Naphazoline eye drops for the treatment of Horner syndrome following radical thyroid cancer surgery: A case report

Abstract

Horner syndrome is a rare complication following thyroid surgery, typically presenting with ptosis, miosis, and ocular congestion. We report the case of a 30-year-old female diagnosed with papillary thyroid carcinoma who underwent left thyroid lobectomy, isthmectomy, and comprehensive left cervical lymph node dissection. On the first postoperative day, the patient developed left-sided ptosis, a constricted pupil, blurred vision, and conjunctival congestion, leading to a clinical diagnosis of Horner syndrome. Initial treatment with oral neurotrophic agents provided limited improvement, with persistent ocular symptoms. Four months postoperatively, the introduction of topical naphazoline eye drops resulted in marked improvement. Ptosis diminished, the palpebral fissure returned to normal, pupil sizes equalized, and conjunctival congestion resolved, with effects lasting approximately 2 h after each application. This case report summarizes the mechanisms of injury leading to Horner syndrome after thyroid surgery, highlighting the importance of understanding the anatomical relationship between the thyroid gland and the cervical sympathetic nerve trunk during thyroidectomy to minimize the risk of Horner syndrome. This case highlights the potential role of topical α₁-adrenergic agonists in managing postoperative Horner syndrome and underscores the need for intraoperative nerve protection strategies.

Introduction

Horner syndrome (HS) was first described by the Swiss ophthalmologist Johann Friedrich Horner in 1869. ¹ The typical clinical features of HS include ptosis, miosis, and a lack or reduction of sweating on the affected side of the face. Despite its recognition, research on HS following thyroidectomy remains limited, and its etiology is still not fully understood. Although there are previous reports of large benign thyroid tumors compressing the cervical sympathetic chain or infiltration of malignant thyroid tumors, leading to HS, the occurrence of HS as a postoperative complication of thyroid surgery is exceptionally rare and has been infrequently reported in the literature. ² Recovery from HS is unpredictable, and no therapy has demonstrated consistent efficacy. Previous reports of pharmacotherapy for HS have mainly focused on apraclonidine, an α₂-adrenergic agonist that transiently dilates the affected pupil but carries the risk of systemic hypotension and rebound congestion. To date, the use of topical naphazoline—a selective α₁-adrenergic agonist with peripheral vasoconstrictive and mydriatic effects—has not been reported for the treatment of postoperative HS. In this report, we demonstrate that naphazoline eye drops achieved both symptom relief and pupil dilation with an excellent safety profile.

Case presentation

A female patient in her early 30s was admitted in mid-March 2022 with a 3-month history of left-sided papillary thyroid cancer. The patient did not report any hoarseness, choking while drinking, sensation of food obstruction, chills, fever, cough, sputum, chest tightness, or shortness of breath and had not received any prior treatment. Physical examination revealed no abnormalities. Thyroid ultrasonography revealed a hypoechoic nodule in the left thyroid lobe, measuring 11 × 7 mm, with incomplete capsule, unclear margins, and vertical growth, classified as TI-RADS 4a. Thyroid function tests showed no significant abnormalities. Fine needle aspiration biopsy of the left thyroid nodule suggested suspicious papillary thyroid carcinoma.

On 18 March, the patient underwent left thyroid lobectomy, isthmectomy, and left-sided lymph node dissection of levels II, III, IV, V, and VI under general anesthesia. Postoperative pathology revealed multifocal micropapillary thyroid carcinoma with two tumors measuring 0.2 cm and 0.9 cm, respectively. The cancerous tissue infiltrated the surrounding fibrous adipose connective tissue.

Left central lymph nodes: four of the five lymph nodes showed metastatic cancer.

Left level V lymph nodes: five lymph nodes showed no evidence of cancer metastasis.

Left levels III and IV lymph nodes: one of the six lymph nodes showed cancer metastasis.

Left level II lymph nodes: one lymph node showed no evidence of cancer metastasis.

Pathological staging (American Joint Committee on Cancer, 8th edition): I (T1a, N1a, cM0).

On the first postoperative day, the patient developed left ptosis, slight redness on the left side of the face, a smaller left pupil compared to the right, blurred vision, and conjunctival congestion (Figure 1(a)). Initial differential diagnosis included anesthesia-related intracranial damage, myasthenia gravis, and ocular disorders. Brain magnetic resonance imaging, cervical and chest computed tomography scans, and other diagnostic tests yielded negative results. After consultations with ophthalmology and neurology specialists, a diagnosis of HS was confirmed. Following the recommendations, oral neurotrophic treatment with methylcobalamin (0.5 mg per dose, three times daily) was started. One week later, her facial redness reduced; however, the left pupil remained slightly smaller than the right, with continued blurred vision and conjunctival congestion. Treatment with methylcobalamin was continued, and diosmin was added. Four months postoperatively, the eye symptoms had not significantly improved; therefore, naphazoline eye drops were introduced. Following drug administration, the left conjunctival congestion disappeared, vision became clear, and the size of the left pupil increased, achieving equalized pupil sizes. The drug’s effect lasted 2 h. Currently, the patient intermittently uses naphazoline eye drops during working hours and remains in good general condition.

Figure 1.

Changes in the patient’s eyelid size and conjunctival congestion before and after treatment with naphazoline eye drops. (a) Before naphazoline eye drops: The left eyelid showed significant drooping compared with the contralateral side, with a narrowed palpebral fissure, constricted pupil, and conjunctival congestion and (b) After naphazoline eye drops: The left eyelid drooping improved, the palpebral fissure returned to normal, pupil sizes became equal bilaterally, and conjunctival congestion resolved.

Changes in the patient’s eyelid size and conjunctival congestion before and after treatment with naphazoline eye drops

Written consent for treatment and consent to publish de-identified data and images were obtained from the patient. The reporting of this study conforms to the Case Report (CARE) guidelines. ³

Discussion

HS, also known as cervical sympathetic nerve syndrome, is a rare complication following thyroid surgery. The overall incidence of HS after thyroid cancer surgery is approximately 0.2%, with a unilateral cervical dissection incidence of approximately 0.8% and bilateral cervical dissection incidence of approximately 1.0%. ⁴ Following cervical sympathetic nerve injury, patients typically present with ptosis, miosis, and enophthalmos on the affected side. These symptoms may be accompanied with the absence or reduction of sweating on the forehead and face. Due to incomplete eyelid closure, some patients may experience conjunctival congestion, mimicking the symptoms of eyelid inflammatory conditions in some cases.

The causes of HS are complex, and it is generally considered that its occurrence is related to cervical sympathetic nerve injury. The cervical sympathetic trunk extends from the skull base to the cervical root and consists of the superior, middle, and inferior cervical ganglia as well as interganglionic branches. This structure is typically located behind the carotid sheath, covered by the prevertebral fascia, and extends along the posterior wall of the carotid sheath, where it may sometimes adhere to the sheath (8.33%).^5,6 The distribution of the terminal nerve fibers of the cervical sympathetic nerve is extensive. Sympathetic nerves that surround the carotid artery follow the artery branches to the eye, where they innervate the dilator pupillae and levator palpebrae superioris muscles. During thyroid surgery, while performing lateral neck lymph node dissection, the dissected area typically includes the lymph nodes around the carotid sheath. In particular, dissecting lymph nodes at levels II, III, and IV frequently leads to injury of the sympathetic nerve plexus surrounding the carotid artery. Studies^7,8 have shown that HS may occur after thyroid cancer surgery because during the dissection of the lower segment of the recurrent laryngeal nerve, there is a high risk of traction and injury to the sympathetic nerve and its connections with the recurrent laryngeal nerve. Moreover, during neck dissection around the carotid sheath, pulling the common carotid artery may lead to traction and compression of the sympathetic nerve. In addition to direct injury to the nerve during surgery, thermal radiation damage to the sympathetic nerve caused by energy devices as well as postoperative factors such as inflammation, edema, and hematoma, are significant contributing factors. Furthermore, Solomon et al. ⁹ speculated that vascular supply to the sympathetic trunk may come from the inferior thyroid artery or its branches, and ligation of these vessels could cause ischemic injury to the sympathetic nerve chain. In this case, the patient developed HS on the first postoperative day. Intraoperatively, multiple lymph node metastases were detected around the left carotid sheath, with adhesions to surrounding tissues and an extensive dissection area. During carotid sheath dissection, the cervical sympathetic nerve chain and its ganglia may have been inadvertently exposed, and the process of lymph node dissection likely resulted in injury to the terminal sympathetic nerve fibers. Additionally, the patient experienced significant drainage from the left thyroid remnant after surgery, indicating postoperative inflammatory edema and hematoma compression of the sympathetic trunk as contributing factors.

Recovery from HS is difficult and largely depends on the specific injury mechanism. When the onset of HS is associated with hematoma formation, inflammation, or ligation of the inferior thyroid artery and its branches, these injuries typically result in transient nerve damage, and HS may resolve spontaneously. The reported recovery time for HS ranges from 1 to 15 months, ⁷ and complete symptom resolution is uncommon. There is no specific treatment for HS following thyroid cancer surgery, and current treatments generally involve neurotrophic agents and corticosteroids, which are effective only in a subset of patients. In this case, the patient’s symptoms did not show any significant improvement after the administration of neurotrophic agents. Four months postoperatively, the patient returned to our hospital for a follow-up visit; the eye symptoms remained largely unchanged. Subsequently, naphazoline eye drops were prescribed. After drug administration, the left conjunctival congestion disappeared, vision improved, and the size of the left pupil increased, achieving equalized pupil sizes (Figure 1(b)), ultimately leading to a favorable clinical outcome.

Naphazoline hydrochloride eye drops combine pheniramine maleate (an antihistamine) and naphazoline hydrochloride (an α₁-adrenergic agonist) and are commonly prescribed for ocular conditions such as allergic keratitis, conjunctivitis, and dry eye syndrome. Pheniramine maleate acts as an H1 histamine receptor blocker, alleviating type I hypersensitivity reactions. Naphazoline hydrochloride acts predominantly on vascular α₁ receptors to constrict conjunctival blood vessels, thereby reducing congestion, redness, and dryness; it also modulates ciliary muscle function. α₁ receptors, primarily located in the vascular smooth muscle, mediate vasoconstriction upon activation; in addition, they are present in the pupillary dilator muscle, where activation induces contraction and pupil dilation. Therefore, in addition to relieving ocular congestion, naphazoline hydrochloride can cause mild mydriasis upon application. Unlike apraclonidine, which reverses anisocoria via central α₂-receptor activation, naphazoline’s peripheral α₁-agonism directly contracts the pupillary dilator muscle and the conjunctival vasculature. This dual action mitigates both miosis and ocular congestion, thereby making it a promising symptomatic therapy for postoperative HS when autonomic recovery is incomplete.

In recent years, with the further standardization of thyroid surgery and advancements in surgical techniques, the occurrence of HS has become rare, even after thorough lateral neck lymph node dissection. However, recovery from HS remains challenging, and currently, no specific treatment has been established. Thus, it is imperative to minimize the risk of cervical zsympathetic nerve injury during surgery to reduce the incidence of HS. Surgeons must have a clear understanding of the course of the cervical sympathetic nerve, develop familiarity with its surrounding anatomical structures, and implement measures to protect the nerve intraoperatively. During dissection of lymph nodes around the carotid sheath, careful handling is essential to avoid unnecessary and excessive exposure. Performing the surgery via the least invasive approach possible is an effective way to prevent this complication. During dissection of the recurrent laryngeal nerve, precise anatomical dissection is crucial for preventing traction or injury to the sympathetic nerve or its connections with the recurrent laryngeal nerve. In patients with lateral neck lymph node metastases, recurrence, or severe adhesions of lymph nodes to surrounding tissues, excessive dissection should be avoided during lymph node clearance. For patients who develop HS postoperatively, in addition to the routine use of neurotrophic agents and steroids, symptomatic treatments with agents such as naphazoline hydrochloride eye drops can effectively alleviate HS symptoms.

The relatively short follow-up period and absence of quantitative pupillometry limit the generalizability of our findings. Future prospective studies with standardized metrics and longer observation periods are warranted to validate the clinical efficacy of α₁-agonists in the management of postoperative HS.