Ocular Surface Characteristics and Impression Cytology in Patients with Active versus Inactive Thyroid Eye Disease

 PURPOSE:To compare the clinical findings, tear film function and impression cytology between patients with active and inactive Thyroid Eye Disease (TED). METHODS:A total of 56 patients with TED and 30 controls were recruited in this prospective observational cohort study. TED patients were divided into active TED and inactive TED types according to a seven-point modified formulation of the Clinical Activity Score (CAS). All participants underwent full eye examinations including Ocular Surface Disease Index (OSDI) score, tear film break-up time (TBUT), fluorescein staining and Schirmer I test. Thirty nine patients with thyroid-associated orbitopathy (TAO) received Nelson's grade with conjunctival impression cytology. Proptosis, palpebral fissure width and lagophthalmos were assessed. RESULTS:Ocular surface parameters including proptosis, palpebral fissure width and lagophthalmos did not differ between active and inactive TED patients (P>0.05). Both active and inactive TED patients obtained higher fluorescein staining scores, lower TBUT scores and significantly lower Schirmer test scores than those of controls (P<0.001 for all). Additionally, the TBUT score was significantly lower and the OSDI score significantly higher in the active TED group compared with those in the inactive TED group (P<0.001 for both). Impression cytology revealed a higher proportion of grade 2-3 changes in the active TED group compared with the inactive TED group (P<0.001). CONCLUSION:Orbital inflammation in TED patients may lead to decreased tear film stability and ocular surface squamous metaplasia.     

Thyroid Eye Disease: A Historical Perspective

Within the short period from 1802 to 1840 four physicians from four different countries (Flajani in Italy, Parry in England, Graves in Ireland and Basedow in Germany) independently described a hitherto unknown disease, the hallmark of which were tachycardia and enlargement of the thyroid. Three of the physicians also noted exophthalmos. In sequence, the disease was attributed to primary cardiac disease, then to increased sympathetic nerve discharge, and finally to thyroid hyper-function. The latter concept failed to explain the exophthalmos, which cannot be reproduced by over-dosage of thyroid hormone. Explanations for the exophthalmos went from cardiac failure (causing swelling of the thyroid and retro-orbital tissues), to sympathetic nerve discharge, to over-secretion of TSH, to production within the pituitary of TSH fragments with exophthalmogenic properties, and finally to shared auto-antigens of thyroidal and retroorbital tissue. The latter theory is favoured today, after it had been recognized that thyroid hyperfunction in Graves’ disease was due to auto-antibodies to the thyroidal TSH receptor; such receptors were postulated also to be present in retroorbital tissue. Thus, each generation of scientists explained the pathogenesis of exophthalmos with the methods and concepts available to medical research at any given time. Although big advances have been made, future research may be good for some unexpected surprises.     

Immunopathogenesis of Thyroid Eye Disease: Emerging Paradigms

Graves disease represents a systemic autoimmune process targeting the thyroid, orbit, and pretibial skin. The thyroid dysfunction is treatable, but no consistently effective medical therapy has yet been described for the orbital manifestations of Graves disease, also known as thyroid-associated ophthalmopathy or thyroid eye disease. Several autoantigens are potentially relevant to the pathogenesis of thyroid eye disease. Activating antibodies generated against the thyrotropin receptor can be detected in a majority of patients, and these drive hyperthyroidism. However, stimulating antibodies against the insulin-like growth factor-1 receptor (IGF-1R) may also play a role in the extra-thyroid manifestations of Graves disease. IGF-1R is overexpressed by orbital fibroblasts derived from patients with thyroid eye disease, whereas IGF-1R⁺ T and IGF-1R⁺ B cells are considerably more frequent in Graves disease. Actions of several cytokines and the molecular interplay peculiar to the orbit appear to provoke the inflammation, fat expansion, and deposition of excessive extracellular matrix molecules in thyroid eye disease. Based upon these new insights, several therapeutic strategies can now be proposed that, for the first time, might specifically interrupt its pathogenesis.     

Rectus Muscle Resection for Vertical Strabismus in Thyroid Eye Disease

Purpose: Rectus muscle resection in thyroid eye disease (TED) is generally avoided due to the risk of worsening restriction or reactivating inflammation. However, for some patients with large-angle strabismus or diplopia in primary gaze despite maximum recession surgery, rectus muscle resection may be beneficial. We report our surgical experience with rectus muscle resection in the management of vertical strabismus associated with TED.

Methods: Retrospective review of eight patients with TED and vertical diplopia who underwent vertical rectus muscle resection by a single surgeon (IBM) at a tertiary referral centre in Liverpool, UK, from 2001 to 2013. The goal of surgery was elimination of diplopia in primary and reading position. Vertical deviations were measured in prism dioptres (^?) before and after surgery at one month, four months and final visit by prism alternate cover testing at ? m and 6 m.

Results: The mean ± standard deviation vertical deviation for near and distance reduced significantly from 14.2^? ± 8.4^? and 15.8^? ± 8.8^? pre-operatively to 5.7^? ± 4.9^? and 6.7^? ± 7^? at the four-month visit, respectively (p< 0.05). At the four-month follow-up, five (62.5%) patients achieved binocular single vision in primary and reading position with either no prisms or prisms less than 5^?. Further recession surgery, Harada-Ito procedure, or lateral rectus resection were necessary in four (50%) patients with persistent diplopia. No patient developed recurrence of inflammation or increased muscle restriction.

Conclusions: Vertical rectus resection could be considered as an additional surgical strategy in the management of TED patients with vertical strabismus without adverse sequelae.     

Low Dose Orbital Radiotherapy for Thyroid Eye Disease

Purpose: The use of low dose orbital radiotherapy for thyroid eye disease (TED) remains controversial. This is a review of patients with TED treated with radiotherapy in our department over the last twelve years.

Methods and Materials: Fifty-nine consecutive patients received low dose orbital radiotherapy of 20 Gray (Gy) for active TED at the Beatson Oncology Centre. Their records were retrospectively reviewed and data including duration of symptoms, clinical activity score (CAS) pre- and post-orbital radiotherapy, immunosuppression requirement, subjective assessment and range of rehabilitative surgery was collected.

Results: Before orbital radiotherapy, all fifty-nine patients had an initial response to glucocorticoids and therefore presumed to have active phase thyroid eye disease. They received retro-orbital radiotherapy of 20 Gy in 12 fractions over 2 weeks. After treatment, only five patients remained on steroids and only one patient had CAS ≥ 3 at last follow up. Response (change in CAS) to orbital radiotherapy was statistically significant from 3.17?±?1.75 standard deviation (SD) to 0.73?±?0.92 SD (P?<?0.001) at mean follow up of 6.5 months. There was a reduction in CAS at each subsequent follow up for all subgroups when the patients were grouped according to disease severity i.e. mild TED(CAS 1–2), moderate (CAS 3–4), severe CAS (5–7) and optic neuropathy.

Conclusions: We believe orbital radiotherapy has a definite role to play in the treatment of active thyroid eye disease. The majority of our patients experienced a reduction in their clinical activity scores after orbital radiotherapy and this was irrespective of the severity of thyroid eye disease.     

Long-term Surgical Outcomes for Vertical Deviations in Thyroid Eye Disease

Introduction: Vertical deviations in thyroid eye disease (TED) can present a surgical challenge due to the difficulty and unpredictability of surgery and the high risk of postoperative drift towards overcorrection. This study reports the postoperative outcomes of patients who underwent adjustable vertical strabismus surgery with Vicryl sutures for thyroid eye disease. Methods: We reviewed the records of patients seen for vertical TED strabismus surgery from January 2005 through December 2009. Clinical details were recorded preoperatively, post-adjustment, and at 3 weeks, 3 months, and 1 year postoperatively. Results: The study included 42 patients. Mean age was 62.4 years and 70% were female. All patients were diplopic preoperatively. The mean near vertical deviation was 21.1 prism diopters (PD) preoperatively, 4.0 PD at 3 weeks postoperatively, 5.0 PD at 3 months, and 4.4 PD at 1 year (all mean results representing undercorrection). 71.4% were free of diplopia postoperatively. Seven patients required further surgery, 2 patients needed further botulinum toxin A. Eight patients experienced an overcorrection; five at 3 weeks, seven at 3 months, and eight at 1 year. There was a significant difference in the mean near angle at tie-off post-adjustment in the patients that overcorrected compared to those that did not reverse (3.1 PD vs 7.1 PD; P=0.005). Discussion: Adjustable surgery for vertical strabismus in thyroid eye disease may result in late overcorrection and the need for further intervention. We propose that aiming for an immediate post-adjustment angle of 8 PD undercorrection for near would allow for postoperative drift and reduce the chances of a late overcorrection. This would require careful preoperative counseling of the patient in order to explain that immediate undercorrection and persistent diplopia were necessary in order to generate a better long-term result.     

Vitamin D and Selenium in a Thyroid Eye Disease Population in Texas

There is growing evidence of thyroid eye disease association with nutritional deficiencies including selenium and vitamin D. We conducted a retrospective chart review of all patients with clinical diagnosis of TED seen at our clinic from 2016 to 2017. Thirty-five patients met inclusion criteria and had serum 25-hydroxyvitamin D levels available, and 19 had selenium levels available. 7/35 (20%) patients had vitamin D deficiency, and 11 (31%) had vitamin D insufficiency, but none had selenium deficiency. Although both selenium and vitamin D supplementation have been recommended for TED, further investigation is necessary to justify supplementation for patients with TED.     

MicroRNA-130a Is Elevated in Thyroid Eye Disease and Increases Lipid Accumulation in Fibroblasts Through the Suppression of AMPK

PurposeThyroid eye disease (TED) is a condition that causes the tissue behind the eye to become inflamed and can result in excessive fatty tissue accumulation in the orbit. Two subpopulations of fibroblasts reside in the orbit: those that highly express Thy1 (Thy1+) and those with little or no Thy1 (Thy1–). Thy1– orbital fibroblasts (OFs) are more prone to lipid accumulation than Thy1+ OFs. The purpose of this study was to investigate the mechanisms whereby Thy1– OFs more readily accumulate lipid.MethodsWe screened Thy1+ and Thy1– OFs for differences in microRNA (miRNA) expression. The effects of increasing miR-130a levels in OFs was investigated by measuring lipid accumulation and visualizing lipid deposits. To determine if adenosine monophosphate-activated protein kinase (AMPK) is important for lipid accumulation, we performed small interfering RNA (siRNA)-mediated knockdown of AMPKβ1. We measured AMPK expression and activity using immunoblotting for AMPK and AMPK target proteins.ResultsWe determined that miR-130a was upregulated in Thy1– OFs and that miR-130a targets two subunits of AMPK. Increasing miR-130a levels enhanced lipid accumulation and reduced expression of AMPKα and AMPKβ in OFs. Depletion of AMPK also increased lipid accumulation. Activation of AMPK using AICAR attenuated lipid accumulation and increased phosphorylation of acetyl-CoA carboxylase (ACC) in OFs.ConclusionsThese data suggest that when Thy1– OFs accumulate in TED, miR-130a levels increase, leading to a decrease in AMPK activity. Decreased AMPK activity promotes lipid accumulation in TED OFs, leading to excessive fatty tissue accumulation in the orbit.     

Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting

Dry eye disease (DED), a multifactorial disease of the tears and ocular surface, is common and has a significant impact on quality of life. Reduced aqueous tear flow and/or increased evaporation of the aqueous tear phase leads to tear hyperosmolarity, a key step in the vicious circle of DED pathology. Tear hyperosmolarity gives rise to morphological changes such as apoptosis of cells of the conjunctiva and cornea, and triggers inflammatory cascades that contribute to further cell death, including loss of mucin-producing goblet cells. This exacerbates tear film instability and drives the cycle of events that perpetuate the condition. Traditional approaches to counteracting tear hyperosmolarity in DED include use of hypotonic tear substitutes, which have relatively short persistence in the eye. More recent attempts to counteract tear hyperosmolarity in DED have included osmoprotectants, small organic molecules that are used in many cell types throughout the natural world to restore cell volume and stabilize protein function, allowing adaptation to hyperosmolarity. There is now an expanding pool of clinical data on the efficacy of DED therapies that include osmoprotectants such as erythritol, taurine, trehalose and L-carnitine. Osmoprotectants in DED may directly protect cells against hyperosmolarity and thereby promote exit from the vicious circle of DED physiopathology.     

Prevalence of Dry Eye Disease in Mongolians at High Altitude in China: The Henan Eye Study

Purpose: To estimate the prevalence of dry eye disease, analyze the associations between dry eye symptoms and signs, and identify the risk factors in an elderly Mongolian population at high altitude in China.

Methods: A population-based survey was conducted in 2006. A total of 2,486 Mongolians age 40 and older were selected. Symptoms of dry eye were assessed using a 6-item validated questionnaire. Dry eye disease was defined if participants reported one or more symptoms often or all the time. Positive signs included a tear-film breakup time of ≤10 seconds, a Schirmer test score of ≤ 5mm, or a fluorescein staining score ≥ 1 in one or both eyes. Presence of dry eye symptoms and positive signs were analyzed. Correlations between symptoms and signs, and risk factors were evaluated in a multivariate model.

Results: Of the 1,816 participants, 50.1% (95% confidence interval, 47.8–52.4) were symptomatic. Tear-film breakup time of ≤ 10 seconds was 37.7% (95% confidence interval, 35.5–39.9). A Schirmer test score of ≤ 5mm was 19.9% (95% confidence interval, 18.4–22.1). Fluorescein staining score ≥ 1 was 6.0% (95% confidence interval, 4.9–7.1). The correlation between dry eye symptoms and positive signs (tear-film breakup time of ≤ 10 seconds[r = 0.414, P < 0.001], Schirmer test score of ≤ 5mm [r = 0.164, P = 0.001], and fluorescein staining score ≥1 [r = 0.361, P < 0.001]) were statistically significant. Independent risk factors included increased age, age-related cataract and pterygium.

Conclusion: This study demonstrates a high prevalence rate of dry eye disease in a Mongolian population. Dry eye signs were significantly associated with dry eye symptoms.     

The Association between Diabetes and Herpes Simplex Eye Disease

Purpose: To evaluate the association between diabetes mellitus (DM) and presence and severity of Herpes simplex eye disease (HSED).

Methods: We conducted two sub-studies. We included the patients seen on the Cornea Service of the Wills Eye Hospital from January 2008 to August 2012. Study 1 included 541 patients with HSED and 3226 controls. Study 2 involved 40 diabetic and 120 non-diabetic ocular surface HSED patients. Severity of ocular surface HSED was graded as mild, moderate, or severe, based on best-corrected visual acuity (BCVA). Patients were excluded if they had fewer than two office visits or had non-Herpes simplex-related vision-threatening conditions. Diabetes was graded as: diet group (DM controlled with diet), oral group (DM controlled with oral medications), and insulin group (DM control required insulin).

Results: Five of 541 (0.93%) HSED patients had type 1 DM, similar to 19/3246 (0.59%) controls (p = 0.375); 48 of 541 (8.88%) HSED patients had type 2 DM, similar to 287/3246 (8.84%) controls (p = 0.981). Using multinomial logistic regression analyses, the probability/risk of being in the severe ocular surface HSED group as opposed to the mild ocular surface HSED group were not statistically significantly different between DM patients and those without DM (p = 0.120; OR, 1.900; 95% CI, 0.846–4.266).

Conclusions: There may not be a positive association between type 2 DM and HSED.     

Unmet Needs and Future Directions in Inflammatory Eye Disease

Purpose: To explore the unmet needs in the management of patients with severe inflammatory eye disease (IED), future directions for research and therapy, and to develop and facilitate access and delivery of better medical care to patients with severe IED.

Methods: The unmet needs and future directions in inflammatory eye disease were identified and discussed by experts in relevant disciplines at a recent international conference.

Results: A total of 14 major unmet needs were identified and discussed by experts in the areas of ophthalmology, rheumatology, infectious disease, and internal medicine, at an international conference. The major areas discussed are summarized in this review.

Conclusions: Identification of unmet needs in IED is seen as a first step in implementing changes in the way we diagnose and treat patients with these sight-threatening IEDs.     

组蛋白去乙酰化酶抑制剂在眼科疾病中应用的研究进展

组蛋白乙酰化是真核生物中重要的翻译后修饰之一,参与染色质结构的重塑。这个过程由组蛋白乙酰化酶（HATs）和组蛋白去乙酰化酶（HDACs）催化完成。HDACs抑制剂是一类以组蛋白去乙酰化酶为靶点的药物,对细胞的增殖、分化、凋亡、迁移等方面有重要的影响,目前已被应用于临床肿瘤治疗中。HDACs广泛存在于眼球各组织中,在眼科疾病的发生发展中发挥着重要的作用。现就HDACs抑制剂在眼科疾病的研究进展作一综述,旨在为眼科疾病临床治疗提供新的策略和思路。     

The Dopaminergic Neuronal System Regulates the Inflammatory Status of Mouse Lacrimal Glands in Dry Eye Disease

PurposeComparison of the parasympathetic and sympathetic neurons, including the dopaminergic neural system, in dry eye (DE)–induced pathophysiology has not been elucidated well. This study investigated the presence of dopamine receptors (DRs) and their functional roles in the lacrimal glands (LGs) of DE-induced mice.MethodsAfter DE was induced in B6 mice for 2 weeks, the expression of tyrosine hydroxylase (TH), dopamine, and DRs (DR1, DR2, etc.) in the LGs and corneas were measured by quantitative RT-PCR, immunoblot, and ELISA. Using flow cytometry and ELISA, immune cell infiltration and inflammatory cytokine expression were determined in DE-induced LGs with or without DR blockers, SCH-23390 (DR1i), or melperone (DR2i). Corneal erosion scores were also investigated.ResultsThe mRNA and protein levels of TH significantly increased in DE-induced LGs. The dopamine concentration of LGs was 9.51 pmol in DE (versus naive: 1.39 pmol; P < 0.001). Both DR1 and DR2 mRNA expression were significantly enhanced in desiccating stress compared with those in naive (3.7- and 2.1-fold, P < 0.001). Interestingly, DR1 and DR2 immunostaining patterns stained independently in DE-induced LGs. CD3⁺ and CD19⁺ cell infiltration was significantly increased by DR2i (P < 0.001) but not by DR1i. Furthermore, IFN-γ, IL-17, and TNF-α were significantly upregulated by DR2i compared with the blow-only condition. The severity of corneal erosion and inflammation was also aggravated by DR2i.ConclusionsUpregulation of DR1 and DR2 was observed in DE-induced mouse LGs. As the inflammatory conditions are aggravated by the inhibition of DRs, especially DR2, their activity may be an important factor preserving ocular surface homeostasis.     

Immunologic Aspects of Thyroid Disease

Graves' disease and Hashimoto's thyroiditis are autoimmune processes considered distinct diseases in light of current knowledge. In Graves' disease, antibodies directed against the thyrotropin receptor of the thyroid cell stimulate the gland to hyperfunction. The ophthalmopathy of Graves' disease may result from a different autoimmune reaction, directed against orbital tissue. In Hashimoto's thyroiditis, humoral and cellular immune processes are directed against elements of the thyroid cell and result in destruction and glandular hypofunction.     

Keratitis in Dry Eye Disease and Topical Ciclosporin A

Tear film alterations in dry eye disease (DED) include reduced tear volume and an increase in inflammatory cytokines. Instability and reduced tear production initiate a vicious cycle where hyperosmolarity, ocular inflammation, and apoptosis may induce damage of the ocular surface including keratitis. Topical cyclosporine (CsA) has been used for the treatment of moderate-to-severe DED; however, previous studies failed to demonstrate its benefits by the European Agency standards. A new formulation of CsA 0.1% has been recently approved in the EU to treat severe keratitis in DED patients. Patients with severe keratitis showed a better improvement after 6 months of treatment with CsA compared with vehicle. HLA-DR expression was significantly reduced by CsA treatment. The clinically significant improvement in keratitis associated with the inflammatory biomarker HLA-DR confirms the efficacy of CsA to improve inflammation and its damaging effect on the ocular surface in DED patients.     

The Role of Genetics in Graves' Disease and Thyroid Orbitopathy

Graves' disease is a complex autoimmune disorder characterized by multiple systemic manifestations of overproduction of thyroid hormone, and in some cases, orbitopathy. The etiology of this disorder is multifactorial, involving heritable abnormalities of immune regulation as well as environmental triggers. The goal of this paper is to provide a review of recent research investigating candidate genes involved in the pathophysiology of both Graves' disease per se and of thyroid orbitopathy.