Intraocular and extraocular manifestations of thyroid dysfunction in Danish patients—A nationwide study

Thyroid eye disease (TED) is an autoimmune orbital disorder manifested through the immune system attacking the thyrotropin receptors on orbital fibroblasts. TED is mostly seen in hyperthyroid patients with Graves's disease but can also manifest in hypo- and euthyroid patients. The disease leads to orbital remodelling and disfigurement and has a wide array of manifestations such as strabismus, proptosis and eyelid retraction. These manifestations can lead to severe outcomes such as recurrent keratitis and, in the worst cases, dysthyroid optic neuropathy and vision loss. In Denmark, the structural end-stage changes caused by the disease can currently only be treated with surgery. This thesis follows the path of a thyroid patient through every stage of their eye disease. First, the patient has abnormal laboratory thyroid function testing and exhibits other ophthalmological manifestations than TED (Study I). Second, the patient is diagnosed with TED (Study II). Finally, the symptoms become so severe that the patient needs surgery (Studies II and III).

TED is an ophthalmological disease that is known to be associated with thyroid disorder. Because there are thyroid hormone receptors located in the retina, it has been suggested that thyroid hormones also may play a role in the pathogenesis of age-related macular degeneration (AMD). Several studies have investigated the association between AMD and thyroid dysfunction, although the results have been contradictory. Cataract surgery has also been suggested to lead to AMD progression. Therefore, we investigated the association between thyroid dysfunction and cataract surgery on exudative AMD. We included all patients who received anti-vascular endothelial growth factor (VEGF) treatment for their AMD in Denmark between 2008 and 2018 by using the Danish nationwide registries. We evaluated 26 998 individuals who developed exudative AMD and found an association between both hyper- and hypothyroidism, but only in patients who had not undergone previous cataract surgery (Study I).

The treatment landscape for patients with TED in Denmark has changed over the past 20 years with the implementation of new medications, national guidelines and centralisation of treatment. Knowledge of the incidence of a disease is important for healthcare planning and patient information. Studying changes in incidence over time provides information on disease patterns and can provide insight into how it has been affected by new treatment approaches. The current data on the incidence of TED originates from studies of selected populations with a relatively small number of patients (n = 120–447; Abraham-Nordling et al., 2011; Bartley, 1994; Laurberg et al., 2012). Therefore, we investigated the incidence of TED in Denmark by using the Danish nationwide registries. Additionally, we studied the cumulative incidence of the ophthalmological sequelae of TED: strabismus, strabismus surgery and decompression surgery. This is the first study to provide information on the nationwide incidence of TED and the cumulative incidence of the ophthalmological sequelae of the disease. We collected data from the Danish nationwide registries and included 4106 incident cases of TED treated at Danish hospitals from 2000 to 2018. The majority of the cases were hyperthyroid and women. We found that the overall average incidence of TED was 5.0 per 100 000 person years: 8.0 per 100 000 person years for women and 1.9 per 100 000 person years for men. For surgical procedures, the 4-year cumulative incidence was the following: 8% for having strabismus surgery performed and 5% for undergoing orbital decompression surgery. The 4-year cumulative incidence was 10% for being diagnosed with strabismus (Study II; Boulakh, Nygaard, et al., 2022).

Patients with TED may need to undergo several surgeries due to their severe eye symptoms. Strabismus causes double vision and can occur as a primary symptom or secondary to decompression surgery. Today, standard strabismus surgery is performed under general anaesthesia. However, topical anaesthesia is time-saving and has fewer side effects than general anaesthesia. Currently, topical anaesthesia is regularly used for strabismus surgery on patients with normal eye muscles. However, it has not been evaluated as an option for patients with TED and altered tight muscles in terms of how much pain the patient experience during surgery and whether the outcomes of the surgery are comparable to other groups of patients. Therefore, in a retrospective case series, we compared patients with and without TED who underwent single muscle recessions with pure topical anaesthesia in terms of the pain score and surgical outcome. We found that single muscle recessions performed with pure topical anaesthesia was well-tolerated among patients with TED (Study III; Boulakh, Toft-Petersen, et al., 2022).

The results from the research presented in this thesis provide new insights in the field of epidemiology and ophthalmological manifestations regarding patients with thyroid dysfunction and TED. Hopefully, these findings can be used to improve the ophthalmological treatment offered to this group of patients.