Authors: Fidela Anne Badilles, Michael Villa
Categories: Case Report, recurrent papillary thyroid carcinoma, ethanol ablation, Horner syndrome
Source: JCEM Case Reports
Horner syndrome after ethanol ablation for radioactive iodine therapy refractory papillary thyroid carcinoma
Authors: Fidela Anne Badilles, Michael Villa
Abstract
Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid malignancy. Although it carries a favorable prognosis, especially for individuals under the age of 45, tumor recurrences in the thyroid bed still occur. In fact, recurrence rates are observed in approximately 20% of patients following initial treatment. For patients who are not candidates for surgery or radioactive iodine therapy, ethanol ablation is a treatment option for recurrences in the thyroid bed and lymph node metastases. This case report details a 31-year-old female patient with a PTC who underwent total thyroidectomy and radioactive iodine therapy. One year later, a locoregional recurrence developed in the thyroid bed. The recurrence was determined to be iodine-refractory, and due to its size and the patient's preference, surgery was not an option; hence ethanol ablation was performed. After the ethanol ablation procedure, the patient exhibited left eyelid drooping. She was diagnosed with Horner syndrome characterized by left upper eyelid ptosis, myosis, and anhidrosis. Although uncommon, Horner syndrome should still be considered as a potential postoperative complication in patients undergoing ethanol ablation for locoregional recurrence of PTC.
Introduction
Papillary thyroid carcinoma (PTC) is an epithelial malignancy with evidence of follicular cell differentiation and a set of distinctive nuclear features [1]. PTC is the most common thyroid malignancy and carries a good prognosis [1, 2]. However, despite the generally good prognosis, approximately 20% of tumor recurrences occur even after gold standard treatment [3-5]. In a study by San Juan et al, disease recurrence was noted to be highest in Filipinos [6]. PTC demonstrated more aggressive disease course in Filipino patients. Compared to patients from Korea and Japan, Filipino individuals with PTC were diagnosed younger, have larger tumor sizes, and have a higher incidence of distant metastases and recurrence rates (30.1%) [7]. Surgical resection is still the standard treatment for locoregional recurrence of PTC with a 94.8% success rate with a low rate of recurrences [8]. However, there is a higher risk of complications compared to the primary surgery [9].
Radioactive Iodine (RAI) is used as an adjuvant treatment for PTC after thyroid surgery [10]. Thyroid carcinomas lose the ability to take up iodine in approximately 25 to 50% of patients, rendering them RAI-refractory [11]. According to the 2025 American Thyroid Association guidelines, the criteria for iodine-refractory differentiated thyroid cancer include “(i) absence of ^131^I uptake on a post-therapy scan in the setting of confirmed disease visible on structural or ^18^FDG-PET imaging. This may occur at the time of initial treatment of metastatic DTC or at the time of a subsequent RAI, and/or (ii) progression of disease less than 6 months after a treatment appropriate administration of therapeutic RAI demonstrated uptake on post-therapy scans.” [12]
In such cases, patients often prefer minimally invasive procedures due to the stigma associated with complications and apprehension of undergoing repeat surgery. Surgeons may also be reluctant to perform reoperation when advanced fibrosis is present and the surgical bed has been anatomically altered by prior surgeries. For patients who are no longer suitable candidates for surgery, ethanol ablation has emerged as a viable treatment option [13]. Ultrasound-guided percutaneous ethanol ablation has been shown to be effective in some patients with recurrent thyroid cancer, even after long-term follow-up. Although ethanol ablation offers benefits for certain patient groups, it carries a higher risk of treatment failure and recurrence compared with surgical management, but with a lower risk of complications [2, 14]. Ethanol ablation may result to complications including temporary hoarseness of voice, local pain, and laryngeal nerve palsy [2]. A very rare complication that has been linked to ethanol ablation is Horner syndrome, which has only been reported in two published case reports [2, 15]. In this case report, we present a case of a patient with known RAI-refractory PTC, underwent ethanol ablation leading to Horner syndrome as a complication.
Case presentation
A 31-year-old female with no other known comorbidities was diagnosed with PTC and underwent total thyroidectomy in 2017. Post-operatively, she developed hoarseness of voice, which resolved spontaneously after 4 months. She subsequently underwent RAI with 100 mCi. Neck ultrasound, thyroglobulin, and thyroglobulin antibody levels were monitored at regular intervals.
Diagnostic assessment
Stimulated thyroglobulin levels increased significantly to 154.08 ng/mL (154.08 μg/L) from 5.16 ng/mL (5.16 μg/L) in April 2019. A total body scan (I-131) was performed and showed small iodine-avid foci in the neck representing recurrent disease, prompting a second RAI with 150 mCi. Post-RAI scan showed functioning thyroid tissue remnants in the left zone 6 of the anterior neck. Six months after the second RAI, there was a significant decrease in thyroglobulin to 3.61 ng/mL (3.61 μg/L) from 154 ng/mL (154 μg/L). Thyroglobulin levels were obtained every 6 months and were consistently suppressed. During the subsequent assessment in February 2022, the patient’s thyroglobulin level rose once again to 82.41 ng/mL (82.41 μg/L). This change raised concerns among her healthcare team, prompting further tests and evaluation of the patient’s treatment options. A neck ultrasound revealed a 0.8 cm hypoechoic nodule in the left thyroid bed. A total body scan (I-131) showed interval non-demonstration of iodine-avid foci in the anterior neck with no scintigraphy evidence of locoregional or distant thyroid metastasis. Positron emission tomography (PET) scan and computed tomography (CT) were performed to evaluate disease recurrence, demonstrating 18F-fluorodeoxyglucose uptake in the left thyroid bed compatible with de-differentiated disease. Consequently, a more aggressive management approach was considered.
The patient expressed a desire for pregnancy and was not amenable to surgery. In addition, the lesions were too small to warrant a central neck dissection. Given these factors, the patient opted for ethanol ablation as a minimally invasive treatment option.
Following the ethanol ablation, the tumor size decreased from 0.8 to 0.7 cm, accompanied by a decline in thyroglobulin levels from 82.41 ng/mL (82.41 μg/L) to 35.93 ng/mL (35.93 μg/L). A second ethanol ablation procedure was considered to achieve a desired low thyroglobulin level.
In August 2023, she underwent her second ethanol ablation procedure, Fig. 1A. After the ethanol ablation procedure, Fig. 1B, the patient exhibited symptoms marked by drooping of the left eyelid, which she initially attributed to her recurrent allergic eye irritation. However, she continued to experience persistent symptoms, prompting her to seek consultation with a neuro-ophthalmologist. During examination, the neuro-ophthalmologist observed drooping of the left upper eyelid, constriction of the left pupil (myosis), and lack of sweating (anhidrosis). As a result, she was diagnosed with Horner syndrome.
Treatment
She was given symptomatic treatment with topical pheniramine and naphazoline.
Outcome and follow-up
Six months following the second ethanol ablation, the tumor size had decreased to 0.7 × 0.5 × 0.3 cm, Fig. 1C, with a thyroglobulin level of 2.03 ng/dL (2.03 μg/L) and thyroglobulin antibody below 0.9 IU/mL (0.9 kIU/L). She reported gradual improvement of the left upper eyelid dropping over 8 to 12 months, however, it has not fully resolved.
Discussion
Horner syndrome was first noted experimentally in 1852 and was initially observed in a soldier with a gunshot injury in his neck presenting with ptosis (drooping of the upper eyelid), myosis (constricted pupil), and facial anhidrosis (absence of sweating) [16]. This syndrome was defined as oculosympathetic denervation caused by disruption to the sympathetic chain [17]. Horner syndrome is an uncommon complication associated with thyroid surgery, occurring in approximately 0.2 to 0.3% of cases. It is rare following ethanol ablation, with only two published case reports documented [2, 18, 19].
The sympathetic innervation of the eye plays a vital role in the pathophysiology of Horner syndrome. There are 3 orders of neurons involved in this tract, which end as the long ciliary nerves to supply the iris dilator and superior tarsal muscles. Central fibers, or first-order neurons, originate from the hypothalamus and descend to the midbrain and pons, extending to the C8-T2 level of the spinal cord. Second-order neurons exit at T1 level and the enter cervical sympathetic chain, then ascend to the superior cervical ganglion at C3-C4, and the third-order neurons follow the external carotid artery and internal carotid artery in the carotid plexus to go into the cavernous sinus to supply the abducens nerve, then exit the cavernous sinus, entering the superior orbital fissure to supply the ophthalmic branch of the Trigeminal nerve as long ciliary nerves [2, 17, 20]. Horner syndrome can occur as a result of disruption of the oculosympathetic pathway at any level of the 3 orders of neurons and may manifest differently depending on the level of the lesion [17, 20].
Ethanol ablation is a minimally invasive, nonsurgical treatment that utilizes ethanol to employ dehydration and protein denaturation, leading to coagulative necrosis of the targeted tissue. It also promotes inhibition of enzymatic activity in surrounding tissues, leading to fibrosis and atrophy [21]. According to Hay et al from Mayo Clinic, 83% of patients with lymph node metastasis were effectively treated by ethanol ablation, in contrast to repeat operation [13, 22]. Another reasonable alternative for this low-volume, asymptomatic, RAI-refractory thyroid bed recurrence was active imaging surveillance, but the patient opted to proceed with intervention rather than observation.
Similar to the mechanisms seen after total thyroidectomy or neck dissection, ethanol that diffuses beyond the target lesion may directly injure the stellate ganglion or cervical sympathetic trunk, or compress the cervical sympathetic chain and its communicating fibers with the recurrent laryngeal nerve. This process can result in neuropathic complications when extravasation occurs [23]. Published data suggest that the amount of ethanol administered should be individualized according to nodule size, with reported volumes ranging from as little as 0.1 mL for small lesions to as much as 3 mL for nodules exceeding 2 to 2.5 cm, although most treatments typically involve only 0.2 to 0.7 mL [13]. While studies show the relationship between ethanol volume and the risk of recurrent laryngeal nerve injury, these data are largely derived from procedures on cystic rather than solid nodules, where diffusion dynamics differ and posterior extravasation may be more difficult to predict [24]. To minimize the risk of neuropathy, the minimally effective volume of the injectate should be administered in slow, fractionated aliquots and carefully monitored using ultrasound, as even the smallest amount of extra-lesional spread can cause nerve damage [21]. Due to the high risk of damaging the recurrent laryngeal nerve, lesions in the neck’s danger triangle, including the deep and paratracheal areas, should not be treated with ethanol ablation [24].
During the ethanol ablation procedure, ultrasonography imaging revealed that tumor was situated beside the external carotid artery. As described, the oculosympathetic tract runs close to the external carotid artery before reaching the ophthalmic branch of the trigeminal nerve. During the ethanol ablation procedure, a sonologist was present and observed that the needle was precisely directed at the lesion. It can be postulated that the injection of ethanol via the needle into the patient may have induced inflammation in the surrounding region, affecting the oculosympathetic tract. Another possibility is that the ethanol that was injected into the lesion may have leaked and irritated the surrounding tissue.
There is currently no established treatment for Horner syndrome. Treatment options focus on addressing the root cause [17]. In one of the case reports that was reviewed, the patient was given high doses of prednisone to counteract the effects of ethanol; however, this only resulted in a partial decrease in the drooping of the eyelids at the 6-month follow-up visit [2]. In the case presented, there was a delay in diagnosing the complication because the patient attributed her symptoms to an allergic reaction and did not seek prompt evaluation and treatment.
Given that the incident occurred 2 weeks earlier, steroids might have been beneficial, although the response would have been variable. The patient's ophthalmologist gave symptomatic treatment with topical pheniramine and naphazoline, which afforded temporary relief of the ptosis.
Shown in Table 1 is a summary of the 2 prior case reports of Horner syndrome from ethanol ablation. The case report of Hussain Ahmed et al [2]. administered 2 mL of 95% ethanol. There was noted improvement after 6 months of administration of prednisone. Pishad et al administered 4 mL of 95% ethanol, which resulted in resolution after 2 months, after being given topical apraclonidine [15]. In our patient, a topical pheniramine and naphazoline were administered, and gradual improvement was observed over 8 to 12 months, however, the condition has not fully resolved.
Learning points
- Horner syndrome is a very rare complication of percutaneous ethanol ablation.
- Although very rare, this complication can be prevented by strict pre-procedural ultrasound assessment, accurate identification of the lesion, and minimizing patient movement throughout the procedure to avoid injury to the neural pathway.
- Early detection of Horner syndrome symptoms can reduce the severity of complications and enable early treatment.
- Thorough risk-benefit analyses and informed consent are necessary for minimally invasive procedures like ethanol injection for recurring thyroid cancer, which may involve complications such as Horner syndrome.