Features Of Dry Eye Disease Research Articles

Clinical characteristics and correlative factors of dry eye disease associated with graft-versus-host disease

Objective: To investigate the clinical features of dry eye disease in patients with graft-versus-host disease (GVHD) and to identify the correlative factors that contribute to its severity. Methods: It was a retrospective case series study. A total of 62 patients with dry eye disease caused by GVHD after allogeneic hematopoietic stem cell transplantation (HSCT) were recruited from the First Affiliated Hospital of Soochow University between 2012 and 2020. The study population comprised 38 males (61%) and 24 females (39%), with an average age of (35.29±11.75) years. Only the right eye of each patient was evaluated. The patients were divided into two groups based on the severity of corneal epitheliopathy: a mild group (15 eyes) and a severe group (47 eyes). Demographic information, including gender, age, primary disease, type of allogeneic HSCT, donor-to-recipient information, source of hematopoietic stem cells, systemic GVHD, and the time from HSCT to the first visit, was collected. Ophthalmologic assessments, including the Schirmer Ⅰ test, tear breakup time, corneal epithelial staining, and eye margin assessment, were performed during the first visit to the ophthalmology department and compared between the two groups. Results: The average time from HSCT to the first visit to the ophthalmology department among the 62 patients was (20.26±13.09) months. The median corneal fluorescein staining score was 4.5 points. In the mild group, the main characteristic of corneal staining was scattered punctate staining in the peripheral region in 80% of cases, while in the severe group, corneal staining fused into clumps in both the peripheral region (64%) and the pupillary zone (28%). Results of the Schirmer Ⅰ test were significantly lower in the severe group compared to the mild group (P<0.05). The median total eyelid margin score in the severe group was higher than that in the mild group [9 (7, 12) points vs. 6 (5, 8) points] (P<0.05). The median eyelid congestion score in the severe group was, also higher than that in the mild group [2 (1, 3) points vs. 1 (0, 2) points] (P<0.05). The compatibility between the blood types of the donor and recipient was found to be statistically significant (P<0.05). There was no significant difference in gender, age, family relationship, human leukocyte antigen matching, gender consistency, source of hematopoietic stem cells, or the occurrence of systemic GVHD between the two groups (P>0.05). Conclusions: Patients in the mild group had scattered punctate corneal staining in the peripheral region, while those in the severe group showed fusion of corneal staining into clumps in both the peripheral and pupillary zones. The severity of dry eye disease caused by GVHD was strongly correlated with eyelid margin lesions. A higher degree of eyelid margin lesions indicated more severe dry eye disease caused by GVHD. Additionally, compatibility between the blood types of the donor and recipient may play a role in the development of GVHD-associated dry eye.

Desiccating Stress Significantly Increases the Risk for Chronic Ocular Graft-versus-Host-Disease

Desiccating stress (DS) is known to induce dry eye disease but has not been studied in the context of ocular graft-versus-host disease (oGVHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are exposed to DS on transplantation wards, which are highly climate-regulated for hygienic purposes. Because oGVHD demonstrates features of dry eye disease, this retrospective study aimed to analyze DS as a risk factor for chronic oGVHD. A total of 444 patients undergoing allo-HSCT were investigated with a maximum follow-up of 5.8 years post-transplantation. Relative humidity (%rH) on the transplantation ward was monitored, and data were correlated with the occurrence, severity, and onset of chronic oGVHD, as well as the occurrence of acute skin GVHD. A logistic regression model was used to predict the development of oGVHD. One hundred three of 213 surviving patients developed oGVHD. oGVHD was significantly correlated with a lower %rH (r=.2; P=.03), and more patients (73%) developed oGVHD after transplantation under DS compared with patients after transplantation under high-humidity conditions (30%; P=.02). Reduced humidity increased the relative risk for oGVHD by 4% for each %rH, but it did not affect the severity or time of first diagnosis of oGVHD. In this study, we demonstrate that DS is an independent risk factor for oGVHD. Adjusting air humidity during allo-HSCT has the potential to serve as a preventive measure with clinical relevance.

Association Between Depression and Severity of Dry Eye Symptoms, Signs, and Inflammatory Markers in the DREAM Study

Depression is more prevalent in patients with dry eye disease (DED) than in the general population; however, the association between severity of DED and depression needs further evaluation. To investigate the association between depression and severity of DED symptoms and signs, including inflammatory markers. Secondary cross-sectional and longitudinal analysis performed in April to December 2020 of data from Dry Eye Assessment and Management (DREAM) study, a randomized clinical trial from October 2014 to July 2016 including patients with moderate to severe symptoms and signs of DED. Enrolled from 27 ophthalmology and optometry centers, both academic and private, in 17 US states, 535 patients were followed up for 1 year. Participants screened positive for depression if they scored 42 or less on the Mental Component Summary (MCS) of the 36-Item Short Form Health Survey. Symptoms of DED were assessed by Ocular Surface Disease Index (OSDI) and Brief Ocular Discomfort Index (BODI) and signs assessed by tear film breakup time, Schirmer test, corneal and conjunctival staining, tear osmolarity, and meibomian gland dysfunction at baseline, 6 months, and 12 months. A composite severity sign score was calculated from all 6 signs. Inflammatory markers (cytokines in tears and HLA-DR expression by conjunctival surface cells) were measured for some trial participants. Features of DED were compared between participants with and without depression and adjusted for age, sex, race, visits, and baseline comorbidities. Among the 535 participants, mean (SD) age was 58 (13.2) years, 434 participants (81%) were women, and 398 (74.4%) were White. Participants who screened positive for depression had worse DED symptoms by OSDI (effect size = 0.45, P < .001) and BODI (effect size = 0.46, P < .001) and composite DED sign score (effect size = 0.21, P = .006). Lower MCS score (ie, worse depression) was correlated with higher OSDI score (ie, worse DED symptoms) at baseline (Spearman ρ = -0.09, P = .03), 6 months (ρ = -0.20, P < .001), and 12 months (ρ = -0.21, P < .001). Inflammatory markers did not differ by depression status. Depression was associated with more severe dry eye symptoms and overall signs, suggesting that among patients with moderate to severe DED, those with depression may be likely to have more severe DED. These findings support consideration of depression as a comorbidity when managing patients with DED. Further study is needed to elucidate the relationship.

Leptin's concentration in tears and dry eye: a clinical observational study.

To investigate the concentration of leptin in tears and its correlation with dry eye symptoms and signs. The study enrolled individuals (n=39) responding to an advertising or dry eye patients (n=58) from the Ophthalmology Department. Tear samples were collected for leptin concentration measuring. Ocular Surface Disease Index (OSDI), tear meniscus height (TMH), tear break up time (TBUT), cornea fluorescein staining, Schirmer test (ST) and impression cytology (IC) were assessed. Leptin concentration in tears of dry eye patients and healthy controls, and its correlation with clinical features of dry eye disease (DED) were analyzed. Age, body mass index (BMI), OSDI scores and cornea fluorescein staining scores showed a negative correlation with leptin concentration in tears (r=-0.340, P=0.001; r=-0.332, P=0.001; r=-0.258, P=0.011; r=-0.424, P<0.001, respectively). ST showed positive correlation with leptin concentration in tears (r=0.206, P=0.045). No significant difference was observed in leptin concentration between dry eye patients and controls (P=0.682). Multivariate linear regression analysis revealed that dry eye, OSDI, corneal fluorescein staining scores and ST correlated with leptin concentration in tears. This is the first study measuring leptin concentration in tears. The correlation between leptin concentration and DED symptoms and signs reveal that leptin level correlated with the dry eye, potentially contributing to repair of ocular damage and dry eye improvement.

Aqueous deficiency is a contributor to evaporation-related dry eye disease

Dry eye disease aetiologies can be classified dichotomously into aqueous deficient and evaporative types although many cases involve combinations of both. Differential diagnosis can be confounded by some features of dry eye disease being common to both aetiologies. For example, short tear break-up times are prime diagnostic findings of tear instability due to lipid and/or mucin deficiencies, but thin tear layers in aqueous deficient eyes also shorten tear break-up times, even at normal range rates of evaporation in eyes without lipid and/or mucin deficiencies. Because tear instability and short tear film break-up times due to thin tear layers can be independent of lipid and/or mucin deficiency, aqueous deficiency can be another form of evaporation-related dry eye. Conversely, tear layers which are thickened by punctal occlusion can be less susceptible to tear break-up. An inflamed lacrimal gland producing reduced quantities of warmer tears can be a basis for thin tear layers and tear instability demonstrated by shorter tear break-up times. Commonly used clinical tests for aqueous deficiency can be unreliable and less sensitive. Consequently, failure to detect or confirm aqueous deficiency as a contributor to short tear break-up times could result in too much weight being given to a diagnosis of meibomian gland deficiency. Less successful treatment outcomes may be a consequence of failing to detect aqueous deficiency. Refining disease classification by considering aqueous deficiency as a contributor to, or even a form of evaporation-related dry eye, could be the basis for more comprehensive and appropriate treatment strategies. For example, some treatment methods for evaporation-related dry eye might be appropriate for aqueous and mucin-deficient as well as lipid-deficient dry eyes. Anti-inflammatory treatment for the lacrimal gland as well as the conjunctiva, may result in increased aqueous production, reduced tear temperature, tear instability and evaporation rates as well as lower osmolarity.

Dose-dependent benzalkonium chloride toxicity imparts ocular surface epithelial changes with features of dry eye disease

PurposeInclusion of the preservative benzalkonium chloride (BAC) in ophthalmic solutions is prevalent, despite the noted potential for exacerbating dry eye disease (DED). Whilst studies incorporating BAC have assessed its’ effects as a mouse model of DED, the impact on limbal epithelia is under-studied. Our investigation aimed to comprehensively assess the impact of different BAC dosing regimens and their suitability as a mouse model of DED. MethodsC57BL/6J mice (n = 72) were administered topical BAC (0.05–0.2%) over 7 days. Fluorescein staining, corneal smoothness index, and immuno-histological analyses were applied to determine architectural and cellular changes on the ocular surface following BAC treatment. The effect of BAC (0.0001–0.01%) on cultivated primary mouse corneo-limbal epithelial cells (CLECs) (n = 6) was examined using morphological and functional assays. ResultsWhilst 0.2% BAC induced severe corneal epithelial defects, 0.1% BAC dispensed once daily over 7 days, induced punctate fluorescein staining without detriment to corneal smoothness. Histochemical staining revealed disorganized basal corneal epithelial cells with enlarged cytoplasmic halos. Furthermore, PAS+ goblet cells were decreased. BAC treatment also modulated K14 expression and distribution within the limbus. In cultured CLEC, BAC triggered cell contraction and vacuolation, increased LDH release and elevated cell necrosis by 4.1-fold. Concentrations of BAC as low as 0.0001% decreased colony formation. ConclusionsThis study describes how exposing C57BL/6 mice to BAC induce some clinicopathological features of DED seen in humans, and therefore provides the foundations to explore the consequences on the ocular surface, particularly on limbal epithelia and its’ stem cells.

Variability of Dry Eye Disease Following Removal of Lacrimal Glands in Rats.

Removal of lacrimal glands is used as a viable model of dry eye disease in rats. However, there is no uniform agreement on the disease severity following different variants of the procedure. The interpretation of the modeled dry eye disease also is biased by the interchangeable use of male and female rats. Therefore, this study seeks to define the features of dry eye disease following removal of the extraorbital lacrimal gland, with or without excision of the infraorbital lacrimal gland in male and female rats. The experiments were performed in 12-week-old female and male Sprague-Dawley rats. The baseline blink rate and fluorescein score were assessed. Subsequently, rats underwent isolated removal of the extraorbital gland, removal of the extraorbital gland combined with excision of the infraorbital gland, or a sham surgical procedure. The assessment of blink rate and fluorescein scores was repeated 28days following surgery. Corneas were collected for histological analysis. We found that the blink rate and fluorescein score increased in all of the experimental groups, except the control group and the male rats that underwent isolated removal of the extraorbital lacrimal gland. Histopathological analysis revealed the thinning and edema of the epithelium in all groups, except the control group. These changes were most pronounced in female rats following combined removal of extraorbital and infraorbital lacrimal glands. In conclusion, severity of dry eye disease in the rat model is influenced by both gender and the extent of surgical removal of lacrimal glands. Combined excision of lacrimal glands in female rats produced the most severe pathological changes, whereas isolated excision of the extraorbital lacrimal gland in male rats led to the least severe changes.

Optical Coherence Tomography Reveals Changes to Corneal Reflectivity and Thickness in Individuals with Tear Hyperosmolarity.

PurposeTo investigate whether tear hyperosmolarity, a feature of dry eye disease (DED), affects central corneal thickness (CCT), corneal light reflectivity, and/or tear film reflectivity.MethodsThis prospective, cross-sectional study involved 48 participants (38 with hyperosmolar tears and 10 controls with normo-osmolar tears). Symptoms and signs of DED (tear osmolarity, sodium fluorescein tear break-up time, ocular surface staining, Schirmer test) were assessed. CCT, and the reflectivity of the cornea and the tear-epithelial interface were quantified relative to background noise using Fourier-domain optical coherence tomography (FD-OCT).ResultsCCT of eyes with severe tear hyperosmolarity, defined as eyes in the upper quartile of the hyperosmolar group, was less than control eyes (539.1 ± 7.4 vs. 583.1 ± 15.0 μm, P = 0.02) and eyes with less severe tear hyperosmolarity, defined as hyperosmolar eyes in the lower quartile (622.7 ± 5.8 μm, P < 0.0001). CCT showed a negative linear relationship with tear osmolarity for values above 316 mOsmol/L (R2 = 0.17, P = 0.01). Central corneal reflectivity was lower in hyperosmolar eyes than normo-osmolar eyes (45.1 ± 0.3 vs. 48.1 ± 0.6 pixels, P = 0.02); the greatest relative difference was in the anterior stroma, where corneal reflectivity was 4.7 ± 1.9% less in hyperosmolar eyes (P < 0.01). Peak reflectivity of the tear-epithelial interface was 4.8% ± 3.5% higher in the hyperosmolar group than the normo-osmolar tear group (P = 0.04).ConclusionIndividuals with significant tear hyperosmolarity and clinical signs of symptoms of DED show reduced CCT and altered corneal reflectivity.Translational RelevanceAnterior segment FD-OCT provides novel insight into corneal microstructural differences in individuals with DED.

Trigeminal brainstem modulation of persistent orbicularis oculi muscle activity in a rat model of dry eye

Altered corneal reflex activity is a common feature of dry eye disease (DE). Trigeminal sensory nerves supply the ocular surface and terminate at the trigeminal interpolaris/caudalis (ViVc) transition and spinomedullary (VcC1) regions. Although both regions contribute to corneal reflexes, their role under dry eye conditions is not well defined. This study assessed the influence of local inhibitory and excitatory amino acid neurotransmission at the ViVc transition and VcC1 regions on hypertonic saline (HS) evoked orbicularis oculi muscle activity (OOemg) in urethane-anesthetized male rats after exorbital gland removal (DE). HS increased the magnitude of long-duration OOemg activity (OOemgL, >200ms) in DE compared to sham rats, while short-duration OOemg activity (OOemgS, <200ms) was similar for both groups. Inhibition of the ViVc transition by muscimol, a GABAA receptor agonist, greatly reduced HS-evoked OOemgL activity in DE rats, whereas injections at the VcC1 region had only minor effects in both groups. Blockade of GABAA receptors by bicuculline methiodide at the ViVc transition or VcC1 region increased HS-evoked OOemgL activity in DE rats. Blockade of N-methyl-D-aspartate (NMDA) receptors at either region reduced HS-evoked OOemgL activity in DE and sham rats. GABAαβ3 receptor density was reduced at the ViVc transition, while NMDA receptor density was increased at both regions in DE rats. Loss of GABAergic inhibition at the ViVc transition coupled with enhanced NMDA excitatory amino acid neurotransmission at the ViVc transition and the VcC1 region likely contribute to altered corneal reflexes under dry eye conditions.

Non-Invasive Diagnosis of Ocular Graft-versus-Host Disease

Ocular graft-vs-host disease (GvHD) is a major complication following allogenic blood stem cell transplantation (aBSCT) leading to a disturbance of the ocular surface integrity with a broad range of severity. Leading symptom is a pronounced autoinflammatory reaction in particular at the ocular surface with typical features of dry eye disease. Potential complications include visual loss, pain and damage to the ocular structures with, e. g. corneal ulcerations. Diagnosis and treatment of ocular GvHD are a challenge for attending ophthalmologists and require intensive interdisciplinary patient care in particular with haemato-oncologists. First and follow-up examinations consist of several diagnostic steps that include quantitative and qualitative analysis of tearfilm, visual acuity, ocular surface and retinal integrity, cataract development and subjective symptoms. Available tests are mostly evaluated for usage in dry eye diagnosis but are, however, mostly unspecific for diagnosing ocular GvHD reliably. Only combinations of several clinical tests together with the experience of specialised ophthalmologists may lead to the certain diagnosis and treatment decisions at state. This review illustrates the available established and innovative non-invasive diagnostic tests and evaluates their potential use for diagnosing ocular GvHD.

Correlation Between Optical Coherence Tomography–Derived Assessments of Lower Tear Meniscus Parameters and Clinical Features of Dry Eye Disease

To measure the correlation between subjective symptom score, conventional clinical tests, and Fourier-domain optical coherence tomography (FD-OCT) of lower tear meniscus parameters in patients with dry eye disease. Eighteen patients with dry eye disease requiring medical therapy and/or punctal occlusion were recruited for this prospective, nonrandomized, observational case series. Severity of symptoms of dry eye disease was assessed using the Indiana University Dry Eye Questionnaire 2002. Clinical assessments were completed using slit-lamp biomicroscopy, rose bengal dye staining, fluorescein tear breakup time (TBUT), and a 5-minute Schirmer test with topical anesthesia. The lower tear meniscus was imaged using an FD-OCT system with 5-μm axial resolution and measured manually by a masked grader using computer calipers. Correlation was assessed using Spearman correlation coefficient (ρ). The mean (±SD) scaled symptom score was 58 ± 21, with a range of 0 to 100. Vital staining test averaged 1.7 ± 3.4, TBUT averaged 4.4 ± 1.8 seconds, and Schirmer tests averaged 10.2 ± 8.1 mm. As determined by optical coherence tomography, the meniscus height was 228 ± 153 μm, depth was 127 ± 79 μm, and cross-sectional area was 0.018 ± 0.021 mm. Optical coherence tomography meniscus area was negatively correlated with the symptom questionnaire score (P < 0.01) and positively correlated with Schirmer test results (P < 0.01). There was no significant correlation between symptom score and rose bengal staining, TBUT, or Schirmer test results (P > 0.01). Lower tear meniscus measurement with FD-OCT is an objective noninvasive test that correlates well with symptoms of dry eye disease and the Schirmer test.

Curcumin protects against hyperosmoticity-induced IL-1β elevation in human corneal epithelial cell via MAPK pathways

Increased tear osmolarity is an essential feature of dry eye disease. Curcumin, a natural polyphenol extracted from herb turmeric, has recently been reported to have anti-inflammatory effects. However, its anti-inflammatory effects have not been investigated in dry eye disease. It has been reported that elevated osmolarity achieved by adding sodium chloride to the culture medium of corneal epithelial cells increased the production of IL-1β, a proinflammation cytokine. This in vitro dry eye model was used to test the anti-inflammatory effects of curcumin. In the present study, a 450 mOsM hyperosmotic medium was produced by adding sodium chloride to the culture medium to reach a final concentration of 90 mM. Human corneal epithelial cells cultured in this hyperosmotic medium for 24 h showed an increase of IL-1β, IL-6 and TNF-α levels in the conditioned medium. IL-1β was also upregulated at mRNA levels. Activation of p38 MAP kinase (p38), JNK MAP kinase (JNK) and NF-κB in cultured corneal epithelial cells were also induced by hyperosmotic conditions. Curcumin at concentrations of 1–30 μM did not affect the cell viability of cultured corneal epithelial cells. Pretreatment of curcumin (5 μM) completely abolished the increased production of IL-1β induced by the hyperosmotic medium. Increased phosphorylation of p38 caused by high osmolarity was also completely abolished by curcumin, whereas the phosphorylation of JNK was only partially inhibited. SB 203580 (p38 inhibitor), but not SP 600125 (JNK inhibitor), completely suppressed hyperosmoticity-induced IL-1β production, indicating that the inhibition of production of IL-1β by curcumin may be achieved through the p38 signal pathway. Curcumin completely abolished a hyperosmoticity-induced increase of NF-κB p65. NF-κB inhibitor suppressed hyperosmoticity-induced IL-1β production. p38 inhibitor suppressed hyperosmoticity-induced NF-κB activation, indicating that NF-κB activation was dependent on p38 activation. The present study suggests that curcumin might have therapeutic potential for treating dry eye disease.

Pharmacological Management of Dry Eye in the Elderly Patient

Dry eye disease is a common and increasingly prevalent condition particularly associated with advancing age and postmenopausal women. Epidemiological studies identify prevalence rates ranging from 7% in the US to 33% in the Asian population. Research increasingly identifies risk factors of increasing age, female sex, smoking, use of video display terminals and use of certain medications as well as environmental stresses as aggravating factors for the disease. Basic and clinical investigations provide cumulative evidence of hyperosmolarity of the tear film and ocular surface/lacrimal gland inflammation as pathogenic features of dry eye disease. A decline in systemic and local levels of sex hormones is associated with advancing age and advancing disease. Pharmacological therapeutic interventions include enhanced lubricants and anti-inflammatory drugs such as topical corticosteroids and ciclosporin (cyclosporine A). Secretagogues and hormonal supplementation are potential future therapies. The increased understanding of the contributing and pathogenetic factors responsible for dry eye provides a rationale for multiple therapeutic options for this multi-factorial disease. In the elderly patient it is important to recognize the physical and cognitive limitations that will influence the selection of appropriate topical medication.

The Features of Dry Eye Disease in a Japanese Elderly Population

The purpose of this study is to assess the features of dry eye disease in a Japanese elderly population. One hundred thirteen left eyes of 113 pensioners (50 males, 63 females; mean age, 67.5 +/- 5.7 years) aged over 60 years were recruited in this study. The subjects underwent careful slit-lamp examinations of the conjunctiva, ocular surface, and the eye lids. Tear film breakup time (BUT) examinations, Schirmer test-I, and fluorescein staining of the ocular surface and transillumination of the eyelids were also performed. Dry eye symptomatology was assessed with a symptom questionnaire. Japanese Dry Eye Diagnostic Criteria were used in this study. Ocular tiredness, irritation, dryness, and foreign body sensation were the most frequently reported symptoms by the patients. A total of 73.5% of the eyes had definite dry eyes. A total of 39.8% of the eyes had a Schirmer test reading <5 mm. Mean Schirmer test value was 9.4 +/- 7.8 mm. The mean BUT score was 4.0 +/- 2.8 seconds. A total of 76.9% of the eyes had positive fluorescein staining of the cornea. Meibomian gland dysfunction and conjunctivochalasis were found as frequent factors in relation to dry eye disease with meibomian grand dropout showing positive correlation with tear instability. Qualitative and quantitative disorders of the tear film were far more common than recognized in this population of elderly subjects, meibomian gland dysfunction being the most common associate of the tear film disorder and dry eye status. Conjunctivochalasis (conjunctival laxity), although commonly associated with dry eye disease in the elderly, was observed not to be related to age or gender in this study.