Hearing Dysfunction After Treatment With Teprotumumab for Thyroid Eye Disease


  • The majority of teprotumumab-treated patients experienced otologic symptoms.

  • Most otologic symptoms resolved after therapy, with the exception of hearing loss.

  • Baseline hearing loss portends higher risk of worsening sensorineural hearing loss.


To characterize the frequency, severity, and resolution of hearing dysfunction in patients treated with teprotumumab for thyroid eye disease (TED).


Prospective observational case series.


Ophthalmic examination and adverse event assessment, including otologic symptoms, were performed at baseline, after infusions 2, 4, and 8, and at 6-month follow-up in consecutive patients who received at least 4 teprotumumab infusions. Laboratory test results were collected at baseline and during treatment. Audiometry, patulous eustachian tube (PET) testing, and otolaryngology evaluation were obtained for patients with new or worsening otologic symptoms, with a subset obtaining baseline and posttreatment testing.


Twenty-seven patients were analyzed (24 females, 3 males, average 56.3 years old). Twenty-two patients (81.5%) developed new subjective otologic symptoms, after a mean of 3.8 infusions (SD 1.8). At 39.2-week average follow-up after the last infusion, most patients with tinnitus (100%), ear plugging/fullness (90.9%), and autophony (83.3%) experienced symptom resolution, whereas only 45.5% (5 of 11) of patients with subjective hearing loss/decreased word comprehension experienced resolution. Six patients underwent baseline and posttreatment audiometry, 5 of whom developed teprotumumab-related sensorineural hearing loss (SNHL) and 1 patient also developed PET. Three of the 5 patients with teprotumumab-related SNHL had persistent subjective hearing loss at last follow-up. A prior history of hearing loss was discovered as a risk factor for teprotumumab-related SNHL ( P = .008).


Hearing loss is a concerning adverse event of teprotumumab, and its mechanism and reversibility should be further studied. Until risk factors for hearing loss are better understood, we recommend baseline audiometry with PET testing and repeat testing if new otologic symptoms develop. Screening, monitoring, and prevention guidelines are needed.

T hyroid eye disease (TED) is an unpredictable autoimmune disease that can significantly impact quality of life (QoL). Conventional treatments often have limited response and high relapse rates with unfavorable side effect profiles. Teprotumumab, an insulin-like growth factor I (IGF-I) receptor antibody, improves proptosis, diplopia, soft tissue inflammation, and QoL , and is the first medication approved by the US Food and Drug Administration for the treatment of TED.

Because of systemic IGF-I signaling inhibition with teprotumumab, side effects are expected. In the ear, IGF-I plays a critical physiologic role in both animals and humans. In the teprotumumab randomized controlled trials (RCTs), 10% of patients experienced mild to moderate hearing dysfunction, , which were reported to be reversible. Details regarding the timing, extent, time to resolution, and formal audiology evaluation were not provided. The mechanism of hearing impairment is unclear. It is known, however, that IGF-I deficiency is characterized by sensorineural hearing loss (SNHL).

In animal models, IGF-I trophic support is vital in the cochleovestibular ganglion’s early development, whereas lack of IGF-I leads to auditory neuron apoptosis, and IGF-I null mice have been proposed as a model of syndromic deafness. Patients with Laron syndrome, a rare congenital disorder characterized by growth hormone (GH) resistance and low IGF-I levels, develop SNHL when young, whereas treatment with recombinant IGF-I preserves hearing.

Low IGF-I is also associated with SNHL in Turner and Noonan syndromes. , In longitudinal aging studies, lower IGF-I levels are associated with an increased risk of developing age-related hearing loss. Interestingly, recombinant IGF-I successfully protects against noise-induced hearing loss in animal models , and can treat sudden-onset SNHL in humans. In one RCT of patients with sudden SNHL, IGF-I delivered through gelatin hydrogels in the middle ear outperformed intratympanic dexamethasone injections in restoring hearing.

The effect of pharmacologic IGF-I inhibition on hearing has not been previously studied ; however, case reports are beginning to emerge. As teprotumumab use expands, an understanding of otologic side effects is crucial, because significant hearing loss can profoundly affect QoL, whereas autophony interferes with daily performance. There are currently no guidelines to screen for, monitor, or treat auditory dysfunction, though surveillance has been recommended. Here we describe our single-center experience with hearing dysfunction in patients treated for TED with teprotumumab.


This is a prospective observational case series of otologic symptoms in consecutive TED patients treated with teprotumumab between February 2020 and May 2021. Institutional review board / ethics committee approval was obtained. This study adheres to the tenets of the Declaration of Helsinki as amended in 2013 and the Health Insurance Portability and Accountability Act. Informed consent was obtained from all patients.

Patients received intravenous teprotumumab (10 mg/kg for the first infusion then 20 mg/kg) every 3 weeks, with a plan for 8 infusions, as per protocol. , Patients were evaluated at baseline, after infusion number 2, 4, and 8, and at 6-month follow-up, with complete eye examination and adverse event (AE) assessment at each visit. Because of government-mandated COVID-19 vaccine production orders, teprotumumab production was halted in December 2020. Infusions were, therefore, interrupted and resumed a few weeks later for 10 patients who were monitored at baseline, throughout treatment, and after therapy. Only patients who received <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='≥’>

4 teprotumumab infusions were included.

Baseline audiometry and patulous eustachian tube (PET) testing were recommended for all patients but not enforced because of COVID-19 restrictions. PET testing is a tympanometry pressure test checking for tympanic membrane movement with regular and with forced nasal breathing through one nostril. Testing was considered baseline if performed within 1 month prior to or within 3 weeks after the first infusion. Audiometry and PET testing were also recommended to patients with new or worsening otologic symptoms during treatment. Because of COVID-19 restrictions, some patients refused testing. If numerous audiograms were available during therapy, only the latest audiogram was considered. At each follow-up, patients were asked about otologic symptoms and symptom onset/resolution (if applicable).

Audiometry included both pure tone testing (thresholds at 500, 1000, 2000, 4000, and 8000 Hz) and speech testing with word recognition scores (percentage correct of single-syllable words presented to patients at an audible level—30 dB louder than their speech reception thresholds). Patients who met American Speech-Language-Hearing Association (ASHA) criteria for ototoxicity (>20 dB pure-tone threshold shift at one frequency, >10 dB shift at each of 2 consecutive frequencies, or threshold response shifting to “no response” at 3 consecutive test frequencies) or who developed abnormal PET testing were evaluated by an otolaryngologist. If testing revealed new significant hearing loss, infusions were halted, and the patient was closely monitored.

Patient gender, ethnicity, thyroid diagnosis and treatments, presence of diabetes, hypertension, smoking status, ototoxic medication use, and history of hearing dysfunction were documented. Baseline and midtreatment (after 4 doses) laboratory data included thyroid-stimulating hormone (TSH), free thyroxine (FT4), total triiodothyronine (T3), hemoglobin A 1c (HbA 1c ), GH, and IGF-I. Patients were classified according to FT4 and T3 levels into 3 categories: normal (normal FT4 and T3), high (high FT4 or T3), or low thyroid hormone levels (low FT4), based on the reference ranges provided by each respective laboratory. TSH levels were not used in this classification, as they lag behind hyperthyroidism correction.

Patient characteristics were described using means and SDs for continuous and proportions for categorical variables. Differences between patients with and without subjective otologic symptoms, and differences between patients with audiometry data suggestive of teprotumumab-related SNHL and asymptomatic patients were characterized with descriptive analyses. Categorical variables were compared using Pearson χ 2 or Fisher exact tests, and continuous variables were compared using Student t test. P value <.05 was considered statistically significant. All statistical analyses were conducted using R 3.6.1 (R foundation for Statistical Computing).



Twenty-seven patients were analyzed—24 females (88.9%) and 3 males (11.1%) with an average age of 56.3 years (SD 15.1). Eighteen patients underwent audiometric and PET testing throughout the study: 6 baseline and posttreatment, 8 posttreatment only, and 4 baseline only. Patients had an average of 7.1 infusions (SD 1.5) and were followed for an average of 55.9 weeks (SD 15.5) after teprotumumab initiation and 39.2 weeks (SD 14.2) after completion of infusions.

Treatment for Graves disease varied. Eleven (40.7%) patients received antithyroid drugs (ATD) alone and 2 (7.4%) patients did not require treatment as they were euthyroid. Eight (29.6%) patients were treated with a combination of modalities (ATDs, radioactive iodine ablation [RAI], and/or thyroidectomy). Six (22.2%) patients underwent a thyroidectomy and 9 (33.3%) received RAI alone or in combination with other modalities.

Pertinent medical history included diabetes, prediabetes, or steroid-induced diabetes (n=9, 33.3%), hypertension (n=7, 25.9%), and subjective baseline hearing loss (n=10, 37%). Most patients had a prior history of ototoxic medication use (n=25, 92.6%) (ibuprofen, aspirin, naproxen, meloxicam, acetazolamide, furosemide, hydrochlorothiazide, paroxetine, duloxetine, vancomycin) ( Table 1 ).


Demographic and Disease Characteristics of Patients With and Without New or Worsening Subjective Otologic Symptoms.

Total (n=27) With New or Worsening Otologic Symptoms (n=22) Without New or Worsening Otologic Symptoms (n=5) P Value a
Mean/N SD/% Mean/N SD/% Mean/N SD/%
Age 56.3 15.1 56.5 13.3 55.4 23.4 .924
Sex .474
Male 3 11.1 2 9.1 1 20.0
Female 24 88.9 20 90.9 4 80.0
Number of infusions 7.1 1.5 7.3 1.4 6.4 1.7 .326
Follow-up time (since first infusion), wk b 55.9 15.5 56.3 14.1 54.4 21.8 .862
Follow-up time (since last infusion), wk b 39.2 14.2 39.6 13.4 37.9 18.7 .856
Prior Graves disease treatment
Antithyroid medication alone 11 40.7 8 36.4 3 60.0
Thyroidectomy alone 2 7.4 2 9.1 0 0.0
Radioactive iodine ablation alone 4 14.8 4 18.2 0 0.0
Multiple therapies 8 29.6 7 31.8 1 20.0
None, euthyroid 2 7.4 1 4.5 1 20.0
Thyroidectomy c >.999
Yes 6 22.2 5 22.7 1 20.0
No 21 77.8 17 77.3 4 80.0
Radioactive iodine ablation c .136
Yes 9 33.3 9 40.9 0 0.0
No 18 66.7 13 59.1 5 100.0
Diabetes .174
Yes 2 7.4 2 9.1 0 0.0
Prediabetic 7 25.9 5 22.7 2 40.0
No 18 66.7 15 68.2 3 60.0
Hypertension >.999
Yes 7 25.9 6 27.3 1 20.0
No 20 74.1 16 72.7 4 80.0
Ototoxic medication use >.999
Yes 25 92.6 20 90.9 5 100.0
No 2 7.4 2 9.1 0 0.0
Subjective baseline hearing loss .124
Yes 10 37.0 10 45.5 0 0.0
No 17 63.0 12 54.5 5 100.0
Onset of otologic symptoms (after no. of infusions) 3.8 1.8
Resolution of otologic symptoms d
Yes 13 68.4
No 6 31.6

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Sep 11, 2022 | Posted by in OPHTHALMOLOGY | Comments Off on Hearing Dysfunction After Treatment With Teprotumumab for Thyroid Eye Disease

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