The role of cell mediated immunopathogenesis in thyroid-associated ophthalmopathy

Currently, thyroid-associated ophthalmopathy (TAO) lacks effective treatment due to our lack of clarity in its immunopathogenesis. Orbital fibroblasts play a key role in altering inflammation and immune response in TAO, and are considered as the key target and effector cells in its pathogenesis. The orbit infiltrating CD34+ fibrocytes add on to the process by expressing high levels of autoantigens and inflammatory cytokines, while also differentiating into myofibroblasts or adipocytes. This review focuses on the role of orbital fibroblasts and CD34+ fibrocytes in the pathogenesis of TAO, highlighting the basis of emerging treatments.

The effect of intravenous high-dose glucocorticoids and orbital decompression surgery on sight-threatening thyroid-associated ophthalmopathy

AIM: To report the effects of intravenous high-dose glucocorticoids(iv GC) and orbital decompression(OD) surgery for treatment of sight-threatening thyroid-associated ophthalmopathy(TAO).METHODS: A retrospective review of medical records from patients with sight-threatening TAO [definite or highly suspected dysthyroid optic neuropathy(DON)] treated with iv GC(60 cases) and OD(25 cases) was conducted at the Zhongshan Ophthalmic Center between January 2001 and January 2009. Patients were initially treated with iv GC(iv GC group). If no significant improvement in visual function was obtained, they then received OD surgery(OD group). The pre-versus post-treatment efficacies of either iv GC or OD in these patients were assessed using several indices, including visual acuity, intraocular pressure, ocular alignment, ocular motility, and exophthalmos. RESULTS: Nighty-one eyes had definite DON while 79 were considered to have highly suspected DON. In the iv GC group, 51 individuals(85.0%) eventually demonstrated normal vision, while 10 patients(16.7%) demonstrated a reduction in deviation(P<0.01), and 35 cases(58.3%) showed slight improvements in ocular motility(P<0.01). In OD group, visual acuity improved in 24 cases(96.0%, P<0.01) and all patients showed varying reductions of exophthalmos(mean: 4.35±1.13 mm, P<0.01). Eight cases(32.0%) experienced an 8-15 PD reduction of deviation and ocular motility improved in 12 cases(48.0%), while 3 patients(12.0%) developed new-onset strabismus with diplopia post-surgically(P<0.01). Patients were followed up at an average of 1.55±1.07 y. CONCLUSION: Both iv GC and OD show good therapeutic efficacy in the treatment of sight-threatening TAO. Thepresence of extremely poor eyesight(≥0.5 log MAR) was corrected in some patients with iv GC alone, thus sparing these patients from subsequent OD surgery. In patients who were refractory to steroids, subsequent OD surgery often provided satisfactory outcomes, however, new-onset strabismus with diplopia was observed in 12.0% of these cases.

CT features of exophthalmos in Chinese subjects with thyroid-associated ophthalmopathy

AIM: To investigate computed tomography (CT) features of exophthalmos in Chinese subjects with thyroid-associated ophthalmopathy (TAO). METHODS: A total of 605 eyes of 325 patients with exophthalmos due to TAO were classified as grade Ⅰ (mild exophthalmos) or Ⅱ (severe exophthalmos) based on orbital CT imaging. The increased orbital volume features, such as changes from extraocular muscles, orbital fat, or both, were analyzed. RESULTS: A total of 605 eyes were analyzed, among them 62.98% presented grade Ⅰ exophthalmos, while 36.02% showed grade Ⅱ exophthalmos. In grade Ⅰ, 56.69% showed orbital fat change, and in grade Ⅱ, 89.29% exhibited extraocular muscle enlargement. CONCLUSION: Orbital fat and extraocular muscle enlargement are likely to be observed on CTs of subjects with mild and severe exophthalmos, respectively. Our results suggest that CT findings may guide TAO clinical therapy recommendations and prognosis.

Orbital decompression surgery and horse chestnut seed extract improved superior orbital vein blood flow in patients with thyroid-associated ophthalmopathy

AIM： To evaluate the efficacy and safety of orbital decomposition （OD） surgery in combination with horse chestnut seed extract （HCSE）, as compared to OD atone, in patients with thyroid-associated ophthalmopathy （TAO）. METHODS： Sixty-two orbits from 62 TAO patients were randomly assigned to OD or OD＋HCSE at 1：1 ratio （31 received OD alone, 31 received OD ＋HCSE）. Forty-two orbits from 21 healthy subjects were used as controls. Complete ophthalmic examination and color Doppler flow imaging （CDFI） were performed before surgery and 3mo post-surgery on all 62 orbits from the TAO patients. CDFI were also performed on the 42 control orbits, The effect of OD ＋HCSE and OD alone on TAO orbits was compared on several endpoints, including superior ophthalmic vein blood flow （SOVBF） parameters, subjective assessment, soft tissue involvement, lid retraction, diplopia, eye movement restriction, degree of exophthalmos, and intraocular pressure. The control orbits were used as reference for the SOVBF parameters. RESULTS： OD surgery with or without HCSE improved SOVBF, symptoms and soft tissue involvement, decreased degree of exophthalmos and intraocular pressure in orbits of TAO patients. The OD ＋HCSE combination led to significantly better improvement of SOVBF than OD alone. The differences between the reductions of SOVBF in the two groups are 1.26 cmls in max-volecity and 0.52 cm/s in min-voiecity （P〈0.0001）. CONCLUSION： SOVBF is significantly reduced in the orbits affected with TAO, indicating that congestion may be an important factor contributing to TAO pathogenesis. OD surgery improves the SOVBF, and combination of HCSE medication and OD surgery further improved venous return than OD surgery alone.

Presence of thyroid-associated ophthalmopathy in Hashimoto's thyroiditis

·AIM: To determine the prevalence of ophthalmopathy in Hashimoto’s patients and to make a comparison in subgroups of patients·METHODS: The study involved 110 Hashimoto’s thyroiditis patients and 50 control subjects attending to the endocrinology department of the hospital. Subgroup classification of patients was made as euthyroid,subclinic and clinic in Hashimato’s thyroiditis. All patients were evaluated by a single experienced ophthalmologist for the prevalence and characteristics of eye signs.·RESULTS:Theoverallprevalencesofeyechanges were22.7%(25 patients) in patients and 4%(2 persons) in control subjects respectively(P =0.002). In patients the most common symptom was retrobulbar eye pain with or without any eye movement. Thirteen patients had significant upper eyelid retraction(11.8%). Six patients had eye muscle dysfunction as reduced eye movements in up gaze. In control patients one person had proptosis and another had lid retraction. The clinical activity score and classification of the ophthalmopathy did not show any significant differences among subgroups.·CONCLUSION:Theeyesignsweremostlymild(22.7%)and the most common eye sign was the presence of upper eyelid retraction(11.8%). Additionally six patients had eye muscle dysfunction as reduced eye movements in up gaze. Therefore we recommend to make a routine ophthalmic examination in Hashimoto’s thyroiditis patients in order not to omit the associated ophthalmopathy.

Epigenetics effect on pathogenesis of thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease.Recent studies have found the aberrant epigenetics in TAO,including DNA methylation,noncoding RNAs,and histone modification.Many genes have an aberrant level of methylation in TAO.For example,higher levels are found in CD14,MBP,ANGLE1,LYAR and lower levels in DRD4 and BOLL.Non-coding RNAs are involved in the immune response(miR-146a,miR-155,miR-96,miR-183),fibrosis regulation(miR-146a,miR-21,miR-29),adipogenesis(miR-27)and are thought to play roles in TAO.MicroRNA is also related to the clinical activity score(miR-Let7d-5p)and may be a predictor of glucocorticoid therapy(miR-224-5p).The quantities of H4 in TAO are increased compared with euthyroid control subjects,and the role of histone modifications in Graves*disease may lead to better understanding of its role in TAO.More studies are needed to explain the role of epigenetics in TAO and provide potential therapeutic strategies.

Frequency of IL-10-producing regulatory B cells associated with disease activity in thyroid-associated orbitopathy

AIM： To investigate the association between IL-10-producing regulatory B（B10） cells and the clinical features of thyroid-associated orbitopathy（TAO）. METHODS： A total of 30 patients with TAO were recruited at Zhongshan Ophthalmic Center from May 2015 to December 2015. Peripheral blood mononuclear cells（PBMCs） were separated from blood samples of 30 TAO patients and 16 healthy controls and stimulated with CD40 ligand and CpG for 48h. The frequency of IL-10＋ B cells was examined by flow cytometry and the correlation between the frequency of IL-10＋ B cells and clinical features of TAO was analyzed by SPSS. RESULTS： The frequency of IL-10＋ B cells among CD19＋ B cells in TAO patients was significantly lower than in healthy controls（TAO： 4.66%±1.88% vs healthy control： 6.82%±2.40%, P〈0.01）. The frequency of IL-10＋ B cells showed a positive correlation with disease activity of TAO measured by Clinical Activity Score（CAS）（r=0.50, P〈0.01）, and became higher in TAO patients with family history of Graves＇ disease（GD）（P=0.04）. CONCLUSION： The decrease of the frequency of IL-10＋ B cells in TAO patients indicates the deficiency of B10 cells in TAO, and the positive association with disease activity suggests its important role in TAO inflammation regulation.

Hertel Exophthalmometry and Computed Tomography for the Evaluation of Exophthalmos in Patients with Thyroid-Associated Ophthalmopathy

Objective: To compare the values of exophthalmos measured by computed tomography (CT) and Hertel exophthalmometry (HE) in patients with thyroid-associated ophthalmopathy (TAO). Material and Methods: One hundred and seventy eyes were examined in 85 patients with TAO. Each patient underwent a complete ophthalmic examination, Hertel exophthalmometry, and CT of the orbits through a 16-slice CT scanner (Bright Speed, General Electric), measuring the extraocular muscles, the total muscle thickness sum (MTS), and proptosis. The patients were divided into two groups-with activity and without TAO activity, the activity being assessed by means of the Clinical Activity Score (CAS) and the severity-according to the EUGOGO classification. Results: TAO activity was detected in 45 patients (90 eyes, 53%) with MTS of 23.54 ± 5.73 mm, IOP of 19.78 ± 4.49 mm Hg, Hertel exophthalmos of 23.08 ± 4.19 mm and measured by CT-23.32 ± 4.33 mm. Forty patients (80 eyes, 47%) were without TAO activity, with MTS of 19.28 ± 4.03, IOP of 16.6 ± 4.51 mm Hg, Hertel exophthalmos of 20.03 ± 3.84 mm and measured by CT-19.84 ± 4.47 mm. A correlation was detected between exophthalmos and: MTS, IOP, the activity and severity of TАО. High congruence was established between the two methods of measuring exophthalmos-CT and HE (Pearson correlation, r = 0.690, p = 0.000). Conclusion: Our results showed a high degree of consistency between Hertel exophthalmometry and multidetector CT for the evaluation of exophthalmos in patients with TAO. Exophthalmos is an important clinical feature and its measurement and monitoring over time assess the clinical course and outcome of treatment.

Reduced choroidal peripapillary capillaries in thyroid-associated ophthalmopathy with early stage of dysthyroid optic neuropathy

AIM: To investigate whether the subtle change of choroidal/retinal vessel densities and volumes in thyroidassociated ophthalmopathy(TAO) could be an early sign to detect dysthyroid optic neuropathy(DON). METHODS: This was a retrospective cross-sectional study, and a total of 98 eyes from 50 subjects were enrolled under certain criteria. Thirty-four eyes of normal controls and 64 eyes of TAO, including 39 eyes of DON and 25 eyes of TAO without DON, underwent optical coherence tomography angiography(OCTA) scanning. All the tested parameters of OCTA scanning including choroid radial peripapillary capillaries(RPC), retinal nerve fiber layer(RNFL), and macular ganglion cell complex(GCC) were compared among groups, and the correlation between OCTA parameters and visual function parameters was also investigated. RESULTS: Whole choroidal RPC was significantly reduced in DON(48.24%±0.4978%) compared to normal(50.33%±0.3173%) and TAO without DON(49.16%±0.5463%;P=0.0041). The reduction of whole choroidal RPC was also correlated with visual field(VF) defect in DON(r=0.5422, n=39). Although vision acuity and VF were improved in all the patients with DON after being treated with medical and surgical decompression, the reduction of RPC density were not reversed.CONCLUSION: There is a notable reduction in choroidal RPC in DON, which is correlated with VF defect. The reduction of RPC density could not be reversed immediately by medical and surgical decompression even when vision and VF were improved. These findings suggest that choroidal RPC could be a useful parameter to diagnose and monitor early stage of DON.

The effect of orbital radiation therapy on thyroid-associated orbitopathy complicated with dysthyroid optic neuropathy

Thyroid-associated orbitopathy （TAO） is an inflammatory autoimmune disorder. The most serious complication of TAO is dysthyroid optic neuropathy （DON）, which can lead to permanent vision loss because of volume expansion in the orbital apex. Orbital radiation therapy （ORT） is an anti-inflammatory treatment used in the treatment of active TAO. Clinical studies support radiotherapy as having a modest effect on DON, and early radiotherapy may protect against disease progression to DON. Current studies suggest that radiotherapy is generally safe. However, risks still exist in some cases. The possible effects of radiotherapy on TAO, especially complicated with DON, are reviewed. The effects of radiotherapy on DON are not completely known, and evidence from standardized, prospective, and multicenter clinical trials is still lacking.

Resolution of Pseudoptosis after Anti-inflammatory Treatment of the Contralateral Eye in Thyroid-associated Ophthalmopathy

Thyroid-associated ophthalmopathy （TAO） is an autoimmune inflammatory disease. Pseudoptosis （or ptosis）, which involves a reduction in the opening of the upper eyelid with a normal levator muscle, is rarely reported in TAO patients. In this article, we reported three cases of unilateral pseudoptosis due to inflammation of the levator in the contralateral eye. The effect of the unilateral use of triamcinolone acetonide （TA） on contralateral lid position and contour was also investigated.

Role of Peripheral Regulatory T Lymphocytes in Patients with Thyroid Associated Ophthalmopathy During Systemic Glucocorticoid Treatment:A Prospective Observational Study

Objective Thyroid-associated ophthalmopathy(TAO)is an autoimmune disorder involving the orbital tissue.This study aimed to understand the role of regulatory T cells(Tregs)in TAO during 12-week systemic glucocorticoid(GC)treatment.Methods Thirty-two moderate-severe TAO patients with a clinical activity score(CAS)≥3/7 or with prolonged T2 relaxation time(T2RT)on at least one side of extraocular muscle(EOM)were enrolled.The percentage of the peripheral CD4+CD25(high)CD127(−/low)Tregs was analyzed using flow cytometry before and after the GC treatment.The activity and severity of TAO,T2RT,and the clinical outcomes after the GC treatment were assessed.Their correlation with the peripheral Tregs was investigated.Results There was no significant association between the baseline Treg fraction and the activity and severity of TAO or the treatment response.A significant reduction of Tregs was observed after the GC therapy merely in patients without any clinical improvement.Conclusion Treg reduction after systemic GC therapy is indicative of a poor therapeutic response.Accordingly,dynamic alterations of Tregs could help to evaluate the effectiveness of the GC treatment.

球后脂肪体积测定对甲状腺相关性眼病治疗时机的判定价值

目的探讨商业化软件计算球后脂肪体积,分析其与甲状腺相关性眼病(TAO)进展及预后的关系。方法收集2016年1月~2016年12月在我院内分泌科确诊的35例(70个眼眶)TAO患者的临床资料。测量1.5T眼眶MRI球后脂肪体积及眼外肌信号强度比值(SIR)分析其与临床各项指标的相关性,并收集12例(24个眼眶)健康人测量球后脂肪体积,初步比较TAO组及健康组体积的差异。结果脂肪体积与病程成正相关(r=0.480,P<0.01),病程6个月以内组与6~12个月组相比,脂肪体积差异不显著(P=0.084)。病程6个月以内组及病程6~12个月组球后脂肪体积均显著低于病程大于12个月组(P<0.01,P<0.05)。脂肪体积与突眼度存在相关性(r=0.622,P<0.01),突眼度每增加1 mm,球后脂肪体积将增加0.88 m L。临床活动性评分(CAS)与SIR值及促甲状腺素受体抗体(TRAb)存在相关性(r=0.536,r=0.416,P<0.01)。TAO组球后脂肪体积显著高于正常组(P<0.01)。结论 TAO病程1年以上可能是球后脂肪组织增多的高峰阶段,球后脂肪体积结合SIR值的测量有助于最佳激素治疗时机的探索及预后分析。

甲状腺相关眼病常见中医证候及证候要素的现代文献研究

通过检索2001~2015年《中国学术期刊全文数据库》收录的有关甲状腺相关眼病(TAO)的中医辨证文献及未发表的相关研究生论文,建立数据库,进行统计分析,总结其中医证候和证候要素特点。从纳入分析的文献中共获取22个证候类型,频率大于5%的证候依次为:肝火亢盛、脾虚痰湿、肝肾阴虚、肝郁气滞、瘀血阻络、痰瘀阻滞;提取证候要素共计17个,其中病位类3个,为肝、脾、肾;病性类13个,频率大于5%的依次为痰凝、血瘀、阴虚、火、气滞。目前TAO的辨证分型主要集中在肝火亢盛、脾虚痰凝、肝肾阴虚等证型,证候要素主要围绕痰、血瘀、气滞。相对于辨证分型,证候要素较为简约,从构成证候的要素入手进行TAO证型研究能够抓住疾病的辨证特征。

激素冲击联合放射治疗应用于中重度活动期甲状腺相关眼病的疗效观察

目的:分析激素冲击联合放射治疗中重度活动期甲状腺相关眼病的应用效果。方法:2017年2月-2019年2月收治中重度活动期甲状腺相关眼病患者10例,均采用激素冲击与放射治疗。分析治疗效果。结果:治疗完成1个月后,总有效率为50.00%;治疗完成6个月后,总有效率为70.00%。治疗1个月后患者各项临床指标水平均降低,差异有统计学意义(P<0.05);治疗6个月后各项临床指标水平进一步降低,差异有统计学意义(P<0.05)。结论:激素冲击联合放射治疗中重度活动期甲状腺相关眼病临床治疗效果显著,且安全性较高。

不同治疗方法对改善甲状腺相关眼病症状的效果评价

目的评价手术加全身激素治疗、球旁局部激素注射、全身激素治疗用于不同病情甲状腺相关眼病(thyroid-associated ophthalmopathy,TAO)的疗效。方法入组36例(72眼)TAO患者,根据病情分为三组并给予相应治疗,手术+全身激素组(手术组)、球旁局部注射激素治疗组(球旁组)和全身激素组(激素组)。比较治疗前及治疗后视力、眼球突出度和临床活动性评分(clinical activity score,CAS)改善情况。结果手术组、激素组患者治疗前、治疗后视力比较,差异无统计学意义(P>0.05),治疗后眼球突出度降低、CAS减少,与治疗前比较,差异均有统计学意义(P<0.05),且眼球突出度降低幅度最大。球旁组治疗后与治疗前比较,视力提高、眼球突出度降低、CAS评分减少,差异均有统计学意义(均为P<0.05)。眼球突出度降低的有效率分别为手术组100.0%、球旁组65.3%、激素组3.2%,手术组、球旁组有效率均优于激素组(均为P<0.05)。对改善视力、降低CAS评分的有效率三组间差异无统计学意义(P>0.05)。结论对严重的TAO患者施行眶减压手术是降低眼球突出度首选治疗方式。球旁局部激素注射总体效果优于全身激素治疗,但是还需要更多的临床研究来比较球旁局部激素注射治疗、长期激素治疗、短期激素冲击治疗三者间的优劣。

甲状腺相关眼病放射治疗靶区自动勾画的人工智能训练研究

目的:通过建立甲状腺相关眼病(TAO)放射治疗靶区人工智能训练的自动勾画模型,测试及对比分析验证其准确性和可靠性。方法:选取于医院行放射治疗的80例TAO患者,分批将30例、40例、50例、60例和70例5组病例的手动勾画靶区载入到AccuLearning人工智能软件中进行训练,分别建立Model 1组(30例)、Model 2组(40例)、Model 3组(50例)、Model 4组(60例)和Model 5组(70例)的5组自动勾画训练模型;其余10例病例作为额外测试集组,在AccuContour人工智能软件中分别采用各模型行自动勾画,与其手动勾画靶区在相似性系数(DSC)、豪斯多夫距离(HD)和体积差值百分比(ΔV%)上行对比分析;将手动靶区的放射治疗计划载入到自动勾画靶区中进行靶区剂量分布评价系数接受95%、100%及110%处方剂量的最小百分体积(V_(95)、V_(100)、V_(110))的比较,并对各模型的组内一致性相关系数(ICC)进行分析,评价自动勾画的准确性和可信度。结果:5组模型的DSC值均>0.89,HD值范围为0.18~0.3 mm,自动勾画与手动勾画靶区的平均ΔV%<2%,自动勾画靶区的平均V_(95)、V_(100)及V_(110)分别在99%、95%和1%左右,各组ICC值均>0.9,表明自动勾画训练模型的准确性好,一致性和可信度高。结论:通过AccuLearning人工智能软件对TAO放射治疗靶区的自动勾画效果较为满意,但日后仍需要更完善的临床研究。

地塞米松及氨甲喋呤静脉冲击治疗Graves眼病的疗效观察

为改进Ｇｒａｖｅｓ眼病的疗效，作者对３５例病情较重或经常规治疗无效的患者，用地塞米松、氨甲喋呤静脉注射或点滴，每周１次，连续４周，并同服小剂量强的松（Ｐ）５日疗法／周，４周后加服硫唑嘌呤（Ａ）或６硫基嘌呤（６ＭＰ）。６周为一疗程，若病情需要，可重复１个疗程，然后用Ｐ＋Ａ巩固治疗并逐渐减量至第６月停药。结果：３３（９４．３％）例眼部症状改善，其眼球突度减少，与治前相比有显著性差异，突眼≤１年比＞１年者更明显。约半数闭目不全和复视者，以及５例暴露性角膜炎及２例溃疡穿孔者经治愈，仅留角膜云翳。

甲状腺相关眼病图形视觉诱发电位的研究

目的 :了解图形视觉诱发电位 (P VEP)在甲状腺相关眼病视神经病变 (DON)早期诊断中的应用价值。方法 :随机选取 39例甲状腺相关眼病 (TAO)和 30例正常对照进行P VEP检查。结果 :P VEP的改变主要为P1振幅 (PA)的降低 (P <0 .0 5 )。结论 :P VEP比较敏感地反映TAO视神经功能的变化 。

胰岛素样生长因子1受体在眼科疾病中的研究进展

胰岛素样生长因子1受体（IGF-1R）是酪氨酸蛋白激酶家族的成员,通过介导IGF-1的活性促进细胞增生、转移并抑制细胞凋亡,与眼科多种疾病的发生和发展密切相关.IGF-1R在脉络膜黑色素瘤中的表达水平与肿瘤的多种生物学特性,如侵袭和转移等密切相关,同时IGF-1R可能与促甲状腺激素受体（TSHR）共同作用并通过多种信号通路参与甲状腺相关眼病的发生和发展,通过胰岛素受体底物1（IRS-1）作用于血管内皮生长因子（VEGF）,从而促进视网膜新生血管性疾病的发生和发展,在眼科其他疾病,如屈光不正、白内障等中也发现IGF-1R相关生物学效应,提示IGF-1R作为分子靶位点将成为眼科疾病基因治疗的一个新课题.就IGF-1R在眼科疾病中的研究进展进行综述.