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Graves' Ophthalmopathy
read review articles here and here and here
typical radiation field for Graves here, typical picture of eyes here and CT scans here

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Some patients with Graves' disease have a swelling of the tissue in the orbits which causes pressure on the eyes. The optimal treatment for this is controversial (see studies below.) Low dose radiation is an option with the best data from Stanford (see below) which concludes that: Retrobulbar irradiation (20 Gy) is safe and effective treatment for progressive Graves' ophthalmopathy, with a 96% overall response rate, 98% patient satisfaction rate, and no irreparable long-term sequelae, with follow-up extending 29 years.
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Graves' disease is an autoimmune process (an immunologic response to one's own body tissue/organ) that includes at least one of the following: hyperthyroidism, ophthalmopathy, or infiltrative dermatopathy. Graves' ophthalmopathy (aka: thyroid ophthalmopathy, thyroid-related ophthalmopathy, thyroid eye disease, orbitopathy related to thyroid disorders) is an autoimmune process that is progressive but self-limited with a variable course extending over 1 to 3 years generally and having possible vision-threatening complications. 
Thyroid ophthalmopathy is clinically apparent in approximately 50% of patients with Graves' disease and requires intensive treatment or surgical intervention in 3 to 5 percent of cases. Graves' ophthalmopathy is usually associated with hyperthyroidism, although patients may be euthyroid (ie. exhibit normal thyroid and hormone levels).

Clinical Presentation

Mild thyroid ophthalmopathy complaints include photophobia (sensitivity of light), foreign body sensation, and increased tearing. Other complaints include discomfort when looking up or restriction of upgaze altogether. Blurred vision from acquired corneal astigmatism (irregularity of the shape of the cornea) is also not unusual. More severe cases may exhibit vertical or horizontal diplopia (double vision). Visual loss may result from corneal ulceration (damage to the cornea) or from optic neuropathy (damage to the optic nerve). (Feldon) "In thyroid ophthalmopathy, a characteristic staring appearance is often present, owing to eyelid retraction. Lid retraction may occur with exophthalmos (abnormal protrusion or bulging forward of the eyeball) or may be an isolated finding. …Early in the course of the disease, this lid retraction may be due to a sympathomimetic (sympathetic nervous system) response, whereas in later stages retraction may be associated with fibrosis (scarring or collagen deposits) of lid tissues. … Patients with thyroid eye disease often complain of excessive lacrimation (tears), gritty sensation, discomfort and photophobia (sensitivity of light)." There may also be conjunctival signs including conjunctival redness and swelling from dilated blood vessels (Albert and Jakobiec, p. 2944-2945). Exophthalmos, also called proptosis, is a characteristic finding in thyroid eye disease, and has been reported to occur in 34% to 93% of patients (Duke-Elder). Abnormalities in the motility of the eyes are common in this disease. Typically the first ocular motility problem is difficult or restricted up-gaze (upward eye rotation) followed later by a limitation of horizontal eye movement. These limitations are often associated with diplopia (double vision). "It should be noted that most thyroid ophthalmopathy patients, including those with no ocular motility symptoms, show some degree of extraocular muscle involvement demonstrated by ultrasonography" (Albert and Jakobiec, p. 2946). Exposure keratitis (corneal inflammation) occurs in these patients and is due to inadequate lid closure due to proptosis and eyelid dysfunction. If left untreated this can result in ulceration of the cornea, perforation, panophthalmitis (inflammation or infection of the entire eye), and loss of the eye. "Visual loss is an important but rare complication of thyroid ophthalmopathy and is usually due to optic neuropathy. The incidence of optic neuropathy is approximately 5% of patients with thyroid ophthalmopathy and affected individuals usually do not have marked proptosis or optic nerve changes on ophthalmoscopy" (Albert and Jakobiec, p. 2947).

Ophthalmopathy occurs most frequently in patients with active or treated Graves' disease and in only 2 percent or less of patients with Hashimoto's disease (Wyse, et al.). Rarely, patients with primary hypothyroidism, thyroid cancer, and those with other forms of thyroid disease or thyroid inflammation may have eye findings. (Albert and Jakobiec, p. 2938). Statistics vary, one source states that 10% to 25% of patients presenting with orbital signs and symptoms typical of Graves' disease have no history of thyroid involvement and will test negative serologically (Lemke).


The most characteristic pathologic finding seen in Graves' ophthalmopathy is enlargement of the extraocular muscles. The earliest sign is edema (swelling) of the fatty and muscular orbital tissues. More advanced changes include infiltration of the tissue by plasma cells, lymphocytes, mast cells, and macrophages. This is followed by fibrosis (collagen deposits, scarring) (Feldon).  

The mechanism of ophthalmopathy in Graves' disease is controversial. Patients with ophthalmopathy may be hyperthyroid, hypothyroid, or euthyroid; however, most patients who are hypothyroid have been treated for hyperthyroidism and most patients with euthyroid ophthalmopathy have subtle thyroid dysfunction (Jacobson & Gorman.). There is evidence that the ophthalmopathy is a distinct autoimmune disorder separable from Graves' hyperthyroidism (Albert and Jakobiec, p.2938). In Graves' hyperthyroidism, autoantibodies (antibodies to self) bind in the region of the thyroid stimulating hormone [TSH] receptor. This binding causes thyroid hormone production. Some abnormal antibodies bind with the same membrane receptors that bind normal TSH (thyroid stimulating hormone). These antibodies are referred to by several names and acronyms including thyroid stimulating immunoglobulin (TSI), thyroid stimulating antibodies (TSAb), TSH-receptor antibody (TRAb), or possibly Long-Acting Thyroid Stimulator (LATS). These antibodies have a prolonged stimulating effect on the thyroid gland (almost 12 times that for the normal TSH). "The antibodies that cause hyperthyroidism almost certainly develop as the result of autoimmunity that has developed against thyroid tissue. Presumably, at some time in the history of the person, an excess of thyroid cell antigens has been released from the thyroid cells, and this has resulted in the formation of antibodies against the thyroid gland itself" (Guyton, p. 953). It is uncertain whether or not these antibodies are also directed against orbital tissue such as the extraocular muscles or orbital tissue or if a separate set of autoantibodies are circulating. Other possible mechanisms include the role of cell-mediated immunity: "It has been suggested that defects in T-cell subsets (sensitized T-lymphocytes) may promote thyroid ophthalmopathy" (Albert and Jakobiec, p. 2941). The current thought on the mechanism is that "antigens found in orbital tissue are the target of cell-mediated or humoral autoimmune response and subsequent cell damage. The exact nature of the orbital antigen and its relationship to thyroid antigen is unknown." It is also possible that the antigens or T-lymphocytes could directly stimulate such cellular functions as glycosaminoglycan or collagen production (Albert and Jakobiec, p. 2941).


Diagnosis is usually made on the basis of the patient's clinical signs and symptoms. However, further tests are clinically useful for determining the type and extent of orbital involvement. The enlarged extraocular muscles can be detected by A-scan or B-scan ultrasonography, or by a CT (computerized tomography) scan. CT scan is especially important when proptosis is not obvious since there is a tendency for apical muscle enlargement in some cases, which can produce compression of the optic nerve. It is also mandatory that patients exhibiting Graves' ophthalmopathy also be examined and assessed for thyroid disease (Feldon).

Differential Diagnosis

The ophthalmologist should also consider other types of orbital inflammation as well as neoplastic disease of the orbit: Other causes of bilateral exophthalmos include: Idiopathic inflammatory pseudotumor, Wegener's granulomatosis/vasculitis, metastatic neuroblastoma, leukemia/lymphoma, histiocytosis X, cavernous-sinus thrombosis, congenital orbitofacial malformations. Causes of Chronic unilateral exophthalmos include: pseudotumor, lymphoma, cavernous hemangioma, lacrimal grand tumor, peripheral nerve tumor, meningioma, mucocele, metastatic and secondary tumors (Jones & Jakobiec). Ultrasound or a CT scan usually differentiates these disorders easily (Feldon).


Graves' ophthalmopathy has two broad phases. The first phase is an acute, active inflammatory/congestive one lasting 6 to 18 months (up to 3 years rarely). This phase is believed to be mediated, at least in part, by lymphocytes and is partially responsive to treatment with corticosteroids, immunosuppression, and local radiation therapies. This acute phase is followed by a chronic/stable phase with hypertrophy (increased size) and fibrosis (scarring) of extraocular muscles, lacrimal glands, and orbital fat together with subcutaneous eyelid changes. These later changes are permanent, will not regress or progress spontaneously, and they are unresponsive to any suppressive treatment. Surgical repair is necessary to improve this second phase (Albert and Jakobiec, p.1906).

There is no consistent effect of any one type of thyroid treatment on the development, progression, or improvement of ophthalmopathy. Thyroid gland treatment affects only one of the end organs of this disease process and does not alter the fundamental autoimmune process causing orbitopathy. Frequently, in managing these patients, treatment of the thyroid gland must be simultaneous but independent of treatment for ophthalmopathy (Albert and Jakobiec, p. 1905). There is no single simple approach to treating Graves' ophthalmopathy. Each patient presents with a unique set of symptoms and with differing signs which vary in severity. Therapy is tailored to the patient's signs and symptoms and disease present. Treatment may be local, systemic, or surgical. A combination of therapeutic approaches is often required (Feldon).

Local or topical therapy is directed at protecting the eyes from exposure and minimizing discomfort while awaiting spontaneous stabilization of the disease process (Albert and Jakobiec, p. 1906). Symptomatic relief can usually be achieved by frequently administering artificial tears, using sunglasses, and taping eyelids closed during sleep. Topical steroids are rarely used and if used the patient should be carefully monitored for corneal ulceration and intraocular hypertension. Ocular exposure is treated with lubricants, moisture chambers, and eyelid taping to maintain the corneal surface. Tarsorrhaphy (stitching the upper and lower eyelids together, partially or completely usually to provide temporary protection to the eye) may be indicated if lubrication becomes a management problem. Lubrication may be tapered or stopped once the active disease phase ceases (Lemke).

Systemic drugs have been used to treat different symptoms: Diuretics may help to temporarily decrease periorbital edema. Anti-inflammatory agents, particularly corticosteroids, have been used when ophthalmopathy is progressing rapidly. In the past, immunosuppressive agents such as Azathioprine or cyclophosphamide were used to treat Graves' disease. The success of such treatment is uncertain but it is still occasionally used for recalcitrant cases. (Feldon)

"If problems such as significant proptosis, strabismus, or eyelid retraction persist after the disease has become quiescent, surgery is usually indicated. The general sequence of surgical procedures performed in the patient with Graves' disease is orbital decompression, strabismus surgery, and eyelid surgery. The rationale for this sequence is that decompression surgery may affect ocular motility and eyelid position, and strabismus surgery may alter eyelid position. In an individual patient any or none of the three procedures may be indicated" (Lemke, p 3).

Optic neuropathy is treated with steroids, radiation, and orbital decompression surgery. High voltage radiation therapy has been used primarily to supplement steroid and surgical treatment of optic neuropathy (Feldon).

Orbital radiotherapy for Graves' ophthalmopathy.

Bartalena L, Marcocci C, Tanda ML, Rocchi R, Mazzi B, Barbesino G, Pinchera A. Thyroid. 2002 Mar;12(3):245-50.

Cattedra di Endocrinologia, University of Insubria, Varese, Italy. l.bartalena@libero.it

Orbital radiotherapy is a well-established method of treatment for severe Graves' ophthalmopathy, because of its anti-inflammatory and locally immunosuppressive effects. It has been used for 60 years. Conventional external x-ray and cobalt therapy have been abandoned, and most groups now use supervoltage linear accelerators (4-6 MeV). Cumulative doses may vary, but in most studies a cumulative dose of 20 Gy delivered over 2 weeks was utilized. Successful outcome depends on the selection of patients, because recent onset, active ophthalmopathy is much more favorably affected than longstanding, inactive disease. Inflammatory signs, recent onset eye muscle dysfunction, and optic neuropathy respond well to orbital radiotherapy, while proptosis and longstanding eye muscle restriction respond poorly. Overall, favorable responses have been reported, with few exceptions, in approximately 60% of cases. Combination of irradiation with high-dose systemic glucocorticoids provides better results than either treatment alone. Orbital radiotherapy is well tolerated and safe. Preexisting retinopathy (e.g., in patients with diabetes) is a contraindication to this treatment for the risk of further retinal damage. No case of radiation-induced tumors has so far been described after orbital radiotherapy for Graves' ophthalmopathy.

Orbital radiotherapy for Graves' ophthalmopathy: useful or useless? Safe or dangerous?

Bartalena L, Marcocci C, Gorman CA, Wiersinga WM, Pinchera A.
Endocrinol Invest. 2003 Jan;26(1):5-16.
Department of Endocrinology, University of Insubria, Varese, Italy. l.bartalena@libero.it

Treatment of Graves' ophthalmopathy does not always provide favorable results. After several decades of efforts, glucocorticoids, orbital radiotherapy (OR) and surgery (orbital decompression) remain the milestones in the management of this disease. OR produce favorable results in about 55-60% of patients. Its effectiveness is increased by the association with systemic glucocorticoids. Recent studies have cast some doubts on its real effectiveness and this is discussed by participants in this Forum. Selection of patients is particularly important to assess treatment outcome, because OR is unlikely to provide beneficial effects in patients with longstanding and inactive eye disease. OR is a safe procedure, with very limited side-effects. It should be used in patients older than 35 years of age. It is recommended that a large, multi-center, prospective, randomized and controlled study with well defined inclusion criteria be carried out to draw sound conclusions on the role of OR in the management of Graves' ophthalmopathy.

The aftermath of orbital radiotherapy for graves' ophthalmopathy.

Gorman CA, Garrity JA,  Ophthalmology. 2002 Nov;109(11):2100-7.

Department of Medicine, Mayo Clinic, Rochester, Minnesota. Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905, USA.

OBJECTIVE: To determine whether long-term improvement could be observed after orbital radiotherapy for Graves' disease; in addition, to evaluate ancillary treatments needed for those who have received radiotherapy, to search for late-emerging adverse consequences of radiotherapy, and to relate orbital changes to serum levels of thyroid-stimulating immunoglobulin (TSI). DESIGN: Three-year follow-up of noncomparative interventional case series. PARTICIPANTS: Forty-two patients. INTERVENTION: All patients had received orbital radiotherapy within 6 months of study entry. Twelve months after study entry, patients were free to select any additional treatment for their ophthalmopathy. MAIN OUTCOME MEASURES: Need for surgery, steroid therapy, volume of extraocular muscles and fat, proptosis, area of diplopia fields and range of extraocular muscle motion, volume changes after decompression and correlations of eye findings with serum TSI levels, retinal status. RESULTS: Half of the patients elected to have a surgical procedure on their eyes or orbits. Among patients who were not decompressed, we found only slight improvement in some of the main outcome measures. TSI did not positively correlate with baseline status or with any observed change in major outcome measures. After orbital decompression, the volumes of both muscle and fat increase, but bony orbital volume increases more and proptosis diminishes. Retinal microvascular abnormalities consistent with radiation retinopathy developed de novo in five eyes of three patients within 3 years of radiation therapy. CONCLUSIONS: In this 3-year uncontrolled follow-up phase, limited evidence for a clinically significant improvement was observed, which may be the result of treatment or of natural remission. In either case, the changes are of little clinical significance. Because it is neither effective nor innocuous, radiotherapy does not seem to be indicated for treatment of mild to moderate ophthalmopathy.

Long-term safety of orbital radiotherapy for Graves' ophthalmopathy.

Marcocci C, Bartalena L, Rocchi R, Marino M, Menconi F, Morabito E, Mazzi B, Mazzeo S, Sartini MS, Nardi M, Cartei F, Cionini L, Pinchera A.    J Clin Endocrinol Metab. 2003 Aug;88(8):3561-6.

Department of Endocrinology, University of Pisa, 56124 Pisa, Italy. c.marcocci@endoc.med.unipi.it

We investigated the long-term side-effects of orbital radiotherapy (OR) in 204 patients with Graves' ophthalmopathy (GO), irradiated from 1972-1996 [44 by cobalt unit (CU) and 160 by linear accelerator (LA), mostly combined with glucocorticoids], with a 5- to 25-yr follow-up (median, 11 yr). Cataract was observed in 21 patients (10%) 3-21 yr after OR, with a higher (not significant) prevalence in CU-treated patients (18% vs. 8% in LA-treated patients). The prevalence of cataract was higher, although not significantly, in CU-treated patients aged less than 60 yr, but not in LA-treated patients, compared with the general population. Mild, asymptomatic retinopathy was observed in 1 of 7 patients (14%) with diabetes and hypertension, in 1 of 31 patients (3%) with hypertension alone, and in 0 of 11 patients with diabetes alone. No tumors were observed in 157 patients submitted to computed tomography scan of orbital and adjacent regions. In conclusion, OR is a safe treatment, not associated with an increased frequency of cataract, provided a high voltage apparatus is used. Hypertension, especially if associated with diabetes, may represent a relative contraindication, as it may cause retinopathy. Although no secondary tumors were detected, due to the long latency of radiation-induced tumors, OR should be restricted to patients older than 35 yr.

Long-term results of irradiation for patients with progressive Graves' ophthalmopathy.

Marquez SD, Lum BL, McDougall IR, Katkuri S, Levin PS, MacManus M, Donaldson SS.   Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):766-74.

Department of Radiation Oncology, Stanford University Medical Center, CA, USA. sdmarquez@yahoo.com

PURPOSE: To determine the long-term outcome of radiotherapy (RT) in patients with progressively symptomatic thyroid eye disease and to evaluate the potential long-term sequelae. METHODS AND MATERIALS: Four hundred fifty-three patients provided written informed consent and received retrobulbar RT for Graves' ophthalmopathy at Stanford University Medical Center; 197 with 1 year of follow-up were retrospectively analyzed. Of the 197 patients, 189 received RT to the bilateral retrobulbar regions, and 4 received unilateral RT. The technical information was unavailable for 4 patients. Patients were assessed by chart review, telephone interview, questionnaire, and multidisciplinary physician examination. Eye impairment was scored using the SPECS system. The end point review included the before and after treatment SPECS score, surgical intervention, and patient satisfaction. Potential complications, including cataract development, retinopathy, and tumor formation, were investigated. Multivariate analyses were performed to assess the prognostic variables. RESULTS: Improvement or resolution was 89% for soft-tissue findings; 70% for proptosis; 85% for extraocular muscle dysfunction; 96% for corneal abnormalities; and 67% for sight loss. The response to RT may take >6 months to stabilize. Factors predictive of response varied in the individual SPECS categories but included the initial SPECS score, pretreatment thyroid status, female gender, a 20-Gy RT dose, and a history of hypertension. Nonpredictive factors included a history of tobacco use, diabetes mellitus, steroids, and prior cataracts. Only 16% required surgical intervention to preserve their vision or restore binocular vision. Twenty-two patients (12%) developed cataracts after irradiation (median 11 years). No patient developed a tumor within the RT field during the follow-up period (range 1-29 years). Ninety-eight percent of patients were pleased with their results, and 2% believed their symptoms progressed despite RT. CONCLUSIONS: Retrobulbar irradiation (20 Gy) is safe and effective treatment for progressive Graves' ophthalmopathy, with a 96% overall response rate, 98% patient satisfaction rate, and no irreparable long-term sequelae, with follow-up extending 29 years. The most common late effect observed was cataract development, which occurred more frequently in older patients and was reversible with extraction. Elective surgical intervention after RT should be withheld until patients have demonstrated a plateau in response.

Effect of steroid pulse therapy with and without orbital radiotherapy on Graves' ophthalmopathy.

Ohtsuka K, Sato A, Kawaguchi S, Hashimoto M, Suzuki Y.   Am J Ophthalmol. 2003 Mar;135(3):285-90.

Department of Ophthalmology, Sapporo Medical University, School of Medicine, Sapporo, Japan. kohtsuka@sapmed.ac.jp

PURPOSE: To report the effect of high-dose intravenous corticosteroid pulse therapy with and without orbital radiotherapy on Graves' ophthalmopathy. DESIGN: Nonrandomized clinical trial. METHODS: We selected 39 Japanese patients (age range, 22-64 years; mean, 48 years; 31 women, 8 men) who had active Graves' ophthalmopathy among 195 consecutive patients. In the first 20 patients, high-dose intravenous methylprednisolone pulse therapy (1 g per day for 3 successive days, repeated 3 times within 3 weeks) followed by 24-Gy orbital radiotherapy was performed. In the other 19 of the 39 patients, high-dose intravenous methylprednisolone pulse therapy without orbital radiotherapy was performed. Coronal computed tomography (CT) of the orbit and exophthalmometry were performed before the corticosteroid pulse therapy, and 1 and 6 months after the corticosteroid pulse therapy. The maximum coronal section area of the most hypertrophic rectus muscle in each eye was measured based on orbital CT imaging. RESULTS: Clinical findings at study entry were not significantly different between the two groups. No significant difference was found in the maximum coronal section area of the most hypertrophic rectus muscle and the results of exophthalmometry measurements in both groups before the therapy. Extraocular muscle hypertrophy was significantly reduced 1 month and 6 months after the therapy (P < .01) in both groups. However, no beneficial therapeutic effect on proptosis was observed in either group at 1 month and 6 months after the therapy. No significant difference in the therapeutic effect on extraocular muscle hypertrophy and proptosis was found between the two groups. CONCLUSIONS: Orbital irradiation after corticosteroid pulse therapy had no beneficial therapeutic effects on rectus muscle hypertrophy or proptosis of active Graves' ophthalmopathy during the 6-month follow-up period.

A long-term follow-up study after retro-orbital irradiation for Graves' ophthalmopathy.

Schaefer U, Hesselmann S, Micke O, Schueller P, Bruns F, Palma C, Willich N
.Int J Radiat Oncol Biol Phys. 2002 Jan 1;52(1):192-7.

Department of Radiotherapy and Radiooncology, University Hospital, Westfaelische Wilhelms University, Muenster, Germany. uschafe@uni-muenster.de

PURPOSE: The aim of this retrospective analysis was to find out whether low-dose radiation, which is used in the treatment of Graves' ophthalmopathy, could cause radiation-induced cancer, which would in turn adversely affect the survival of the irradiated population and cause an increase in the cancer-specific death rate. METHODS AND MATERIALS: From 1963 to 1978, 250 patients received bilateral orbital irradiation for a progressive Graves' ophthalmopathy. Median age was 49 years. Overall survival and causes of death were evaluated with the help of patients still living, registration offices, medical records, referring physicians, and relatives. Survival curves were calculated with the Kaplan-Meier method. The outcome for each patient was compared with data from life tables regarding gender, age, and calendar period-specific person-years at risk. In addition, treatment outcome for living patients was evaluated with a questionnaire. RESULTS: After a median follow-up of 31 years, 102 patients are still alive, 123 patients have died, and 25 patients have been lost to follow-up. The 10-year, 20-year, and 30-year survival rates were 89%, 68%, and 49%, compared with the age-adapted survival rate of the normal population of 92%, 76%, and 52%. Evaluation of cancer-specific survival was possible in 166 cases. The 10-year, 20-year, and 30-year cancer-specific survival rates were 98%, 92%, and 88%, compared with 97%, 93%, and 87% in the normal population. Treatment response was evaluable in 94 cases. A complete response was reported in 41 patients, a partial response in 39 patients, and no change in 14 patients. CONCLUSIONS: No significant evidence of radiation-induced cancer death was seen in this small cohort of patients treated with radiotherapy for Graves' ophthalmopathy. The long-term treatment results seem to be satisfactory. Studies with greater numbers of patients are necessary to examine the risks and benefits more precisely.