thyroid eye disease

Abstract: Orbital decompression is a surgical procedure aimed at increasing the orbital volume and/or decreasing the volume of the orbital fat. The indications for orbital decompression are determined in the course of thorough eye examination. An important objective of examination of a patient with thyroid eye disease (TED) is determination of inflammation activity and severity. Orbital decompression is a surgical procedure that can be performed in both the active and non- active stages of the disease. However, the indications for the surgery in these cases are different. Optic neuropathy and severe corneal disease are threatening complications that may lead to per- manent visual loss and generally occur in the presence of active orbital inflammation. If treatment with high-dose corticosteroids has proven ineffective, an urgent surgical procedure consisting of orbital decompression and, in case of involvement of the cornea, eyelid and corneal surgery has to be performed. Owing to significant progress in technology, improvement of methods and accumulated experience over the past decade, the indications for bone orbital decompression have extended compared to the time when this procedure was used only in patients with extremely severe TED. The most common complication of the orbital decompression is the development or deteriora- tion of previously existing binocular diplopia and strabismus. In addition, other parameters may change as well, including the position of the globe, the eyelids, the angle of deviation of the eye, and intraocular pressure. Thus, bone orbital decompression is a major step of a comprehensive, often multistage, system of rehabilitation of patients with severe refractory TED.

This is to certify that this dissertation titled “CORRELATION OF CLINICAL PARAMETERS AND OBJECTIVE ASSESSMENT TOOLS IN ACTIVE THYROID EYE DISEASE” is a bonafide record of the research work done by DR.G.SENTHAMARAI, post graduate in the Regional Institute of Ophthalmology & Government Ophthalmic Hospital, Madras Medical College and Research Institute, Chennai – 03, in partial fulfillment of the regulations laid down by The Tamil Nadu Dr. M.G.R. Medical University for the award of M.S. Ophthalmology Branch III, under my guidance and supervision during the academic years 2010 – 2013.

Patients with appearance-altering conditions may be dissatisfied with the outcomes of reconstructive surgery due to unmet expectations. This study explored patients’ expectations of orbital decompression surgery for thyroid eye disease (TED) and whether these were met. Semi-structured interviews were conducted at two times: (1) in the weeks after patients were listed for decompression surgery and before surgery; (2) up to 12 months after surgery. Thematic analysis was performed for each time point, to identify themes within the data.

Aim: To evaluate the efficacy of transcutaneous triamcinolone acetonide (TA) injection for the treatment of upper eyelid retraction and swelling in thyroid eye disease (TED) patients. Patients and methods: This is a case series. Three euthyroid TED patients with features of both upper eyelid retraction and swelling were recruited. TED signs appeared within 6 months prior to treatment. Next, 0.5 mL of TA (40 mg/mL) was transcutaneously injected targeting the orbital fat around the levator palpebrae superioris (LPS) muscle. At each visit, eyelid retraction was evaluated by palpebral fissure height and the presence of scleral show above the superior corneoscleral limbus. Eyelid swelling was judged by the appearance of upper eyelid bulging and the lack of an eyelid sulcus. In addition, the LPS muscle, orbital and retro-orbicularis oculi fat were observed using MRI before and after treatment.

Figure 1 Pathophysiology of thyroid eye disease. In TED, B-lymphocytes, T-lymphocytes, and CD34+ fibrocytes infiltrate the orbit. CD34+ fibroblasts, originating from bone marrow-derived fibrocytes, further differentiate into myofibroblasts or adipocytes. Both CD34+ and residential CD34− fibroblasts are present within the orbit, and depending upon microenvironment-mediated signaling, can produce cytokines, including IL-1β, IL-6, IL-8, IL-16, TNF-α, RANTES, and CD40 ligand, which activate orbital fibroblasts. CD34+ fibroblasts express low levels of TSH-R, thyroglobulin, and additional thyroid antigens. TSIs activate the TSH-R/IGF-1R complex inducing inflammatory molecule expression and glycosaminoglycan synthesis. Furthermore, immunoglobulins directed against IGF-1R induce orbital fibroblast signaling, thereby increasing cytokine and hyaluronan production, and subsequent orbital tissue expansion, leading to proptosis and compression of the optic nerve. Adipogenesis also leads to orbital fat expansion. From N Engl J Med, Smith TJ, Hegedus L, Graves’ disease, 375(16), 1552–1565. Copyright © (2016) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 4

Methods: Retrospective chart review of 31 men and 31 women with untreated thyroid eye disease. Subjective complaints, smoking status, thyroid status, and objective findings pertinent to the clinical activity score (CAS) and “NO SPECS” classification were recorded. Overall disease asymmetry was defined as having simultaneous asymmetry of both more than one symptom and more than one external finding. Asymmetry was compared across sex and thyroid status. CAS and NO SPECS severity were compared across sex, symmetry, and thyroid status.

Figure 1. The potential variables to be used in the hierarchical multiple regression to explore factors associated with quality of life. Framework adapted from Clarke et al. 24 BFNE ¼ Brief Fear of Negative Evaluation; CARSAL ¼ Centre for Appearance Research Salience Scale; CARVAL ¼ Centre for Appearance Research Valence Scale; CAS ¼ Clinical Activity Scale; DAS24 ¼ Derriford Appearance Scale 24; GO-QOL ¼ Graves ’ Ophthalmopathy Quality of Life; HADS ¼ Hospital Anxiety and Depression Scale; INCOM ¼ Iowa-Netherlands Comparison Orientation Measure; logMAR ¼ logarithm of the minimum angle of resolution; MRD1 ¼ margin re fl ex distance 1; MRD2 ¼ margin re fl ex distance 2; MSPSS ¼ Multidimensional Scale of Perceived Social Support; SPK ¼ super fi cial punctate keratitis; TED ¼ thyroid eye disease.

Over the years research on thyroid eye disease (TED) has focused on what causes the disease and how to treat it effectively. Less research has focused on the psychological impact of having TED. There has been growing interest in how TED affects overall quality of life in recent years however and Caroline Terwee and colleagues in The Netherlands developed a useful questionnaire to help this area of research develop. By asking people with TED to help design the questionnaire – the Graves’ Ophthalmology Quality of Life Questionnaire (or GO-QOL) – it captures issues central to TED, including feeling stared at in the street by others, having difficulty reading, and avoiding appearing in photographs 1 . The authors urged researchers to use the questionnaire in every trial that investigates a new treatment for TED, to assess whether treatments improve these important aspects of peoples’ lives and not just clinical criteria 2 .

Abstract: Thyroid eye disease is a heterogeneous autoimmune orbital reaction typically manifesting in middle age. The inflammation may parallel or remain isolated from a related inflammatory cascade in the thyroid called Graves’ disease. The orbital manifestations can lead to severe proptosis, dry eyes, strabismus, and optic neuropathy. In this article, we will discuss this unique condition including the ophthalmic findings and management.

A cohort of 655 consecutive patients with TED who vis- ited and were managed at the Orbital Unit of the De- partment of Visual Science of the University of Naples “Federico II” from January 1995 to December 2009, were retrospectively reviewed. The aim was to determine the percentage of patients presenting with unilateral TED with the appearance of unilateral exophthalmos and who had previous clinical history with no remarkable changes in their appearance and to evaluate the percentage of pa- tients who developed over time exophthalmos on contralateral non-proptotic eye. To ensure a reasonable time period that produces suitable data for statistical analysis, the minimum follow-up time for the patients was 10 years. Data was extracted from a special TED form which is routinely completed for each patient in our Orbital Unit. The study adheres to the declaration of Helsinki. The form included different sections regard- ing age, sex, thyroid gland disorder, associated systemic diseases, medication history, and eye symptoms at presen- tation of TED. It also included a section for visual function tests including best corrected visual acuity, optic disc, color vision, visual field, intraocular pressure (IOP) in pri- mary and up-gaze, Hertel exophthalmometry, eyelid examination, ocular motility examination [13], slit-lamp examination and findings on orbital imaging. The examin- ation included a clinical activity score (CAS) and a NOSPECS severity score [14]. In the case of asymmetric severity and/or activity scores, the worst score was consid- ered for statistical analysis. To help enhance the accuracy of data collection, the charts of patients with more

Permanent repository link: http://openaccess.city.ac.uk/id/eprint/12452/ Link to published version: http://dx.doi.org/10.1016/j.ophtha.2015.08.030 Copyright and reuse: City Research Onli[r]

Glucocorticoids, orbital radiotherapy, orbital decom- pression, immunosuppressive therapy and biological drugs are available for the management of TED [3]. Iv-MP and prompt orbital decompression, if necessary, are is still considered to be the standard treatment for DON [3]. A randomized trial including 15 patients with active TED and DON suggested that immediate surgery does not result in better outcomes, and systemic gluco- corticoids appeared to be the optimal first-line treatment [6]. To the best of our knowledge, no reports are avail- able regarding the treatment of patients with DON with contraindications to steroids and surgical intolerance. Orbital radiotherapy plays an important role in control- ling the inflammatory process of TED by inducing apop- tosis or disrupting the functions of B and T lymphocytes, macrophages, or orbital fibroblasts and therefore reducing the secretion of proinflammatory cy- tokines from activated lymphocytes [7, 8]. A total dose of 20 Gy is commonly used [9, 10]. Grassi et al. reported significant early reduction in CAS and ocular motility disturbances after orbital radiotherapy in patients without DON [8]. Another study demonstrated that all patients with TED showed regression of the dis- ease with combined iv-MP and orbital radiotherapy or iv-MP therapy alone. Two of fifty-nine patients undergoing iv-MP therapy developed DON during the follow-up period, but no patients receiving combined iv-MP and orbital radiotherapy developed DON [11]. In addition, some studies have indicated that the high incidence of IgE elevation in Graves ’ disease sug- gested a difference in the autoimmune processes of

One other questionnaire to assess quality of life in TED has recently been developed (TED-QOL; Fayers & Dolman, 2011) that consists of three items that ask “How is your eye disease currently affecting your overall quality of life/ your ability to carry out daily activities/ your satisfaction with your appearance?” The authors report this tool to be a valid and reliable measure of quality of life in TED (Fayers & Dolman, 2011). However, with only 3 items this questionnaire is designed to be used in busy hospital clinics as a “snap shot” rather than for developing our understanding of the areas of quality of life most impacted upon. This questionnaire also has yet to be used in any studies evaluating treatment for TED and therefore no MCID has been provided. Son et al. (2014) recently used this questionnaire to measure quality of life in Korean patients with TED and found there to be significant and substantial ceiling effects on all three items making it difficult to distinguish between the most affected patients. In follow-up interviews, two patients suggested a need for additional items (Son, Lee & Yoon, 2014).

23 Abraham-Nordling M, Wallin G, Traisk F, Berg G, Calissendorff J, Hallengren B, Hedner P, Lantz M, Nystrom E, Asman P, Lundell G, Torring O, The Thyroid Study Group of TT 96 2010 Thyroid-associated ophthalmopathy; quality of life follow-up of patients randomized to treatment with antithyroid drugs or radioiodine. European Journal of Endocrinology 163:651-657.

In addition to the restricted number of trial subjects, there are many factors in the natural history and clinical evalu- ation of TED which pose challenges to the objective and scientific comparison of treatment outcomes. For exam- ple, the control of systemic thyroid dysfunction reduces disease severity, but delay in TED treatment until a 2 month period of euthyroidism has been maintained (as has been advocated by other investigators [7,9,14,18]) in order to prevent this confounding interpretation of treat- ment efficacy, potentially misses the opportunity to obtain maximal benefit from immunosuppression in the earliest, most active phase of the disease. A patient's smok- ing status, previous exposure to steroids and disease sever- ity can also independently influence their response to treatment. Furthermore, measures of disease activity and severity are notoriously subjective [58,59], and although some outcome measures have been used more often than others in previous studies, there is no single standardised and robustly validated scoring system to use in the assess- ment of treatment efficacy.

3 eyes of the 3 unilateral TED patients. We had found similar results in the analyses of right eyes or left eyes. Although a trend for thicker LLT in active TED was noted, the wide range of standard deviation resulted in a non-significant difference. Thus, we classified both eyes of the same patient into the same CAS group, which might have caused a bias. However, all patients with ac- tive TED (CAS 2−3) in our study had ocular signs of similar severity, only 2 patients with inactive TED (CAS 0−1) had single eye involvement. One eye in the active TED group was excluded due to previous eyelid surgery. Furthermore, most patients routinely used eye ointment for lubrication at night. The usage of topical ointment should be more strictly limited to avoid its influence on LLT. The ingredients of an eye ointment might affect the tear film composition, yet all patients had ceased ointment application at least 12 h before examination. Moreover, we set LLT as 100 nm for the 5 eyes with LLT > 100 nm, which may have caused underestimation of the average value of LLT. Because the LipiView® II Ocular Surface Interferometer did not have a sensor to identify the blinking force, we cannot clearly prove the association between LLT and forceful blinks. A further study adopting simultaneous electromyography of the eyelid should be considered to verify this causality. Fi- nally, the small sample size implies that our results should be interpreted with some caution. Subgroup ana- lysis revealed that inactive TED eyes were not signifi- cantly different from non-TED eyes in terms of MG performance and LLT, but a trend for greater MGd and thicker LLT was observed between active TED eyes and non-TED eyes. Thus, a small proportion of active TED patients in our subjects might be the reason for the lack of statistically significant differences in many parameters between the TED group and the non-TED group. The performance of MGs in TED patients should be verified in a future study with a larger sample.

diarrhea without abdominal pain. He was diagnosed with hyperthyroidism 4 months ago when he presented with loss of weight. Carbimazole 30 mg daily was started by his primary physician. However, he defaulted treatment and follow-up after taking the medication for 6  weeks as his symptoms had improved. On physical examination, he was febrile at 38°C and was noted to be in atrial fibrillation (AF) with heart rate of 170 bpm, blood pressure of 102/42 mmHg, and hypoxic, with oxygen saturation of 92% on room air. He was initially alert and coherent with a Glasgow Coma Scale (GCS) of 15. He had signs of thyroid eye disease, with bilateral exophthalmos and lid retraction. There was no enlarged goiter or thyroid bruit. Cardiorespiratory examination revealed signs of congestive cardiac failure, with elevated jugular venous pressure, bilateral expiratory wheezing and bilateral pitting pedal edema up to mid shins.

A close relationship that emphasizes education and coopera- tion between patients and physicians is crucial to the man- agement of GO. Medical therapy for GO has evolved little during the past few decades and generally focuses on con- ventional approaches of nonspecific immuno-suppression. This may be explained partly by a poor understanding of GO at a cellular and molecular level, as well as challenges of disease classification at a clinical level. On both fronts, progress is being made. Newer classes of treatment agents hold promise to more selectively target underlying cellular and molecular alterations in GO. Also, cooperation between multiple medical centers, as evidenced by the European Group on Graves’ Orbitopathy (EUGOGO) and the recent formation of the International Thyroid Eye Disease Study Group (ITEDS), have the potential to better standardize the language and tests used in GO.

Inside, abundance thyroid hormones are additionally focusing on the thoughtful sensory system, always setting us up for a danger that is not by any means there. Resting metabolic rate assembles, causing weight diminishment. Resting heart rate hops unpredictably (arrhythmia) or increments to more than 100 pulsates every moment (tachycardia). Warmth bigotry and overwhelming sweat are additionally manifestations. Diagnosis of Graves' through blood tests relies largely on high- circulating levels of T3 and T4 and low TSH levels, as well as antibodies for TSH receptors. Every so often, an iodine uptake test is utilized for affirmation. In this test, the patient devours a low dosage of radioactive iodine. Since thyroid cells actively take up iodine, the degree and location of overactive cells present in radiography as darkened areas of the thyroid.

PNN, GRNN, LVQ, and SVM, by considering five categories for thyroid disease such as being healthy, hyperthyroidism, hypothyroidism, hyperthyroidism under clinical conditions, and hypothyroidism under clinical conditions, and by using hormone tests such as TSH, T4, T3, TBG, FT4, FT3, T3U, by considering clinical conditions of hair loss, weight gain, dry skin, moist and warm skin, tachycardia, and heart beat for designing networks that can have the best performance for categorizing thyroid disease. The obtained results indicated that these networks can diagnose with a high accuracy, for example for diagnosing hyperthyroid disease, the GRNN network reported 99.5% positive response 10 .