Thyroid eye disease (TED) is an autoimmune inflammatory disorder that affects the periocular soft tissues. TED is associated with Graves disease (GD) and is synonymous with Graves orbitopathy/ophthalmopathy and thyroid-related orbitopathy/ophthalmopathy, among other names. The term TED is used by the authors because it is simple, universal, and understandable to patients and multidisciplinary clinicians. Although the majority of patients with TED experience mild disease, marked primarily by expansion of orbital fat volume and eyelid retraction, approximately one-third of patients experience more aggressive disease. In these cases, rapidly progressive expansion of the extraocular muscles can deliver compressive forces to the vasculature and optic nerve, threatening vision, and causes patients to have dry, bulging eyes, orbital pain, and double vision ( Fig. 18.1 ).
TED generally follows a biphasic course, with an active, inflammatory phase lasting 6 to 18 months, followed by a durable inactive, fibrotic phase. In patients who smoke, the active phase can be prolonged. This conceptual framework for the natural history of TED was first informed by Rundle’s detailed observations of two patients in 1945, and TED clinical severity over time is referred to as following Rundle’s curve. Whereas mild cases may have a barely perceptible worsening curve, more aggressive disease has a steep curve. Furthermore, after a prolonged period of quiescence and inactivity, disease reactivation may occur years later. Treatment options for active TED include immunomodulatory agents, radiation therapy, and orbital decompression surgery. Treatment options for inactive disease are primarily surgical. Because appropriate therapy, both modality and timing, is informed by an accurate understanding of disease severity and activity phase, detailed assessment and observation over time are essential.
This chapter reviews TED pathogenesis, risk factors, clinical manifestations, differential diagnosis, and disease activity classification, and includes a brief overview of TED management with consideration for the role of endoscopic surgical approaches.
Epidemiology
In the United States, the incidence of TED has been reported as 16 in 100,000 women and 3 in 100,000 men. There is a bimodal age distribution in women, peaking at 40 to 44 and 60 to 64 years. In men this bimodal distribution shifts slightly older with peaks at 45 to 49 and 65 to 69 years. Among patients diagnosed with TED, approximately 90% have hyperthyroidism, 5% are euthyroid, 3% have Hashimoto thyroiditis with hypothyroidism, and 1% have primary hypothyroidism. Of patients with Graves hyperthyroidism, 30% to 50% will experience TED, depending on diagnostic criteria. TED symptoms and signs begin at approximately the same time that hyperthyroidism is diagnosed in almost a third of patients with TED; TED onset precedes the diagnosis of hyperthyroidism in 7.5% of patients and follows it in 63%. Overall, TED and the dysthyroid state occur within 18 months of each other in 85% of cases.
Pathophysiology
The clinical signs and symptoms of TED are due to inflammation, expansion, and fibrosis of the orbital soft tissues, primarily orbital fat and the extraocular muscles. Because these soft-tissue changes occur acutely within the fixed volume of the bony orbit, their expansion displaces the globe anteriorly and can impede venous outflow, causing congestion and further expansion of orbital soft tissues. The immunologic drivers of this process include elements of both cellular and humoral immunity, including CD4 + and CD8 + T cells, mononuclear cells, and resident macrophages, which infiltrate the orbit and secrete cytokines and other mediators of inflammation.
Stimulated by autoimmune attack, orbital fibroblasts are thought to play a central role in TED ( Fig. 18.2 ). Developmentally plastic, neural crest–derived orbital fibroblast precursors can differentiate into adipocytes, causing an expansion of orbital adipose tissue. Additionally, orbital fibroblasts can produce hyaluronan, a hydrophilic, osmotically active glycosaminoglycan that accumulates locally and further exacerbates orbital edema. The extraocular muscle bodies are enlarged in early, active stages of the disease, whereas the muscle cells themselves are intact and widely separated by locally secreted hyaluronan. However, as the disease becomes inactive, the resolving inflammatory process within the muscles may result in fibrosis and strabismus.
The central role of the orbital fibroblast in TED is due to its surface expression of thyroid-stimulating hormone receptor (TSHR). The hyperthyroidism of GD is caused by autoantibodies directed against the TSHR on thyroid follicular cells, and orbital fibroblasts share this antigenic epitope. In addition, activation of helper T cells recognizing TSHR peptides presented by orbital fibroblasts or resident antigen-presenting cells leads to the local secretion of inflammatory cytokines and chemokines. Further, ligation of TSHR on orbital fibroblasts by circulating autoantibodies results in increased hyaluronan production and enhanced adipogenesis within the orbital fibroblast population. The ensuing connective tissue remodeling leads to varying degrees of extraocular muscle enlargement and orbital fat expansion. Recent studies have also described a subset of orbital fibroblasts that express CD34 are derived from bone marrow and reach the orbit and other sites of inflammation via the circulation. As these cells express particularly high levels of TSHR and are capable of producing copious cytokines and chemokines, they may represent an important subpopulation. In addition to TSHR, orbital fibroblasts from patients with TED express high levels of insulin-like growth factor 1 receptor Early studies suggested that these receptors may engage in cross-talk induced by TSHR ligation to synergistically enhance TSHR signaling, hyaluronan production, adipogenesis, and the secretion of inflammatory mediators.
Sibling and twin studies have identified the major histocompatibility complex class II as an important genetic factor involved in the development of GD. More recently, other immune regulatory or thyroid-specific genes have been implicated, including cytotoxic T-lymphocyte–associated protein 4 ( CTLA-4 ), PTPN22 , FOXP3 , CD40 , CD25 , thyrotropin receptor ( TSHR ), and thyroglobulin. Despite these findings, no consistent genetic associations have been found to be more prevalent in patients with GD and TED than in those with GD alone. Accordingly, TED likely possesses a multifactorial etiology with environmental factors contributing to epigenetic modification.
Modifiable Risk Factors
Smoking
Smoking is the most significant modifiable risk factor and may double the risk of TED. TED risk is proportional to the number of cigarettes smoked per day, and former smokers have significantly lower risk than do current smokers. In addition, patients who smoke are less responsive to therapeutic intervention. Although mechanisms underlying the association between smoking and TED are unclear, contributors may include hypoxia or the free radical production, both of which promote orbital fibroblast proliferation. A recent genome-wide expression study also found that gene expression differences, including genes affecting the immune system, may be attributable to smoking and are largely reversible after smoking cessation. With this overwhelming evidence, smoking cessation or reduction should be actively encouraged.
Radioactive Iodine Therapy
Radioactive iodine therapy (RAI) therapy has also been extensively studied as a risk factor for the development and progression of TED. Risks of 33% to 39% for RAI, 10% to 21% for antithyroid drugs, and 16% for thyroidectomy have been reported. In a large randomized study, methimazole therapy was compared with RAI treatment either with or without concurrent corticosteroids. Within 6 months of treatment, TED progression was seen in 15% of patients treated with RAI alone, in 3% of patients treated with methimazole, and in no patient treated simultaneously with RAI and corticosteroids. Patients with inactive TED do not experience this risk. These data suggest that alternative modalities for controlling hyperthyroidism should be considered during the active phase of TED for patients with moderate to severe disease. In appropriate, low-risk cases, such as nonsmokers with mild active TED, RAI with prophylactic corticosteroids may be considered and should include prophylactic corticosteroids. The best-studied regimen is oral prednisone (0.4-0.5 mg/kg per day) started 1 to 3 days after RAI therapy, continued for 1 month and tapered over the subsequent 2 months. However, lower doses of prednisone (0.2 mg/kg per day) for 6 weeks may be equally effective. Absolute contraindications to RAI include pregnancy, lactation, suspicion of thyroid cancer, or females planning pregnancy within 4 to 6 months.
Thyroid Dysregulation
Abnormal thyroid levels may increase TED risk and severity. In a retrospective study, an odds ratio of 2.8 was found for patients with more severe TED who had current thyroid dysfunction compared with patients who had milder eye disease. In a prospective study, the beneficial impact on TED of early levothyroxine supplementation beginning 2 weeks after RAI therapy was demonstrated. These data suggest that persistent hyperthyroidism or iatrogenic hypothyroidism after RAI therapy or methimazole should be avoided. The optimal thyroxine replacement protocol for prevention of hypothyroidism after RAI is presently unknown.
Hyperlipidemia
Hyperlipidemia is an emerging potential risk factor in TED. In a review of 8404 patients with GD, the use of oral statin pharmacotherapy was associated with a 40% decreased hazard for the development of TED. However, in the same study, non-statin cholesterol-lowering medication did not affect the development of TED. A subsequent cross-sectional study of 250 patients with GD found in a multivariate analysis that hyperlipidemia, both total cholesterol and low-density lipoprotein cholesterol, correlated with the presence of TED. In this analysis, TED severity did not correlate with serum lipid levels but did correlate with elevated total cholesterol. Additionally, a small, prospective, case-control study of six patients analyzed orbital adipose tissue in severe TED and identified differential expression of genetic transcripts that included upregulation of very-low-density lipoprotein and low-density lipoprotein receptor relative to control samples. These upregulated genes may reflect cellular activities central to orbital adipogenesis, including fatty acid uptake. Overall, these data suggest that cholesterol may play a role in the development and severity of TED, but additional confirmatory investigations are needed.
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) has also emerged as a possible additional modifiable risk factor in TED. In a recent retrospective study, patients with TED were screened with an OSA risk assessment tool. In these patients, the prevalence of high risk of OSA was significantly higher in patients with compressive optic neuropathy (59.2%) compared to those with noncompressive TED, controlling for sex (32.8%; P = .006). Presently unpublished data by the authors also suggest that risk of OSA in TED may be associated with worse color vision, visual fields, proptosis, and double vision. Similar to smoking, the exact pathophysiologic mechanism is unknown but is hypothesized to be related to elevated serologic and tissue inflammatory mediators, including interleukin (IL)-6, IL-8, IL-1, and tumor necrosis factor alpha. Although this hypothesis follows logically and mechanistically, additional prospective and interventional data are needed to validate this association.
Diagnosis and Clinical Workup
No single clinical finding or laboratory test is universally diagnostic of TED or its activity phase. The diagnosis is made on the basis of a careful history, physical examination, laboratory studies, and imaging studies. In cases of suspected TED, it is helpful to consider three elements that aid in establishing the diagnosis. The diagnosis of TED can be reliably established when at least two of these elements are present:
- 1.
Typical clinical features
- 2.
History of Graves hyperthyroidism or serologic evidence of autoimmune thyroidopathy
- 3.
Typical radiographic findings
Typical clinical features of TED include the classic triad of unilateral or bilateral upper eyelid retraction, exophthalmos, and extraocular motility restriction in a pattern consistent with TED (most commonly restrictive supraduction or abduction deficits). Retraction of the upper and lower eyelids is the most common and specific manifestation of TED and is present in more than 90% of patients. Other common features include lid lag in downgaze and dull orbital pain. Nonspecific symptoms include tearing, sensitivity to light, blurred vision, and ocular surface irritation. The dermal and bony manifestations of GD, dermopathy and acropachy, are relatively rare and almost never develop in patients with mild orbitopathy.
If neither current nor past hyperthyroidism can be identified, the presence of either TSHR-binding or TSHR-stimulating antibodies in a patient with a clinical presentation compatible with TED is suggestive of the diagnosis. In contrast, thyroid peroxidase (TPO) antibodies may not support the diagnosis, as the prevalence of anti-TPO antibodies in the general population is high. Although the absence of elevated TSHR autoantibodies does not rule out the diagnosis of TED, it necessitates further evaluation and/or observation over time.
Inconstancy or inadequacy of the clinical features or endocrine history warrants further investigation with imaging. The radiographic hallmarks of TED have been well described and include fusiform enlargement of the rectus muscles with relative sparing of the tendinous insertions ( Fig. 18.3 ). The most commonly enlarged rectus muscles are, in order, superior rectus/levator complex, inferior rectus, medial rectus, and lateral rectus. The oblique muscles are less commonly involved. It is important to examine the superior rectus/levator complex carefully, as the magnitude of enlargement is relatively small, but the apical volume may be disproportionately consequential to the development of compressive optic neuropathy.
Diagnostically, computed tomography (CT) and magnetic resonance imaging are equivalent and contrast is not required. Accordingly, considerations of surgical planning, radiation exposure, claustrophobia, and facility quality and location should be considered. For surgical planning, CT is preferred, as the bony walls are more clearly defined for possible decompression.
Pediatric TED may be particularly difficult to diagnose. In this setting, the clinical manifestations are often limited to progressive proptosis. The typical inflammatory signs and symptoms of the older phenotypes of the disease are strikingly absent (see Fig. 18.1 ). Proptosis in children typically results from orbital fat expansion alone. Accordingly, imaging may not be helpful diagnostically, as the typical fusiform enlargement of the rectus muscles is absent. Fat enlargement is inconspicuous when imaged by CT or magnetic resonance imaging, as there is no well-validated algorithm for assessing pathologic fat volume expansion. Similarly, very early-phase TED can present clinically with nonspecific manifestations of inflammation (i.e., conjunctival or lid injection and ocular surface irritation).
Differential Diagnosis
Despite the effectiveness of the aforementioned diagnostic approach, in a small subset of outliers in which the imaging results may be inconclusive or when there is coexisting disease, diagnosis can sometimes be difficult. The differential diagnosis of TED broadly overlaps with other conditions that may produce orbital inflammation or congestion, eyelid malposition, strabismus, and optic neuropathy.
Interpretation of the orbital imaging can also be challenging. Similar patterns of extraocular muscle enlargement can result from cavernous sinus fistula, metastatic disease, lymphoma, prior strabismus surgery, and other inflammatory pathologies. In these cases, a combined analysis of the clinical and radiographic features is required to establish the correct diagnosis. Moreover, the diagnostic picture can be further complicated by the coincidence of TED and other orbital diseases. These have included optic nerve meningioma, orbital tumors, ocular myasthenia gravis, primary open-angle glaucoma, and various retinal disorders.
Classification and Disease Activity
Given the implication of TED severity and activity on the appropriateness and effectiveness of medical and surgical intervention, accurate and reproducible disease classification is desirable. Historically, several attempts have been made to classify TED over the past 60 years. Although each system has addressed a particular clinical question, none is perfect in fulfilling all clinical and research requirements. These classification systems include NOSPECS, EUGOGO (EUropean Group on Graves’ Orbitopathy) Atlas, CAS (Clinical Activity Score), and VISA (Vision, Inflammation, Strabismus, Appearance) Classification.
The NOSPECS classification system is an acronym that describes and grades the clinical features of TED ( N : no signs or symptoms, O : only signs, S : soft-tissue signs and symptoms, P : proptosis, E : extraocular muscle involvement, C : corneal involvement, S : sight loss). Although useful as a descriptive tool in individual cases, the system does not correlate well with disease severity or activity and has been of limited use in research studies. The EUGOGO Atlas of TED is a valuable and comprehensive research tool but is time consuming to use in clinical settings. A companion to the EUGOGO Atlas is the CAS. Initially developed as a predictor of response to corticosteroid therapy, the CAS features a binary scale to describe seven clinical signs and symptoms. These include eye pain at rest, eye pain with motion, lid erythema, lid swelling, conjunctival erythema, chemosis, and caruncular edema. Although the first visit is scored out of a total of 7, follow-up visits also include an additional point for significant progression in motility restriction, proptosis, or onset of optic neuropathy. Although the CAS is useful in predicting the response to corticosteroids, it may be misleading in the patient with persistent orbital congestion, improving clinical symptoms that have not fully resolved, and in young patients and individuals of East Asian ancestry in whom compressive optic neuropathy without inflammatory signs often develops. Furthermore, its only measure of optic nerve function is Snellen visual acuity, an insensitive and nonspecific measure of optic neuropathy, and as with NOSPECS, the CAS fails to weigh appropriately the importance of optic neuropathy.
In an attempt to address these limitations, the VISA classification was introduced in 2006 by Dolman and Rootman and has been more recently adopted by the International Thyroid Eye Disease Society. The VISA classification grades severity and activity for both subjective and objective measures of TED. The recording form is a single page and data entry rows from a routine clinical examination. At the end of the form, there is a summary grade for severity and progression of each of the disease parameters individually instead of a summed grade to include all of the parameters, including quality of life. This facilitates detailed assessment and surveillance of patients with TED.
Management of Thyroid Eye Disease
When evaluating a patient with TED, differentiating between active and quiescent disease is preeminently important. Generally speaking, active inflammatory disease is managed with immunomodulation, and inactive disease is managed surgically. An exception is orbital decompression surgery, which may be considered in the active phase to relieve orbital congestion, proptosis, and optic nerve compression in the most severely affected cases. Whenever possible, surgery is postponed until the quiescent phase, when necessary interventions can be performed more safely, effectively, and predictably. The overall goal of managing a patient with TED is to support the patient, treat symptoms, monitor progression, and intervene when indicated. The goal of any medical intervention should be to improve morbidity, prevent the development of vision-threatening sequelae, and decrease the surgical rehabilitation necessary once the active phase has resolved.
The clinical evaluation and management of TED is optimally accomplished in a multidisciplinary fashion that involves endocrinologists and ophthalmologists with consultation from other specialties (e.g., radiology, otolaryngology, and radiation oncology) when indicated. Although care roles often overlap, endocrinologists typically manage the patient’s thyroid function and address the reversible risk factors for TED. The ophthalmologist monitors TED progression and intervenes with medical or surgical therapy when indicated. Management of TED should include a full discussion with the patient regarding his or her concerns and priorities.
Mild Disease
In both active and inactive mild TED, symptom relief may be achieved using supportive measures. Ocular lubrication with artificial tears or gels addresses corneal symptoms of dryness, photophobia, and foreign body sensation. The application of viscous gels or ointment at bedtime is particularly useful for patients with nocturnal lagophthalmos who may have prominent symptoms on awakening. In these cases, tape tarsorrhaphy, Glad Press and Seal wrap, or moisture chambers may also be useful. Approximately 60% of patients with mild disease experience spontaneous improvement within about 6 months, 40% remain stable, and only a few percent worsen during that period. Accordingly, most patients with mild TED can be treated with supportive care and observation. However, in some patients with mild disease, the quality of life is significantly diminished and additional intervention may be warranted.
An additional consideration is selenium supplementation. Selenium is an oral antioxidant that was studied in a prospective trial in which patients with mild TED were randomly assigned to receive selenium (100 μg twice daily), pentoxifylline (another antioxidant), or a placebo. Greater improvement in several ocular parameters as well as in quality of life was found at 6 and 12 months in patients in the selenium group. No adverse effects were identified. However, the patients in this study were from a population with marginally decreased selenium levels, leaving it unclear whether selenium supplementation is beneficial to selenium-sufficient patients or those with moderate to severe disease.
Moderate to Severe Active Disease
The goal of intervention in the active phase of disease is to decrease disease burden and reduce the magnitude or necessity of surgical rehabilitation in the subsequent inactive phase. Accordingly, immunomodulatory therapy consisting of glucocorticoids, nonsteroidal immunomodulatory agents, orbital radiotherapy, and thyroidectomy can be considered in patients with progressive TED with significant inflammatory scores and evidence of extraocular muscle involvement.
Corticosteroids
Although oral glucocorticosteroids (GCs) are commonly used in TED management, evidence from several prospective clinical trials suggests that GCs given intravenously (IVGCs) are more effective with fewer side effects. In the largest trial comparing oral GC and IVGCs, 70 patients with severe and active TED were randomly assigned to receive either oral prednisone (starting at 100 mg/day and tapered by 10 mg daily at weekly intervals for a total dose of 4.0 g) or intravenous methylprednisolone (500 mg weekly × 6 weeks then 250 mg weekly × 6 weeks for a total dose of 4.5 g). After 3 months, the composite outcome (improvement in three or more of the following: intraocular pressure, diplopia, muscle size, proptosis, lid fissure width, and visual acuity) was met in 77% of patients treated with IVGCs but in only 51% of those treated with oral GCs. However, 10% to 20% of patients experienced relapse after a course of IVGCs, and optic neuropathy may still develop in them. Compared with oral GC therapy, IVGC is associated with fewer adverse events, improved quality of life, and fewer subsequent ocular surgeries. Severe hepatotoxicity is a potential complication of IVGC therapy, but it appears to be dose dependent and is thought to occur only in patients receiving a cumulative dose greater than 8 g of methylprednisolone. Other severe complications of IVGC include cardiovascular or cerebrovascular events, autoimmune encephalitis, and liver test abnormalities greater than fourfold the upper limit of normal. Therefore relative contraindications for IVGC therapy include chronic viral infections, autoimmune diathesis, and preexisting hepatic abnormalities. Liver function should be monitored during therapy.
Nonsteroidal Immunomodulatory Agents
Nonsteroidal immunosuppressant agents have also been studied in TED, both in combination with corticosteroids and as steroid-sparing monotherapy. These agents inhibit specific points in the immunopathologic pathway of TED. Those that have demonstrated efficacy in treating TED in vivo include agents targeting T lymphocytes (e.g., teplizumab, cyclosporine), B lymphocytes (e.g., rituximab), IL-6 (e.g., tocilizumab), tumor necrosis factor (e.g., infliximab), and insulin-like growth factor 1 receptor (e.g., teprotumumab). Agents that have demonstrated in vitro efficacy target platelet-derived growth factors (e.g., imatinib), TSHR, and IL-1 (e.g., anakinra). Although these treatments may ultimately represent significant therapeutic advances, many have been studied only in small pilot studies or in case series, and true efficacy and long-term safety are yet to be determined. Additionally, intravenous immunoglobulin therapy has been found to be as effective as oral GCs with a low rate of adverse effects. However, the high cost limits its use as a first-line therapy. Somatostatin analogs were studied in four placebo-controlled trials that demonstrated no benefit and troublesome gastrointestinal side effects. There is also evidence that nonsteroidal anti-inflammatory agents may be of benefit.
Orbital Radiotherapy
Orbital radiotherapy, or ORT, has been used in treating TED for more than 80 years. Typically external beam radiation is used, but there may be a role for brachytherapy. The efficacy of ORT in TED is hypothesized to be related to the modulation of the permanent resident components of the autoimmune process. It has also been appreciated that ORT induces terminal differentiation of progenitor fibroblasts, decreases adhesion of blood-borne lymphocytes to activated endothelial cells, and reduces the secretion of proinflammatory cytokines from activated lymphocytes. Given the immunomodulatory mechanism of ORT, ideal candidates for ORT are patients in the early, active phase of TED with moderate to severe or rapidly progressive disease, including patients with significant motility deficits and thyroid eye disease–compressive optic neuropathy (TED-CON). ORT should generally be used in conjunction with corticosteroid therapy when a response to corticosteroids demonstrates the immunomodulatory therapeutic potential of ORT. Patients with mild or inactive disease will not benefit from ORT compared to the natural history of the disease. ORT has the largest effect on dysmotility, some effect on soft-tissue swelling, and minimal effect on exophthalmos. ORT may be particularly useful in cases of TED-CON and may obviate the need for surgical decompression. A large body of evidence accumulated over time suggests that ocular and systemic sequelae of ORT may be minimal when used judiciously.
Thyroidectomy
It has been observed that treatment of hyperthyroidism with either antithyroid drugs or thyroidectomy is followed by a gradual decrease in TSHR antibody levels, with disappearance in most patients after 18 months. In contrast, RAI therapy leads to an increase in TSHR antibody levels that may span a year and decline only slowly thereafter. A retrospective study compared near-total thyroidectomy with total thyroidectomy plus RAI (total thyroid ablation) in patients with active TED. Both patient groups received postoperative IVGCs as TED therapy. Using a composite outcome (proptosis, CAS, eyelid fissure height, diplopia), results at 9 months after surgery suggested that total thyroid ablation was superior to near-total thyroidectomy. The previously referenced longitudinal cohort study of 8404 patients also found that surgical thyroidectomy alone or in combination with medical therapy was associated with a 74% decreased hazard for the development of TED compared with RAI alone. Whether total thyroid ablation (or near-total thyroidectomy) is to be favored over methimazole therapy in patients with hyperthyroidism with significant TED awaits future prospective studies that directly compare these modalities.
Inactive Thyroid Eye Disease
The management of inactive TED is primarily surgical. After resolution of the active, inflammatory phase, patients often do not return to their predisease state and may be left with significant proptosis, eyelid retraction, and restrictive strabismus. It is during this period of stability that planned surgical rehabilitation can be considered. Most surgeons agree that, in the absence of vision-threatening complications, surgical intervention for TED should be performed only in patients whose disease has been inactive for at least 6 months, as demonstrated by stability of their clinical examination results, including orthoptic measurements. However, even during periods of apparent disease quiescence, reactivation of TED can occur. Recurrence of active phase orbitopathy may occur in up to 15% of cases and typically occurs at an interval of 10 years after initial onset.
Before any surgical intervention medical therapy should be optimized and a thorough discussion regarding risks and anticipated benefits of any intervention should occur with the patient. The need for each procedure is considered in an attempt to restore the patient to his or her premorbid state from both the functional and aesthetic perspectives. In cases of elective intervention, surgical rehabilitation is typically staged, proceeding in the following sequence:
- 1.
Orbital decompression surgery
- 2.
Strabismus (eye muscle) surgery
- 3.
Eyelid surgery
This progression attempts to optimize the effectiveness of each intervention and minimize the need for repeat surgery, as each procedure has an effect on the magnitude or necessity of the subsequent procedures. In the appropriate clinical context, unnecessary steps may be omitted from this surgical progression, and, occasionally, multiple steps may be combined. The gold standard for any surgical intervention should be to return the patient to the predisease state as guided by prior photographs.
Surgical Decompression of the Orbit
Surgical decompression is used to address proptosis or optic nerve compression and can involve surgical removal of orbital fat or removal of the orbital walls. It is most effectively performed when customized to the individual patient, taking into account the amount of proptosis reduction desired, the nature of the soft-tissue expansion that produced the proptosis, and the relative risk associated with each surgical approach. The surgical effect of bone removal is additive; the more bone removed, the greater the proptosis reduction. Of note, endoscopic approaches to the medial wall and floor have the advantage of easier access to the most posterior air cells, which is particularly important when the surgical goal is apical decompression. In addition, sinus outflow can be managed from an endoscopic approach, as it provides superior visualization to the deeper spaces in the periorbital sinuses.
Strabismus Surgery
TED strabismus is caused by fibrosis of the rectus muscles. Therapeutic options for double vision include prism glasses, botulinum toxin injection to the extraocular muscles, and surgical repositioning of the extraocular muscles. The goal is to provide a zone of single binocular vision in primary gaze and downgaze. Peripheral diplopia often persists but may improve after surgery. Although the most commonly affected extraocular muscles are the inferior and medial recti, it is important to consider the role of the superior recti and the secondary effect of each of these muscles in the surgical plan. Intraoperatively, forced duction testing should guide the surgical plan and recession of the Tenon capsule from the conjunctiva may improve globe rotation.
Eyelid Retraction Surgery
Upper and lower eyelid retraction can result from multiple mechanisms, including exophthalmos, fibrosis of the eyelid protractors and conjunctiva, overaction of the superior rectus–levator complex secondary to restriction of the ipsilateral inferior rectus muscle, and overaction of the Müller muscle secondary to persistent hyperthyroidism. Recession of the inferior or superior rectus muscle can also create or worsen retraction of the associated eyelid. Upper lid retraction repair has been addressed historically by a variety of surgical procedures, but the recently described full-thickness blepharotomy has the advantages of simplicity, patient comfort, speed, limited intraoperative swelling, and good outcomes in terms of lid height and contour. Lower eyelid retraction can be treated with release of the lower eyelid retractors in mild cases, but moderate to large retraction typically requires the use of spacer grafts. Options for spacer grafts include autografts (free tarsal/conjunctival, oral mucosa, nasal mucosa, or auricular cartilage), allografts (acellular dermal matrix), and xenografts (e.g., porcine acellular dermal matrix).
Considerations in Thyroid Eye Disease Optic Neuropathy
The most severe clinical manifestation of TED is vision loss due to TED-CON. Theoretical mechanisms for optic neuropathy are direct compression of the optic nerve by pathologically enlarged rectus muscles, generalized compression from enlargement of both the rectus muscles and the orbital fat resulting in annular pressure delivered to the optic nerve, and stretching of the optic nerve, typically caused by profound expansion of the orbital fat compartment. Treatment of TED-CON can be surgical or nonsurgical. Surgical treatment is effective but has limitations, including increased risks and less predictable postoperative outcomes. Moreover, decompression surgery in the acute phase does not routinely shorten the course of the orbitopathy. When performed in the presence of enlarged extraocular muscles, decompression of the orbital apex is most important. In cases of annular compression or optic nerve stretch producing optic neuropathy in stable-phase cases, reversal of the optic neuropathy can be achieved by removal of orbital fat alone.
Alternatively, when TED-CON is present in the active disease, corticosteroids can rapidly reduce inflammation and quickly improve optic nerve function. If response to corticosteroid therapy is evident in TED-CON, the addition of ORT can be considered. However, if a 2-week trial of prednisone (1 mg/kg) fails to reverse TED-CON, then the addition of ORT is unlikely to be effective. In such cases, the authors proceed to surgical decompression. The authors believe that treatment with ORT after corticosteroids favorably shortens the active phase of TED and reverses TED-CON in a high percentage of patients, allowing for corticosteroids to be discontinued without recurrence of CON. The effect of ORT is first appreciated by 4 weeks, but the full benefit may not be seen until 3 months. The dose of corticosteroids can be tapered during this period at a rate titrated against the response of the optic neuropathy. After ORT and corticosteroids reverse TED-CON and stabilize patients with TED, orbital decompression surgery can be performed electively in the stable phase, if indicated. Furthermore, the administration of ORT in moderate to severe, noncompressive disease may prevent TED-CON in a patient in who it might otherwise develop.
Conclusions
TED is an autoimmune inflammatory disease that causes significant discomfort, disfigurement, and threat to visual function. A complete understanding of the immunologic mechanisms is evolving, but the process likely involves both cellular and humoral immunity targeting developmentally plastic orbital fibroblast precursors. In patients with active TED, smoking cessation should be encouraged, RAI should generally be avoided, and patients should be screened for OSA and hyperlipidemia. Medical optimization should be achieved in conjunction with an endocrinologist, and surgical thyroidectomy can be considered in appropriate cases. Given its biphasic disease course—with the active, inflammatory phase preceding the inactive, fibrotic phase—accurate assessment of disease activity is preeminent in guiding appropriate therapy, which may be aided by use of the VISA classification system. Active-phase treatments, when indicated by rapidly progressive disease or by vision-threatening sequelae such as optic neuropathy, are typically immunomodulatory in nature and may include corticosteroids, ORT, and other immunosuppressive agents. With the exception of orbital decompression surgery, which may be considered in the active phase, surgical intervention should be deferred to the inactive phase of the disease when interventions are more safe, predictable, and effective. Although there are some exceptions, surgical rehabilitation generally should follow the sequence of orbital decompression surgery, strabismus surgery, and eyelid surgery. Future studies of immunomodulatory agents may eventually move them to the forefront of therapy for this debilitating disease.
References
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