|Year : 2022 | Volume
| Issue : 4 | Page : 279-283
Thyroid eye disease: Etiopathogenesis and management
G Seethapathy1, VG Madanagopalan2
1 Department of Ophthalmology, Manipal Hospital, Salem, Tamil Nadu; Department of Ophthalmology, KMC, Mangalore (Mahe), Karnataka, India
2 JB Eye Hospital, Salem, Tamil Nadu, India
|Date of Submission||22-Aug-2022|
|Date of Decision||17-Sep-2022|
|Date of Acceptance||02-Oct-2022|
|Date of Web Publication||19-Dec-2022|
Department of Ophthalmology, Oculoplastic and Orbital Surgeon, Manipal Hospital, Salem, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Thyroid eye disease has been a well-recognized clinical entity related to thyroid gland dysfunction for more than a century. However, the last couple of decades devoted to specific clinical research regarding this entity has significantly contributed to understanding the etiopathogenesis of the disease that has directed further research towards true disease-modifying therapies. The authors wish to present a comprehensive review of the disease with focus on the recent advancements in management of the same.
Keywords: Autoantibodies, clinical activity scoring, disease-modifying therapies, orbital surgical management, thyroid eye disease
|How to cite this article:|
Seethapathy G, Madanagopalan V G. Thyroid eye disease: Etiopathogenesis and management. TNOA J Ophthalmic Sci Res 2022;60:279-83
| Introduction|| |
Thyroid eye disease (TED) is an autoimmune disorder that runs parallel to systemic thyroid dysfunction. It is caused by self-reactive lymphocytes that escape immune tolerance. It is one of the autoimmune inflammatory disorders that has been extensively studied and researched in the last decade, resulting in a paradigm shift in its management.
TED—synonymously known as thyroid-associated ophthalmopathy (TAO)—is characterized by the infiltration of immune cells in the orbital tissues with the activation of orbital fibroblasts. The activated orbital fibroblasts secrete inflammatory regulators, growth factors, and chemokines, thereby maintaining and amplifying the immune responses.
The interactions between the orbital fibroblasts and lymphocytes lead to the expansion and the remodelling of the orbital tissues, thereby presenting the clinical manifestations of TAO. The activated orbital fibroblasts differentiate into adipocytes and myofibroblasts and promote hyaluronic acid synthesis, all of which contribute to an increase in volume of the orbital tissues and a remodelling of the orbit. This is explained well by the “Cone Model”.
Clinical activity scoring (CAS) forms an important part of assessing disease severity. The most popular and commonly used grading systems are based on the European Group on Graves' Orbitopathy (EUGOGO) guidelines and the more extensive VISA Classification system.
TED is managed based on the phase of the disease. The acute inflammatory phase is most commonly managed medically. The recent development of immunomodulatory agents including teprotumumab is showing great promise as disease-modifying agents. Orbital radiotherapy as a second line of treatment modality also plays a limited role.
Surgery for TED is reserved in the acute phase for sight-threatening dysthyroid optic neuropathy that is non-responsive to medical therapy. In the quiescent stable phase, rehabilitative surgery is performed for the fibrotic sequelae of the disease which sequentially includes orbital surgery followed by strabismus surgery followed by eyelid surgery.
| Etiopathogenesis of Thyroid Eye Disease|| |
TED or TAO is still popularly known as Grave's disease after the eminent Irish surgeon Robert Graves who described this entity coexisting with goitrous enlargement of the thyroid gland back in the 19th century. However, the disease entity was described much earlier in ancient medical literature way back in the 12th century!
Grave's disease is an autoimmune syndrome that involves the thyroid gland, orbital tissue, and specific skin sites. The most common extra-thyroidal manifestation of Grave's disease is TED.
Genetic and environmental triggers have been implicated as causative factors. A set of genes on the short arm of chromosome 6 are referred to as the Major histocompatibility complex (MHC) region. Human leukocyte antigen (HLA) region is a part of the MHC region and HLA class 1 and class 2 molecules have been implicated in the occurrence of TED.
Skewed X chromosome inactivation has been postulated as the cause for the observed female preponderance of the disease.
The most common modifiable risk factor in TED is smoking (tobacco) which makes cessation of smoking very essential to initiation of treatment in TED.
Iatrogenic triggers for the disease including radio-iodine therapy and alemtuzumab (a humanized monoclonal antibody used in treating multiple sclerosis) have also been consistently identified.
Clinical associations or coexistence with other autoimmune conditions like myasthenia gravis and type 1 diabetes mellitus have also been observed.
TED is a T cell–mediated, autoimmune, inflammatory disease that targets the orbital fibroblasts located in the connective tissues of the orbit. These fibroblasts express thyroid-stimulating hormone receptors (TSHRs), which is the central autoantigen in TED. Recent studies have demonstrated the expression of insulin-like growth factor type 1 receptor (IGF-1R) in orbital fibroblasts in these patients. This is the clinical basis of assessing antibodies to TSHR and antibodies to IGF-1R as reliable indicators of disease activity in TED. The antigen-presenting cells that recognize these receptors activate the T lymphocytes when autoimmune tolerance is disrupted. The T cells in turn activate B cells, thereby stimulating the production of autoantibodies, promoting the expression of adhesion molecules, and producing inflammatory cytokines. These would manifest as the various clinical features of TED.
Applied anatomy and the cone model
The clinical features of TED manifest by virtue of compartmentalization of the orbital cavity. The intraconal space, extraconal space, and the orbital apex are the key anatomical compartments that, when altered by disease, manifest as the different clinical features of TED. The intraconal space comprises the posterior sclera, the recti muscles (superior, inferior, medial, and lateral recti), and their respective intermuscular septa. The muscle cone is anchored to the orbital apex and includes the posterior globe, muscle bellies, fat pad, blood circulation, optic nerve, and CSF sheath. The extraconal pad of fat is limited anteriorly by the orbital septum. Two primary pathogenic mechanisms occurring in TED during the active inflammatory phase are swelling of the extraocular muscles—predominantly recti muscles—by increased glycosaminoglycan deposition (hyaluronic acid) and expansion of orbital fat due to increased adipocyte tissue turnover. This essentially amounts to an expanding muscle cone (and its anatomical contents mentioned above) against a rigid bony orbit. This concept that simplifies the pathogenesis of TED is referred to as the cone model. This model clearly demonstrates progression of the disease in three phases, each with specific clinical manifestations.
Phase 1 is that of circumferential expansion characterized by expansion of the recti muscles and orbital fat, which happens against a limiting (rigid) bony orbit. This in turn causes forward displacement of the extraconal fat and stretching of the orbital septum.
Phase 1 progresses to phase 2 with axial elongation characterized by stretching of the extraocular muscles. Additionally, there is increased intraconal pressure which in turn can secondarily raise the intraocular pressure. The optic nerve also is mechanically stretched during this phase which by itself can contribute to optic nerve dysfunction (stretch optic neuropathy).
If not checked, the above will eventually progress to the third phase: impedance of venous outflow. This refers to impaired venous drainage of the orbit through the superior ophthalmic vein to the cavernous sinus. This in turn causes conjunctival venous flow reversal. This manifests as eyelid swelling, chemosis, and raised intraocular pressure.
Clinical course of the disease
TED follows a biphasic course originally described by F. F. Rundle as being characterized by an initial phase of rapid progression reaching its peak between 6 and 24 months (active inflammatory phase) followed by a plateau phase of varying duration and then a cold inactive phase (with incomplete regression of symptoms) and fibrotic sequelae.
TED is asymmetrically or symmetrically bilateral at presentation in most instances and in few can present unilaterally too. Patients with unilateral disease at presentation can manifest similar disease in the fellow orbit months to years later. Patients may experience retrobulbar discomfort, pain on eye movements, inability to close the eyes fully, “staring” appearance, progressive prominence of either or both eyes, binocular double vision, foreign body sensation, redness at the corners of the eye or the whole eye surface (especially on waking up), photophobia, and defective vision.
(Please note that numerous eye signs in TED have nomenclature related to the clinician who first described them. However, for ease of application in clinical practice, the author has mentioned only the specific eye signs instead of the named signs). TED can present with the following clinical signs:
Eyelid signs: Eyelid oedema, eyelid erythema, upper lid retraction, inferior scleral show lower eyelid retraction, lagophthalmos, upper eyelid lag in downgaze.
Adnexal signs: Plical congestion, caruncular congestion, chemosis, bulbar conjunctival congestion especially near the insertion of the horizontal recti muscles and lacrimal gland enlargement, axial proptosis, strabismus, ocular motility restriction, diminution of convergence, resistance of the globe to retropulsion, pupillary relative afferent pupillary defect (RAPD when unilateral) or pupillary light-near dissociation (LND) when bilateral.
The fundus in TED: The signs seen on routine fundus examination are usually related to the optic disc and include optic disc hyperaemia, disc oedema, secondary glaucomatous optic disc cupping, and diffuse disc pallor in established optic atrophy. Additionally, in cases with significant proptosis, there may be choroidal folds. Rarely, secondary vein occlusions (central retinal vein or branch retinal vein with or without macular oedema) may complicate severe TED with their characteristic clinical picture.
Clinical assessment of patients with TED
Examining patients with TED include first visit and follow-up assessments. This would start with visual acuity measurement, colour vision, pupil examination, ocular motility assessment, visual fields, intraocular pressure check, and dilated fundus examination. In addition to these, the proptosis has to be measured using a Hertel exophthalmometer.
Clinical activity score: Clinical activity scoring helps the following:
1. classifying the disease as mild/moderate/severe
2. deciding the choice of treatment
3. monitor response to treatment.
The severity of the disease was first described by Werner's NOSPECS classification (1977) from class 0 to class 6
Class 0: no signs/symptoms.
Class 1: only signs.
Class 2: soft tissue involvement with symptoms and signs.
Class 3: proptosis.
Class 4: extraocular muscle involvement.
Class 5: corneal involvement.
Class 6: sight loss.
Clinical activity scoring (CAS)
This is popularly known as Mourit's score, after Dr. Maarten P. Mourits and is the forerunner of the current clinical activity scoring systems including the popular EUGOGO guideline–based scoring and the vision, inflammation, strabismus, and appearance (VISA) classification system.
The CAS is based on four classical signs of inflammation, namely, pain, redness, swelling, and impaired function. Mourits's scoring system considers 10 items. In the presence of each, one point score is given. Patients with an inflammatory score of <4, >4 to 6, and >6 would roughly correspond to mild, moderate, and severe disease, respectively.
The 10 items of the CAS are as follows (Mourits et al.).
Pain 1: painful, oppressive feeling on or behind the globe during the last four weeks.
2: pain on attempted up, side, or down gaze during the last four weeks.
Redness 3: redness of the eyelid(s).
4: diffuse redness of the conjunctiva, covering at least one quadrant.
Swelling 5: swelling of the eyelid (s).
7: swollen caruncle.
8: increase of proptosis of >2 mm during a period of one to three months.
Impaired Function 9: decrease of eye movements in any direction of >5° during a period of one to three months.
10: decrease of visual acuity of >1 line(s) on the Snellen chart (using a pinhole) during a period of one to three months
The most popular CAS systems currently used are based on the EUGOGO guidelines in the UK and in European countries and the VISA scoring system that is more familiar in the USA and Canada.
Investigations in thyroid eye disease
Evaluation of systemic thyroid function (FT3, FT4, and TSH assays) and achieving a euthyroid state continue to remain one of the most important clinical goals of TED management. Hence, through the course of treatment periodic monitoring of thyroid function and review with the endocrinologist are very essential.
Autoantibodies in thyroid eye disease
Autoantibody assay correlate well with the CAS in almost all patients with TED. The thyroid-stimulating immunoglobulins (TSI) can be a helpful biomarker of TED.
The TSH receptor antibody (TRAb) that was discovered more than 50 years ago is thought to play a key role in the pathogenesis of TED and is found to be expressed in orbital fibroblasts. Baseline and serial TSH receptor antibody levels are very useful in monitoring disease progression and response to treatment in TED patients. Clinical studies have shown that normalization of TRAb levels over a mean of 18.5 ± 6.5 months roughly correspond to Rundle's curve. It is also interesting to note that smoking prolongs the persistence of elevated TRAb levels in patients with active TED. The IGF-1R is another autoantigen expressed in orbital fibroblasts that can cause functional complexes with TSH-R, and circulating antibodies to IGF-1R have also been consistently demonstrated in patients with active TED.
Imaging in thyroid eye disease:
Imaging of the orbits, especially the orbital apex, is one of the essentials in evaluation of the potential complication of active TED, namely, dysthyroid optic neuropathy (DON).
DON has been observed to occur via two mechanisms, both of which can be demonstrated radiologically, namely,
1. Stretch optic neuropathy that refers to straightening of the tortuous course of the orbital segment of the optic nerve
2. Apical crowding due to enlarged extraocular muscles as well as venous impedance in the posterior orbit that amounts to compressive optic neuropathy.
Though orbital ultrasound and Doppler provide limited clinical information in TED, CT helps to assess apical crowding and stretch optic neuropathy better while magnetic resonance imaging (MRI) helps to assess inflammatory activity within the muscle and orbital adipose tissue.
In addition to the above, the functional assessment of the optic nerves also include visual field assessment and visually evoked potential (VEP) recording.
Management of thyroid eye disease
The treatment of TED begins with the cessation of smoking.
Treatment of active phase of TED is primarily medical. Surgery is reserved usually for the cold, inactive TED. The core principle of medical management is orbital soft tissue volume reduction by immunomodulation.
Oral selenium of up to 200 mcg/day is found to be useful in mild TED.
Corticosteroids remain the mainstay of management of sight-threatening and acute inflammatory TED and are usually administered intravenously. Challenges faced in steroid therapy include coexistent type 1 (autoimmune) diabetes mellitus or type 2 diabetes mellitus that would need cautious monitoring and co-management. Intravenous methylprednisolone is administered as pulsed therapy in cases of severe sight-threatening DON and as weekly injections of 250 mg to 1 g per week [Figure 1]. Severe hepatotoxicity is a potentially life-threatening complication of steroid therapy but is dose-dependant and is usually seen when the cumulative dose exceeds 8 g of methylprednisolone.
|Figure 1: Clinical photograph showing the congestive signs before (a) and after (b) medical therapy with intravenous methyl prednisolone|
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Systemic sepsis, especially coexistent fungal infections, are absolute contraindications to steroid therapy in TED patients. Low-dose orbital radiotherapy (up to 20 Gy in fractionated doses) is used in conjunction with steroid therapy and may also be considered as an alternative to steroids when the latter is contraindicated. Steroid-sparing immunosuppressants like azathioprine also play a limited role in treating TED.
Immunotherapy with antigen-specific monoclonal antibodies in finding use in TED. Rituximab therapy has shown promising results, as observed in other autoimmune conditions like rheumatoid arthritis and antineutrophil cytoplasmic antibody (ANCA)-related vasculitis. The paradigm shift in the medical management of TED in the current decade is the development of teprotumumab, which is an IGF-1R antagonist antibody that is showing promise as a true disease modifying agent in TED.
Other supportive measures in TED include the use of topical tear substitutes for dry eye, nocturnal corneal protection like moist chamber or eye shield, topical antiglaucoma medication to treat secondary intraocular pressure rise that is often seen in TED patients. Visual aids for diplopia including frosted glasses and prisms are also useful in TED patients with ocular motility problems.
Surgery for thyroid eye disease
Surgery is done very rarely in the acute inflammatory phase for sight-threatening, relentlessly progressive DON that does not respond to medical therapy. Surgery is usually reserved for the fibrotic sequelae and is done electively in cold inactive TED with a low CAS. The choice of orbital surgery is based on the relative contribution of extraocular muscle enlargement versus orbital fat expansion. Orbital surgery aims at improving the disfiguring proptosis and this is done most commonly through a balanced, two-walled, orbital decompression. The deep external wall decompression is done by the lateral orbitotomy approach. The medial wall decompression is done endoscopically by the trans-nasal route or through the conjunctival (transforniceal/transcaruncular approach). Bony and soft tissue (fat decompression) are done. Anatomical studies have shown that the maximal space for orbital volume expansion is obtained by removing the fossa for the lacrimal gland in the superolateral orbit, a portion of the greater wing of sphenoid, and the basin of the inferior orbital fissure that lies lateral to the inferior orbital canal in the floor of the orbit [Figure 2].
|Figure 2: Clinical photographs of a patient before (a) and after (b) orbital decompression surgery. The resolution of proptosis can be seen in the lateral views as well (c and d)|
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Strabismus surgery is reserved for patients with severe extraocular muscle sequelae, and multiple squint surgeries with adjustable suture technique may be required in these patients. Careful patient selection and preoperative counselling are essential pre-requisites to treating strabismus in TED.
Eyelid surgery aims at improving eyelid retraction and lagophthalmos and includes surgeries on both the upper and lower eyelids. Upper eyelid surgeries include blepharoplasty, müllerectomy, levator lengthening, upper eyelid transverse blepharotomy, and upper eyelid spacer graft application [Figure 3]. Lower eyelid surgery includes lower eyelid retractor space lengthening, lateral tarsal strip procedure, and lower eyelid blepharoplasty [Figure 4]. The choice of the procedure has to be tailored to the patient's requirements.
|Figure 3: Clinical photographs of a patient before (a) and after (b) orbital decompression and eyelid surgery|
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|Figure 4: Clinical photographs of a child before (a) and after (b) eyelid surgery|
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The authors have observed both from published evidence and from evidence-based clinical experience that the most modifiable risk factor for TED is smoking (tobacco usage). Newer autoantibody assays are immensely useful in monitoring disease activity, and the development of drugs like teprotumumab have paved the way for true disease modification, thereby leading to a paradigm shift in management of the disease in the last decade.
However, unless disease modifying therapies are freely made available across the globe after multi-centre randomised control trials (level 1 evidence), the current standard medical and surgical therapies will continue to play a significant role in managing these patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]