Fig. 9.1
Pathophysiology of thyroid eye disease. Self-tolerance to the autoantigens TSHR and IGF-1R is lost for unclear reasons. Antigen-presenting cells (APC) internalize TSHR and IGF-1R and present them to helper T cells, which become activated and may either induce B cells to produce autoantibodies (GD-IgGs) or become autoreactive T cells themselves. GD-IgGs interact with TSHR on thyroid epithelial cells, leading to follicular hyperplasia and hypertrophy. Autoreactive CD4 T cells travel to orbital tissues in response to T-cell chemoattractants and interact with orbital fibroblasts (OF), which leads to the mutual activation of both cell types. Various inflammatory cytokines are secreted by T and B cells and OFs. Each of these cell types also overexpresses IGF-1R, which can interact with GD-IgGs, resulting in cellular activation. On the surface of OFs, IGF-1R and TSHR form a physical and functional complex that can interact with GD-IgGs. Some of the OFs in TED patients may be derived from infiltrating fibrocytes derived from the bone marrow. Activated OFs can differentiate into either adipocytes or myofibroblasts and have increased hyaluronan synthesis. Together, these processes lead to the expansion of orbital soft tissue in TED
The aberrant activation of OFs in TED likely involves at least two autoantigens, the thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R). TSHR autoantibodies, a key player in the pathogenesis of GD, are detectable in up to 98 % of TED patients [41, 42]. Moreover, the titers of these autoantibodies positively correlate with TED activity and severity [42–46]. Accumulating evidence suggests that both TSHR and IGF-1R are upregulated in OFs and fibrocytes in TED [20, 47]. Further, IGF-1R-expressing T and B cells are more abundant in GD patients compared with controls [48, 49]. Immunizing mice with fragments of TSHR leads to the development of TSHR and IGF-1R autoantibodies and orbital changes that clinically, radiographically, and pathologically resemble those observed in humans with TED [50]. In vitro studies implicate both the TSHR and IGF-1R signaling pathways in the activation of OFs in TED, leading to hyaluronan synthesis, cytokine production, and fibroblast differentiation [20, 24, 25, 34, 43, 51–54]. These two receptors seem to form a physical and functional complex as immunofluorescence staining demonstrates co-localization of these receptors and blocking the IGF-1R pathway leads to attenuation of TSHR-mediated signaling as well [54–56]. Hence, these two autoantigens may work in a concerted fashion in the pathogenesis of TED.
Summary for the Clinician
OFs are the principal effector cells implicated in orbital soft tissue enlargement in TED, through hyaluronan synthesis, cytokine production, and fibroblast differentiation.
Fibrocytes are bone-marrow-derived, fibroblast-like, progenitor cells that may play a role in TED pathogenesis.
The aberrant activation of OFs and fibrocytes in TED likely involves the autoantigens TSHR and IGF-1R.
9.3 Clinical Presentation and Diagnosis
The clinical manifestations of TED mostly arise from the enlargement of the orbital soft tissues. Confined within the rigid orbital walls, such tissue enlargement leads to increased intraorbital pressure, orbital congestion, mechanical tissue compression, and further inflammation [9]. Common clinical findings in TED include exophthalmos, eyelid retraction and lateral flare, lid lag on down gaze, lagophthalmos, and strabismus. The combined effects of exophthalmos and eyelid retraction can lead to corneal exposure, with severity ranging from epithelial erosions to impending perforation. When mechanical tissue compression occurs at the orbital apex and involves the optic nerve, a compressive optic neuropathy (CON) occurs. The most useful clinical signs in diagnosing CON are decreased visual acuity, dyschromatopsia, relative afferent papillary defect (unless the condition is bilateral), and optic disc swelling or atrophy [57–59]. Visual field defects have been reported in approximately 71 % of patients with CON, but they are not specific for CON [58, 60–64].
If the clinical history and exam suggest a diagnosis of TED, thyroid status should be assessed using thyroid function tests (thyroid hormones T3 and free T4 and thyroid-stimulating hormone). Thyroid-stimulating immunoglobulin titers should be obtained, as this autoantibody is present in up to 98 % of TED patients [4, 42]. Abnormalities in these studies would support the clinical diagnosis, but false negatives may occur, especially in long-standing TED. Orbital imaging is informative but not necessary in establishing the diagnosis. Orbital computed tomography (CT) is the imaging modality of choice. The principle advantage of CT is its precise visualization of the orbital bony architecture including the orbital apex. Orbital CT is also indispensable in surgical planning for orbital decompression. Magnetic resonance imaging may show soft tissue inflammatory changes in active TED, but does not provide sufficient details about the bony anatomy [65]. Similarly, while ultrasonography can be used to measure the caliber and internal reflectivity of the extraocular muscles, it provides no information about the bony structures and is highly dependent on technician expertise [65].
TED can be classified into three categories based on the severity of subjective symptoms and objective signs (i.e., the European Group on Graves’ Orbitopathy classification): mild, moderate-to-severe, and sight-threatening disease (Table 9.1) [66]. Most cases of TED are mild and self-limited [5, 67]. Only 15–25 % of these patients progress to more severe disease [4]. Up to one third of TED patients have moderate-to-severe disease on presentation [7, 68]. Sight-threatening disease affects 4–8.6 % of TED patients [7, 57, 69]. Another severity classification system for TED is the NO SPECS classification, which generates a global score for disease severity (Table 9.2) [70]. TED can also be classified based on disease activity. There are two phases of TED: an active phase lasting from 6 to 24 months, followed by an inactive phase, where the disease plateaus and remains quiescent [71]. Active TED presents with evidence of periorbital soft tissue inflammation. The clinical activity score (CAS) uses these features of inflammation to estimate the activity of disease (Table 9.3) [72]. The VISA classification system assesses for both disease severity and activity [73].
Table 9.1
European Group on Graves’ Orbitopathy (EUGOGO) severity classification
Sight-threatening | CON and/or corneal breakdown. Immediate intervention is warranted. |
Moderate to severe | No sight-threatening TED. One or more of: lid retraction ≥2 mm, moderate-or-severe soft tissue involvement, exophthalmos ≥3 mm above normal for race and gender, inconstant or constant diplopia. Disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). |
Mild | One or more of: minimal lid retraction <2 mm, mild soft tissue involvement, exophthalmos <3 mm above normal for race and gender, transient or no diplopia, and corneal exposure responsive to lubricants. Only minor impact on daily life, insufficient to justify immunosuppressive or surgical treatment. |
Table 9.2
NO SPECS classification
Class | Grade |
|---|---|
0 | No physical signs or symptoms |
I | Only signs (eyelid retraction) |
II | Soft tissue involvement 0, absent; a, minimal; b, moderate; c marked |
III | Proptosis 0, absent; a, minimal; b, moderate; c, marked |
IV | Extraocular muscle signs 0, absent; a, limitation in extremes of gaze; b, evident restriction; c, fixation of globe(s) |
V | Corneal involvement 0, absent; a, stippling; b, ulceration; c, clouding, necrosis, perforation |
VI | Sight loss 0, VA better than 20/25; a, VA 20/30 to 20/60; b, VA 20/70 to 20/150; c, VA 20/200 or worse |
Table 9.3
Clinical activity score
Pain | Painful feeling behind globe within the last 4 weeks Pain on attempted gaze within the last 4 weeks |
Redness | Redness of eyelid(s) Redness of conjunctiva |
Swelling | Chemosis Swelling of eyelid(s) Swelling of carbuncle Increase of proptosis of ≥2 mm within the last 1–3 months |
Impaired function | Decrease in visual acuity of ≥1 line(s) on the Snellen chart within the last 1–3 months Decrease in eye movements of ≥5° within the last 1–3 months |
Summary for the Clinician
Common clinical findings of TED include exophthalmos, eyelid malposition, and strabismus.
Clinical history and exam form the basis of diagnosis for TED, but abnormalities in thyroid function and immunological tests would support the diagnosis.
Orbital CT is the imaging modality of choice for TED.
Various severity and activity grading systems exist for TED.
9.4 Management
9.4.1 Risk Factor Modifications
Three main modifiable risk factors are associated with the development of de novo or worsening TED: smoking, diabetes mellitus, and dysthyroidism. Smoking is the most important modifiable risk factor for TED [74–76]. Patients with Graves’ disease who smoke are more likely to develop TED [5, 75, 76] than nonsmokers, and patients with TED who smoke tend to have more severe disease and are less responsive to therapy [76–78]. Therefore, smoking cessation should be discussed upon diagnosis and remain a critical element of management for all patients with TED. Diabetes mellitus is an important risk factor associated with the development of CON. Patients with CON are more likely to be diabetic, and TED patients with diabetes mellitus are more likely to develop more severe CON with worse visual prognosis [60, 69, 79]. Diabetic microvasculopathy in the optic nerve may sensitize it to compressive pressure [79]. No studies have established a dose-response relationship between glycemic control and the development of CON. Nevertheless, upon diagnosing TED in a diabetic patient, it would be prudent to alert the primary care provider of this diagnosis and emphasize to the patient the importance of glycemic control.
Persistent dysthyroidism is another modifiable risk factor for more severe TED [80]. The restoration and maintenance of euthyroidism is associated with improvement of TED and should be the goal in every patient with TED [5]. Three treatment modalities are used to normalize thyroid function: radioablation using iodine−131 (RAI), antithyroid medication, and total or partial thyroidectomy. RAI therapy is associated with the development or worsening of TED in 15–35 % of patients [81–83], possibly related to the destruction of thyroid tissue, release of thyroid autoantigens, and subsequent exacerbation of the autoimmune reaction [84]. This adverse effect of RAI may be prevented or reduced by concomitant administration of low-dose (0.2 mg/kg/day) systemic oral glucocorticoids beginning 1 week prior to RAI and gradually tapered over 6 weeks following RAI [75, 82]. For patients with active TED and moderate-to-severe or sight-threatening TED, other treatment modalities such as antithyroid medication or thyroidectomy should be considered, as neither has been shown to affect the course of TED [85].
Summary for the Clinician
Smoking cessation is of paramount importance for all patients with GD and TED.
TED patients with diabetes mellitus are at increased risk to develop CON.
Euthyroidism should be achieved and maintained in all patients with TED.
RAI should be given with concomitant low-dose systemic glucocorticoids to prevent new development or exacerbation of TED.
RAI should be avoided in patients with active TED and moderate-to-severe or sight-threatening TED.
9.4.2 Mild Disease
Most cases of TED are mild, and most mild cases of TED improve spontaneously [5, 67, 86]. Nevertheless, even mild TED can have significant impact on patients’ quality of life with disturbing symptoms [87]. The mainstay of treatment for mild TED is to use conservative measures to alleviate these symptoms [88]. Ocular surface lubricating artificial tears and ointment with or without moisture chamber at night time is used to address symptoms of exposure. Cold compresses, low sodium diet, and head elevation during sleep may decrease dependent orbital edema [1, 66, 75]. Prisms or patching can be helpful for symptomatic diplopia.
Recent evidence suggests that patients with mild TED should be offered selenium supplementation upon diagnosis [88]. Selenium is a trace element incorporated into serum selenoprotein P, which acts as an antioxidant and has immunomodulatory effects [4, 75]. In a randomized controlled trial, treatment of patients with mild TED using sodium selenite (100 mg twice daily by mouth) for 6 months was associated with lower rate of progression to more severe TED and improvement in ocular involvement and quality of life compared to placebo [89]. Most of the patients in this study were from marginally selenium-deficient areas, so whether selenium supplementation would be as beneficial for those living in selenium-sufficient areas remains to be established.
Summary for the Clinician
Conservative measures are the mainstay of treatment for mild TED.
Patients with mild TED could be offered a course of selenium supplementation.
9.4.3 Moderate-to-Severe or Sight-Threatening Disease
The therapeutic approach for moderate-to-severe or sight-threatening TED depends on the activity of disease. If the disease is active, systemic glucocorticoids should be the first line of therapy with or without adjunctive low-dose external beam radiotherapy. The goal of treatment is to abort or shorten the acute inflammatory phase. If the disease is sight-threatening and is refractory to systemic glucocorticoids, then urgent orbital decompression surgery should be performed. If the disease is inactive, neither systemic glucocorticoids nor orbital radiotherapy (ORT) tend to be effective [90]. Instead, rehabilitative surgery may be considered.
9.4.3.1 Active Disease
Systemic Glucocorticoids
The current first line of therapy for active moderate-to-severe and sight-threatening TED is systemic glucocorticoids [66, 90]. In addition to having anti-inflammatory and immunosuppressive properties [91], glucocorticoids can also decrease hyaluronan synthesis by OFs [92]. Over the past two decades, five randomized controlled trials have shown that glucocorticoids are more effective when given intravenously than by mouth in treating moderate-to-severe and sight-threatening TED (response rates of approximately 80 and 60 %, respectively) [91]. The intravenous route of administration is also associated with fewer side effects (side effect rates of 56 and 85 %, respectively) [66, 93]. Therefore, intravenous glucocorticoids are currently the first line of therapy for active TED.
The optimal regimen of IV glucocorticoids for TED has not been established. The commonly used regimen is 12 infusions of methylprednisolone, 500 mg weekly for 6 weeks, followed by 250 mg weekly for 6 weeks [88, 94]. The cumulative dose should not exceed 8 g in each 12-week treatment course, and infusions should not be given on consecutive or alternate days. For patients with sight-threatening disease, especially CON, IV methylprednisolone high-dose pulse therapy is typically given: 1 g daily for three consecutive days, repeated in the second week if necessary [95]. If the response is sufficient, an oral prednisone taper is initiated upon completion of pulse therapy. Immediate orbital decompression surgery appears to have no advantage over initial pulse therapy for CON [96]. Orbital decompression surgery should be performed in cases of severe orbital congestion, if the response to pulse therapy is insufficient or if glucocorticoids are contraindicated [88, 97, 98].
Systemic glucocorticoids therapy has a multitude of adverse effects. A meta-analysis of 1,461 patients with moderate-to-severe TED treated with IV glucocorticoids reported a morbidity and mortality rate of 6.5 and 0.6 %, respectively [91]. The mortalities were due to acute liver failure and cerebrovascular or cardiovascular events [88, 99–103]. These serious systemic side effects appear to be dose related, as nearly all of these patients received a cumulative dose of 8 g or more when the fatal adverse event occurred [88]. Systemic risk factors such as uncontrolled hypertension, uncontrolled diabetes mellitus, cardiac arrhythmias, hypokalemia, or liver dysfunction including a history of viral or autoimmune hepatitis may constitute contraindications to systemic glucocorticoids therapy [99, 100, 102, 104, 105]. During each course of IV glucocorticoids therapy, patients should be carefully monitored for the development of side effects.
Summary for the Clinician
The first line of therapy for moderate-to-severe TED is 12 infusions of IV methylprednisolone, 500 mg weekly for 6 weeks, followed by 250 mg weekly for 6 weeks.
The first line of therapy for CON is IV methylprednisolone pulse therapy, 1 g daily for three consecutive days, and repeated in the second week if necessary, followed by oral prednisone taper.
For CON, if the response to pulse therapy is insufficient, emergent orbital decompression surgery is indicated.
Patients must be carefully assessed for systemic risk factors prior to initiating glucocorticoids therapy and followed closely during treatment for the development of side effects.
Orbital Radiotherapy
Low-dose external beam ORT is an adjunctive treatment for TED but its efficacy remains uncertain [106]. The effects may be mediated by interfering with the nitric oxide pathway [90, 107]. ORT can also impair the function of lymphocytes that infiltrate the orbit [106] and reduce the capability of OFs to synthesize hyaluronan [108]. Similar to glucocorticoids therapy, ORT appears to offer most utility in active TED. Whereas the effects of glucocorticoids therapy are immediate in onset but short-lasting, the effects of ORT are delayed, often taking weeks to months for the maximal clinical effect. For this reason, ORT is typically not used as the initial treatment, but rather as an adjunctive therapy to maintain remission during glucocorticoids taper, or in patients who cannot tolerate or have insufficient response to glucocorticoids therapy [108]. Whether or not the combination therapy of IV glucocorticoids with ORT truly offers additional benefit compared with IV glucocorticoids alone remains to be established [4, 93, 97, 98, 109, 110].
ORT with modern standardized protocols is well tolerated and relatively safe [111, 112]. The conventional regimen is to deliver a total of 20 Gy, divided over ten fractions, aimed at the retrobulbar tissue of each orbit [113]. Lower dosing regimens may have similar response rates and be better tolerated [111, 114, 115]. Randomized controlled studies are needed to assess not only the efficacy of ORT as adjuvant therapy but also its optimal regimen. Potential side effects of ORT include skin erythema, temporary focal alopecia, conjunctival injection, cataract, radiation retinopathy, and optic neuropathy [110–112, 114]. Uncontrolled hypertension and diabetes mellitus are contraindications to ORT due to an increased risk of de novo or deteriorating retinopathy [111]. Finally, there is a theoretical cumulative lifetime risk of up to 1.2 % of developing secondary malignancies in the radiated field after low-dose ORT [111, 112, 116]. Therefore, even though no such cases have yet been reported, ORT should be restricted to TED patients older than 35 years of age due to the long latency of these tumors.
Summary for the Clinician
ORT can be used as an adjunctive therapy for active TED with IV glucocorticoids as the first line of therapy.
The clinical effects of ORT tend to be more delayed than those of IV glucocorticoids.
The conventional protocol is to deliver a total of 20 Gy external beam radiation divided over ten fractions, but lower doses may be effective.
Uncontrolled hypertension and diabetes mellitus are contraindications to ORT due to an increased risk of retinopathy.
ORT should be restricted to patients older than 35 years of age due to a theoretical risk of secondary ORT-induced malignancy.
Novel Therapeutic Agents
Lacking in our current therapeutic armamentarium for TED are disease-modifying agents that alter the underlying pathologic process. Various novel biologic agents have been purported to be beneficial in treating moderate-to-severe TED in small, uncontrolled studies [117–122]. Yet, none have shown definitive advantage over IV glucocorticoids with or without ORT in long-term disease outcome [117–122]. Several randomized controlled trials are being conducted to assess the efficacy of three of these agents: rituximab, an IGF-1R monoclonal antibody, and zidovudine [4, 119].
Rituximab is a CD20+ B-cell-depleting monoclonal antibody. It is one of the most promising disease-modifying agents for TED [123]. Rituximab blocks B-cell proliferation and maturation (Fig. 9.1) and has been shown in several retrospective reports and open-label studies to be effective in treating moderate-to-severe and sight-threatening TED [124–132]. To date, 43 patients with TED have been treated with rituximab; disease became inactive in 91 % of these patients [123]. Importantly, the treatment effect of rituximab may occur as rapidly as within 1–3 h, making it an attractive option for sight-threatening TED [125]. Side effects have been reported in one third of the patients, most of which are infusion-related reactions [123]. Rituximab is currently reserved for patients who do not tolerate IV glucocorticoids or have disease that is refractory to conventional therapy. Three randomized controlled trials are underway to evaluate the efficacy of rituximab in treating TED.
Summary for the Clinician
Rituximab is a CD20+ B-cell-depleting monoclonal antibody that can block B-cell proliferation and maturation.
Using rituximab to treat moderate-to-severe and sight-threatening TED has shown a 91 % response rate so far in uncontrolled studies.
Large-scale randomized controlled trials to evaluate the efficacy of rituximab in treating TED are underway.
Urgent Surgical Management
Surgical management of TED is typically reserved for inactive disease. However, if sight-threatening TED is refractory to medical therapy, or if IV glucocorticoids are contraindicated or poorly tolerated, then urgent surgical management is indicated, even if the disease is active [133].
Orbital Decompression Surgery
The goal of orbital decompression surgery is to remove parts of the bony orbital walls and/or orbital fat, thereby allowing the enlarged and congested orbital soft tissues to expand into new effective orbital space, relieving intraorbital pressure [133, 134]. For patients with CON, if there is insufficient response after 3 days of IV methylprednisolone pulse therapy, urgent surgical decompression should be performed. The decompression should focus on the posteromedial orbit and the orbital apex and is shown to have a rapid and beneficial effect on vision [135–139]. Specifically, the deep medial wall including the middle and posterior ethmoidal air cells, the posteromedial orbital floor, and the posterior infraorbital strut are removed [140]. The deep lateral wall can also be decompressed to further relieve compression of the posterior orbit [4].
For patients with significant exophthalmos leading to severe exposure keratopathy, various approaches to orbital decompression can be used. The desired extent of exophthalmos reduction dictates the amount of orbital fat and the number of orbital walls to be removed. Orbital fat resection should be considered in all patients undergoing decompression. Resection of orbital fat alone can lead to an average reduction of 1.8 mm in exophthalmos [113, 141], as well as intraorbital pressure reduction [113, 135, 137, 141–145]. If CON is not present, the lateral wall is often the first choice of orbital walls to be removed, as this is associated with a lower risk of postoperative diplopia compared with medial wall or orbital floor decompression [146–148]. Traditionally, the zygoma from the frontozygomatic suture to just above the zygomatic arch is removed [140, 149, 150]. A modified technique, the deep lateral wall approach, removes the lateral wall and the marrow of the sphenoid extending to the orbital fissures and anteriorly to the orbital rim [135, 151]. This technique allows posterior axial displacement of the globe rather than horizontal or inferior displacement, thereby reducing the risk of postoperative diplopia [135, 146].
Decompression of the medial wall is most commonly performed endoscopically or externally using the transcaruncular approach. The osteotomy extends superiorly to the level of the anterior and posterior ethmoidal arteries, anteriorly to the posterior lacrimal crest, and inferiorly to the bony maxilloethmoidal strut [140]. Though rarely necessary decompression of the orbital floor can also be performed endoscopically or using a transconjunctival approach through the inferior fornix [136, 152–155]. The osteotomy extends anteriorly to the orbital rim, posteriorly to the posterior wall of the maxillary sinus, laterally to the inferior orbital fissure, and medially to the medial orbital wall. Care is taken to preserve the infraorbital canal and neurovascular bundle. Depending on the level of exophthalmos, a “balanced” decompression (medial and lateral walls) or a “three-wall decompression” (medial and lateral walls and orbital floor) may be performed [140, 151, 156].
The most common adverse effect of orbital decompression surgery is de novo or worsening diplopia [157, 158], which occurs in 10–30 % of patients [159]. This is mostly caused by the displacement of the rectus muscles away from the orbital axis [160–162]. The risk of postoperative diplopia is significantly higher with medial wall and orbital floor decompression (up to two third of patients) compared with lateral wall decompression (2–7 % of patients) [146–148]. Leaving the maxilloethmoidal strut intact reduces the risk of postoperative diplopia [163]. Medial wall decompression may also lead to sinusitis and cerebrospinal fluid leak. Orbital floor decompression carries a risk of hypoesthesia of the cheek and lower eyelid due to damage to the infraorbital nerve. Other potential complications of orbital decompression may be caused by intraoperative damage to important anatomical structures such as the optic nerve or rectus muscles. Stereotactic guidance during decompression surgery may be helpful in allowing precise localization and visualization of the extent of bone removal in real time, which may decrease the risk of iatrogenic injury to important anatomical structures [108, 164].
Temporizing Eyelid Procedures
Patients with severe exposure keratopathy due to exophthalmos and eyelid retraction may need to undergo emergent eyelid retractor recession with or without temporary suture tarsorrhaphy in addition to orbital decompression to protect the ocular surface. The eyelid retractor recession procedures will be discussed in detail in the next section. These patients should also receive intensive topical lubrication with moisture chamber. The usage of botulinum toxin has been described for upper eyelid retraction in active TED as a temporizing measure [165–167]. However, its effect is limited, delayed (by up to 48 h), and unpredictable [4]. Further, there is a risk that the adjacent superior rectus could be inadvertently affected by the toxin, leading to reduced Bell’s phenomenon, thereby exacerbating corneal exposure [4].
Summary for Clinicians
If sight-threatening TED is insufficiently responsive to IV glucocorticoids, then urgent surgical management is indicated.
To treat CON, surgical decompression needs to focus on the posteromedial orbit, relieving compression at the orbital apex.
Orbital decompression surgery to reduce exophthalmos can involve orbital fat resection and removal of parts of the lateral wall, medial wall, and, rarely, orbital floor.
The most common adverse effect of surgical decompression is postoperative diplopia, which is more common after medial wall and orbital floor decompression than lateral wall decompression.
Patients with severe exposure keratopathy in the active phase may also require eyelid retractor recession with or without suture tarsorrhaphy.
9.4.3.2 Inactive Disease
Surgical rehabilitation may be indicated for inactive TED with significant residual cosmetic and functional changes. Prior to rehabilitative surgery, TED must be nonprogressive for at least 6 months, and the patient should have been stably maintained in euthyroidism. The first step of surgical rehabilitation is orbital decompression for significant exophthalmos. The second step is extraocular muscle surgery for ocular misalignment, performed at least 3 months after orbital decompression to allow the globe to settle in its new position, and after at least 6 months of stable alignment measurements. The last step is eyelid surgery for eyelid malposition, performed at least 2 months after extraocular muscle surgery. This is because the vertical extraocular muscles can impact upper and lower eyelid positioning.
Orbital Decompression Surgery
The principles of orbital decompression in inactive TED are similar to those for active disease, as discussed in the previous section.
Extraocular Muscle Surgery
The enlargement and fibrosis of extraocular muscles in TED leads to their decreased elasticity while preserving contractility. This results in restrictive strabismus, which should be repaired by extraocular muscle recession. The inferior rectus is the most commonly affected muscle, followed by the medial rectus. Inferior rectus recession may lead to worsened lower eyelid retraction. Recession in general can worsen exophthalmos. Therefore, if both orbital decompression and extraocular muscle recessions are indicated, one should aim for overcorrection of the former in anticipation for worsened exophthalmos after the latter. Due to the complexity of the ocular misalignment in TED, the overarching goal of surgery is to restore binocular single vision in the primary position at distance and near [133]. Residual diplopia may persist in other positions of gaze. Numerous operations may be required to achieve satisfactory results.
Eyelid Surgery
Eyelid retraction repair is generally indicated for eyelid retraction of more than 1 mm, lateral flare, or asymmetry between the palpebral apertures [133]. Upper eyelid retraction may be caused by sympathetic stimulation or fibrosis of the levator palpebrae superioris or Muller’s muscle [168]. Repair requires recession of one or both of these muscles through an anterior (eyelid crease incision) or posterior (conjunctival) approach, respectively. Disinsertion of the lateral horn of the levator aponeurosis from the tarsus can correct lateral flare. Upper eyelid retraction repair has an average success rate of 70–80 % [133].
Lower eyelid retraction may occur due to fibrosis of the lower eyelid retractors or after inferior rectus recession during extraocular muscle surgery. Repair is typically performed through a posterior (conjunctival) approach, but minimally invasive techniques such as en glove lysis of the lower eyelid retractors have been described [169]. The lower eyelid retractors are disinserted from the tarsus, and a spacer is placed in between to lengthen the lower eyelid. Various organic and synthetic spacer materials have been used [170–178]. The amount of desired lower eyelid elevation determines the size of the spacer. The effect of lower eyelid lengthening can be enhanced by a lateral tarsal strip procedure and/or a tarsorrhaphy [172].
Another indication for eyelid surgery in TED is dermatochalasis and increased preaponeurotic and subdermal fat leading to the appearance of bulging eyelids. Blepharoplasty with fat excision can be performed for both upper and lower eyelids. Skin excision in the lower eyelid should be conservative as excessive excision may lead to lower eyelid retraction or ectropion [155]. In patients who have prolapsing fat but without excess skin, fat excision can also be performed through a transconjunctival approach without blepharoplasty.
Summary for Clinicians
TED must be stable and nonprogressive for at least 6 months prior to surgical rehabilitation.
TED rehabilitative surgery should be performed in the following sequence: orbital decompression, extraocular muscle surgery, and eyelid surgery.
TED-associated restrictive strabismus should be corrected by extraocular muscle recession.
Upper eyelid retraction involves recession of the upper eyelid retractors. Lower eyelid retraction repair requires both recession of the lower eyelid retractors and the insertion of a spacer graft.
Compliance with Ethical Requirements
Shannon S. Joseph and Raymond S. Douglas declare that they have no conflict of interest.
No human or animal studies were carried out by the authors for this article.
