Abstract
Objective
Thyroid eye disease (TED), an autoimmune inflammatory process involving the orbital tissues around the eye, is the most common extra-thyroidal manifestation of Graves’ disease (GD). Due to changes in the patient’s appearance, TED is a socially and visually disabling condition with significant impacts on quality of life. The aim of this study is to assess predictors of strabismus, a severe manifestation of TED.
Design
Single-institution retrospective case-control study. Cases of Graves’ ophthalmopathy patients with strabismus were matched 1:1 to controls of Graves’ ophthalmopathy patients without strabismus by age and sex.
Patients
Patients ≥18 years old with severe Graves’ ophthalmopathy who received their medical care at UCLA with strabismus between 2012 and 2015.
Measurements
Eligibility criteria for cases was a diagnosis of Graves’ ophthalmopathy with a subsequent diagnosis of strabismus. Using conditional logistic regression, the odds ratios of developing strabismus following the diagnosis of Graves’ disease were assessed. The prognostic indicators assessed include race, ethnicity, cigarette smoking (active), serum thyroid peroxidase (TPO) antibody positivity, serum thyroglobulin (Tg) antibody positivity, antithyroidal medication use, and steroid use.
Results
The study sample (45 cases 1:1 matched against 45 controls) was comprised primarily of non-Hispanic, non-Latino Caucasian women with TED (mean ± SD age 63.0 ± 13.1 years). There were no significant predictors for the development of strabismus, including cigarette smoking (active), serum thyroid peroxidase (TPO) antibody positivity, serum thyroglobulin (Tg) antibody positivity, antithyroidal medication, and steroid use.
Conclusions
No significant predictors of strabismus, a severe manifestation of Graves’ ophthalmopathy, were identified following a diagnosis of TED in this study.
Keywords: Graves’ disease, Graves’ ophthalmopathy, Strabismus, Thyroid eye disease
Introduction
Approximately 50% of patients with Graves’ disease have signs and/or symptoms of Graves’ ophthalmopathy, and 5% have severe thyroid eye disease (TED) [1]. TED is an immunomediated inflammatory disorder characterized by a diverse set of well-described signs and symptoms, which range from extremely common (i.e. eyelid retraction) to relatively rare (i.e. dysthyroid optic neuropathy) [2]. Each of these physical effects can occur along a scale of severity, affecting quality of life variably. One of the most common and severe physical sequelae of TED is strabismus. Diplopia is well known to significantly affect quality of life [3] and may lead to disability in life functioning.
Although strabismus is a well characterized aspect of TED, predicting and preventing its occurrence has proven to be challenging. Although major modifiable risk factors associated with the development of in TED patients such as cigarette smoking, exposure to radioactive iodine (RAI), and thyroid dysfunction have been identified, none have been specifically associated with strabismus [4]. Additionally, a recent report has demonstrated that thyroidectomy or statin use may significantly reduce the relative risk of developing TED, while increased serum thyrotropin levels and exposure to RAI increased this risk [5]. Such risk factors have not been specifically associated with the development of more severe manifestations of TED, such as strabismus. This case-control study investigates demographic, medication, and laboratory-based prognostic indicators of strabismus, a severe manifestation of TED.
Materials and methods
In this case-control study, patients with TED who received care from the University of California Los Angeles (UCLA) from 2012 to 2015 were screened for study entry utilizing data from a health system wide electronic medical record database.
Inclusion criteria for subjects was a diagnosis of TED with a subsequent diagnosis of strabismus according to International Classification of Diseases, Ninth Revision (ICD-9) codes.
The following diagnosis title was used to determine a diagnosis of Graves’ eye disease: thyrotoxic exopthalmos. The following diagnoses titles were used for a diagnosis of strabismus: diplopia – primary, esotropia, excyclotropia, eye motility disorder, hypotropia, mechanical strabismus. There were no exclusion criteria for this study.
Cases of TED patients with strabismus were 1:1 matched against TED patients without strabismus by age and gender. Prognostic indicators assessed were race, ethnicity, cigarette smoking (active), serum thyroid peroxidase (TPO) antibody positivity, serum thyroglobulin (Tg) antibody positivity, antithyroidal medication use, and steroid use. The status of these prognostic indicators was evaluated at any date following the diagnosis of TED.
Conditional logistic regression was used to estimate the odds ratios (OR) and its 95% confidence intervals (CI) of strabismus in patients with TED related strabismus. P-values < 0.05 were considered significant. The study was approved by the UCLA Institutional Review Board (IRB).
Results
The study cohort consisted of 45 cases with TED who were subsequently diagnosed with strabismus during the study period (Table 1). Mean (SD) age for the cohort was 63.0 (13.1) years and the cohort was 62.2% female and 68.9% Caucasian. 5.6% of the cohort reported being active cigarette smokers, 5.6% reported using steroid medications, and 5.6% reported using antithyroidal medications. Controls were matched by age and gender. Race and ethnicity were self-reported, as recorded in the medical record.
Table 1.
Subject Demographics.
| Strabismus Patients (N = 45) | Matched TED Patients Without Strabismus (N = 45) | |
|---|---|---|
| Age (yrs), Mean ± SD | 63.0 ± 13.1 | 63.1 ± 12.9 |
| Age Range | 23.4–89.4 | 21.3–90.3 |
| Female, N (%) | 28 (62.2%) | 28 (62.2%) |
| Race, N (%) | ||
| White or Caucasian | 31 (68.9%) | 28 (62.2%) |
| Asian | 3 (6.7%) | 3 (6.7%) |
| Other | 11 (24.4%) | 14 (31.1%) |
| Ethnicity, N (%) | ||
| Not Hispanic or Latino | 41 (91.1%) | 33 (73.3%) |
| Hispanic and Other | 4 (8.9%) | 12 (26.7%) |
In logistic regression analysis, no significant predictors for the development of strabismus were identified. Among the predictors assessed were: cigarette smoking (active), serum thyroid peroxidase (TPO) antibody positivity, serum thyroglobulin (Tg) antibody positivity, antithyroidal medication use, and steroid use, with the exception of non-Hispanic, non-latino ethnicity (Table 2).
Table 2.
Multivariate Conditional Logistic Regression.
| Odds Ratio | 95% CI | p-Value | |
|---|---|---|---|
| Hispanic and Other Ethnicities | Reference | – | – |
| Non-Hispanic Ethnicity | 6.91 | (1.20, 39.70) | 0.0301 |
| Cigarette Smoking (Former) | Reference | – | – |
| Cigarette Smoking (Active) | 0.15 | (0.01, 2.16) | 0.1621 |
| Cigarette Smoking (Other)* | 0.63 | (0.18, 2.21) | 0.4676 |
| Serum TPO Ab Positivity | 1.40 | (0.26, 7.62) | 0.6982 |
| Serum Tg Ab Positivity | 1.38 | (0.15, 12.68) | 0.7756 |
| Antithyroidal Medication Use | 0.32 | (0.04, 2.62) | 0.2856 |
| Steroid Use | 2.81 | (0.29, 27.24) | 0.3716 |
Other includes never, not asked, and passive.
Discussion
Strabismus impacts quality of life through both functional and psychosocial factors [3] and thus is considered a severe manifestation of thyroid eye disease.
This case-control study of subjects with TED seen over a 13-year period at a large, urban academic medical center was not able to elucidate clinically meaningful prognostic indicators for the development of strabismus after a diagnosis of TED.
In contrast to previous studies linking active cigarette smoking to increased rates of strabismus surgery [6], [7], active cigarette smoking was not found to be a significant predictor within this study population. However, many previous studies compare such outcomes to the general GD population [8], while this study matches against TED subjects specifically in order to focus on the population as they present with TED. As such, the discrepancy in findings may be attributed to the association between GD and the development of thyroid eye disease that includes strabismus, rather than the development of strabismus within the more narrow restriction of TED patients specifically. However, it may also be due to the smaller cohort of smokers in this population of this study. In the study from Moorfields Eye Hospital, more than 50% were active smokers [6] whereas in our cohort this proportion was closer to 5%.
Other risk factors for severe disease have been discussed in the literature. For instance, men are more highly represented in population of TED patients with severe disease [9]. Dysthyroid optic neuropathy has additionally been associated with lower socioeconomic status in Great Britain [10] and type II diabetes mellitus in Italy [11]. These studies did not specifically examine the relationship with strabismus, and we did not demonstrate such associations.
This study demonstrates no clinically meaningful significant risk factors for the development of strabismus in patients with TED, a severe manifestation of thyroid eye disease, following the diagnosis of TED. This finding tends to confirm clinical experience in that it is often difficult to identify individuals who will be at risk of developing strabismus and fibrotic restrictive disease before they demonstrate clinical findings. Further research into potential blood borne, genetic and/or proteomic biomarkers may be an interesting area of research. Identification of reliable indicators may provide guidance for how aggressively to treat patients with GD with or without associated TED, as well as modifiable targets for potential intervention earlier in these disease courses.
Acknowledgements/Funding
Supported by NIH K23HD068552 (AML) and NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881.
References
- 1.Bahn Chair R.S., Burch H.B., Cooper D.S., Garber J.R., Greenlee M.C., Klein I. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011;21(6):593–646. doi: 10.1089/thy.2010.0417. http://www.ncbi.nlm.nih.gov/pubmed/21510801 Available from: [Internet] [DOI] [PubMed] [Google Scholar]
- 2.Bartley G.B., Fatourechi V., Kadrmas E.F., Jacobsen S.J., Ilstrup D.M., Garrity J.A. The incidence of Graves’ ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol. 1995;120(4):511–517. doi: 10.1016/s0002-9394(14)72666-2. http://www.ajo.com/article/S0002939414726662/fulltext Available from: [Internet] [DOI] [PubMed] [Google Scholar]
- 3.Chang M.Y., Velez F.G., Demer J.L., Isenberg S.J., Coleman A.L., Pineles S.L. Quality of life in adults with strabismus. Am J Ophthalmol. 2015;159(3):539–544. doi: 10.1016/j.ajo.2014.12.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wiersinga W.M., Bartalena L. Epidemiology and prevention of graves’ ophthalmopathy. Thyroid. 2002;12(10):855–860. doi: 10.1089/105072502761016476. http://www.liebertonline.com/doi/abs/10.1089/105072502761016476 Available from: [Internet] [DOI] [PubMed] [Google Scholar]
- 5.Stein J.D., Childers D., Gupta S., Talwar N., Nan B., Lee B.J. Risk factors for developing thyroid-associated ophthalmopathy among individuals with graves disease. JAMA Ophthalmol. 2014;48105:1–7. doi: 10.1001/jamaophthalmol.2014.5103. http://www.ncbi.nlm.nih.gov/pubmed/25502604 Available from: [Internet] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rajendram R., Bunce C., Adams G.G.W., Dayan C.M., Rose G.E. Smoking and strabismus surgery in patients with thyroid eye disease. Ophthalmology. 2011;118(12):2493–2497. doi: 10.1016/j.ophtha.2011.06.003. [DOI] [PubMed] [Google Scholar]
- 7.Thornton J., Kelly S.P., Harrison R.A., Edwards R. Cigarette smoking and thyroid eye disease: a systematic review. Eye (Lond) 2007;21:1135–1145. doi: 10.1038/sj.eye.6702603. [DOI] [PubMed] [Google Scholar]
- 8.Vestergaard P. Smoking and thyroid disorders: a meta-analysis. Eur J Endocrinol. 2002;146(2):153–161. doi: 10.1530/eje.0.1460153. http://www.ncbi.nlm.nih.gov/pubmed/11834423 Available from: [internet] [DOI] [PubMed] [Google Scholar]
- 9.Perros P., Dayan C.M., Dickinson A.J., Ezra D., Estcourt S., Foley P. Management of patients with Graves’ orbitopathy: initial assessment, management outside specialised centres and referral pathways. Clin Med. 2015;15(2):173–178. doi: 10.7861/clinmedicine.15-2-173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Edmunds M.R., Huntbach J.A., Durrani O.M. Are ethnicity, social grade, and social deprivation associated with severity of thyroid-associated ophthalmopathy? Ophthal Plast Reconstr Surg. 2014;30(3):241–245. doi: 10.1097/IOP.0000000000000077. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4014637&tool=pmcentrez&rendertype=abstract Available from: [internet] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Le Moli R., Muscia V., Tumminia A., Frittitta L., Buscema M., Palermo F. Type 2 diabetic patients with Graves’ disease have more frequent and severe Graves’ orbitopathy. Nutr Metab Cardiovasc Dis. 2015;25(5):452–457. doi: 10.1016/j.numecd.2015.01.003. [DOI] [PubMed] [Google Scholar]