1. Aetna considers orbital decompression surgery, eye muscle surgery and/or eyelid surgery medically necessary for members with severe Graves' ophthalmopathy (especially individuals with marked proptosis and optic neuropathy) when both of the following measures have not been successful:

   1. A trial of conservative measures, such as elevating the head at night, cool compresses, sunglasses, lubricating eyedrops, and if the member has strabismus, prisms for glasses; and
   2. A trial of medications, such as diuretics, methimazole, prednisone, and propylthiouracil.

      Note: According to available literature, surgical treatment should not be undertaken until stability of the thyroid-related orbitopathy (TRO) has been demonstrated.  One of the advantages of waiting for stability of TRO is that some cosmetic problems may resolve or improve without intervention.  Fat pad removal is commonly requested with surgery for exophthalmos and is generally cosmetic in nature, and therefore, is considered not medically necessary.

2. Aetna considers orbital radiotherapy medically necessary for the treatment of members with severe Graves' ophthalmopathy when both of the afore-mentioned criteria are met.

3. Aetna considers the use of banked human tissue graft (e.g., Alloderm) to elevate the lower eyelids in members with lower eyelid retraction associated with Graves ophthalmopathy experimental and investigational because there is insufficient evidence to support this approach.

4. Aetna considers the following interventions experimental and investigational for the treatment of Graves' ophthalmopathy because their effectiveness for this indication has not been established.

Graves' disease (also known as Parry's or Basedow's disease) is a complex disease whose pathogenesis is believed to be autoimmune.  It is a disorder that affects mainly females, and although it may occur at any age, has a peak incidence in the 3rd and 4th decades.  Graves' disease has 3 principal manifestations: (i) hyperthyroidism with diffuse goiter, (ii) ophthalmopathy, and (iii) dermopathy; however, they do not necessarily appear simultaneously.

Graves' ophthalmopathy, also known as thyroid-associated ophthalmopathy (TAO), occurs in 2 to 7 % of patients with Graves' disease with the major manifestations being proptosis, ophthalmoplegia, optic neuropathy, and/or eyelid retraction.  Thyroid-associated ophthalmopathy is the commonest cause of proptosis in adults.  The term exophthalmos is used exclusively to describe the proptosis of TAO; exophthalmos may be unilateral early but usually becomes bilateral with time.  The term exophthalmic ophthalmoplegia refers to the ocular muscle weakness that results in impaired upward gaze and convergence and strabismus with varying degree of diplopia.

Physicians recommend treatment of Graves' ophthalmopathy according to each patient's symptoms.  Sometimes combinations of the following procedures are used:

• Elevating the head at night, cool compresses, sunglasses, lubricating eyedrops, or prisms for glasses;
• Eye muscle surgery, eyelid surgery, or both;
• Medications or radiation to shrink tissue;
• Orbital decompression surgery.

An assessment by the National Institute for Health and Clinical Excellence (2005) found that retrobulbar irradiation to be an effective procedure in patients for whom other treatments are inadequate or are associated with significant side effects.

Orbital Decompression Surgery

In orbital decompression surgery, the bone between the orbit and the sinuses is removed.  A successful procedure improves vision and provides room for the eye to slip back into the orbit's protection.  Orbital decompression is indicated in patients with severe ophthalmopathy refractory to medications and radiotherapy, especially in the presence of marked proptosis and optic neuropathy.

Eye Muscle Surgery

Diplopia often occurs because the eyes are misaligned.  Usually, mis-alignment is caused by 1 or more eye muscles that are too short or “tight” due to scar tissue from Graves' ophthalmopathy.  This scar tissue results from changes surrounding the eye because of swelling.  The goal of eye muscle surgery is to attain single vision when looking straight ahead and looking down when reading.  During eye muscle surgery, the muscle is cut from its attachment to the eyeball and re-attached further back on the eye.  Usually eye muscle surgery does not require an over-night stay in the hospital.  The physician evaluates the final results about 2 months later.  More than 1 operation is sometimes required.

If orbital decompression and eye muscle surgery are to be performed, the orbital decompression surgery generally is carried out first.

Eyelid Surgery

Graves' ophthalmopathy generally causes the eyelids to open more widely.  The front surface of the eyeball becomes exposed beyond the eyelid and causes excessive tearing and discomfort.  Lid retraction may be improved by orbital decompression, especially the lower lid.  However, the backward and downward movement of the globe following decompression may accentuate upper lid retraction.  Surgical re-positioning (recession) of the upper lid retractors may have to be performed as an adjunct.

If orbital decompression, eye muscle, and eyelid surgery are required, the eyelid procedure is generally performed as the final operation in a series.

Acellular human dermis is being investigated for elevating the lower eyelids in lower eyelid retraction associated with Graves ophthalmopathy.  However, current evidence in the peer-reviewed medical literature is limited to case reports and small, retrospective case series.

Orbital Radiation

Zoumalan and colleagues (2007) noted that thyroid eye disease (TED, Graves' ophthalmopathy, thyroid ophthalmopathy) is the most common cause of orbital inflammation and proptosis in adults.  There is no agreement on its management although corticosteroids and external beam orbital radiation have traditionally been believed to provide benefit in active inflammation.  A review of the published literature in English disclosed an overall corticosteroid-mediated treatment response of 66.9 % in a total of 834 treated patients who had moderate or severe TED.  Intravenous corticosteroids used in repeated weekly pulses were more effective (overall favorable response = 74.6 %, n = 177) and had fewer side effects than daily oral corticosteroids (overall favorable response = 55.5 %, n = 265).  A combination of corticosteroid and radiation therapy seemed to be more effective than corticosteroids alone.  However, the authors stated that these conclusions are tempered by a notable lack of standardization within and between study designs, treatment protocols, and outcome measures.  Accordingly, the North American Neuro-Ophthalmology Society, American Society of Ophthalmic Plastic and Reconstructive Surgery and the Orbital Society, in conjunction with Neuro-Ophthalmology Research and Development Consortium, will investigate the design and funding of a multi-center controlled trial.

A technology assessment on orbital radiation for Graves ophthalmopathy by the American Academy of Ophthalmology (Bradley et al, 2008) examined if orbital radiation offers effective and safe treatment for Graves ophthalmopathy.  Medical literature databases were searched to identify all published reports relating to orbital radiation treatment for Graves ophthalmopathy.  To be included in the technology assessment, reports had to provide original data, to report on a case series or uncontrolled trial of at least 100 subjects or a randomized clinical trial (RCT) of any size, to focus on orbital radiation for the treatment of Graves ophthalmopathy, and to follow-up patients for at least 3 months.  Abstracted data included study characteristics, patient characteristics, treatment response, and safety information.  A total of 14 studies were included in the technology assessment: 5 observational studies and 9 RCTs.  Three of the observational studies reported on treatment response, with overall favorable outcomes for 40 % to 97 % of patients.  Three of the observational studies provided intermediate-term safety data.  The risk of definite radiation retinopathy is 1 % to 2 % within 10 years after treatment.  Patients treated with orbital radiation did not have an increased risk of secondary malignancy or premature death.  The 9 RCTs were qualitatively heterogeneous.  Patients with optic neuropathy generally were excluded from participating in the RCTs.  Three of the RCTs were sham-controlled.  None of these studies showed that orbital radiation was more effective than sham irradiation for improving proptosis, lid fissure, or soft tissue changes such as eyelid swelling.  Two of the 3 sham-controlled RCTs demonstrated improved vertical range of motion in radiation-treated subjects compared with controls.  The authors concluded that systematic review of the effect of orbital radiation on Graves ophthalmopathy is limited by the lack of standardization and variable quality of published reports.  Extra-ocular motility impairment may improve with radiotherapy, although the evidence of a treatment effect is mixed in clinical trials.  Future studies are needed to determine if a potentially beneficial motility effect results in improved patient function and quality of life.  Level I evidence indicates that proptosis, eyelid retraction, and soft tissue changes do not improve with radiation treatment.  The effectiveness of orbital radiation for compressive optic neuropathy resulting from Graves ophthalmopathy has not been investigated in clinical trials and merits further study.  Radiation retinopathy, although rare, is a risk of orbital radiation, even in patients without diabetes who receive appropriate radiation dose and delivery.

Guidance on retrobulbar irradiation for thyroid eye disease from the National Institute for Health and Clincial Excellence (NICE, 2005) concluded: "Current evidence on the safety and efficacy of retrobulbar irradiation for thyroid eye disease appears adequate to support the use of this procedure in patients for whom other treatments are inadequate or associated with significant side effects."

Other Treatments

Bartalena and Tanda (2009) noted that RCT have not shown a benefit of somatostatin analogs (e.g., lanreotide and octreotide) for Graves' ophthalmopathy.  They stated that there are also few data to support the use of intravenous immune globulin for this condition.  This is in agreement with the consensus statement of the European Group on Graves' orbitopathy on the management of Graves' orbitopathy (Bartalena et al, 2008), which stated that treatments of marginal or unproven value include somatostatin analogs and intravenous immunoglobulins.

In a retrospective, interventional case series, Khanna and colleagues (2010) examined the effectiveness of rituximab in patients with severe, corticosteroid (CS)-resistant TAO.  Responses to rituximab therapy were graded using standard clinical assessment and flow cytometric analysis of peripheral lymphocytes.  Main outcome measures were clinical activity score (CAS), proptosis, strabismus, treatment side effects, and quantification of regulatory T cells; 6 patients were studied.  Systemic CS failed to alter clinical activity in all patients (mean CAS +/- standard deviation, 5.3 +/- 1.0 before versus 5.5 +/- 0.8 during therapy for 7.5 +/- 6.4 months; p = 1.0).  However, after rituximab therapy, CAS improved from 5.5 +/ -0.8 to 1.3 +/- 0.5 at 2 months after treatment (p < 0.03) and remained quiescent in all patients (CAS, 0.7 +/- 0.8; p < 0.0001) at a mean follow-up of 6.2 +/- 4.5 months.  Vision improved bilaterally in all 4 patients with dysthyroid optic neuropathy (DON).  None of the 6 patients experienced disease relapse after rituximab infusion, and proptosis remained stable (Hertel measurement, 24 +/- 3.7 mm before therapy and 23.6 +/- 3.7 mm after therapy; p = 0.17).  The abundance of T regulatory cells, assessed in 1 patient, increased within 1 week of rituximab and remained elevated at 18 months of follow-up.  The authors concluded that in progressive, CS-resistant TAO, rapid and sustained resolution of orbital inflammation and DON followed treatment with rituximab.

In a systematic review and meta-analysis on treatment modalities for Graves' ophthalmopathy, Stiebel-Kalish et al (2009) concluded that current evidence demonstrates the effectiveness of intravenous corticosteroids in decreasing CAS in patients with moderate-to-severe Graves' ophthalmopathy.  Intravenous pulse corticosteroids therapy has a small but statistically significant advantage oral therapy and causes significantly fewer adverse events.  Somatostatin analogs have marginal clinical efficacy.  The efficacy of orbital radiotherapy as single therapy remains unclear, whereas the combination of radiotherapy with corticosteroids has better efficacy than either radiotherapy or oral corticosteroids alone.  Rituximab is not listed as a therapeutic option.  Furthermore, Hegedus (2009) stated that no data as yet support the routine use of biological therapies (e.g., rituximab).  The author stated that prospective, randomized trials comparing available and any novel therapeutic options for Graves' disease are needed.

Bartalena et al (2010) stated that non-surgical treatments for moderate to severe and active Graves' orbitopathy (systemic glucocorticoids with or without orbital radiotherapy) have limited effects on the underlying autoimmune process causing the disease.  Although the clinical responses to treatment are often good, at least one-third of patients with Graves' orbitopathy are eventually dissatisfied with the treatment outcome.  Advent in the understanding of the autoimmune basis of Graves' orbitopathy (although still incomplete) made it possible, similar to other autoimmune disorders, to envision the use of novel immunomodulating drugs.  Among the currently available biologic agents, the CD20+ B cell-depleting agent, rituximab, and tumor necrosis factor-alpha inhibitors (e.g., etanercept and infliximab) are presently the drugs that have the best chance of being employed in the future for the treatment of Graves' orbitopathy.  However, the authors noted that RCTs to support their use are needed.

Viani et al (2012) evaluated the effectiveness of radiotherapy (RT) with total dose of 20 Gy (RT 20 Gy) in the treatment of Graves' ophthalmopathy.  A systematic review and meta-analysis of RCTs was performed comparing RT 20 Gy with or without glucocorticoid to clinical treatments for Graves' ophthalmopathy.  The MEDLINE, EMBASE, Cochrane Library databases and recent relevant journals were searched.  Relevant reports were reviewed by 2 reviewers.  Response to radiotherapy was defined as clinical success according to each trial.  These investigators also evaluated the quality of life and whether RT to produce fewer side effects than other treatments.  A total of 8 RCTs (439 patients) were identified.  In the subgroup analysis, the overall response to treatment rates was better for: RT 20 Gy plus glucocorticoid versus glucocorticoids alone, OR = 17.5 (95 % CI: 1.85 to 250, p = 0.04), RT 20 Gy versus sham RT, OR = 3.15 (95 % CI: 1.59 to 6.23, p = 0.003) and RT 20Gy plus intravenous glucocorticoid versus RT 20Gy plus oral glucocorticoid, OR = 4.15(95 % CI: 1.34 to 12.87, p = 0.01).  There were no differences between RT 20 Gy versus other fractionations and RT 20 Gy versus glucocorticoid alone.  Radiotherapy 20 Gy with or without glucocorticoids showed an improvement in diplopia grade, visual acuity, optic neuropathy, lid width, proptosis and ocular motility.  No difference was seen for costs, intra-ocular pressure and quality of life.  The authors concluded that these findings showed that RT 20 Gy should be offered as a valid therapeutic option to patients with moderate-to-severe ophthalmopathy.  The effectiveness of orbital radiotherapy can be increased by the synergistic interaction with glucocorticoids.  Moreover, RT 20 Gy is useful to improve a lot of ocular symptoms, excluding intra-ocular pressure, without any difference in quality of life and costs.

Tanda and Bartalena (2012) examined the safety and effectiveness of orbital radiotherapy (OR) for graves' orbitopathy (GO).   The major source of data acquisition included PubMed strategies.  Original articles, systemic reviews and meta-analyses, and other relevant citations were screened.  Randomized clinical trials evaluating the effectiveness of OR are limited.  However, available data suggest that OR is a safe treatment, which seems to be effective particularly on ocular motility impairment, especially if it is of recent onset.  Orbital radiotherapy seems to be effective also on soft tissue changes, whereas exophthalmos and long-standing extra-ocular muscle dysfunction are poorly affected. The effectiveness of OR on dysthyroid optic neuropathy is uncertain.  The combination of OR and oral glucocorticoids (GCs) is more effective than either treatment alone, suggesting a synergistic effect of the 2 treatments.  There is no available evidence that the addition of OR to intravenous GCs provides an advantage over intravenous GCs alone.  The authors concluded that OR can be considered a safe second-line treatment for patients with moderate-to-severe and active GO but less effective than GCs.  A possible strategy may include its use in combination with intravenous GCs in patients whose GO has only partially responded to a first-course of intravenous GCs alone and is still active.

In a Cochrane review, Minakaran and Ezra (2013) examined the effectiveness and safety of rituximab for the treatment of TAO.  These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (the Cochrane Library 2013, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to April 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the EU Clinical Trials Register (www.clinicaltrialsregister.eu).  They did not use any date or language restrictions in the electronic searches for trials.  They last searched the electronic databases on April 15, 2013.  These researchers manually searched references of review articles and used the Science Citation Index to identify additional studies citing trials.  They contacted the lead investigators of relevant trials on ClinicalTrials.gov and the WHO ICTRP for information and data from as yet unpublished clinical trials.  They contacted experts in the field for information about any ongoing trials; and contacted the manufacturers of rituximab for details of any sponsored trials.  These researchers included RCTs of rituximab treatment by intravenous infusion for the treatment of patients with TAO, compared with placebo or intravenous glucocorticoid treatment.  Two review authors independently scanned titles and abstracts, as well as independently screened the full reports of the potentially relevant studies.  At each stage, the results were compared and disagreements were solved by discussion.  No studies were identified that met the inclusion criteria.  There are 3 ongoing studies that are likely to meet inclusion criteria once published, and thus be included in future updates of this review.  The authors concluded that there is currently insufficient evidence to support the use of rituximab in patients with TAO.  There is a need for large RCTs, investigating rituximab versus placebo or corticosteroids in patients with active TAO to make adequate judgment on the safety and effectiveness of this novel therapy for this condition.

Melcescu et al (2014) noted that GO often remains a major diagnostic and therapeutic challenge.  It has become increasingly important to classify patients into categories based on disease activity at initial presentation.  A Hertel exophthalmometer measurement of greater than 2 mm above normal for race usually categorizes a patient as having moderate-to-severe GO.  Encouraging smoking cessation and achieving euthyroidism in the individual patient are important.  Simple treatment measures such as lubricants for lid retraction, nocturnal ointments for incomplete eye closure, prisms in diplopia, or botulinum toxin injections for upper-lid retraction can be effective in mild cases of GO.  Glucocorticoids, orbital radiotherapy, and decompression/rehabilitative surgery are generally indicated for moderate-to-severe GO and for sight-threatening optic neuropathy.  Future therapies, including rituximab aimed at treating the molecular and immunological basis of GO, are under investigation and hold promise for the future.