Ocular manifestations of liver disease: an important diagnostic aid.

PURPOSE: This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and immune liver conditions. METHODS: Recent data were compiled from PubMed from 2000 to 2020 using keywords that were relevant to the assessed pathologies. Ocular presentations of several liver pathologies were researched and then summarized in a comprehensive form. RESULTS: Several ocular manifestations of liver disease were related to vitamin A deficiency, as liver disease is associated with impaired vitamin A homeostasis. Alcoholic liver cirrhosis can result in vitamin A deficiency, presenting with Bitot spots, xerosis, and corneal necrosis. Congenital liver diseases such as mucopolysaccharidoses and peroxisomal disorders are also linked with ocular signs. Viral causes of liver disease have associations with conditions like retinal vasculitis, keratoconjunctivitis sicca, retinopathies, Mooren's ulcer, and Sjogren's syndrome. Autoimmune hepatitis has been linked to peripheral ulcerative keratitis and uveitis. CONCLUSIONS: Building strong associations between ocular and liver pathology will allow for early detection of such conditions, leading to the early implementation of management strategies. While this review outlines several of the existing connections between hepatic and ophthalmic disease, further research is needed in the area in order to strengthen these associations.

Ocular manifestations of rheumatoid arthritis.

PURPOSE OF REVIEW: This article summarizes the pathophysiology of rheumatoid arthritis and common ocular manifestations that it is associated with: keratoconjunctivitis sicca, episcleritis, scleritis, and peripheral ulcerative keratitis. RECENT FINDINGS: Newer biologic agents are being used to effectively treat rheumatoid arthritis and its ocular manifestations. SUMMARY: The eye is a frequent extra-articular site of inflammation in patients with rheumatoid arthritis. Ocular involvement can range from more benign conditions such as keratoconjunctivitis sicca and episcleritis, to potentially vision and globe-threatening diseases like scleritis and peripheral ulcerative keratitis. Clinicians should be aware of these ophthalmic manifestations and the various treatment options that are available. Coordination between ophthalmology and rheumatology is helpful in the treatment of these patients.

Clinical Profile in Genetically Proven Blau Syndrome: A Case Series from South India.

Purpose: To report the clinical profile of genetically proven Blau syndrome in seven cases from a single center in South India.Materials & Methods: Retrospective case seriesResults: There were four females and three males. All cases had a history of skin and joint involvement of varying severity. Flexion contractures of the proximal interphalangeal joints were seen in all cases except Case 2. Ocular involvement was bilateral and included keratoconjunctivitis sicca (six cases), granulomatous panuveitis (three cases), granulomatous anterior uveitis (three cases), conjunctival granulomas (three cases), subepithelial corneal opacities (one case), and subretinal granuloma (one case). Other ocular findings included band-shaped keratopathy (five cases) and cataract (three cases). All cases received oral steroids and methotrexate with an addition of mycophenolate mofetil in one case. Visual prognosis was good in all cases.Conclusions: Blau syndrome is underreported in India. This is the largest case series of genetically proven Blau syndrome from South India and highlights the clinical profile of Blau syndrome seen in India.

Clinical-dosimetric relationship between lacrimal gland dose and keratoconjunctivitis sicca in dogs with sinonasal tumors treated with radiation therapy.

BACKGROUND: Dogs with sinonasal tumor can develop keratoconjunctivitis sicca (KCS) after radiation therapy (RT). In humans, the incidence of xerophtalmia is associated with the mean radiation dose received by the ipsilateral lacrimal gland (LG). HYPOTHESIS/OBJECTIVES: The eyes receiving a higher mean LG dose are more likely to develop KCS. The aim of the study was to determine a starting threshold dose to use as dose constraint for intensity-modulated radiation therapy (IMRT). ANIMALS: Dogs with nasal tumors treated with RT between August 2013 and December 2016. METHODS: Case control retrospective study of dogs with sinonasal tumor treated with 42 Gray (Gy) in 10 fractions using IMRT. Dogs were included if development of KCS after RT was documented (cases) or adequate follow-up information with Schirmer tear test (STT) result for ≥6 months after RT was available (controls). Lacrimal glands were contoured and dose distribution was calculated using the original treatment plan to determine prescribed doses to LGs. RESULTS: Twenty-five dogs were treated with RT and 5 dogs (20%) developed KCS. Fifteen dogs met the inclusion criteria including 5 unilateral KCS and 10 control dogs, resulting in 5 KCS eyes and 25 control eyes. KCS developed at a median of 111 days (84-122) after 1st RT. The mean LG dose reached using a 4.2 Gy per fraction was 33.08 Gy (range: 23.75-42.33) for KCS eyes and 10.33 Gy (1.8-24.77) for control eyes (P < .001). The minimum LG mean dose for developing KCS was 23.75 Gy. No eyes that received a mean LG dose <20 Gy developed KCS versus 5/7 (71%) developed with >20 Gy. CONCLUSION AND CLINICAL IMPORTANCE: Contouring and applying a dose constraint on LGs should be performed when using IMRT in dogs with sinonasal tumors to reduce the risk of KCS.

Phenotypic features and predictors of the clinical severity of keratoconjunctivitis sicca and salivary gland dysfunction in patients with Sjögren's syndrome: a longitudinal analysis of the Korean Initiative of primary Sjögren's Syndrome (KISS) cohort.

OBJECTIVE: The aim was to investigate prevalence and degree of ocular and oral involvement in patients with primary Sjögren's syndrome (PSS). METHOD: We analysed 134 participants from the Korean Initiative of PSS cohort who completed a 2 year follow-up oral and ocular sign test. The severity of keratoconjunctivitis sicca (KCS) was determined with the Schirmer I test value (STV) [abnormal (AB) ≤ 5 mm/5 min; normal (N) > 5 mm/5 min]. Salivary gland dysfunction (SGD) was determined by unstimulated whole salivary (UWS) flow rate [moderate to severe (MS) < 0.1 mL/min; mild (Mi) ≥ 0.1 mL/min]. Subgroups were divided into three groups according to STV and severity of SGD: AB-STV/MS-SGD, AB-STV/Mi-SGD, and N-STV/MS-SGD groups. We analysed the changes in STV and SGD during the follow-up period. RESULTS: Among the 134 participants enrolled in this study, 105 (78%) were placed in the AB-STV/MS-SGD group, 16 (12%) in the AB-STV/Mi-SGD, and 13 (10%) in the N-STV/MS-SGD at the 2 year follow-up. The AB-STV/Mi-SGD group was younger than the other two groups, and had a lower Xerostomia Inventory score and lower level of ß2-microglobulin. Participants in the N-STV/MS-SGD group had less hyperimmunoglobulinaemia, rheumatoid factor (RF), and antinuclear antibodies (ANAs). Patients and those with positive RF or ANA ≥ 1:320 at baseline were more likely to have abnormal STV at the 2 year follow-up. CONCLUSIONS: Patients with PSS and positive RF or ANA ≥ 1:320 at baseline may benefit from regular ophthalmology examinations, even if they do not have KCS at baseline or dry eye symptoms.

Severity of Sjögren's Syndrome Keratoconjunctivitis Sicca Increases with Increased Percentage of Conjunctival Antigen-Presenting Cells.

This study investigated the relationship between clinical severity and percentage of conjunctival antigen-presenting cells (APCs) in Sjögren's syndrome (SS)-associated keratoconjunctivitis sicca (KCS). KCS clinical severity was based on symptom severity, tear volume, tear break-up time, and ocular surface dye staining. Conjunctival goblet cell density (GCD) was measured in periodic acid Schiff (PAS)-stained membranes. Conjunctival cells obtained by impression cytology were used for flow cytometry to measure percentages of CD45⁺HLA-DR⁺ APCs and mature CD11c⁺CD86⁺ dendritic cells (DCs). Compared to normal conjunctiva, the percentages of HLA-DR⁺ and CD11c⁺CD86⁺ cells were higher in the conjunctiva of the KCS group (p < 0.05). The percentage of CD45⁺HLA-DR⁺ cells positively correlated with clinical severity (r = 0.71, p < 0.05) and negatively correlated with GCD (r = -0.61, p < 0.05). Clinical severity also negatively correlated with GCD (r = -0.54, p < 0.05). These findings indicate that a higher percentage of APCs and mature DCs in the conjunctiva is associated with more severe KCS in SS. These APCs may contribute to the generation of the pathogenic Th1 cells that cause goblet cell loss in KCS.

Rheumatoid factor isotype and Ro epitope distribution in primary Sjögren syndrome and rheumatoid arthritis with keratoconjunctivitis sicca.

Primary Sjögren syndrome (pS) is associated with autoantibodies such as rheumatoid factor (RF) and anti-nuclear antibodies such as anti-Ro (SS-A) and/or La (SS-B). Recent developments within autoimmune diagnostics allow quantitation of RF subclasses and anti-Ro epitopes. Will this refinement by autoimmune diagnostics help predicting development of extraglandular manifestations (EGM) in pS patients? A cohort of pS and rheumatoid arthritis (RA) patients with keratoconjunctivitis sicca (n = 35 and 16, resp) was included. Of the pS patients, 54% developed one or more EGM. Antibodies quantitated were IgM-RF, IgA-RF, IgG-RF, anti-Ro52, and anti-Ro60. Upon analysis of RF isotypes, pS patients generally displayed higher IgA-RF concentrations than RA patients (126 versus 49 U/ml, p = 0.015), while the dominant RF isotype in RA patients was IgM-RF (82.5 versus 38 U/ml, p = 0.012). No differences were observed regarding IgG-RF concentrations. In pS without/with EGM, the median RF IgM concentrations were similar, while RF IgA and IgG concentrations tended to be lower in pS patients with EGM > 1. Both Ro epitopes were strongly recognized by almost all pS patients, independent from EGM, while these antibodies were absent in RA patients. Primary Sjögren syndrome and RA patients have distinct serological profiles when analysing RF and Ro-specific antibodies. A longitudinal study of switched RF isotypes in pS patients is worthwhile from an immunological point of view, but its value is limited regarding identification of pS patients prone to developing EGM or RA patients prone to developing secondary sicca symptoms.

A Review of Ocular Graft-Versus-Host Disease.

: Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic hematopoietic stem cell transplantation, which is a potential curative therapy used in a variety of malignant or benign hematological diseases. Graft-versus-host disease primarily occurs in many organs, but most notably in the skin, lungs, gastrointestinal tract, liver, eyes, mucosa, and musculoskeletal system. Ocular manifestations of GVHD may precede other systemic GVHD findings, and it may be a poor prognosis for mortality. While all parts of the eye may be affected, ocular GVHD occurs primarily in the ocular surface. Dry eye disease or keratoconjunctivitis sicca is the most common presenting manifestation of chronic ocular GVHD. Dry eye disease in ocular GVHD is a multifactorial process, which involves destruction and fibrosis of lacrimal glands and conjunctiva, leading to tear film deficiency and instability. Depending on the severity of ocular involvement and response to treatment, ocular GVHD may cause decreased quality of life. Management of GVHD begins with prevention by understanding risk factors and by implementing prophylactic treatment after allogeneic hematopoietic stem cell transplantation. A multidisciplinary approach to the prevention and treatment of GVHD is important, and there are currently no preventive therapies available for ocular GVHD. Once diagnosed, ocular GVHD treatment strategies target ocular surface lubrication and support, tear film stabilization, inflammation reduction, and surgical intervention. The goal of this review is to define ocular GVHD and its categorical manifestations, as well as to describe the importance of comprehensive assessment, diagnosis, and ophthalmologic treatment and management of ocular GVHD with a multidisciplinary approach.

Scleral lenses for severe chronic GvHD-related keratoconjunctivitis sicca: a retrospective study by the SFGM-TC.

Chronic GvHD-related keratoconjunctivitis sicca (cGvHD-related KCS) can significantly alter the quality of life of patients after allogeneic hematopoietic stem cell transplantation. The aim of this work was to assess the efficacy and tolerability of scleral lenses to treat severe cGvHD-related KCS. In this retrospective, multicenter study, we included 60 consecutive patients diagnosed with cGvHD-related KCS and fitted with scleral lenses. Patients were evaluated at baseline and at 2 months with the following tests: the Ocular Surface Disease Index (OSDI) to assess quality of life, the Oxford score to grade corneal damage and the logarithm of minimal angle of resolution (Log MAR) scale to determine visual acuity. We observed improvement in quality of life in 58 patients (97%). All parameters improved at 2 months. We observed significant differences at 2 months compared with baseline for the mean OSDI (86 versus 30, respectively, P<0.001), the mean Oxford score (3.2 versus 1.3, respectively, P<0.001) as well as visual acuity (Log MAR of 0.33 versus 0.10, respectively, P<0.001). Treatment with scleral lenses was discontinued in only 5 patients (8%) with a median follow-up of 20.5 months (range: 2-125 months). Scleral lenses were very efficient and well tolerated in patients with severe cGvHD-related KCS.

Sensitivity of Diagnostic Tests for Dry Eye in Patients with Blepharospasm.

The aim of the study was to evaluate diagnostic tests for keratoconjunctivitis sicca (Schirmer test, tear break-up time (TBUT) test, and corneal staining with fluorescein and lissamine green dye) in patients with blepharospasm. This prospective study included 60 female patients older than 40 with blepharospasm, divided into two groups according to clinical symptoms. For fluorescein test, the surface under the ROC curve was 1.0 with standard error (SE) 0 and 95% confidence interval (95% CI) 0.940-1.0; for Schirmer test, the surface under the ROC curve was 0.817 with SE 0.0555 and 95% CI 0.696-0.905; for lissamine green test, the surface under the ROC curve was 0.813 with SE 0.056 and 95% CI 0.691-0.902; and for TBUT test, the surface under the ROC curve was 0.772 with SE 0.061 and 95% CI 0.645-0.870. According to the results of ROC curve, which determines the sensitivity and specificity of normal values, comparison of diagnostic tests for keratoconjunctivitis sicca used in this study showed that fluorescein test had the best sensitivity and specificity. Schirmer test should be avoided in patients with blepharospasm because its results are influenced by frequent blinking and are not appropriate for study interpretation. Despite the pathologic values of TBUT test (numerically), this test is still acceptable for patients with blepharospasm because its interval takes more time than the interval between two blinks.

Reduced Levels of Tear Lacritin Are Associated With Corneal Neuropathy in Patients With the Ocular Component of Sjögren's Syndrome.

PURPOSE: To determine whether levels of endogenous tear protein, lacritin, are linked to altered corneal innervation and dry eye severity in patients with Sjögren's syndrome (SS). METHODS: Clinical data were obtained from 10 SS and 10 age-matched controls. Enzyme-linked immunosorbent assay was used to assess total tear lacritin extracted from Schirmer strips. Western blot was used to detect active lacritin monomer (∼25 kDa), active lacritin fragment (∼12-15 kDa), and inactive tissue transglutaminase-generated lacritin (≥40 kDa). In vivo confocal microscopy was used to assess nerve fiber density (NFD) and length (NFL). Relationships between nerve morphology and tear lacritin were examined by Spearman correlation. Diagnostic performance of tear lacritin was analyzed using receiver operating characteristic. RESULTS: Active tear lacritin was significantly reduced in SS patients (3.72 ± 5.62 [SS] versus 18.17 ± 4.57 ng/100 ng total tear protein [controls]; P < 0.001), while inactive lacritin was increased (84.99% ± 11.15% [SS] versus 51.04% ± 12.03% [controls]; P < 0.001). Nerve fiber density (21.70 ± 18.93 vs. 31.80 ± 9.35; P = 0.03) and NFL (4.18 ± 3.44 vs. 6.54 ± 2.47; P < 0.05) were significantly decreased in SS patients compared to controls. Reduced NFL (r = 0.74, P < 0.01) and NFD (r = 0.70, P < 0.01) were highly correlated with reduced tear lacritin. Similarly, total tear lacritin was highly correlated with Schirmers (r = 0.77, P < 0.01), ocular staining (r = -0.80, P < 0.01), and corneal sensitivity (r = 0.81, P < 0.01). Tear lacritin showed equivalent or better diagnostic performance compared to traditional clinical measures for SS (100.00% sensitivity, 85.71% specificity, cutoff = 14.50 ng/100 ng tear protein). CONCLUSIONS: Reduced tear lacritin levels in SS patients are highly correlated with clinical signs of dry eye, as well as decreased NFD and NFL. Lacritin and its components provide excellent diagnostic sensitivity and specificity in SS.

[Hyperosmolarity: Intracellular effects and implication in dry eye disease]. / Hyperosmolarité : effets intracellulaires et implication dans la sécheresse oculaire.

Dry eye disease is a multifactorial disease affecting the lacrimal functional unit and which has a significant impact on the quality of life of patients. This pathology works as a vicious circle at the ocular surface in which hyperosmolarity of the tear film plays a key role. This review intends to describe the different reported intracellular effects induced by hyperosmolarity in cells: alteration of cytoskeleton, cell cycle slowdown, adaptation mechanisms triggered as restoration of cell volume and accumulation of compatible osmolytes, the crucial role of the osmoprotectant factor Nuclear Factor of the Activated T cells-5 (NFAT5), apoptosis, as well as oxidative stress and inflammatory responses caused by this particular condition. Reported effects of hyperosmolarity in the experimental studies specific of dry eye disease concerning ocular surface cells will be described in parallel. Indeed, these data allow to understand a part of the pathophysiology of the disease, and specially the links between tear hyperosmolarity and inflammation of the ocular surface, the second key of the pathology phenomenon.

The management of dry eye.

Dry eye disease (also called keratoconjunctivitis sicca) is a common condition, with a prevalence ranging from 8-34%, depending on the criteria used.(1) It becomes more common with increasing age and affects more women than men. Artificial tears and ocular lubricants are considered the mainstay of treatment and there is a very wide range of these products available. In England in 2014, over 6.4 million prescription items for artificial tears, ocular lubricants and astringents were dispensed in the community at a cost to the NHS of over £27 million.(2) In this article we review the management of dry eye disease, focusing on artificial tears and ocular lubricants.

Systemic lupus erythematosus: An update for ophthalmologists.

Systemic lupus erythematosus (SLE) is a life-threatening multisystem inflammatory condition that may affect almost any part of the eye. We provide an update for the practicing ophthalmologist comprising a systematic review of the recent literature presented in the context of current knowledge of the pathogenesis, diagnosis, and treatment of this condition. We review recent advances in the understanding of the influence of genetic and environmental factors on the development of SLE. Recent changes in the diagnostic criteria for SLE are considered. We assess the potential for novel molecular biomarkers to find a clinical application in disease diagnosis and stratification and in the development of therapeutic agents. We discuss limited forms of SLE and their differentiation from other collagen vascular disorders and review recent evidence underlying the use of established and novel therapeutics in this condition, including specific implications regarding monitoring for ocular toxicity associated with antimalarials.

[Gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to chronic graft-versus-host disease]. / Traitement des sécheresses oculaires sévères secondaires à la maladie du greffon contre l'hôte chronique par lentilles sclérales perméables à l'oxygène.

INTRODUCTION: Graft-versus-host disease is a major complication of allogeneic hematopoietic stem cell transplantation. Severe keratoconjunctivitis sicca is common in patients with chronic GVH disease. The goal of this study was to evaluate the safety and efficacy of a gas-permeable scleral lens in the management of severe dry eye disease associated with chronic GVH. PATIENTS AND METHODS: This is a retrospective study from June 2009 to November 2013. Patients fitted with scleral lenses for severe keratoconjunctivitis sicca associated with chronic GVH were included. The main outcomes measured were best-corrected visual acuity and quality of life (OSDI and NEI-VFQ25) composite scores before and six months after scleral lens fitting. RESULTS: Sixteen patients were included. The mean age was 52 years (19-69 years). Mean follow-up was 20 months (3-48 months). All patients reported improvement of their ocular symptoms. Best corrected visual acuity improved from 0.21 ± 0.26 to 0.1 ± 0.14 logMAR (P = 0.002), OSDI score improved from 92.1 ± 11.3 to 23.5 ± 11.2 (P = 0.002) and NEI-VFQ25 improved from 41.3 ± 7 to 83.1 ± 15.9 (P = 0.003), 6 months after scleral lens fitting. No serious adverse events, infectious, hypoxemic or allergic complications attributable to the scleral lens occurred. CONCLUSION: Gas-permeable scleral lens use appears to be safe and effective in patients with severe dry eye related to chronic GVH.

Incidence and risk factors for ocular GVHD after allogeneic hematopoietic stem cell transplantation.

We analyzed the incidence and risk factors for ocular GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Korea. In this retrospective, noncomparative, observational study, 635 subjects were included who had at least 2 years of follow-up ophthalmological examinations after allo-HSCT from 2009 to 2012 at Seoul St Mary's Hospital, Seoul, Korea. The mean duration between allo-HSCT and onset of ocular GVHD was 225.5±194.3 days. The adjusted incidence for acute ocular GVHD was 1.33% and that for chronic GVHD was 33.33%. In the multivariate analysis, preexisting diabetes mellitus (odds ratio (OR): 4.22, 95% confidence interval (CI): 1.66-10.72), repeated allo-HSCT (OR: 29.10, 95% CI: 1.02-8.28) and the number of organs that chronically developed GVHD by stage I (OR: 14.63, 95% CI: 9.81-21.84) increased risk of ocular GVHD. Careful monitoring of ocular GVHD is needed in patients with chronic GVHD in multiple organs and preexisting diabetes.

Automated Grading System for Evaluation of Superficial Punctate Keratitis Associated With Dry Eye.

PURPOSE: To develop an automated method of grading fluorescein staining that accurately reproduces the clinical grading system currently in use. METHODS: From the slit lamp photograph of the fluorescein-stained cornea, the region of interest was selected and punctate dot number calculated using software developed with the OpenCV computer vision library. Images (n = 229) were then divided into six incremental severity categories based on computed scores. The final selection of 54 photographs represented the full range of scores: nine images from each of six categories. These were then evaluated by three investigators using a clinical 0 to 4 corneal staining scale. Pearson correlations were calculated to compare investigator scores, and mean investigator and automated scores. Lin's Concordance Correlation Coefficients (CCC) and Bland-Altman plots were used to assess agreement between methods and between investigators. RESULTS: Pearson's correlation between investigators was 0.914; mean CCC between investigators was 0.882. Bland-Altman analysis indicated that scores assessed by investigator 3 were significantly higher than those of investigators 1 and 2 (paired t-test). The predicted grade was calculated to be: Gpred = 1.48log(Ndots) - 0.206. The two-point Pearson's correlation coefficient between the methods was 0.927 (P < 0.0001). The CCC between predicted automated score Gpred and mean investigator score was 0.929, 95% confidence interval (0.884-0.957). Bland-Altman analysis did not indicate bias. The difference in SD between clinical and automated methods was 0.398. CONCLUSIONS: An objective, automated analysis of corneal staining provides a quality assurance tool to be used to substantiate clinical grading of key corneal staining endpoints in multicentered clinical trials of dry eye.