The Comprehensive Management of Thyroid Orbitopathy

Thyroid orbitopathy is the most common cause of proptosis (bulging of the eye) in adults. Management of thyroid orbitopathy can be daunting. The goal of this review is to provide the reader a conceptual framework for understanding and treating thyroid related orbitopathy. To do this, it is necessary to look beyond the NOSPECS classification of thyroid orbitopathy. Instead we encourage readers to think about a spectrum of manifestations. Thyroid related orbitopathy represents a dynamic inflammatory process that leads to the enlargement of orbital soft tissues: fat, muscles, and connective tissue. Clinical manifestations represent the results of inflammation and soft tissue enlargement within the confines of the orbit. The clinical challenge is to determine where a given patient is in the course of the inflammatory cycle and the degree to which the ocular contents of the orbit are compromised by the processes of thyroid related orbitopathy.

The normal orbit is usually a highly compliant soft tissue complex. The most serious consequences of thyroid orbitopathy result from the loss of soft tissue compliance. Optic neuropathy results when enlarged extraocular muscles at the orbital apex compress the optic nerve. Corneal compromise occurs when fibrosis prevents lid closure and interferes with a normal Bell’s phenomena. Double vision is the result of restrictive myopathy that occurs from the fibrosis that follows inflammatory infiltration of the extraocular muscles. Generalized compressive orbitopathy can lead to orbital venous congestion, raised intraocular and orbital pressure, and frank pain.

Management of thyroid orbitopathy must be individualized. Only a minority of patients with thyroid eye disease will have significant orbital changes. The majority of patients will experience relatively mild orbital disease requiring only supportive measures. The reader will find a detailed discussion of the clinical evaluation of these patients, which forms the basis for determining who is at greatest risk for functional loss. As will be detailed below, conservative measures such as education and treatment for dry eye are often utilized for patients with noninfiltrative orbitopathy. When the disease has run its inflammatory course, surgical rehabilitation can then be performed to help restore the premorbid orbital status. For patients with infiltrative orbitopathy, early intervention may be required to preserve visual function. This often includes a trial of corticosteroids and orbital irradiation. When these interventions fail, orbital surgery during the active phase of orbital inflammation may be needed to preserve vision.

Once patients reach the quiescent phase of the orbital inflammatory cycle, surgical rehabilitation is performed. It is the goal of surgical rehabilitation to restore patients as much as possible to the orbital status that existed prior to the onset of the orbitopathy. Necessarily, surgery must be performed in a logical, staged fashion. These stages and the details of the surgical methods are discussed at length. In brief and in order, there are four stages of surgical rehabilitation97: 1. Orbital decompression surgery; 2. Strabismus surgery; 3. Eyelid margin repositioning surgery; and 4. Aesthetic restorative blepharoplasty and soft tissue repositioning. The proper sequencing of these surgeries is of critical importance as the preceding surgical stage affects the subsequent stage. Performing surgery out of sequence can result in the need for additional surgeries that could have been avoided if the proper sequence was followed. Patients with Graves’ disease often present undiagnosed with ophthalmic manifestations to the ophthalmologist. Therefore, it is essential that the ophthalmologist be familiar with the systemic manifestation of hyperthyroidism and the laboratory assessment of thyroid status. Hyperthyroidism due to Graves’ disease may be treated in a number of ways. Generally, an endocrinologist, family practitioner, or internist will manage the thyroid status. However, the ophthalmologist will find it very helpful to be conversant in the treatment of the hyperthyroidism of Graves’ disease. Recent evidence has shown that the treatment of the hyperthyroidism with radioactive iodine is associated with an exacerbation of the orbitopathy. This has generated the need for consultation between the endocrinologist and the ophthalmologist when thyroid ablation with radioactive iodine is contemplated.

Thyroid Related Orbitopathy

A. Pathogenesis and Pathophysiology

1. Spectrum of autoimmune disease Clinical evidence of orbitopathy is present in 25-50% of individuals with Graves’ disease.106 It is significant that orbitopathy is also associated with Hashimoto’s thyroiditis, and can also be seen in individuals with no thyroid disease, so called euthyroid Graves’. Approximately 80% of individual who develop thyroid related orbitopathy do so within 18 month of detection of the thyroid disorder.34 In the majority of individuals who remain euthyroid there is laboratory evidence of an autoimmune process directed at the thyroid including antibodies to thyroid peroxidase, thyrotropin receptors, or in vitro antibody dependent, cell mediated cytotoxicity against thyroid follicular cells.90

A number of studies have evaluated environmental and immunogenetic factors in the development of thyroid related orbitopathy. The strongest environmental factor is cigarette smoking.62,84,94 In fact women with Graves’ hyperthyroidism predominate over men as much as 7:1. However the sex distribution among individuals with thyroid related orbitopathy is more equal.22,52 It has been suggested the higher prevalence of cigarette smoking among men and a role for smoking in the etiology of the orbitopathy accounts for this difference.94 If this is true then it can be expected that studies in the future will document a larger number of women with thyroid orbitopathy reflecting their increased prevalence as smokers. The actual basis for this observation is unknown but smoking may effect immune modulation or enhance the release of autoantigens from the thyroid. Various HLA types have been associated with Graves’ orbitopathy especially HLA-DR3 but no specific gene has been found to confer strong susceptibility.25 Therefore, it is currently thought that certain genetic characteristics together with appropriate environmental factors give rise to thyroid relate orbitopathy.

2. Cellular responses It has been suggested that in patients with Graves’ disease, circulating T cells directed against an antigen on the thyroid follicular cells recognize this same antigen on orbital fibroblasts. The activated T cells come to infiltrate the orbit and interact with orbital fibroblasts. As a result cytokines including interferon-gamma, interleukin-1alpha, and tumor necrosis factor beta are released into the surrounding tissues. These or other cytokines facilitate the expression of immune modulator proteins including the 72 kDa heat shock protein. The resulting chronic stimulation of the orbital fibroblasts appears central to the production and accumulation of glycosaminoglycans in the orbit thereby increasing tissue volume.5

Orbital infiltration primarily composed of activated T cells, some B cells and lessor numbers of macrophages and mast cells is accompanied by the activation of orbital fibroblasts and the production of glycosaminoglycans. Orbital histopathology demonstrates an increase in glycosaminoglycans in the connective tissue of patients with thyroid related orbitopathy.15 The orbital fibroblasts which produce the glycosaminoglycans are thought to be important effector cells in this process.4 These hyrdophilic macromolecules result in enlargement of the orbital fat and muscle. Proptosis results from the increase in orbital volume. Ultimately the mucinous edema is eventually replaced by fibrosis and fatty infiltration. Initial orbital changes are characterized by increased orbital volume, vascular congestion, and inflammation. The inflammation does not damage the muscle fibers.16 Rather, the infiltrate evolves into a fibrotic condition resulting in a restriction in the muscle. Muscle fibrosis coupled with increase muscle volume results in restrictive dysmotility and diplopia. The inferior rectus muscle is most frequently involved leading to a common clinical finding of restricted ocular motility and elevated intraocular pressure in up gaze.26,58 Patients may present with a chin up position in severe cases.

B. Clinical presentation

1. Clinical syndromes Acute changes in the orbit relate both to the increased orbital volume and to orbital inflammation. Inflammation is associated with orbital pain, particularly with eye movement, chemosis, and eyelid erythema and edema. Increase volume of extraocular muscle can result in proptosis. It has also been demonstrated that muscle enlargement may result in vascular obstruction contributing to proptosis, an element in the syndrome of compressive orbitopathy.45 This syndrome is not widely appreciated and needs to be distinguished from compression of the optic nerve at the orbital apex. Recent studies with direct orbital manometery have elegantly demonstrated that there is an increase in obital pressure with thyroid related orbitopathy. 86 It is clear that compression at the orbital apex can compromise and elevate the optic nerve, but now there is evidence that the reduced orbital compliance and elevated orbital pressure can also create a situation of optic nerve compromise associated with elevated intraocular pressure.18 This may be related to venous congestion. This syndrome has generally been interpreted as glaucoma but is not truly glaucoma.47 It has been clearly shown that in this situation, intraocular pressure responds to orbital decompression surgery.20

Contrast this situation to a more localized optic nerve compromise when there is sufficient enlargement of the extraocular muscles at the orbital apex (Figure 2). The resulting optic nerve dysfunction is known as thyroid related compressive optic neuropathy. This is reported to occur in 5-8% of individuals with thyroid related orbitopathy. In some cases, muscle enlargement is primarily limited to the orbital apex with very little or no associated proptosis. In the absence of a high index of suspicion these cases of optic neuropathy may be under diagnosed.

Clinically, patients describe symptoms consistent with dry eye syndrome including grittiness or foreign body sensation, blurred vision, photophobia, lacrimation, epiphora. Other complaints may include a deep orbital pain, and double vision. Patients may notice and complain of certain signs including diplopia, conjunctival chemosis and injection, altered color perception, and abnormal lid position. Table 3 lists the eponymous signs associated with these findings. Patients and close family may be unaware of even significant proptosis. It is often helpful to review family photography albums with the patient in order to date the onset of proptosis or eyelid retraction. Younger patients are more likely to present with chronic orbital changes. In contrast, older patients are more likely to present with acute or subacute orbitopathy and typically have a more severe presentation. Overall, younger women are affected more commonly but men older than 50 present with more severe orbital involvement.52

2. Classification systems The orbital status has been traditionally classified using the system developed by Sidney Werner and adopted by the American Thyroid Association in 1969 (table 4).115 This is the so called NOSPECS classification system. Various indexes have been developed based on this system. It is widely criticized because used as a disease index it enjoys poor intraobserver agreement and has no prognostic value.35,69 Additionally patients with the same score may be blind at one extreme or have minimal soft tissue changes at the other. The NOSPECS system does not reflect the disease process in a precise or meaningful way. From a pedagogic standpoint, the NOSPEC classification creates a flawed paradigm for understanding thyroid orbitopathy. Intentionally or not, the classification implies a linear progression from one class to the next. However, thyroid related orbitopathy is a complex, dynamic, and nonlinear process.

It was the consensus opinion of committees for the American Thyroid Association and several other international thyroid associations that the NOSPECS system be abandoned for the objective assessment of thyroid related orbitopathy and essentially only be retained for the purposes of reminding the clinician of the orbital changes associated with the condition. The interested reader is referred to a recent excellent review on the classification of thyroid orbitopathy.8 Other systems have been proposed that more closely match clinical orbital practice but there are no well defined classification systems that are satisfactory. 68 Consequently, a number of clinical parameters are evaluated to define a baseline for follow up assessment.

C. RUNDLE’S CURVE

In a landmark study Rundle followed the natural history of 226 patients with thyroid ophthalmopathy.89 He described how orbital changes followed a typical cycle of disease activity. This cycle described by Rundle’s curve has three phases. The initial dynamic phase is associated with eyelid retraction and proptosis. Inflammation is most active and it is during this phase that the most dramatic orbital changes occur. This phase is followed by a static phase where little improvement occurs. And finally there is a quiescent phase where there may be gradual improvement in lid retraction and a degree of improvement in ocular motility. As Rundle and Hales demonstrated in a 15 year follow up study, proptosis improves very little even over long periods of time.38 Of the original 226 patients studied, 104 were available for follow up examination at 15 years. In 75 patients the proptosis was unchanged and worse another 24. Proptosis had regressed in only 5 patients fifteen years after the onset of their disease. Therefore much of the increase in orbital content volume represents an irreversible change. What had improved in many of these patients was upper lid retraction. In 60% upper eyelid retraction had disappeared, leaving about 50% of patients with conspicuous orbital changes 15 years after their initial presentation. Other long-term studies are consistent with these results. 9

It is essential to fix the concept of Rundle’s curve in one’s mind when evaluating thyroid related orbitopathy. The processes are dynamic and an essential part of treatment planning rests on determining where a particular patient is in the inflammatory cycle described by Rundle. As will be discussed, orbital treatment varies depending on disease activity.

D. Clinical Assessment

Clinical assessment includes a through medical history, which explores thyroid status. Then orbital symptoms are elicited. Old photographs are invaluable in dating the onset of orbital changes (Figure 3). The orbital examination routinely includes a refraction for best corrected visual acuity, exophthalmometery, evaluation of orbital compliance as judged by increase resistance to retrodisplacement of the globes, ocular motility conveniently evaluated with red cover testing, color vision, contrast sensitivity, pupillary testing, confrontational visual fields, basic tear secretion, slit lamp biomicroscopy, applanation tonometery in primary, up and down gaze, and dilated fundoscopic examination. Ptosis should prompt consideration of myasthenia gravis which may rarely co-exist in the setting of thyroid related orbitopathy. Thyroid function testing is indicated if the patient’s thyroid status is unknown and this is discussed above in the section on the management of hyperthyroidism. Visual fields, color vision testing, and in selected cases, visual evoked potential, which are very sensitive, may be helpful in detecting optic neuropathy.74 Imaging is necessary when investigating optic neuropathy to evaluate orbital crowding and when planning orbital decompression. Typically there is enlargement of the extraocular muscle belly and crowding of the orbital apex may be evident. Recent studies have investigated the value of magnetic resonance imaging T2 relaxation times and ultrasonographic eye muscle reflectivity in predicting response to immunosuppresive treatment. 76,83 Both techniques rely on the fact that acutely inflamed and swollen muscles have different physical properties than fibrotic muscles. Another recently reported technique is color orbital Doppler.73 Color Doppler imaging is able to detect venous stasis in the orbit by detecting posteroanterior venous blood flow, a reversal of normal blood flow, a situation most common in apically crowded orbits.

E. Clinical Management

Rootman roughly divides patients into two categories: Noninfiltrative and infiltrative.87 This corresponds to Nunnery’s concept of type I and II disease.75 About 90% of individual with thyroid related orbitopathy have noninfiltrative or type I disease. They have mild symptoms, lid retraction, and minimal if any proptosis with soft orbits. These individuals tend to be younger. Infiltrative thyroid related orbitopathy tends to occur in older individual and consists of significant soft tissue changes, marked proptosis, infiltrative myopathy with diplopia, and compressive optic neuropathy. When a patient is first examined, it is essential to determine where their disease process is along Rundle’s curve. Early in the inflammatory course inflammatory signs predominate with conjunctival injection, pain, lacrimation, tearing and chemosis. As inflammation resolves orbital congestive signs particularly for cases of infiltrative orbitopathy may come to predominate. Congestive signs relate to reduced orbital compliance and impaired venous drainage. These signs include dilated conjunctival vessels, increased intraocular pressure, and signs of optic neuropathy and eyelid swelling in the absence of orbital inflammation(Figure 4). Imaging may demonstrate enlargement of the superior ophthalmic vein due to apical enlargement of the extraocular muscles impeding posterior drainage of the ophthalmic vein. 17 The management of an individual just entering the acute inflammatory phase with significant proptosis and evidence of optic neuropathy will be much different than an individual with a fifteen year history of stable proptosis.

1. Noninfiltrative disease

Initial management is tailored to the needs of the individual patient. Recognizing that many patients will have minimal orbital changes, the goal must be to identify patients at risk for the most severe forms of orbitopathy and intervene appropriately. Individuals with noninfiltrative orbitopathy can be managed conservatively with supportive measures until they have entered the quiescent phase. Typically this includes education, follow up evaluation and treatment for dry eye. The inflammatory period may last between 18 to 36 months. In these individuals who are at low risk for optic neuropathy and infiltrative myopathy, orbital irradiation and corticosteroids are not warranted unless disabling symptoms of orbital inflammation are present. When the process enters the quiet phase and the orbital status has remained unchanged for 6 to 12 months, surgical rehabilitation for residual orbital changes can be planned.

2. Infiltrative disease

In contrast, patients with infiltrative orbitopathy tend to be older, have enlarged muscles with dysmotility and more significant degrees of proptosis and compressive optic neuropathy. There is often elevated intraocular pressure that is much worse in up-gaze. Soft tissue signs such as a palpable lacrimal gland and marked orbital fat herniation reflect the increased orbital volume. Corneal breakdown may be evident due to decreased tear production, frank lagophthalmos, and absent Bell’s phenomena related to inferior rectus tethering. Again disease activity is characterized by the inflammatory cycle described by Rundle’s curve. However, when there is compromise of visual function, it is not acceptable to wait until the disease has run its course before intervening. Under these circumstances, treatment is directed at arresting disease activity with the objective of preventing further deterioration of visual function. This is achieved with the use of systemic corticosteroids and orbital irradiation. While these treatments improve the orbital status by quenching inflammation, they do not undo the secondary changes to the orbital fat and muscles related to stimulation of the orbital fibroblasts. Anti- inflammatory therapy seems to accelerate progress through Rundle’s curve. We have no evidence that it changes the end point. When anti-inflammatory therapy fails to adequately relieve optic nerve compression, urgent surgery may be needed, even in the inflammatory stage.

a. Corticosteroids

When patients are first seen, it is essential to classify the acuity of their orbital inflammation in relation to Rundel’s curve. Obviously thyroid orbitopathy that is essentially in the quiescent phase is unlikely to respond to anti- inflammatory therapy. Corticosteroids and orbital irradiation are mainstays of immunosuppressive therapy. Patients are initially started on prednisone as a trial of anitinflammatory therapy. The response to corticosteroids is relatively rapid, typically 1 to 2 weeks. Improvement is usually seen by a reversal of soft tissue signs, increased orbital compliance, improved ocular motility, and improvement in visual function due presumably to decreased optic nerve compression. Typically patients are initially started on 1 mg/kg of prednisone per day. However, in cases of frank optic neuropathy, a higher initial dose may be chosen. In clinical studies approximately 60% respond to corticosteroids.117 Unfortunately, corticosteroids are not well tolerated and it is virtually impossible to maintain patients on these drugs without significant complications. Patients who do improve on corticosteroids demonstrate unequivocally that they have active orbital inflammation. Under this circumstance, discontinuation of corticosteroids is generally associated a relapse of symptoms and signs.78 As a very effective alternative to maintaining patients on corticosteroids, our practice is to irradiate the orbits. Other immunosuppresive therapy has been attempted. Cyclosporine is much less effective than prednisone with response rates of 22% versus 61%.82 Intravenous immunoglobulin appears to be very effective but also very expensive.2 Azothioprine, Ciamexone, and cyclophosphamide have been tried without much success.13,48,79

b. Orbital Irradiation

Controlled studies have demonstrated that the combination of radiotherapy and high dose corticosteroids are more effective than radiotherapy alone.63 Similarly it has been shown that the combination of orbital irradiation and systemic corticosteroids is more effective than steroids alone.7 Radiation suppresses orbital inflammation. It is thought that radiation kills orbital lymphocytes involved in thyroid related orbitopathy as well as suppressing orbital fibroblasts active in the production of glycosaminoglycans.116 Typically, orbital irradiation consists of 2 Gy delivered in 10 daily fractions over two weeks with a linear accelerator. We currently favor a slightly lower total dose of 1.5 Gy. The effectiveness of doses in the 6-8 Gy range are equivocal and doses higher than 20 Gy do not appear to add any additional benefit.80,91 The dose is directed to avoid irradiating the contralateral lens. We do not advocate prophylactic orbital irradiation prior to iodine-131 treatments.

Studies suggest that orbital irradiation is effective in 50% of cases.91 The first effects of irradiation are seen at 2-3 weeks but gradual improvement can be seen for several months. The response seen is lessening of soft tissue change, improved ocular motility, and improved orbital compliance. Proptosis is not improved in a clinically significant way. However, orbital irradiation does accelerate resolution of orbital inflammation and therefore hastens the opportunity to begin surgical rehabilitation of residual orbital changes. When patients with thyroid related compressive optic neuropathy fail to respond to irradiation, orbital decompression must be performed to relieve apical orbital pressure compromising the optic nerve.

The most common side effect of orbital irradiation is transient worsening of dry eye symptoms. The incidence of cataractogenesis is very low due to minimal scatter and posterior direction of the irradiation port.80 Oncogenesis essentially does not occur. Radiation retinopathy appears to be related to the coexistence of diabetic retinopathy or to dosimetric errors.53 Some investigators have raised concerns about irradiating diabetics for fear of inducing radiation retinopathy.12 However, diabetic are at greater risk for compressive optic neuropathy.50 Rather than deny patients the benefits of irradiation, we have chosen to use a lower dose of radiation.

3. Effect of iodine-131 thyroid ablation on orbitopathy Until recently, it was debated if radioactive iodine worsened thyroid related orbitopathy. Uncontrolled studies found conflicting results. Some studies reported no relationship between iodine-131 and a deterioration of orbitopathy and other studies came to the opposite conclusion.3,37,99 Tallstedt and co-workers studied 168 patients with hyperthyroidism due to Graves’ disease.105 Patients were stratified by age. All patients received thyroid replacement except the patients randomized to iodine-131. Among the younger patients, ages 20 to 34, there was no difference in developing or worsening of orbitopathy. However, among the older patients, ages 35 to 55, 33% treated with iodine-131 had worsening orbitopathy compared to 10% among those treated medically and 16% among those treated with surgery. This difference was found statistically significant. This study has been used to disfavor iodine-131 treatment. However, the conclusions were controversial for the following reasons: 1) It is theorized that failure to treat patients who received iodine-131 with thyroid replacement may induce a rise in TSH which could be associated with an exacerbation of orbitopathy. 2) The groups were not balanced with respect to cigarette smoking with a disproportionate number of smokers among those receiving iodine-131. 3) The ophthalmologist examining the patients was not fully blinded with respect to treatment. 4) Tallstedt’s study was purely categorical-was there progression or not? The study in no way established if the progression was clinically significant.

The recent excellent study by Bartelena and co-workers has effectively established that treatment with iodine-131 does cause development or worsening of mild orbitopathy when compared to treatment with methimazole.6 Among the patients studied, these changes were not clinically significant. The worsening of orbitopathy caused by the iodine-131 was ablated with the use of oral prednisone. It is our clinical impression that the mild exacerbation of noninfiltrative orbitopathy does not warrant the routine use of prednisone. However, treatment for patients with more severe orbitopathy must be individualized and they should be monitored closely. In individuals with infiltrative orbitopathy, exacerbation of the orbitopathy could result in a compressive optic neuropathy and visual deterioration. Given the reliability of iodine-131 treatment, we support iodine-131 ablation if this is recommended by the treating endocrinologist.

F. Surgical Management

1. Acute intervention versus staged rehabilitation Surgical intervention is used to address to two distinct circumstances in the management of thyroid related orbitopathy: 1) Orbital decompression to relieve compressive optic neuropathy in patients who fail to respond to anti-inflammatory therapy and 2) Comprehensive surgical rehabilitation once the orbitopathy has reached the quiescent phase of Rundle’s curve. It is essential not to confuse these two circumstances. It would be inappropriate to perform muscle surgery while the orbital inflammatory process is still active. Similarly when the disease has reached a quiescent phase, decompressive surgery should not be limited to apical decompression even if there evidence of optic neuropathy if a definitive orbital decompression can be reasonably performed instead. The aim of surgical rehabilitation is to stage surgery in order to minimize the total number of surgeries required. We will first discuss orbital decompression for patients with compressive optic neuropathy and then consider the comprehensive surgical rehabilitation of patients who have entered the quiescent phase of their disease and have remained stable for 6-12 months.

The reader will not find a discussion of eyelid tarsorrhaphy among the surgical options for the management of thyroid orbitopahty. This is because this disfiguring surgery is rarely needed and sometimes ill advised in the management the thyroid orbitopathy. The great American architect Louis Henri Sullivan said “form ever follows function.” This is also true for eyelid anatomy. By following a staged program of rehabilitate surgery, patients are unlikely to need tarsorrhaphy. Tarsorrhaphy is performed to protect the corneal surface. However, corneal decompensation is often also associated with the greatest activity of orbital inflammation. Appropriate intervention with corticosteroids, orbital irradiation, and maximal ocular lubrication and occlusion of the ocular surface are often more appropriate alternatives to a tarsorrhaphy. However, there are clinical circumstances when a temporary tarsorrhaphy may be indicated.

Currently, the transconjunctival/transcaruncular approach to the orbital apex is the preferred approach for the relief of compressive optic neuropathy when patients fail to respond to orbital irradiation. This approach was developed by Henry Baylis and popularized by Norman Shorr (Shorr N. Transcaruncular/transconjunctival Approach to the medial orbit and orbital apex. Presented before the Ophthalmic Plastic and Orbital Surgery Scientific Session. American Academy of Ophthalmology Annual Meeting, San Francisco, 1994). This approach provides direct, unobstructed access to the medial orbital wall. (Figure 5) The surgical approach does not leave a skin scar. In contrast, the Lynch incision leaves an unsightly scar in the multicontoured medial canthal region. The transcaruncular approach permits an isolated medial wall decompression into the ethmoid sinus space to the orbital apex. This permits decompression of the orbital apex without sacrificing the orbital strut and floor. This is an advantage since it is impossible to predict the ultimate need for orbital decompression in a patient with active orbital inflammation. This limited medial decompression typically is associated with a 2 or 3-mm reduction in proptosis so that unwanted orbital decompression is avoided (figure 6). Again the purpose of early orbital decompression is for relief of optic nerve compression not expansion of the orbit to improve proptosis. Final orbital decompression is left until the disease process has entered the quiescent phase.

2. Surgical rehabilitation

a. Concept of staged surgery Once disease activity has subsided and clinical parameters have remained stable for 6 -12 months, definitive surgical rehabilitation can begin. Surgical rehabilitation must follow in an ordered sequence to avoid unnecessary surgery. There are four stages of surgical rehabilitation: 1) orbital decompression, 2) muscle surgery, 3) lid margin surgery, and 4) blepharoplasty.97 These stages are sequential because each proceeding stage will have an impact on the subsequent stage. Orbital decompression will effect ocular motility, muscle surgery will effect lid position, and lid position surgery will impact on aesthetic restorative blepharoplasty. A particular patient may not need one or more of the stages of surgical rehabilitation. However, even in these cases the order of surgical stages is respected by passing the unneed stage and proceeding to the next subsequent stage.

b. Orbital Decompression Decompressive surgery is indicated to relieve compressive optic neuropathy, severe corneal exposure and to reduce proptosis prior to strabismus surgery and for aesthetic restorative purposes. In the past aesthetic restorative orbital decompression was reserved for those with “grotesque orbital and periorbital distortion who suffered altered body image and self- concept to the point of reclusiveness.”97 This approach to severely limit orbital decompression for rehabilitation of facial appearance was justified by the relatively high incidence of post orbital decompression diplopia.57 New approaches to orbital decompression have significantly reduced the incidence of post decompressive diplopia.29,30,59,60 Therefore rather than offering patients camouflaging surgical procedures that only serve to partially minimize the deformity, a more definitive approach can now be offered to individuals whose altered appearance is a significant psychological burden. The techniques of orbital decompression have evolved enormously in the past few years.

Orbital decompression was first described by Moore in 1920.67 His surgery involved the resection of orbital fat via an inferior fornix incision. Hirsh describe decompressed the orbit by removing the orbital floor.43 Naffziger, a neurosurgeon, performed orbital decompression for progressive exophthalmos associated with hyperthyroidism by unroofing the orbit. His first report was in 1931 and he stated that his patients enjoyed a 2-6 mm reduction in proptosis.71,72 Swift introduced the use of the Kronlein lateral orbitotomy for decompression in 1935.54,104 The pterional approach was first described in 1943 by Welti and Offret.114 Walsh and Ogura combined the Sewall and Hirsh decompression with a transantral approach.112 These historical approaches are summarized in figure 7. Recent innovations in orbital surgery have focused on tailoring the surgical approach to the needs of the patient with the use of coronal, transconjunctival, transcaruncular, and endoscopic approaches.31,33,51,110

The traditional approaches were handicapped either by the degree to which they reduced proptosis or by the frequency with which complications were induced. The effectiveness of orbital decompression is governed by the observation that for every 1 ml of bone or orbital tissue removed or prolapsed into an opened sinus, there is roughly a 0.8 mm reduction in proptosis. An isolated Kronlein lateral orbitotomy with partial thinning or removal of the lateral orbital wall is associated with a 2-3 mm reduction in proptosis. An isolated medial orbital decompression is also associated with a 2-3 mm reduction in proptosis. A transantral resection of the orbital floor and medial wall is associated with a average 5 mm reduction of proptosis.10 However, this approach commonly produces or worsens diplopia with a 30% incidence of new diplopia following decompression.96 The incidence of diplopia and hypoglobus has been considerably improved by preserving the so-called orbital strut, a ridge of bone between the floor of the orbit and medial orbital wall and is supported by the bone spans between the superomedial antral wall and the ethmoid compartment.32 Preserving this strut reduces somewhat the effectiveness of the decompression but helps to support orbital tissues reducing post decompression diplopia.

Newer approaches involve the concepts of a balanced decompression, decompression into the temporal fossa, and preservation of the orbital strut.29,30 A balanced decompression is carried out by decompressing at least the medial and lateral walls. This can be accomplished by combining a lateral subcanthal approach to the lateral orbital wall with a transcaruncular approach to the medial orbital wall. The lateral wall is reached through the upper eyelid crease. The periorbita is incised exposing the bone of the lateral orbital wall. This bone is thinned with a high-speed burr superiorly to the level of the outer calverial table, inferiorly to the inferior orbital fissure and laterally until the temporal muscle is just exposed (Figures 8, 9, and 10). The orbital rim is left intact.30 Decompression laterally is then balanced with medial wall decompression via a transconjunctival/transcaruncular approach to the medial wall where an ethmoidectomy is performed. The medial wall can also be approached via a nasal endoscopic route.36,110 The periorbita is opened medially and laterally to permit the prolapse of fat into the new expanded orbital space. This procedure is associated with a lower incidence of decompression induced diplopia because there is a balanced expansion of the muscle cone. Displacement of the inferior rectus is thought to be one reason A- pattern esotropia is often worse following orbital decompression.46 An increase in the mechanical advantage of the superior oblique muscle following decompression may also play a role in the incidence of torsional diplopia.27 A two wall balanced decompression can result in a 4-5 mm reduction in proptosis.

Combined three wall surgery, via the coronal or via the combined transconjunctival and transcaruncular approaches , has also become an important method of achieving a significant reduction in proptosis.30,33 This approach has been especially helpful in significantly fibrotic orbits. Typically orbital decompression works because when the periorbita is opened orbital fat can prolapse to the newly expanded orbit. However when there is significant fibrosis of orbital fat, prolapse of fat does not occur as readily if at all. Using a combined approach, it is possible to obtain better results by removing the greater wing of the sphenoid between the superior orbital fissure and the inferior orbital fissure until the dura covering the temporal lobe is just exposed. There is approximately 4-5 ml of bone that can be removed from the greater wing of the sphenoid bone, the so- called “orbital door jamb.” (Figure 10).30 This region may be reached either through a lid incision or via a coronal incision. From the coronal approach temporalis muscle is elevated from the temporalis fossa to expose the posterior aspect of the frontal process of the zygoma and the greater wing of the sphenoid to permit removal of this bone with a high- speed burr. The coronal approach has the added advantage of providing excellent access to the medial orbital wall and orbital floor (figure 9) consequently the floor and medial wall can be decompressed in this fashion. Decompressions of up to 10 millimeters are possible with this approach.

Removal of the bone walls of the orbit is not the only means to effect a decompression of the orbit. All three approaches may be complimented by orbital fat removal. 41,109 In cases of limited proptosis, this may be the only orbital decompression required. 77 This technique has the potential risk of harming important structures that traverse the orbital fat. A recent study has identified the inferior-lateral orbit as a relatively safe area for orbital fat removal.98 Beyond these techniques, it is possible to achieve additional expansion of the orbital confines by advancing and rotating the lateral orbital wall, or advancing the inferior orbital rim through various techniques (figure 12).33,88,102,117

As was mentioned above, symptomatic diplopia is the most common complication associated with orbital decompression.32 With the trend away from transantral surgery and toward inferior fornix surgery, diplopia is a less common problem. Typically the onset diplopia post operatively is seen in individuals with restricted motility preoperatively. Other complications include infraorbital nerve anesthesia or hypesthesia. Usually this is not a permanent condition. As with any coronal surgery, a careful dissection must be made to avoid damaging the temporal branch of the facial nerve. Blindness is a rare complication as is postoperative infection. There can be significant conjunctival chemosis post operatively but this is usually transient. While much of the decompressive effect is seen shortly after surgery, the reduction of proptosis often continues to improve for several months consequently, patients are allowed to recover for several months following orbital decompression before additional surgical rehabilitation is performed.

c. Extraocular muscle surgery Orbital decompressive surgery, even balanced orbital decompressive surgery can worsen diplopia, it is logical to defer stabismus surgery until after decompressive surgery. 27 Following recuperation from orbital decompressive surgery, symptomatic diplopia is addressed with extraocular muscle surgery. The inferior rectus and medial rectus muscles are most frequently involved followed less frequently by the superior rectus and the lateral rectus muscles. The diplopia is caused by muscle fibrosis in the affected muscles producing a restrictive strabismus. The majority of patients with diplopia have combined vertical and horizontal deviations. A pattern esotropia is common with V pattern esotropia seen less frequently. 55 Patients will often present with a compensatory head tilt or posture. In measuring ductions and versions, it is important to control the head position. The goal of muscle surgery is the creation of as large a field of fused single binocular vision as possible. The greatest attention must be paid to obtaining stable fusion in primary and down gaze.

Strabismus surgery is accomplished with a combination of adjustable muscle recessions and fixed muscle recessions. There is usually no role for muscle resections. Strabismus surgery with adjustable sutures has made a significant difference in the management of restrictive strabismus associated with thyroid related orbitopathy. 56 Secondary muscle surgery is technically very difficult because the muscle is often supermaximally recessed. Consequently efforts are directed to making the muscle surgery definitive. Minimal narcotics, sedatives and anesthetics are used intraoperatively so that patients can be fully cooperative within a few hours after surgery. Intraoperatively, once the muscle is detached from the globe forced ductions are performed to rule out tethering of the muscle. In particular attachments to the lower eyelid retractors are dissected as much as feasible to reduce post-operative lower eyelid retraction.66 The muscle is recessed 1-2 mm more than predicted because it is much easier to reduce a recession post operatively. The sutures are tied on an adjustable surgical knot (figure 13). When indicated the conjunctiva is also recessed. Once the patient has recovered from surgery and can cooperate, the adjustment is performed. This can be done on the same day or on the first postoperative day.

Recessions tend to leave the patient weak in the field of action of the recessed muscle, a particularly important fact for obtaining single binocular vision in downgaze for reading. Therefore the adjustment must be done in both the primary position and in downgaze. The most common complication following muscle surgery for thyroid related orbitopathy is worsening of lower eyelid retraction. Patients are routinely counseled to expect this. They are also cautioned about the potential need for additional strabismus surgery particularly to address late overcorrection of hypotropia. 44,119

d. Eyelid malposition correction The third stage of surgical rehabilitation addresses eyelid malposition: Upper and lower eyelid retraction. In the quiescent phase of thyroid orbitopathy, residual upper and lower eyelid retraction is likely due to fibrosis and retraction in the levator and inferior rectus respectively.63 Upper eyelid retraction is addressed either by levator aponeurotic recession or graded Mullerectomy (figure 14).70,85 Small degrees of lower eyelid retraction may be successfully treated by lower eyelid retractor recession.66 More typically, lower eyelid retraction requires the use of a spacer in the posterior lamella. A number of materials have been used as a spacer material.11,19,21 However, we currently favor the use of mucoperiosteum harvested from the hard palate. A lateral canthotomy and cantholysis are performed and the lower eyelid retractors are dissected from the inferior edge of the tarsus. Adhesions in the middle lamella of the lower eyelid are lysed and a hard palate graft is sewn into the dissection bed effectively lengthening the lower eyelid (figure 15). The eyelid is then resuspended laterally and the lid is supported by Frost suture to the brow for a week. A firm patch helps prevent eyelid movement as the lower eyelid heals on a stretch. This method has proven to be very successful it addressing even large degrees of lower eyelid retraction. This technique is identical to surgery to address vertical insufficiency in the lower eyelid following blepharoplasty.19,95

e. Rehabilitative blepharoplasty Once the first three stages of surgical rehabilitation are complete, rehabilitative blepharoplasty can be considered. By laying a structural foundation with the proceeding surgical stages, it is possible with blepharoplasty to return patients to an appearance they had before the onset of their thyroid related orbitopathy. This has a significant benefit by returning to them a sense of wholeness and self-identity that they may have been lacking since the onset of the orbitopathy. In approaching blepharoplasty, a conservative philosophy is best. Often patients retain some degree of proptosis and lagopthalmos. They commonly have a post-inflammatory dry that may have been exacerbated by orbital irradiation. Removing too much skin and fat in the upper eyelid may worsen lagopthalmos or make obvious the relative prominence of the eyes. Therefore blepharoplasty must be performed conservatively in this setting.

IV. Summary We have reviewed current thinking in the pathogenesis and pathophysiology of the orbitopathy and hyperthyroidism associated with Graves’ disease. Clinical assessment of the orbital status continues to defy simplification and requires rigorous investigation. This necessitates a paradigm shift away from the clinical concepts created by the NOSPECS classification toward an appreciation of the dynamic nature of the thyroid related orbitopathy as represented by Rundle’s curve. On the horizon are promising imaging methods that may be able to correlate MRI and ultrasound characteristics with disease activity and predict response to treatment.76,83 Treatment of orbitopathy is supportive unless there is evidence of infiltrative disease. When compressive orbitopathy fails to respond to orbital irradiation, orbital apical decompression must be considered during the inflammatory course of the orbitopathy. Once the orbitopathy has run its course and has been quiescent for 6-12 months, surgical rehabilitation can be considered to address residual orbital changes. There are four states of orbital rehabilitation: 1) orbital decompression, 2) muscle surgery, 3) lid position surgery, 4) rehabilitative blepharoplasty. Patients first developing thyroid related orbitopathy must be educated about the disease process. Fears can be met with reassurances that comprehensive care is available to help them cope with their orbital changes.

References

  1. Allanic H, Fauchet R, Orgiazzi J, et al. Antithyroid drugs and Graves’ disease: a prospective randomized evaluation of the efficacy of treatment duration. J Clin Endocrinol 70: 675-679, 1990
  2. Antonelli A, Saracino A, Alberti B., et al. High Dose intravenous immunoglobulin treatment in Graves’ ophthalmopathy. Acta Endocrinol. 1992; 126:13-23.
  3. Aranow H Jr, Day RM. Management of thyrotoxicosis in patients with ophthalmopathy: antithyroid regimen determined primarily by ocular manifestations. J Clin Endocrinol Metab. 1965;25:1-10.
  4. Bahn RS, Heufelder AE. Retroocular fibroblasts: Important effector cells in Graves’ ophthalmopathy. Thyroid. 1992; 2(1):89-94.
  5. Bahn RS, Heufelder AE. Pathogenesis of Graves’ ophthalmopathy. NEJM. 1993; 329(20):1468-1475.
  6. Bartelena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 338: 73-78, 1998
  7. Bartelena L, Marcocci C, Chiovato L, Laddaga M, Lepri G, Andreani D, Cavallacci G., Baschieri L, Pinchera A. Orbital cobalt irradiation combined with systemic corticosteroids for Graves’ ophthalmopathy: comparison with systemic corticosteroids alone. J Clin. Endocrinol Metab. 1983;56:1139.
  8. Bartley GB. Evolution of classification systmes for Graves’ ophthalmopathy. Ophthalmic Plast Reconstr Surg. 1995; 4: 229-237
  9. Bartey GB, Fatourechi V, Kadrmas EF, et. al. Long-term follow-uo of Graves’ opthalmolpathy in an incident cohort. Ophthalmology. 1996; 103:958-62
  10. Baylis HI, Call B, Shibata CS. The transantral orbital decompression (Ogura technique) as performed by the ophthalmologist. Ophthalmology. 1980; 80:1005-1012.
  11. Baylis HI, Rosen N, Neuhaus RW. Obtaining auricular cartilage for reconstructive surgery. Am J Ophthalmol. 1982; 93:709-12.
  12. Beckendorf V, Maalouf T, George J, et al. Place of radiotherapy in the treatment of Graves’ orbitopathy. Int J Radiation Ocology Biol Phys. 1999; 43: 805-815
  13. Bigos Sth, Nisula BC, Daniels GH, Eastman RC, Johnson HH, Kohler PO. Cyclophosphamide in the management of advanced Graves’ ophthalmopathy. A preliminary report. Ann Intern Med. 1979;90:921-923.
  14. Brix TH, Christensen K, Holm NV, Harvald B, Hegedus L. A population-based study of Graves’ disease in Danish twins. Clin Endocrinol 48: 397-400, 1998
  15. Campbell RJ. Pathology of Graves’ ophthalmopathy. In Gorman CA, Waller RR, Dyer JA, eds. The eye and orbit in thyroid disease. New York:Raven Press, 1984:25-31.
  16. Campbell RJ. Immunology of Graves’ ophthalmopathy: retrobulbar histology and histochemistry. Acta Endocrinol. 1989;121 (supp 2):9-16.
  17. Cmelo J, Chynoransky M, Zvac J, Rybar M. Hodnotenie retrobulbarneho priestoru pri Graves’ovej orbitopatii pomocou farebbnej Dopplerovskej ultrasonografie. Cesk Slov Oftalmol 1997, 53: 106-11
  18. Cockerham KP, Pal C, Jani B, Wolter A, Kennerdell JS. The prevalence and implications of ocular hypertension and glaucoma in thyroid-associated orbitopathy. Ophthalmology. 1997, 104:914-7
  19. Cohen MS, Shorr N. Eyelid reconstruction with hard palate mucosa grafts. Ophthalmic Plast Reconstr Surg. 1992; 8: 1 83-95
  20. Dev S, Damji KF, Debacker CM, et al. Decrease in intraocular pressure after orbital decompression for thyroid orbitopathy. Can J Ophthalmol. 1998; 33: 314-9
  21. Feldman KA, Putterman AM, Farber MD. Surgical treatment of thyroid-related lower eyelid retraction: a modified approach. Ophthalmic Plast Recontr Surg. 1992; 8: 278-86.
  22. Fells P, Doniach D, Lawton NF. Diangosis and management of dysthyroid exophthalmos. In Proceedings of the 2nd International Symposium on Orbital Disorders Amsterdam 1973. Modern Probems in Ophthalmololgy, Basel:Karger, 14,409-413, 1975.
  23. Franklyn JA, Maisonneuve P, Sheppard M, Betteridge J, Boyle P. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet 353: 2111-2115, 1999
  24. Franklyn J, Sheppard M. Radioiodine for hyperthyroidism. Br Med J 305: 727-728, 1992
  25. Frecker M, Stenszky V, Balazs C, Kraszits E, Farid NR. Genetic factors in Graves’ ophthalmopathy. Clin Endocrinol (Oxf) 1986;25:479-85.
  26. Gamblin GT, Harper DG, Galentine P, et al. Prevalence of increased intraocular pressure in Graves’ disease- evidence of frequent subclinical ophthalmopathy. NEJM. 1983;308:420-4
  27. Garrity JA, Saggau DD, Gorman CA, et al. Torsional diplopia after transantral orbital decompression and extraocular muscle surgery associated with Graves’ orbitopathy. Am J Ophthalmol. 1992;113:363-73.
  28. Glinoer D, Hesch D, Lagasse R, Laurberg P. The management of hyperthyroidism due to Graves’ disease in Europe in 1986. The results of an international survey. Acta Endocrinologica 115 (Supplement 285)
  29. Goldberg RA. The evolving paradigm of orbital decompression surgery. Arch Opthalmol. 1998; 116:95-96
  30. Goldberg RA, Kim AJ, Kerivan KM. The lacrimal key hole, orbital door jamb, and basin of the inferior obital fissure. Three areas of deep bone in the lateral orbit. Arch Ophthalmol. 1998; 116: 1618-1624.
  31. Goldberg RA, Lessner AM, Shorr N, Baylis H. The transconjunctival approach to the orbital floor and orbital fat: A prospective study. Ophthal Plast Reconstr Surg. 1990; 6:241-246.
  32. Goldberg RA, Shorr N, Cohen MS. The medial orbital strut in the prevention of postdecompression dystropia in dysthyroid ophthalmopathy. Ophthal Plast Reconstr Surg. 1992; 8:32-4.
  33. Goldberg RA, Weinberg DA, Shorr N, Wirta D. Maximal, three wall, orbital decompression through a coronal approach. Ophthalmic Surg Lasers. 1997; 28:832-843.
  34. Gorman CA. Temporal relationship between onset of Graves’ ophthalmopathy and diagnosis of thyrotoxicosis. Mayo Clin Proc. 58:515, 1983
  35. Gorman CA. Clever is not enough: NOSPECS is form in search of function. Thyroid. 1991;1:353-355.
  36. Graham SM, Carter KD. Combined-approach orbital decompression for thyroid-related orbitopathy. Clin Otolaryngol. 1999; 24: 109-13.
  37. Gwinup G, Elias AN, Ascher MS. Effect on exophthalmos of various methods of treatment of Graves’ disease. JAMA. 1982;247:2135-8.
  38. Hales IB, Rundle FF. Ocular changes in Graves’ disease. Quarterly J Med. 1960; 29:113-126.
  39. Harvey JT, Anderson RL. The aponeurotic approach to eyelid retraction. Ophthalmology. 1981;88:513-524.
  40. Hashizume K, Ichikawa K, Sakurai A, et al. Administration of thyroxine in untreated Graves’ disease: effects on the level of antibodies t thyroid stimulating hormone receptors and on the risk of recurrence of hyperthyroidism. N Engl J Med 324: 947-953, 1991
  41. Hecht SD, Guibor P, Wolfley D, Wiggs EO. Orbital dissection defatting technique for Graves’ disease. Ann Ophthalmology. 1984; 16: 314-8.
  42. Hershman JM, Givens JR, Cassidy CE, Astwood EB. Long-term outcome of hyperthyroidism treated with antithyroid drugs. J Clin Endocrinol Metab 26: 803-807, 1966
  43. Hirsh KO, Urbanek J. Behandlung eines excessives exophthalmos (Basedow) durch entfernung von orbitalfett von der Kieferhohle aus. Monatsschr Ohrenheilkd. Laryngorhinol. 1930; 64:212-213.
  44. Hudson HL, Feldon SE. Late overcorrection of hypotropia in Graves’ ophthalmopathy. Ophthalmology. 1992; 99:356-360.
  45. Hudson HL, Levin L, Feldon SE. Graves’ Exophthalmos unrelated to extraocular muscle enlargement: Superior rectus muscle inflammation may induce venous obstruction. Ophthalmology. 1991; 98:1495-1499.
  46. Jampolsky A. Surgical leashes and reverse leashes in strabismus surgery surgical management. In: Symposium on Strabismus. Transactions of the New Orleans Academy of Ophthalmology, St Louis: CV Mosby, 1978;244-68.
  47. Jamsen K. Thyroid disease, a risk factor for optic neuropathy mimicking normal-tension glaucoma. Acta Ophthalmol Scand. 1996; 74: 456-60.
  48. Kahaly G, Lieb W, Muller-Forell W, et al. Ciamexone in endocrine orbitopathy. A radomized double blind, placebo- controlled study. Acta Endocrinol. 1990;122:13-21.
  49. Kalk WJ, Durbach D, Kantor S, Levin J. Post-thyroidectomy thyrotoxicosis. Lancet i: 291-293, 1978
  50. Kalmann R, Mourits MP. Diabetes mellitus: a risk factor in patients with Graves’ ophthalmopathy. Br J Ophthalmol. 1999; 83: 463-5.
  51. Kalman R, Mourtis MP, van der Pol JP, Koornneef L. Coronal approach for rehabilitative orbital decompression in Graves’ ophthalmopathy. Br J Ophthalmol. 1997; 81:41-45.
  52. Kendler DL, Lippa J, Rootman J. The initial clinical characteristics of Graves’ ophthalmopathy vary with age and sex. Arch Ophthalmol. 1993;111:197-201.
  53. Kinyoun JL, Kalina RE, Brower SA, Mills RP, Johnson RH. Radiation retinopathy after orbital irradiation for Graves’ ophthalmopathy. Arch Ophthalmol. 1984; 102:1473-1476.
  54. Kronlein RU. Zur pathologie und operativen behandlung der dermoidcystern der orbita. Beitrage zur Klinischen Chirurgie. 1888;4: 149-163.
  55. Kushner BJ. Torsional diplopia after transantral orbital decompression and extraocular muscle surgery associated with Graves’ orbitopathy.(letter) Am J Ophthalmol. 1992; 114:239.
  56. Lueder GT, Scott WE, Kutschke PJ, Keech RV. Long-term results of adjustable suture surgery for strabismus secondary to thyroid ophthalmopathy. Ophthalmology. 1992; 99: 993-997.
  57. Lyons CJ, Rootman J. Oribtal decompression for disfiguring exophthalmos in thyroid orbitopathy. Ophthalmology. 1994;101:223-230.
  58. Lyons DE. Postural changes in IOP in dysthyroid exophthalmos. Trans Ophthalmol Soc UK. 1971;91:799-803.
  59. McCord CD. Orbital decompression for Graves’ disease: Exposure through lateral canthal and inferior fornix incision. Ophthalmology. 1981;88:533-541.
  60. McCord CD. Current trends in orbital decompression. Ophthalmology. 1985;92:21-33.
  61. McIver B, Rae P, Beckett GJ, et al. Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N Engl J Med 334: 220-224, 1996
  62. Mack WP, Stasior GO, Cao HJ, Stasior OG, Smith TJ. The effects of cigarette smoking constituents on the expression of HLA-DR in orbital fibroblasts derived from patients with Graves’ ophthalmopathy. Ophthal Plast Reconstr Surg. 1999, 15:260-71.
  63. Marcocci C, Bartelna L, Bogazzi, F, Bruno-Bossio G., Lepri A., Pinchera A. Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves’ ophthalmopathy is more effective than radiotherapy alone: results of prospective randomized study. J Endocrinol Invest. 1991;14:853-860.
  64. Marcocci C, Bruno-Bossio G, Manetti L, et al. The course of Graves’ ophthalmopathy is not influenced by near- total thyroidectomy: a case-control study. Clin Endocrinol 51: 503-508, 1999.
  65. Maugendre D, Gatel A, Campion L, et al. Antithyroid drugs and Graves’ disease - prospective randomized assessment of long-term treatment. Clin Endocrinol 50: 127-132, 1999
  66. Meyer DR, Simon JW, Kansura M. Primary infratarsal lower eyelid retractor lysis to prevent eyelid retraction after inferior rectus muscle recession. Am J Ophthalmol. 1996; 122: 331-339.
  67. Moore RF. Exophthalmos in Graves’ disease. Lancet. 1920;2:701.
  68. Mourits MP, Koornneef L, Wiersinga WM, Prummell MF, Berghout A, and Gaag R. Clinical criteria for the assessement of disease activity in Graves’ ophthalmopathy: A novel approach. Br J Ophthalmol. 1989; 73:639-644
  69. Mourtis MP, Prummel MF, Wiersinga WM, Koornneef L. Measuring eye movement disorders in Graves’ ophthalmopathy. Ophthalmology. 1994;101:1341-1346.
  70. Mourtis MP, Sasim IV. A single technique to currect various degrees of upper lid retraction in patients with Graves’ orbitopathy. Br J Ophthalmol. 1999; 83: 81-4.
  71. Naffziger HC. Progressive exophthalmos following thyroidectomy; its pathology and treatment. Annals of Surgery. 1931;94:582-586.
  72. Naffziger HC. Progressive exophthalmos associated with disorders of the thyroid gland. Annals of Surgery. 1938;108:529-544.
  73. Nakase Y, Osanai T, Yoshikawa K, Inoue Y. Color doppler imaging of orbital venous flow in dysthyroid optic neuropathy. Jpn J Ophthalmol. 1994;38:80-86.
  74. Neigel JM, Rootman J, Belkin RI, Nugent RA, Drance SM, Beattie CW, Spinelli JA. Dysthyroid optic neuropathy: The crowded orbital apex syndrome. Ophthalmology. 1988;95:1515-1521.
  75. Nunery WR, Nuner CW, Martin RT, Truong TV, Osborn DR. The risk of diplopia following orbital floor and medial wall decompression in subtypes of ophthamic Graves’ disease. Ophthal Plast Reconstr Surg. 1997; 13:153-60
  76. Ohnishi T, Noguchi S, Murakami N, Tajiri J, Harao M, Kawamoto H, Hoshi H, Jinnouchi S, Futami S, Nagamachi S, Watanabe K. Extraocular muscles in Graves’ ophthalmopathy: Usefulness of T2 relaxation time measurements. Radiology. 1994;190:857-862.
  77. Olivari N. Transpalpebral decompression of endocrine ophthalmopathy ( Graves’ disease) by removal of intraorbital fat: experience with 147 operations over 5 years. Plast Reconstr Surg. 1991; 87:627-41.
  78. Panzo GJ, Tomsak RL. A retrospective review of 26 cases of dysthyroid optic neuropathy. Am J Ophthalmol. 1983, 96:100-.
  79. Perros P, Weightman DR, Crombie AL, Kendall-Taylor P. Azathioprine in the treatment or thyroid-associated ophthalmopathy. Acta Endocrinol. 1990; 122:8-12.
  80. Peterson IA, Donaldson SS, McDougall IR, Kriss JP. Prognostic factors in the radiotherapy of Graves’ ophthalmopathy. Int J Radiat Oncol Biol Physiol. 1989; 19:259-264.
  81. Philippou G, McGregor AM. The aetiology of Graves’ disease: what is the genetic contribution? Clin Endocrinol 48: 393-395, 1998
  82. Prummel MF, Mourits MP, Berghout A, et al. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N Eng J Med. 1989;321:1353-1359.
  83. Prummel MF, Suttorp-Schulten MS, Wiersinga WM, Verbeek, AM, Mourits MP, Koorneef L. A new untrasonographic method to detect disease activity and predict response to immunosuppresive treatment in Graves’ ophthalmopathy. Ophthalmology. 1993;100:556-561.
  84. Prummel MF, Wiersinga WM. Smoking and risk of Graves’ disease. JAMA. 1993; 269:479-82
  85. Putterman AM, Fett DR. Muller’s muscle in the treatment of upper eyelid retraction: a 12-year study. Ophthalmic Surg. 1986; 17:361-7.
  86. Riemann CS, Foster JA, Kosmorsky GS. Direct orbital manometery in patients with thyroid-related orbitopathy. Ophthalmology. 1999; 106:1296-302.
  87. Rootman J: Diseases of the Orbit: A Multidisciplinary Approach. Philadelphia, Lippincott Company, 1988, pp 243-245.
  88. Rootman J, Stewart B, Goldberg RA: Orbital Surgery: A Conceptual Approach. Philadelphia, Lippincott-Raven, 1995, pp 380-383.
  89. Rundle FF, Wilson CW. Development and course of exophthalmos and ophthalmoplegia in Graves’ disease with special reference to the effect of thyroidectomy. Clin Sci 5:177-194.
  90. Salvi M, Zhang Z-G, Haegert D, et al. Patients with endocrine ophthalmopathy not associated with overt thyroid disease have multiple thyroid immunological abnormalties. J. Clin Endocrinol Metab. 1990;70:89-94
  91. Sautter-Bihl ML. Orbital radiotherapy: recent experience in Europe. In: Wall JR, How J, eds. Graves’ ophthalmolpathy. Cambridge: Blackwell; 1990; 145-157.
  92. Schleusner H, Schwander J, Fischer C et al. Prospective multicenter study on the prediction of relapse after antithyroid drug treatment in patients with Graves’ disease. Acta Endocrinologica 120: 689-701, 1989
  93. Seth J, Kellett HA, Caldwell G, et al. A sensitive immunoradiometric assay for serum TSH - a replacement for the thyrotrophin releasing hormone test? Br Med J 289: 1334-1336, 1984
  94. Shine B, Fells P, Edwards OM, Weetman AP. Association between Graves’ ophthalmopathy and smoking. Lancet 1990;335:1261-3.
  95. Shorr N. Madame butterfly procedure with hard palate graft: management of the post-blepharoplasty round eye and scleral show. Facial Plast Surg. 1994; 10:57-63.
  96. Shorr N, Neuhaus RW, Baylis HI. Ocular motility problems after orbital decompression for dysthyroid ophthalmopathy. Ophthalmology. 1982:89:323-328.
  97. Shorr N, Seiff SR. The four stages of surgical rehabilitation of the patients with dysthyroid ophthalmopathy. Ophthalmology. 1986;93:476-83.
  98. Sires BS, Lemke BN, Dortzbach RK, Gonnering RS. Characterization of human orbital fat and connective tissue. Ophthalmic Plast Reconstr Surg. 1998; 6: 403-414.
  99. Solem JH, Segaard E, Ytteborg J. The course of endocrine ophthalmopathy during antithyroid therapy in a prospective study. Acta Med Scand. 1979;205:111-4.
  100. Solomon B, Glinoer D, Lagasse R, Wartofsky L. Current trends in the management of Graves’ disease. J Clin Endocrinol Metab 70: 1518-1524, 1990
  101. Spencer C, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem 33: 1391-1396, 1987
  102. Steinsapir KD, Shorr N. Subortial augmentation, in Bosniak S (ed.): Principles and Practice of Ophthalmic Plastic and Reconstructive Surgery, vol 1. Philadelphia, WB Saunders Company, 1996, pp 484-503.
  103. Sugrue D, Drury MI, McEvoy M, et al. Long term follow-up of hyperthyroid patients treated by subtotal thyroidectomy. Br Med Surg 70: 408-412, 1983
  104. Swift GW. Malignant exophthalmos and operative approach. Western Journal of Surgery, Obstetrics, Gynecology. 1935;43:119-126.
  105. Tallstedt L, Lundell G, Torring O, Wallin G, Ljunggren JG, Blomgren H, Taube A, and the thyroid study group. Occurance of ophthalmopathy after treatment for Graves’ hyperthyroidism. N Engl J Med. 1992;326:1733-8.
  106. Teng CS, Yeo PPB. Ophthalmic Graves’s disease: natural history and detailed thyroid function studies. BMJ. 1977;1:273-5.
  107. Törring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, and radioiodine - a prospective randomized study. J Clin Endocrinol Metab 81: 2986-2993, 1996
  108. Toft AD, Irvine WJ, Sinclair I, et al. Thyroid function after surgical treatment of thyrotoxicosis. A report of 100 cases treated with propranolol before operation. N Engl J Med 298: 643-647, 1978
  109. Trokel S, Kazim M, Moore S. Orbital fat removal: Decompression for Graves’ ophthalmopathy. Ophthalmogy. 1993; 100:674-682.
  110. Ulualp SO, Massaro BM, Toohill RJ. Course of proptosis in patients with Graves’ disease after endoscopic decompression. Laryngoscope. 1999; 109: 1217-22.
  111. Vitti P. Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment. Thyroid 7: 369-75, 1997
  112. Walsh TE, Ogura JH. Transantral orbital decompression for malignant exophthalmos. Laryngoscope. 1957: 67:544-568.
  113. Weetman AP, Wiersinga WM. Current management of thyroid-associated ophthalmopathy in Europe. Results of an international survey. Clin Endocrinol 49: 21-28, 1998
  114. Welti H, Offret G. Indications et technique de la trepanation decompressive de l’orbite dans le traitement des exophtalmies malignes basedowiennes. Lyon Chirurgical. 1943;38:542-554.
  115. Werner SC. Classification of the eye changes of Graves’ disease (letter to the editor). J Clin Endocrinol Metab. 1969 29:782-784. Weinberg DA, Goldberg RA, Hoenig J, Shorr N, Baylis HI. Management of relative proptosis with a porous polyethylene orbital rim implant. Ophthal Plast Reconstr Surg. 1999; 15:67-73.
  116. Wiersinga W. Retrobulbar radiation in Graves’ ophthalmopathy. J Clin Endocrinol Metab. 1995;80:345-347.
  117. Wiersinga WM, Smit T, Schuster-Uittenhoeve ALJ, Gaag Rv, Koornneef L. Therapeutic outcome of prednisone medication and orbital irradiation in patients with Graves’ ophthalmopathy. Ophthalmologia. 1988;197:75-84.
  118. Winsa B, Rastad J, Åkerström G, et al. Retrospective evaluation of subtotal and total thyroidectomy in Graves’ disease with and without endocrine ophthalmopathy. Eur J Endocrinol 132: 406-412, 1995
  119. Wright KW. Late overcorrection after inferior rectus recession. Ophthalmology. 1996; 103:1503-7

Table 3. Eponymous signs in thyroid orbitopathy

Ballet’s sign:
External ophthalmoplegia due to muscle fibrosis
Boston’s sign:
Jerking of the upper eyelid with infraversion

Dalrymple’s sign:
Upper eyelid retraction with widened palpebral fissure
Enroth’s sign:
Edema of the upper eyelid near the orbital rim
Gifford’s sign:
Restriction of upper eyelid eversion
von Graefe’s sign:
Lagging of the upper eyelid with infraversion
Griffith’s sign:
Lagging of the lower eyelid with supraversion
Jellinek’s sign:
Generalized brownish pigmentation of the eyelids
Joffroy’s sign:
Absence of forehead corrigation with supraversion
Kocher’s sign:
Globe lag with rapid supraversion
Mobius’s sign:
Impaiment of convergence
Rosenbach’s sign:
Fine tremor of the eyelids with gentle closure
Stellwag’s sign:
Infrequent and incomplete blinking
Topalanski’s sign:
Perilimbal injection
Wilder’s sign:
Globe twitch with shifts of horizontal gaze

Table 4 NOSPECS Classification of Ocular Signs and Symptoms*

Classes Ocular Symptoms and Signs

    0 No signs and symptoms
  1. Only signs, no symptoms ( signs limited to upper lid retraction and stare, with or without lid lag and proptosis:
    o Absent proptosis (20 mm or less)
    a Minimal (21-23 mm)
    b Moderate (24-27 mm)
    c Marked (28 mm or more)
  2. Soft tissue involvement ( no diplopia)
    o Absent
    a Minimal edema, conjucntival injection, fullness of lids and lacrimal gland
    b Moderate (above plus chemosis, lagophthalmos)
    c Marked
  3. Proptosis associated with classes 2-6
    o Absent (20 mm or less)
    a Minimal (21-23 mm)
    b Moderate (24-27mm)
    c Marked (28 mm or more)
  4. Extraocular muscle involvement ( usually with diplopia)
    o Absent
    a Minimal ( limitation of motion at extremes of gaze)
    b Moderate ( evident restriction of motion)
    c Marked ( globe(s) fixed in position)
  5. Corneal Involvement ( primarily due to lagophthalmos)
    o Absent
    a Minimal (corneal stippling)
    b Moderate (ulceration)
    c Marked (clouding, frank necrosis, frank perforation)
  6. Sight loss (due to optic nerve involvement)
    o Absent
    a Minimal (disc pallor, choked disc, visual field defect, or vision 20/20-20/60)
    b Moderate (same, vision 20/70-20/200)
    c Marked (Vision less than 20/200)

    7. Modified from Werner SC. Classification of the eye changes of Graves’ disease. J Clin Endocrinol Metab. 1969; 29:982-984 with permission of the journal.