Hypotropia in Thyroid Eye Disease
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Disease Entity
Disease
Thyroid eye disease, also known as Graves' Orbitopathy, is an autoimmune disease associated with a current or past history of thyroid dysfunction, most commonly hyperthyroidism (4% are hypothyroid and 6% are euthyroid). However, not all patients with hyperthyroidism develop Thyroid Eye Disease. In approximately 20% of patients who do, it occurs in the six month period preceding the diagnosis; in 20% it occurs concurrently with the diagnosis, and in 40%, the features of TED present more than six months after the diagnosis of hyperthyroidism [1] . About 15% of patients with Thyroid Eye Disease suffer from a symptomatic ocular motility disturbance [2]. Thyroid eye disease (TED) course involves an initial active period characterized by inflammation and then transitions to an inactive and fibrotic period after 1 to 3 years (Douglas et al 2020).
Etiology
The etiology for Thyroid Eye Disease is under investigation and still incompletely understood. The etiology for hypotropia associated with Thyroid Eye Disease is due to a restrictive strabismus secondary to a fibrotic inferior rectus muscle.
Risk Factors
Smoking, [3]thyroid dysfunction, and a positive family history of thyroid eye disease are known risk factors.
General Pathology
Thyroid Eye Disease has an acute inflammatory phase followed by a fibrotic and stable phase. Most features associated with Thyroid Eye Disease are due to the inflammatory process which affects the eyelids and extraocular muscles.
Pathophysiology
Biopsy specimens have shown a lymphocytic infiltration compatible with a myopathy, with an autoimmune etiology. The primary target cell in the orbit for the immune process is the fibroblast (Mechanical disorders of ocular motility). There are several hypotheses about the pathophysiology of Thyroid Eye Disease.
It has been proposed that the TSH receptor may be the shared thyroid-orbital antigen [4]. Antibodies toward TSH receptor have been found in thyroid patients.
It has been proposed that the fibroblast activity may be modulated by cytokines, which are inflammatory mediators derived from T-cells [5]
There is an association between Thyroid Eye Disease and smoking. Smoking affects the immune system either by altering T-cell function and thereby changing the balance of the immune chain, or through byproducts of cigarette smoke having a direct immunological effect. Also, it has been theorized that hypoxia in smoking patients is associated with the progression of TED as well.
Recent studies and clinical trials have shown that immunomodulatory agents like teprotumumab, an insulin-like growth factor I receptor (IGF-IR) inhibitor, are beneficial in improving proptosis, clinical activity scores, diplopia, and quality of life in patients with active thyroid eye disease. [6]
Diagnosis
A diagnosis of Thyroid Disease itself is made with laboratory assessment of T3 and T4. These levels are reduced in patients who have hypothyroidism and elevated in those with thyrotoxicosis. TSH level should also be drawn; it is usually reduced for hyperthyroid patients and elevated in hypothyroid patients. In addition, the presence of thyroid autoantibodies may be found in affected patients.
History
A complete ophthalmic and medical history is necessary. Asking about thyroid function and family history of thyroid eye disease are important.
Physical examination
A comprehensive ophthalmologic examination should be carried out to evaluate patients with hypotropia due to Thyroid Eye Disease. A complete sensorimotor orthoptic evaluation should be done, including stereopsis, measurement of ductions and versions, and measurement of the ocular misalignment using prism alternate cover testing in all gaze positions. Investigation of optic nerve function should include visual field testing and color vision evaluation, as well as serial visual evoked potentials wherever indicated.
Signs
The most common signs are upper eyelid retraction, proptosis, upper eyelid lag on downgaze, periorbital edema, mechanical restriction of ocular motility causing ocular misalignment most commonly hypotropia and esotropia, exophthalmos, and compressive optic neuropathy. In the case of associated hypotropia, patients will have a vertical diplopia which may be smaller or resolved in downgaze or with a chin-up anomalous head posture. The condition is usually bilateral but is often asymmetric.
Symptoms
Ocular discomfort and epiphora, which can be due to drying of corneal epithelium from proptosis and upper eyelid retraction. Patients with hypotropia in Thyroid Eye Disease experience vertical binocular diplopia, which may improve in downgaze or when the patient adopts a chin-up head posture. In some cases, patients may experience vision loss or acute color vision changes from compressive optic neuropathy.
Clinical diagnosis
Clinically, the diagnosis of hypotropia in Thyroid Eye Disease is made with a positive cover test for hypotropia in the affected eye, sometimes together with other extraocular muscle involvement, as well as involvement of the eyelids, orbital tissues and globe (causing exophthalmos), and in some cases optic nerve compression.
Laboratory tests
T3, T4, TSI (Thyroid Stimulating Immunoglobulin), TSH (Thyroid Stimulating Hormone), and Thyroid Peroxidase Antibodies (TPO).
Imaging:
In doubtful cases, orbital imaging with CT or MRI of orbit which shows tendon sparing extraocular muscle enlargement can also help confirm the diagnosis. The extraocular muscles affected in thyroid eye disease in decreasing order of severity and frequency are inferior rectus, medial rectus, lateral rectus and superior rectus muscle.
Differential diagnosis
Differential diagnosis for Thyroid Eye Disease in general includes carotid-cavernous fistula, idiopathic orbital inflammation, myasthenia gravis, orbital neoplasm, vasculitis, sarcoidosis. Differential diagnosis for hypotropia associated with Thyroid Eye Disease includes monocular elevation deficiency, superior oblique palsy in the contralateral eye, sagging eye syndrome, or isolated superior rectus palsy.
Management
Medical therapy
Diplopia due to hypotropia associated with Thyroid Eye Disease can sometimes be managed using prisms. These can be temporary press-on Fresnel prisms or ground-in prisms in the patient’s glasses. It is often difficult to correct the diplopia in all gazes because of its incomitant nature, but prisms can usually help to provide binocular single vision in the primary position.
Recent studies have shown that Teprotumumab, an insulin-like growth factor I receptor (IGF-IR) inhibitor (a monoclonal antibody that blocks the IGF-1R signaling) infusions are beneficial in improving proptosis, clinical activity scores, diplopia, and quality of life in patients with active thyroid eye disease.[6] Teprotumumab has been shown to be effective in active as well as chronic thyroid eye disease. [7] Few reported adverse effects of this drug were muscle spasms, nausea, alopecia, diarrhea, fatigue, hyperglycemia, and hearing impairment. [7]
In addition to managing the diplopia, it is important to also manage any corneal exposure issues and/or optic nerve compression issues.
Medical follow up
The patient will need to be followed on a regular basis to monitor for any changes.
Surgery
Strabismus surgery is always done after orbital decompression surgery. Strabismus surgery is reserved for patients who are either euthyroid or have a stable condition, with measurements that are generally stable over at least a 3-6 month period. It is important for patients to know that the unstable nature of the disease process may necessitate further surgery in the future.
Forced duction testing is performed to confirm the presence and severity of mechanical restrictions. The generally accepted surgical treatment for hypotropia associated with Thyroid Eye Disease is recession of the inferior rectus muscle of the hypotropic eye. Resections are traditionally avoided. Some authors have noted that the inferior rectus recession procedure often can result in a marked overcorrection within several months following the surgery. This may happen because sutures are absorbed too quickly. To avoid this problem, non-absorbable sutures are used to prevent this late overcorrection. Because Thyroid Eye Disease is commonly bilateral, it has also been suggested that this overcorrection may be attributable to the presence of some marked restriction to upgaze in the contralateral eye [8]. Another surgical alternative, taking this theory of restriction into consideration, is bilateral asymmetric inferior rectus recession. Surgical success is commonly measured in terms of obtaining a field of binocular single vision in primary and reading positions.
Surgical follow up
Patients need to be followed postoperatively on a regular basis.
Complications
Overcorrection and under corrections following strabismus surgery for hypotropia are the main complications to be considered.
Prognosis
Most patients who have strabismus surgery for Thyroid Eye Disease obtain a significant improvement in their double vision symptoms. Sometimes patients may require the use of a small prism postoperatively to aid in maintaining binocular single vision. The reported success rate is high; 71% after one procedure and 89% after more than one procedure using fixed sutures [9].
Additional Resources
References
- ↑ Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA. Chronology of Graves' ophthalmopathy in an incidence cohort. Am J Ophthalmol. 1996 Apr;121(4):426-34.
- ↑ Scott WE, Thalacker JA. Diagnosis and treatment of thyroid myopathy. Ophthalmology 1981;88: 493-8.
- ↑ Hägg E, Asplund K. Is endocrine ophthalmopathy related to smoking? Br Med J (Clin Res Ed). 1987 Sep 12;295(6599):634-5
- ↑ Heufelder AE, Bahn RS. Graves' immunoglobulins and cytokines stimulate the expression of intercellular adhesion molecule-1 (ICAM-1) in cultured Graves' orbital fibroblasts. Eur J Clin Invest. 1992 Aug;22(8):529-37.
- ↑ Bahn RS. The fibroblast is the target cell in the connective tissue manifestations of Graves' disease. Int Arch Allergy Immunol. 1995 Mar;106(3):213-8.
- ↑ 6.0 6.1 Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, Fleming JC, Fowler BT, Marcocci C, Marinò M, Antonelli A, Dailey R, Harris GJ, Eckstein A, Schiffman J, Tang R, Nelson C, Salvi M, Wester S, Sherman JW, Vescio T, Holt RJ, Smith TJ. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med. 2020 Jan 23;382(4):341-352.
- ↑ 7.0 7.1 Kossler AL, Douglas R, Dosiou C. Teprotumumab and the Evolving Therapeutic Landscape in Thyroid Eye Disease. J Clin Endocrinol Metab. 2022 Aug 8;107
- ↑ Sprunger DT, Helveston EM. Progressive overcorrection after inferior rectus recession. J Pediatr Ophthalmol Strabismus 1993;30: 145-8.
- ↑ Mourits MP, Koornneef L, van Mourik-Noordenbos, AM et al. Extraocular muscle surgery for Graves’ ophthalmopathy: does prior treatment influence surgical outcomes? British Journal of Ophthalmology 1990;74: 481-3.
- Ansons, Alec M. and Davis, Helen. Diagnosis and Management of Ocular Motility Disorders, Third Edition.
