Alpha-1 antagonist treatment for eyelid retraction in patients with thyroid eye disease—a prospective pilot study

Abstract

Background

Sympathetic overstimulation of Müller’s muscle is a suggested mechanism underlying upper eyelid retraction in thyroid eye disease (TED). We examined the effect of tamsulosin, an alpha-1 antagonist, on eyelid retraction in patients with TED.

Methods

A single-centre prospective study. Patients with TED and associated eyelid retraction were treated with oral 0.4 mg/day tamsulosin for 3 months. Upper eyelid margins-to-reflex distance (MRD1), vertical palpebral fissure height (PFH), subjective improvement, signs and symptoms of dry eye, and lubricants use were assessed at baseline and at each subsequent visit.

Results

Eleven suitable patients (mean age 47.5 ± 9.68, 8 females) enrolled in the study. Three patients discontinued the drug due to mild adverse effects (dizziness, bradycardia, nausea, and gastrointestinal distress), which resolved immediately upon stopping treatment. The other eight patients tolerated the drug well and reported no side effects. Five patients experienced an objective improvement in eyelid position and subjective improvement in eye discomfort. The mean MRD1 decreased by −1.04 ± 0.81 mm (P = 0.015), and mean PFH decreased by −1.46 ± 1.33 mm (P = 0.039). Mean duration of tamsulosin treatment was 84.63 ± 71.9 days. Patients discontinued the drug due to no improvement in MRD1 (n = 3), referral for eyelid surgery with stable inactive TED (n = 2), treatment with intravenous methylprednisolone due to worsening active TED (n = 2), and patient choice after 5 months of treatment with spontaneous resolution of symptoms (n = 1).

Conclusions

Tamsulosin is a safe potential treatment for eyelid retraction in TED and can be used as a temporary alternative therapeutic approach for patients unsuitable for surgery.

Introduction

Upper eyelid retraction is the most common sign of thyroid eye disease (TED), with a prevalence of up to 90% of affected patients [1, 2]. Upper eyelid retraction can cause exposure keratopathy ranging from mild ocular irritation to sight-threatening corneal ulcers. Additionally, it contributes considerably to the change in appearance and facial expression, and can have a profound negative psycho-social effect on the patients [1, 3]. Treatments focus upon minimising exposure and improving lubrication of the ocular surface during the active phase of TED. Definitive surgical interventions to recess the retracted eyelids are preferentially reserved for the inactive phase of the disease [4].

The causes of upper eyelid retraction may be multifactorial. Proposed mechanisms include increased sympathetic activity causing overstimulation of Müller’s muscle, hypertrophy of the muscle fibres of the levator palpebrae superioris (LPS) muscle, inflammation, scarring, and fibrosis of the LPS, an increase in the tone of the LPS-superior rectus muscle complex in response to hypertrophy and fibrosis of the inferior rectus muscle, and a result of exophthalmos [2]. We hypothesised that relaxation of Müller’s muscles by means of non-invasive oral medication may have a beneficial effect on upper eyelid retraction.

Tamsulosin, a long-acting selective alpha1-adrenoreceptor antagonist, is commonly used to relax the prostate smooth muscle for the treatment of benign prostatic hyperplasia, and has a well-known favourable safety profile [5–7]. Given that Müller’s muscle is a smooth muscle with alpha-adrenergic receptors [8], we designed this pilot study with the aim of examining the effect of tamsulosin in treating eyelid retraction in patients with TED.

Methods

The study was conducted in accordance with good clinical practice guidelines and adhered to the tenets of the Declaration of Helsinki. Ethical approval was granted by the institutional review board, and written informed consent was obtained from all participants. This study was registered prospectively with clinicaltrials.gov (identifier, NCT04359979).

Patients and methods

This is a single-centre prospective interventional study involving patients enrolled in our TED clinic from February 2020 to August 2022 and diagnosed with TED-associated eyelid retraction in one or both eyes. Patients who were pregnant or breastfeeding, younger than 18 years of age, had undergone eyelid surgery or sustained eyelid trauma, underwent neurotoxin injection to the eyelids, and had severe exposure keratopathy that posed a serious and immediate risk for vision were excluded. Eligible and consenting patients were offered the use of oral tamsulosin (Omnic, Astellas Pharma Europe Ltd., The Netherlands). They all received information about the medication, including the positive potential effect on eyelid retraction, the possible side effects, and the alternative treatment options for retraction.

The study patients were treated with oral tamsulosin 0.4 mg daily taken at bedtime for 2 weeks, after which they were examined for initial effects and adverse events. If the drug had been well tolerated, the patients tried switching to taking the drug in the morning and continued treatment for 3 additional months. Follow-up visits at 1 and 3 months included the evaluation of upper eyelid margin-to-reflex distance (MRD1), lower eyelid margin-to-reflex distance (MRD2), vertical palpebral fissure height (PFH), subjective improvement in appearance and comfort, signs and symptoms of dry eye, and the use of eye lubricants. All patients were photographed at baseline and at each subsequent visit. Those who were deemed by their treating physician to need systemic steroids or eyelid surgery discontinued tamsulosin treatment and were dropped from the study.

Outcome measures

The primary outcome measure was change in MRD1. Secondary outcome measures were changes in PFH, subjective improvement in appearance, eye discomfort as reported by patients, clinical signs of dry eye, use of lubricants, exposure keratopathy, adverse reactions, and the need for an alternative treatment for the retraction.

Measurement techniques

The patients’ photographs were evaluated, and MRD1 and vertical PFH were calculated by ImageJ software (National Institutes of Health). A mean corneal diameter of 11.64 mm for women and 11.77 mm for men was used as a reference to set the scale for each photograph [9]. The MRD1 was measured from the light reflex on the patient’s cornea to the level of the centre of the upper eyelid margin [10]. PFH was measured as the maximal vertical distance between the upper and lower eyelid margin. MRD2 was calculated as the difference between PFH and MRD1 for each eye. The left eye of all patients was arbitrarily selected for statistical analysis.

Statistical analysis

The statistical software GraphPad Prism version 9.1.0.221 (GraphPad, Inc., Boston, MA, USA) was used for data analysis. Statistical significance was set at P < 0.05. The Wilcoxon matched-pairs signed rank test was applied to compare differences of MRD1, MRD2, and PFH over time.

Results

Eleven suitable patients were enrolled in the study. Their mean age was 47.5 ± 9.68 (range 36–68) years, and 8 of them were females. The median time from TED diagnosis to study entry was 3 years (range 0.5–11 years). Active TED was diagnosed in four patients with a mean clinical activity score of 0.9 ± 1.4, and nine patients were diagnosed with bilateral upper eyelid retraction. The patients’ baseline characteristics are summarised in Table 1. Three patients discontinued the medication within the first 2 weeks due to mild adverse effects of lightheadedness and nausea (n = 2) and gastrointestinal discomfort (n = 1). All adverse effects resolved completely and spontaneously within 1 day of stopping treatment. All the remaining eight patients tolerated the drug well with no reported side effects, and they were included in the final analysis.

Table 1.

Baseline characteristics.

Parameter	Patients (n = 11)
Age, mean  ±  SD	47.5 ± 9.68
Female:male, n	8:3
Initial CAS, mean ± SD	0.9 ± 1.4
Active TED, n	4
Bilateral upper eyelid retraction, n	9
Median years from TED diagnosis, n (range)	3 (0.5–11)
Previous systemic treatment, n
Thyroidectomy	3
Anti-thyroid medications	6
Systemic steroids	4
Ocular surgery	4
Immunotherapy	1

CAS clinical activity score, SD standard deviation, TED thyroid eye disease.

We observed a mean change of −1.04 ± 0.81 mm (P = 0.015, median −0.845, range −0.5 to −2.24 mm) in MRD1, −1.46 ± 1.33 mm (P = 0.039, median −1.67, range 1 to −2.8 mm) in PFH, and −0.51 ± 1.29 mm (P = 0.382) in MRD2 (Figs. 1, 2). Five patients showed both objective improvement in eyelid position and reported improvement in eye discomfort. At the last follow-up visit, five patients displayed objective signs of dry eye and required lubricant use, and four of them also reported dry eye symptoms. Four patients had an improvement in MRD1 > −2 mm.

Fig. 1. Improvement in eyelid retraction with tamsulosin treatment.

Photographs of a patient with thyroid eye disease and bilateral upper eyelid retraction before (A) and 4 weeks after (B) treatment with oral tamsulosin.

Fig. 2. Improvement in eyelid retraction with tamsulosin treatment.

Photographs of a patient with thyroid eye disease and bilateral upper eyelid retraction before (A) and 4 weeks after (B) treatment with oral tamsulosin.

Patients were treated with tamsulosin for a median of 52 days (range 12–224). Discontinuation of the drug was due to the following reasons: no subjective or objective improvement in MRD1 (n = 3), a decision for definitive eyelid surgery with stable inactive TED (n = 2), treatment with intravenous methylprednisolone due to worsening active TED (n = 2), and patient decision after 5 months of treatment resolution of symptoms (n = 1). Two patients also reported additional non-ocular beneficial effects of the medication consisting of alleviation of migraine attacks in one and less difficulty in urination in the other. No adverse events were reported for eight patients treated with tamsulosin. No patient required urgent eyelid surgery, and no sight-threatening complications were observed during the follow-up period.

Discussion

We aimed to evaluate the efficacy of tamsulosin in the treatment of eyelid retraction as an alternative to surgery in patients with TED. Five of the eight study participants with TED who were treated with daily oral tamsulosin exhibited both objective and subjective improvement in upper eyelid retraction. Tamsulosin succeeded in providing them with temporary relief until their disease activity improved (spontaneously or with systemic steroids) or until definitive surgery could be offered.

TED affects the eye by means of various mechanisms, with upper eyelid retraction being seen in up to 90% of patients [1, 2]. It has a negative psycho-social effect on patients due to the typical “stare” and has been reported to cause social isolation, depression, anxiety, and a decline in confidence [1, 11]. Eyelid retraction also plays a role in worsening corneal exposure as a result of reduced blink and lagophthalmos and can lead to sight-threatening complications. For this reason, clinicians are often faced with the need to specifically address eyelid retraction early in the course of the disease when it is in its active or inflammatory phase. While topical lubricants are used to improve corneal health and counteract the effects of increased exposure in mild to moderate cases, they may not suffice in many cases. Systemic anti-inflammatory agents, such as steroids, which remain the recommended first-line treatment according to the 2021 EUGOGO guidelines, improve swelling, erythema, and pain but do not specifically address eyelid retraction.

Teprotumumab remains mostly unavailable outside the United States. It has shown efficacy in improving proptosis, but studies have shown inconsistent results regarding eyelid position [12]. Definitive corrective surgery for eyelid recession is preferably deferred until the disease is deemed inactive and morphologic changes stabilise. With the lack of better options, other measures are used to improve eyelid retraction, including temporary tarsorrhaphy and periocular injections, which are invasive and not without complications. Chemo-denervation by means of botulinum toxin A injections has a variable and temporary effect that needs to be titrated, with possible transient complications, such as ptosis and diplopia [13]. Hyaluronic acid injections that aim to add weight to the upper eyelid were shown to be effective for mild cases but not for most TED patients, in addition to being expensive and requiring titration [14, 15]. Triamcinolone acetonide injections aimed to reduce inflammation in the LPS and in Müller’s muscles were shown to improve MRD1 in both active and inactive diseases [16]. However, repeated injections are sometimes needed, and complications, such as intraocular pressure elevation in up to 50% of patients, transient ptosis, superior sulcus defect, high eyelid crease, and thinning of the levator and Müller’s muscles have been reported [16, 17].

Compared with the above options, oral tamsulosin offers the advantage of a non-invasive daily oral route of self-administration. It is a widely used drug for urologic indications in both men and women, with available generic preparations and a well-established safety profile [5–7]. In many patients with TED, an improvement of 1–3 mm is all that is required to significantly improve exposure keratopathy and a more natural appearance. The results in our study revealed an average of −1.46 ± 1.33 mm improvement in PFH for the entire group, but 50% of patients had greater than −2 mm of change and a self-reported subjective improvement in appearance and eye comfort.

Adverse effects of tamsulosin are well-documented in previous large-scale investigations [5, 6]. Three of our 11 patients sustained mild orthostatism or gastrointestinal discomfort with complete resolution of symptoms within 24 h once treatment was stopped. They did not require additional medical treatment, and there were no long-term sequelae. Other known side effects of tamsulosin, such as retrograde ejaculation, were not reported, and, overall, the drug was well tolerated with no noticeable side effects by the other eight patients. Of note, intraoperative floppy iris syndrome is another potential well-documented side effect of long-term tamsulosin use that should be discussed with patients. This was not encountered in the current study since none of the patients underwent cataract surgery during the study period.

We did not identify any clinical marker to predict which patient would be more likely to respond to oral tamsulosin treatment. The pathophysiology of eyelid retraction in TED may be multifactorial, with mechanisms other than sympathetic over-activity playing a role [3]. We hypothesise that patients with sympathetic overactivation of Müller’s smooth muscles may benefit more from the alpha-adrenergic blockade, while patients with severe inflammatory or fibrotic components of the LPS muscle may not respond as well. This hypothesis will need to be validated in future studies.

This is the first prospective interventional pilot study to assess the effect of tamsulosin on TED-related eyelid retraction. The limitations of our study are mainly its relatively small sample size in a single-centre setting.

In conclusion, tamsulosin appears to be a safe potential treatment for eyelid retraction in TED and can be used as a temporary alternative therapeutic approach for patients unsuitable for surgery. Further large-scale studies with prospective designs are warranted to establish the efficacy of this treatment.

Summary

What was known before

• Sympathetic overstimulation of Müller’s muscle is one of the suggested mechanisms underlying upper eyelid retraction in thyroid eye disease (TED). Tamsulosin, a long-acting selective alpha1-adrenoreceptor antagonist, is commonly used to treat benign prostatic hyperplasia, and has a well-known favourable safety profile.

What this study adds

• Tamsulosin improved eyelid retraction among TED patients. Tamsulosin is a safe potential treatment for eyelid retraction in TED and can be used as a temporary alternative therapeutic approach for patients unsuitable for surgery.

Author contributions

RA—analysing data, writing, editing, and reviewing the protocol and article. HG—extracting and analysing data. GBS, AP, OZ—examining patients, extracting data, and editing the manuscript. DL, TCY, NAL—extracting data and editing the manuscript, OS—study planning, analysing data, examining patients, and critical review of the manuscript.

Data availability

Data are available upon reasonable request.

Competing interests

The authors declare no competing interests.