, we are looking for research results including new findings in the fields of ocular surface and dry eye disease. The aim is to broaden the direction and possibilities of dry eye research. We are looking forward to and will be welcoming your invaluable work in this issue.

This is the joint Special Issue both in IJMS and Diagnostics.

Assoc. Prof. Murat Dogru
Dr. Takashi Kojima
Guest Editors

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Keywords

Dry eye
Basic research
Clinical research
Treatment
Animal model
Neuropathic pain
Ocular surface
Pathophysiology
Diagnosis

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Dry Eye and Ocular Surface Disorders 2.0 in Diagnostics (1 article)

Published Papers (11 papers)

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Research

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13 pages, 839 KiB

Open AccessArticle

Corneal In Vivo Laser-Scanning Confocal Microscopy Findings in Dry Eye Patients with Sjögren’s Syndrome

by Yukihiro Matsumoto, Osama M. A. Ibrahim, Takashi Kojima, Murat Dogru, Jun Shimazaki and Kazuo Tsubota

Diagnostics 2020, 10(7), 497; https://doi.org/10.3390/diagnostics10070497 - 20 Jul 2020

Cited by 24 | Viewed by 3096

Abstract

Purpose: To evaluate the changes in cornea in Sjögren’s syndrome (SS) with a novel confocal microscopy device. Methods: Twenty-three right eyes of patients with SS (23 women; mean age, 65.4 ± 11.4 years) and 13 right eyes of 13 age- and sex-matched control subjects (13 women; mean age, 68.8 ± 9.8 years) were studied. Furthermore, eight right eyes of patients with SS (8 women; mean age, 66.9 ± 9.6 years) were studied to evaluate the corneal microscopic alterations after the treatment with topical 3% diquafosol sodium eye drops. All cases had tear quantity, tear breakup time (BUT), ocular surface staining measurements, and corneal in vivo laser-scanning confocal microscopy examinations. The density and area of corneal epithelial cells (superficial, wing, and basal), density of corneal stromal cells (anterior, intermediate, and posterior), density and area of corneal endothelial cells, density and morphology of corneal sub-basal nerve plexus, density of corneal sub-basal inflammatory cells were also assessed. Results: The tear quantity, stability, and vital staining scores were significantly worse in patients with SS than in control subjects (p < 0.0001). Corneal superficial epithelial cell density was significantly lower in SS compared with control subjects (p < 0.0001). Corneal superficial epithelial cell area was significantly larger in SS compared with control subjects (p = 0.007). Corneal sub-basal nerve fiber density was lower in SS compared with control subjects (p < 0.0001). Morphological abnormality of nerve fibers was observed in SS patients. Corneal sub-basal inflammatory cell density was significantly higher in SS patients compared with control subjects (p < 0.0001). Furthermore, the mean corneal superficial epithelial cell density and area, inflammatory cell density, corneal sub-basal nerve fiber density, and morphological abnormality of nerve fibers, were improved with topical 3% diquafosol sodium treatment in the dry eye patients with SS (p < 0.05). Conclusions: The diagnostic modality using in vivo laser-scanning confocal microscopy was a useful method for the evaluation of the corneal cell density and area, nerve fiber density and morphology, and inflammatory cell density in patients with SS and also a useful tool in the assessment of treatment effect with topical 3% diquafosol sodium in the SS patients. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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11 pages, 1204 KiB

Open AccessArticle

Validation of the Use of Automated and Manual Quantitative Analysis of Corneal Nerve Plexus Following Refractive Surgery

by Jia Ying Chin, Lily Wei Yun Yang, Angel Jung Se Ji, Mario Nubile, Leonardo Mastropasqua, John Carson Allen, Jodhbir S. Mehta and Yu-Chi Liu

Diagnostics 2020, 10(7), 493; https://doi.org/10.3390/diagnostics10070493 - 18 Jul 2020

Cited by 21 | Viewed by 4161

Abstract

Following refractive surgery, the cornea is denervated and re-innervated, hence a reproducible tool to objectively quantify this change is warranted. This study aimed to determine the repeatability and reproducibility of corneal nerve quantification between automated (ACCMetrics) and manual software (CCMetrics) following refractive surgery. A total of 1007 in vivo confocal microscopy images from 20 post-small incision lenticule extraction (SMILE) or post-laser-assisted in situ keratomileusis (LASIK) patients were evaluated by two independent observers using CCMetrics for corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fibre length (CNFL). Intra-observer and inter-observer reproducibility and repeatability, as well as agreement and correlation between the measurements obtained by ACCMetrics and CCMetrics, were assessed. We found that CNFL demonstrated the best intra- and inter-observer agreement followed by CNFD (intra-class correlation coefficient (ICC) = 0.799 and 0.740, respectively for CNFL; 0.757 and 0.728 for CNFD). CNBD demonstrated poorest intra- and inter-observer ICC. There was an underestimation in ACCMetrics measurements compared to CCMetrics measurements, although the differences were not significant. Our data suggested that both automated and manual methods can be used as reliable tools for the evaluation of corneal nerve status following refractive surgery. However, the measurements obtained with different methods are not interchangeable. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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14 pages, 4402 KiB

Open AccessArticle

Determination of Tear Lipid Film Thickness Based on a Reflected Placido Disk Tear Film Analyzer

by Pin-I Fu, Po-Chiung Fang, Ren-Wen Ho, Tsai-Ling Chao, Wan-Hua Cho, Hung-Yin Lai, Yu-Ting Hsiao and Ming-Tse Kuo

Diagnostics 2020, 10(6), 353; https://doi.org/10.3390/diagnostics10060353 - 28 May 2020

Cited by 6 | Viewed by 3490

Abstract

This study aims at determining the thickness of the tear lipid layer (LL) observed from a placido-disc-based tear film analyzer. We prospectively collected reflections of placido-disk LL images using a tear film analyzer (Keratograph^® 5M, Oculus) from subjects with dry eye symptoms. The LL thickness (LLT) over the inferior half of the cornea was estimated with the use of interference color analysis and the preprocessing of images with and without ring segmentation were obtained and analyzed. Moreover, LLTs before and after 1 h of applying topical ointment (Duratears, Alcon) were compared to validate the estimation of LLT. Our results suggested that the tear LLT can be assessed using a placido-disk-based tear film analyzer and interference color analysis. We verified a high correlation between non-segmented and segmented LL images and estimated LLT increase after applying ointment. In addition, we concluded that LLT can be evaluated by direct interference analysis without segmentation preprocessing. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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11 pages, 1741 KiB

Open AccessArticle

Comparing the Japanese Version of the Ocular Surface Disease Index and Dry Eye-Related Quality-of-Life Score for Dry Eye Symptom Assessment

by Takenori Inomata, Masahiro Nakamura, Masao Iwagami, Akie Midorikawa-Inomata, Yuichi Okumura, Keiichi Fujimoto, Nanami Iwata, Atsuko Eguchi, Hurramhon Shokirova, Maria Miura, Kenta Fujio, Ken Nagino, Shuko Nojiri and Akira Murakami

Diagnostics 2020, 10(4), 203; https://doi.org/10.3390/diagnostics10040203 - 07 Apr 2020

Cited by 11 | Viewed by 3806

Abstract

The aim of this study was to compare patient-reported symptoms of dry eye disease (DED) between the Japanese version of the Ocular Surface Disease Index (J-OSDI) and the Dry Eye-Related Quality-of-Life Score (DEQS). A total of 169 participants were enrolled between September 2017 and May 2018. Patients were administered the J-OSDI and DEQS questionnaires at their first (baseline) and follow-up visits to evaluate DED-related symptoms. The correlations between the J-OSDI total score and DEQS (Frequency and Degree) scores were evaluated using Pearson’s correlation coefficient, and their clinical differences were assessed using the Bland–Altman analysis. At the baseline visit, the J-OSDI score and DEQS (Frequency and Degree) were significantly correlated (r = 0.855, r = 0.897, respectively). Moreover, a significant correlation was found between the J-OSDI score and DEQS (Frequency and Degree) at the follow-up visit (r = 0.852, r = 0.888, respectively). The Bland–Altman analysis revealed a difference (bias) of 4.18 units at the baseline and 4.08 units at the follow-up between the scores of the two questionnaires. The J-OSDI and DEQS were significantly correlated with negligible score differences, suggesting that the J-OSDI can be reliably used for Japanese patients, allowing for cross-country comparisons. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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10 pages, 364 KiB

Open AccessArticle

Tear Break-Up Time and Seasonal Variation in Intraocular Pressure in a Japanese Population

by Masahiko Ayaki, Kazuno Negishi, Kenya Yuki, Motoko Kawashima, Miki Uchino and Kazuo Tsubota

Diagnostics 2020, 10(2), 124; https://doi.org/10.3390/diagnostics10020124 - 24 Feb 2020

Cited by 5 | Viewed by 2689

Abstract

Purpose: To evaluate seasonal variation in intraocular pressure (IOP) with and without short tear break-up time (SBUT, BUT ≤5 s) since dry eye and IOP are known to have seasonal variation. Methods: This study enrolled 176 patients who visited one of six eye clinics, in Japan, four times for IOP measurement, in every season. The mean patient age was 67.9 years, including 79 males. Participants were divided into four groups based on the presence of glaucoma and/or SBUT and we compared the seasonal variation in IOP (winter and summer) among the four groups. Results: The IOP (mmHg) in winter and summer, respectively, was 12.8 ± 3.7 and 12.8 ± 3.1 for non-glaucoma patients without SBUT (n = 47, p = 0.964), 14.8 ± 3.4 and 13.3 ± 3.4 for non-glaucoma patients with SBUT (n = 57, p < 0.001), 14.3 ± 3.2 and 14.1 ± 3.4 for glaucoma patients without SBUT (n = 36, p = 0.489), and 13.3 ± 3.0 and 11.6 ± 2.9 for glaucoma with SBUT (n = 36, p < 0.001). Seasonal variation was largest across the seasons in the glaucoma with the SBUT group, and the magnitude of seasonal variation correlated with BUT (β = 0.228, p = 0.003). Conclusions: Seasonal variation tended to be larger in patients with SBUT than those without SBUT. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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8 pages, 1824 KiB

Open AccessArticle

Combination of Two Rapid Ophthalmic Test Kits for Improved Diagnosis in Cases of Severe Binocular Conjunctivitis

by Asako Kodama, Fumitaka Kobayashi, Hao Yung Yang, Kazumi Fukagawa, Hiroyuki Yazu and Hiroshi Fujishima

Diagnostics 2020, 10(2), 109; https://doi.org/10.3390/diagnostics10020109 - 17 Feb 2020

Cited by 4 | Viewed by 3254

Abstract

Introduction: Diagnosis of conjunctivitis can be sometimes difficult, especially in cases of severe conjunctivitis and those involving both eyes. In this study, we performed commercial tests for adenovirus (Capilia Adeno Eye^®) and total tear IgE (Allerwatch^®) in a single visit in patients with bilateral conjunctivitis to examine if, and by how much, the combination of these two tests would improve the diagnostic accuracy of conjunctivitis. Methods: The study included sixty patients with relatively severe conjunctivitis in both eyes within a week of consulting our clinic and who had no previous treatment. Capilia Adeno Eye^® and Allerwatch^® tests were performed. Results: A significantly higher number of cases (55/60) were diagnosed when both tests were evaluated than with either test (Capilia Adeno Eye^® (12/60; p < 0.001) or Allerwatch^® (44/60; p < 0.005)) alone. The positivity rate of Allerwatch^® was significantly higher than that of Capilia Adeno Eye^® (p < 0.001). The diagnosis rate of atopic keratoconjunctivitis was 100% in patients with allergic conjunctivitis, but there was no significant difference in positivity compared with other types of allergic conjunctivitis. Conclusions: Testing patients with both Capilia Adeno Eye^® and Allerwatch^® improves the diagnostic accuracy for conjunctivitis and can diagnose more than 90% of cases. Detection of adenovirus antigen and IgE in tears, using these simple and rapid methods, will be useful for early diagnosis and prevention of adenoviral conjunctivitis. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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10 pages, 3943 KiB

Open AccessArticle

The Effects of 3% Diquafosol Sodium Eye Drops on Tear Function and the Ocular Surface of Cu, Zn-Superoxide Dismutase-1 (Sod1) Knockout Mice Treated with Antiglaucoma Eye Medications

by Yukari Yagi-Yaguchi, Takashi Kojima, Kazunari Higa, Murat Dogru, Osama MA. Ibrahim, Takahiko Shimizu, Kazuo Tsubota and Jun Shimazaki

Diagnostics 2020, 10(1), 20; https://doi.org/10.3390/diagnostics10010020 - 01 Jan 2020

Cited by 6 | Viewed by 3911

Abstract

Anti-glaucoma eye drop treatment often induces dry eyes and can lead to poor medication adherence. This study aimed to investigate the effects of 3% diquafosol sodium eye drops on tear function and the ocular surface epithelium in Sod1^−/− mice after treatment with anti-glaucoma eye drops. The mice were divided into four groups: group 1, control group; group 2, anti-glaucoma eye drop; group 3, anti-glaucoma eye drops followed by a secretagogue eye drop (3% diquafosol); and group 4, simultaneous anti-glaucoma and secretagogue eye drop. Mice underwent assessments of tear quantity, tear film breakup time, and vital staining score. Mice in groups 3 and 4 showed significantly better tear stability and lower corneal staining scores than mice in group 2 after eye drop instillations (p < 0.05). Mice in group 4 showed significantly better tear stability, lower corneal staining scores, and higher goblet cell densities than those in group 1 after eye drop instillations (p < 0.05). The conjunctival epithelium showed stratification and abundance of Muc5AC-positive goblet cells in group 4, whereas thinning with desquamation was observed with a few goblet cells in group 2. Thus, simultaneous administration of 3% diquafosol sodium eye drops with topical anti-glaucoma drops showed favorable effects on tear stability and the corneal epithelium against the ocular surface toxicity inflicted by the anti-glaucoma eye drops. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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11 pages, 1008 KiB

Open AccessArticle

Ocular Surface Workup in Patients with Meibomian Gland Dysfunction Treated with Intense Regulated Pulsed Light

by Luca Vigo, Leonardo Taroni, Federico Bernabei, Marco Pellegrini, Stefano Sebastiani, Andrea Mercanti, Nicola Di Stefano, Vincenzo Scorcia, Francesco Carones and Giuseppe Giannaccare

Diagnostics 2019, 9(4), 147; https://doi.org/10.3390/diagnostics9040147 - 13 Oct 2019

Cited by 19 | Viewed by 3865

Abstract

The purpose of the present study was to evaluate changes of signs and symptoms in patients with meibomian gland dysfunction (MGD) treated with intense regulated pulsed light (IRPL), and to further investigate which parameter could predict positive outcomes of the procedure. Twenty-eight patients who bilaterally received three IRPL sessions at day 1, 15, and 45 satisfied the criteria and were included in the study. Non-invasive break-up time (NIBUT), lipid layer thickness (LLT), meibography, tear osmolarity, and ocular discomfort symptoms were measured before and 30 days after the last IRPL session. Qualified or complete success was defined in the presence of an improvement of symptoms associated with an increase of NIBUT (< or ≥ 20%). After IRPL treatment, median NIBUT and LLT increased from 7.5 to 10.2 s and 2.0 to 3.0, respectively (p <0.001); tear osmolarity decreased from 304.0 to 301.0 mOsm/L (p = 0.002). Subjective symptoms improved after IRPL in 26 patients. Qualified success was reached in 34 eyes, while complete success in 16 eyes. Patients with lower baseline break-up time (BUT) values showed better response to treatment (p = 0.04). In conclusion, IRPL improved signs and symptoms in MGD patients, while lower baseline NIBUT values were predictive of better response to IRPL. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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Review

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23 pages, 3532 KiB

Open AccessReview

Novel Approaches for Imaging-Based Diagnosis of Ocular Surface Disease

by Doreen Schmidl, Andreas Schlatter, Jacqueline Chua, Bingyao Tan, Gerhard Garhöfer and Leopold Schmetterer

Diagnostics 2020, 10(8), 589; https://doi.org/10.3390/diagnostics10080589 - 13 Aug 2020

Cited by 21 | Viewed by 5609

Abstract

Imaging has become indispensable in the diagnosis and management of diseases in the posterior part of the eye. In recent years, imaging techniques for the anterior segment are also gaining importance and are nowadays routinely used in clinical practice. Ocular surface disease is often synonymous with dry eye disease, but also refers to other conditions of the ocular surface, such as Meibomian gland dysfunction or keratitis and conjunctivitis with different underlying causes, i.e., allergies or infections. Therefore, correct differential diagnosis and treatment of ocular surface diseases is crucial, for which imaging can be a helpful tool. A variety of imaging techniques have been introduced to study the ocular surface, such as anterior segment optical coherence tomography, in vivo confocal microscopy, or non-contact meibography. The present review provides an overview on how these techniques can be used in the diagnosis and management of ocular surface disease and compares them to clinical standard methods such as slit lamp examination or staining of the cornea or conjunctiva. Although being more cost-intensive in the short term, in the long term, the use of ocular imaging can lead to more individualized diagnoses and treatment decisions, which in turn are beneficial for affected patients as well as for the healthcare system. In addition, imaging is more objective and provides good documentation, leading to an improvement in patient follow-up and education. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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21 pages, 288 KiB

Open AccessReview

A Review of Dry Eye Questionnaires: Measuring Patient-Reported Outcomes and Health-Related Quality of Life

by Yuichi Okumura, Takenori Inomata, Nanami Iwata, Jaemyoung Sung, Keiichi Fujimoto, Kenta Fujio, Akie Midorikawa-Inomata, Maria Miura, Yasutsugu Akasaki and Akira Murakami

Diagnostics 2020, 10(8), 559; https://doi.org/10.3390/diagnostics10080559 - 05 Aug 2020

Cited by 66 | Viewed by 6060

Abstract

Dry eye disease (DED) is among the most common eye diseases and is becoming increasingly prevalent. Its symptoms cause a long-term decline in patients’ health-related quality of life (HRQL). Inconsistencies often occur between the clinical findings and the subjective symptoms of DED. Therefore, a holistic, balanced, and quantitative evaluation of the subjective symptoms and HRQL using patient-reported outcome questionnaires, in addition to clinical findings, is crucial for accurate DED assessment in patients. This paper reviewed the characteristics of current dry eye questionnaires, including their objectives, number of questions, inclusion of HRQL-related items, and whether they were properly evaluated for psychometric properties. Twenty-four questionnaires were identified; among them, the following six questionnaires that included items assessing HRQL and were properly evaluated for psychometric properties are recommended: the Ocular Surface Disease Index, Impact of Dry Eye in Everyday Life, Dry Eye-Related Quality-of-life Score, University of North Carolina Dry Eye Management Scale, Chinese version of Dry Eye-Related Quality of Life, and 25-Item National Eye Institute Visual Function Questionnaire. Dry eye questionnaires have different objectives and are available in different languages. Therefore, medical practitioners should confirm the characteristics of applicable questionnaires before selecting the most appropriate ones. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

32 pages, 2145 KiB

Open AccessReview

Why Chain Length of Hyaluronan in Eye Drops Matters

by Wolfgang G.K. Müller-Lierheim

Diagnostics 2020, 10(8), 511; https://doi.org/10.3390/diagnostics10080511 - 23 Jul 2020

Cited by 21 | Viewed by 5595

Abstract

The chain length of hyaluronan (HA) determines its physical as well as its physiological properties. Results of clinical research on HA eye drops are not comparable without this parameter. In this article methods for the assessment of the average molecular weight of HA in eye drops and a terminology for molecular weight ranges are proposed. The classification of HA eye drops according to their zero shear viscosity and viscosity at 1000 s⁻¹ shear rate is presented. Based on the gradient of mucin MUC5AC concentration within the mucoaqueous layer of the tear film a hypothesis on the consequences of this gradient on the rheological properties of the tear film is provided. The mucoadhesive properties of HA and their dependence on chain length are explained. The ability of HA to bind to receptors on the ocular epithelial cells, and in particular the potential consequences of the interaction between HA and the receptor HARE, responsible for HA endocytosis by corneal epithelial cells is discussed. The physiological function of HA in the framework of ocular surface homeostasis and wound healing are outlined, and the influence of the chain length of HA on the clinical performance of HA eye drops is illustrated. The use of very high molecular weight HA (hylan A) eye drops as drug vehicle for the next generation of ophthalmic drugs with minimized side effects is proposed and its advantages elucidated. Consequences of the diagnosis and treatment of ocular surface disease are discussed. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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