16.3 Treatment of GO

16.3.1Active Inflammatory Phase

Treatment is indicated in patients mainly with active moderate-to-severe GO with a clinical activity score of four or more.

16.3.1.1Glucocorticoid Treatment

Glucocorticoids (GC) have been used in the management of GO administered locally, orally, or through i.v. [23].

Oral GC therapy (starting dose, 80–100 mg or 1 mg/kg body weight) requires high doses for prolonged periods of time. No randomized, placebo-controlled study, evaluating oral glucocorticoid treatment was ever performed. Open trials or randomized studies, in which oral GC were compared with other treatments, show a favorable response in about 33–63% of patients, particularly concerning soft tissue signs, eye muscle involvement of recent onset, and DON. Eye disease frequently flares up on tapering out or withdrawing of oral GC therapy. Side e ects are frequent.

Local retrobulbar or subconjunctival administration of glucocorticoids is less e ective than oral GC.

Intravenous GC pulse therapy is more e ective than oral GC (dose: 250 mg–1 g/week, over 6–12 weeks or 500 mg–1 g for 3 consecutive days, followed by oral GCs); response rates of about 80% are reported [24]. Evidence for the superiority of any of the di erent i.v. GC schedules as well as studies on the optimal cumulative dose is still lacking. Although i.v. GCs are tolerated better than oral GCs, life-threatening liver failure has been reported in association with very high cumulative doses in 0.8% of patients. Intravenous administration appears to be safe, if the cumulative dose is below 8 g methylprednisolone in each course of therapy.

16.3.1.2Orbital Radiotherapy

The reported response rate to orbital radiotherapy (OR) in open trials is about 60%. Total doses between 10 and 20 Gy are commonly absorbed per orbit, fractionated in single doses between 1 and 2 Gy over a 2–20 week period. Higher doses are no more e ective. The response to OR did not di er from oral prednisone in a randomized controlled trial (RCT), but glucocorticoids are faster acting. Two recent RCTs have shown that OR is more e ective than sham irradiation in improving diplopia and eye muscle motility [25, 26]. OR is usually well tolerated, but may cause transient exacerbation of ocular symptoms,

which is preventable if corticosteroids are administered simultaneously. Data on long-term safety are reassuring, but theoretical concerns about carcinogenesis remain for younger patients, particularly those under the age of 35 years. Retinal microvascular abnormalities have been detected in a minority of patients, mostly in those with concomitant severe hypertension or diabetic retinopathy. Consequently, these two comorbidities are considered absolute contraindications to OR. It is possible that diabetes, even in the absence of retinopathy, represents a risk factor for the development of retinal changes after OR, but the evidence is less persuasive [21, 27].

16.3.1.3Combined Therapy: Glucocorticoids and Orbital Radiotherapy

Combination of systemic GC (either orally or locally) with OR is more e ective than either treatment alone. It is unclear whether combining i.v. GCs with OR is more e ective than i.v. GCs alone [28]. Representative studies are summarized in Table 16.4.

16.3.1.4Other Immunosuppressive Treatments and New Developments

One major problem is recurrent activity of GO after maximal doses of i.v. glucocorticoid therapy and orbital radiotherapy. In most of the cases, poor control of thyroid function, high TSH-receptor-antibody levels, and nicotine abuse are among the underlying reasons. A thyroid specialist should always be consulted. In cases of expected low chance of remission or uncontrolled thyroid function, definitive therapy of the thyroid has to be initiated. Thyroidectomy is preferred because radioiodine therapy carries a risk of deterioration of active GO. In patients with marked proptosis, orbital decompression has to be considered because apart from proptosis reduction, decompression may also silence orbital inflammation − probably due to improvement of orbital lymphatic and venous drainage. If activity still does not decline, other immunomodulatory agents have to be considered. Two studies have shown the superiority of the combination of oral GCs and cyclosporine over either treatment alone. Recent treatment studies of GO patients with the B-lymphocyte depleting monoclonal antibody Rituximab have shown promising results. Administered together with standard methimazole-therapy, it prolongs remission of thyroid function in comparison with methimazole monotherapy. Also, the stimulatory capacity of TRAbs was reduced markedly. Clinical activity of GO significantly decreased after injection of 1,000 mg i.v. Rituximab

twice at 2-week interval. Even proptosis was significantly reduced. Subsequent randomized controlled trials with Rituximab need to be performed [30–32]. The anti-TNF a drug Etanercept is described as e ective as well in an open trial [33].

Treatments of marginal or unproven value include somatostatin analogs, azathioprine, ciamexone, and i.v. immunoglobulins.

Frequent topical lubricants, moisture chambers, tarsorrhaphy, amnion epithelium membrane as shield, and botulinum toxin injections in the levator muscle (doses for therapeutic ptosis: e.g., 30 IE Dysport®) should be applied immediately. Surgical decompression or lid lenghthening a chaud should be considered when the above measures alone are ine ective [21].

16.3.1.5Therapy of Dysthyroid Optic Neuropathy (DON) and Sight-Threatening Corneal Breakdown

High-dose i.v. GCs are the preferred first-line treatment for DON (3 × 500 mg–1 g at consecutive days within 1 week, if necessary repeated the following week). If the response to i.v. GCs is absent or poor after 1–2 weeks, or the dose/duration of steroid required induces significant side e ects, orbital decompression should be carried out promptly. Orbital decompression should be recommended promptly to patients with DON or corneal breakdown who cannot tolerate glucocorticoids. Both i.v. GC therapy and orbital decompression surgery should only be performed in clinical centers with the appropriate expertise.

Sight-threatening corneal breakdown must be treated as an emergency as well.

16.3.1.6Other Simple Measures

that may Alleviate Symptoms

The symptoms of corneal exposure (grittiness, watering, and photophobia) should be treated with lubricant eyedrops. Nocturnal ointment is of great benefit if eyelid closure is incomplete.

Prisms may correct intermittent or constant diplopia. Sleeping with the head in an upright position may improve lymphatic drainage and alleviate early morning eyelid swelling. Diuretics are rarely useful. Upper lid retraction can be reduced by injecting botulinum toxin (e.g., 5–15 IU Dysport®) subconjunctivally in the tarsal muscle (Mueller muscle). Full e ect is evident after 2–3 days and persists for about 4–6 weeks. The outcome is variable and the dose of botulinum toxin must be adjusted individually. Transient double vision and ptosis may occur in 10–20%. This procedure should be carried out in specialized centers [34].