Teprotumumab used in patient with compressive optic neuropathy
A 65-year-old woman presented to the New England Eye Center with 4 weeks of decreased vision and 6 months of progressive ocular irritation, redness and retro-orbital pain in both eyes.
She noted an unusual prominence of her eyes but denied any double vision or pain with extraocular motility. Her medical history was notable for non-insulin-dependent diabetes, hypertension, hyperlipidemia, atrial fibrillation and a recent diagnosis of Graves’ disease, which was under good control. The patient was euthyroid and on a stable dose of methimazole. Her ophthalmic history was otherwise unremarkable, and she did not use tobacco products.
Examination and testing
Visual acuity was 20/60 in the right eye and 20/50 in the left eye; pinhole improved the vision in both eyes to 20/40. Pupils were equal in size and had a sluggish reaction to light; however, there was no relative afferent pupillary defect. IOPs were 23 mm Hg in the right eye and 25 mm Hg in the left eye. Extraocular motility testing demonstrated –3 in supraduction and –1 in abduction in the right eye, and –3 in supraduction, –3 in abduction and –1 in adduction in the left eye. The patient identified 1/7 Ishihara color plates in the right eye and 0.5/7 in the left eye. Exophthalmometry measurements were 25 mm on the right and 26 mm on the left.
The external and anterior segment exams were notable for eyelid retraction, lateral flare, eyelid edema, mild conjunctival chemosis and moderate superficial punctate keratopathy. Fundus exam was notable for a cup-to-disc ratio of 0.1 and trace bilateral optic nerve edema. There was bilateral thinning of the retinal nerve fiber layer temporally on OCT (Figure 1) and inferior, nonspecific depression of the visual field in both eyes (Figure 2).
What would you do next?
See answer below.
Compressive optic neuropathy
High-dose oral steroids (1 mg/kg) were initiated for compressive optic neuropathy with a plan to transition to IV steroids if there was improvement. Bilateral orbital decompression was considered, and an orbital CT scan was ordered for surgical planning. The Clinical Activity Score (CAS) determined that the patient was in a state of active thyroid eye disease, and an application for teprotumumab was submitted to her insurance. Thyroid labs were verified with the outside endocrinologist and did not require medication adjustment.
CT imaging demonstrated bilateral proptosis and enlargement of the extraocular muscles (Figure 3). One week after initiating high-dose oral steroids, our patient had no improvement in her ocular irritation, examination or optic nerve function, and she declined to continue steroids due to symptoms of insomnia and agitation. She was referred to ENT for endoscopic orbital decompression of the medial wall and floor. The patient was not comfortable with simultaneous bilateral orbital decompression, and surgery was planned on the more affected left side first, with subsequent right-sided decompression.
Thyroid eye disease (TED) is an autoimmune inflammatory disorder of orbital fibroblasts that is most commonly associated with Graves’ disease. In Graves’ disease, autoantibodies against the thyrotropin receptor on the thyroid gland lead to release of thyroid hormone. Orbital fibroblasts also possess a thyroglobulin receptor and, when stimulated by anti-thyroglobulin antibodies, release inflammatory cytokines and upregulate production of the hydrophilic substances hyaluronan and glycosaminoglycan. The release of proinflammatory cytokines and the osmotic draw of extracellular polysaccharides lead to local congestion and swelling of orbital tissues. In addition, stimulated orbital fibroblasts can differentiate into myofibroblasts and adipocytes, which further contribute to congestion and crowding of the orbit.
TED has a bimodal distribution in the fourth and sixth decades, with a female to male predominance of six to one. Symptoms of ocular irritation, retro-orbital pain and photophobia are common. Clinically, eyelid retraction is the most common manifestation (90% of patients), followed by exophthalmos (60%), lid lag on downgaze (50%) and restrictive extraocular motility (40%). Optic neuropathy occurs from compression at the orbital apex from orbital fat and rectus muscle expansion, occurring in 5% of TED. In the active phase, swelling and erythema of the eyelids, conjunctiva and caruncle may be seen.
Diagnosis of TED can be made when two of three findings are present: current/recent thyroid dysfunction; characteristic ocular findings; or extraocular muscle enlargement on imaging. The management of TED is informed by disease activity and severity. TED is a self-limited process with an active inflammatory phase that lasts approximately 1 year in nonsmokers and 2 to 3 years in smokers. After the active phase, inflammation slowly improves, but permanent sequelae and tissue remodeling can persist. The goal of treatment is to identify and treat patients in the active phase to reduce morbidity in the static phase. Several scoring systems exist to help identify and grade patients in the active phase of disease. The CAS is commonly used in our clinic and is the scale used to determine eligibility for teprotumumab by many major insurers.
The importance of establishing a euthyroid state and smoking cessation should be counseled in all patients with active TED, as both interventions decrease the duration of the active phase. Additionally, limiting salt intake and sleeping upright may decrease orbital fluid retention and congestion, and oral selenium supplementation may improve disease course in selenium-deficient patients. Mild cases of TED are managed with supportive care such as ocular lubrication, patching or prism glasses for strabismus and consideration of Botox (onabotulinumtoxinA, Allergan) for lid retraction or restrictive strabismus. In more severe disease, oral or intravenous steroids may be used to blunt the inflammatory response. Orbital decompression is reserved for optic neuropathy or severe exposure keratopathy that is unresponsive to medical therapy. Until recently, refractory cases were treated with radiotherapy or immunomodulatory therapy, with highly debated success rates and conflicting scientific evidence of efficacy.
In January 2020, the first and only treatment for active TED was approved by the FDA. Tepezza (teprotumumab, Horizon Therapeutics) is a human monoclonal antibody against the IGF-1 receptor. In orbital fibroblasts, a functional relationship exists between the IGF-1 receptor and the thyroglobulin receptor. Inhibition of the IGF-1 receptor attenuates activation and signaling of the thyroglobulin receptor, resulting in decreased activation of orbital fibroblasts in autoimmune TED. In clinical trials of active TED, this medication was shown to decrease proptosis by 2 mm or more in 83% of patients, with an average decrease of 3.3 mm — results comparable to single-wall orbital decompression. Compared with placebo, patients who completed 24 weeks of teprotumumab treatment were approximately three times more likely to have a CAS of 1 or less (59% vs 21%), indicating a substantial decrease in the duration of the active phase of disease. Initial teprotumumab studies excluded patients with optic neuropathy, and to date, no large, controlled trials have studied this medication as a primary treatment for TED optic neuropathy.
To date, optic neuropathy from TED has been an exclusion criterion in major teprotumumab studies, although several case series and the clinical course of our patient suggest this novel therapy may be a suitable alternative to orbital decompression in appropriately counseled patients. Our experience with teprotumumab is limited given its recent FDA approval and challenges in obtaining insurance authorization, but we have seen extraordinary responses in patients who have received this treatment.
One week before the scheduled endoscopic left medial and lateral wall orbital decompression, teprotumumab was approved. Postponing orbital decompression in the hopes of a positive response to teprotumumab was discussed; however, given the uncertainty of clinical response to this new medication and severity of our patient’s optic neuropathy, a decision was made to proceed with both teprotumumab infusion and orbital decompression. Seven days before the left endoscopic orbital decompression, she received her first infusion of teprotumumab.
Two weeks after the left orbital decompression (3 weeks after the first teprotumumab infusion), our patient returned for follow-up. On the decompressed left side, vision improved to 20/25 (from 20/40 pinhole), she was able to see all color plates on Ishihara testing, and there was a 3-mm reduction in proptosis. To our surprise, there were identical visual acuity and color plate improvements on the non-operated right side. Both eyes had marked improvements in extraocular motility with only trace residual supraduction and abduction limitations, and there was resolution of bilateral eyelid and conjunctival inflammation. Reduction in proptosis and improvement in optic neuropathy on the left side could be explained by her orbital decompression; however, the bilateral improvement in extraocular motility and inflammation cannot be explained by orbital decompression and appears to have been a result of a single teprotumumab infusion.
Our patient’s examination and symptoms continued to improve with subsequent teprotumumab infusions, and after four infusions, her visual field defects had resolved (Figure 4).
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- For more information:
- Gavin Gorrell, MD, and Alison B. Callahan, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Allison V. Coombs, DO, MS, and Nisha S. Dhawlikar, MD, MPH. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.