INTRODUCTION

The decision of whether the ophthalmopathy must be treated should rely on the assessment of two different features, the severity and activity of the disease. Severity and activity of GO are not synonymous. If the ophthalmopathy is nonsevere, no aggressive medical or surgical treatment is required, although the disease shows some signs of activity. If the patient has severe ocular involvement, assessment of the degree of activity is important, because patients with active orbital disease are likely to respond to medical treatment (especially glucocorticoids and=or orbital radiotherapy), whereas such a treatment is unlikely to be of benefit in patients with inactive GO, who are then candidates to surgical treatment (orbital decompression or rehabilitative surgery) (4). The present discussion will focus on the current medical management of GO.

NONSEVERE GRAVES’ OPHTHALMOPATHY

Most patients with Graves’ disease have mild ocular manifestations that do not require any aggressive treatment. In these cases, local supportive measures are usually sufficient to obtain symptomatic relief until the eye disease becomes inactive, for example, photophobia can be alleviated by the use of sunglasses, and a foreign body, gritty sensation is usually controlled by the use of lubricating eye drops. If lagophthalmos is present, taping the eyelids shut during the night is useful to prevent nocturnal corneal drying. Prisms may be beneficial for correction of mild diplopia, if they are tolerated by the patient.

Thus, in patients with nonsevere ophthalmopathy, the most important therapeutic measure is probably reassuring the patient that the chance of his=her ophthalmopathy progressing to more severe forms is very low. Elimination of controllable risk factors for progression of ophthalmopathy (e.g., smoking) is also very important.

SEVERE GRAVES’ OPHTHALMOPATHY

Management of severe GO represents a difficult task that does not consistently provide favorable results. The recent

years have seen the proposal of novel treatments that add to the list of established treatments (glucocorticoids, orbital radiotherapy, and orbital decompression).

Glucocorticoids

Glucocorticoids represent a well-established method of treatment for GO, owing to anti-inflammatory and immunosuppressive actions (3). In addition, they reduce the synthesis and secretion of glucosaminoglycans (GAG) by orbital fibroblasts.

Glucocorticoids have been used in GO through different routes, oral, local (retrobulbar or subconjunctival), and more recently, intravenous (IV) (4). Oral glucocorticoids have usually been employed at high doses (prednisone 60–100 mg= day, or equivalent doses of other steroids) and for prolonged periods of time (several months). Many studies have documented a high effectiveness of high-dose oral glucocorticoids on soft tissue changes and optic neuropathy, whereas the decrease in proptosis and improvement in ocular motility were not always impressive. Recurrence of active disease is a rather frequent problem with oral glucocorticoid therapy, not only when the drug is withdrawn but also when its dose is tapered. Interestingly, in one study the rate of recurrence was abated when cyclosporine was administered concomitantly with and after glucocorticoid therapy (5). In summary, favorable effects of high-dose oral glucocorticoids are reported in slightly more than 60% of cases (range, 40–100%).

In the last 10 years or so, glucocorticoids have also been used intravenously by the acute administration of high doses of methylprednisolone acetate (0.5–1.0 g) at different intervals (4). In general, favorable effects have been observed on inflammatory signs and optic nerve involvement, whereas the effects on extraocular muscle involvement and, especially, proptosis have not been constantly impressive. The available results seem to indicate a higher percentage of favorable results in patients treated with IV glucocorticoids, compared to patients treated with oral glucocorticoids. In a randomized prospective study, we recently shown that IV glucocorticoids combined with orbital radiotherapy are more effective, and

that oral glucocorticoids combined with orbital radiotherapy are better tolerated and associated with a lower rate of side effects (6).

A major drawback of systemic glucocorticoid therapy is represented by the rather high rate of its side effects and complications. In addition to transient cushingoid features, adverse effects, such as diabetes, depression, reactivation of chronic diseases, infections, hypertension, osteoporosis, increased body weight, peptic ulcer, hirsutism, and cataract, have been reported during prolonged glucocorticoid therapy for GO, although their precise prevalence is uncertain. This prompted us compare in a prospective study the effectiveness of local (retrobulbar or subconjunctival) glucocorticoid therapy combined with orbital irradiation (7). The overall results of local glucocorticoid therapy were less satisfactory than those obtained with the systemic administration of steroids. Side effects were limited to transient ocular discomfort or pain and few cases of conjunctival hemorrhages. Thus, local glucocorticoid therapy may be considered in patients with active ophthalmopathy and with major contraindications to the systemic administration of glucocorticoids.

Orbital Radiotherapy

The rationale for the use of radiotherapy for GO resides both in its nonspecific anti-inflammatory effect and in the high radiosensitivity of lymphocytes infiltrating the retroorbital space (8). In addition, radiotherapy might also reduce GAG production by orbital fibroblasts. Whether the reported effectiveness of orbital radiotherapy in GO is related to its nonspecific anti-inflammatory action, to specific immunosuppressive effects, or to both remains to be elucidated.

Most centers today utilize linear accelerators delivering 4–6 MeV and use a 4 4-cm lateral field slightly angled posteriorly to avoid as much as possible irradiation to the contralateral lens (8). The use of higher energy sources did not prove particularly advantageous. The commonest cumulative dose is 20 Gy per eye, fractionated in 10 daily doses over a 2-week period. Recently, Kahaly et al. (9) reported that 1 Gy

per week over a 20-week period is equally effective and better tolerated than the 2-week scheme. The use of higher cumulative doses (30 Gy vs. 20 Gy) does not improve the results. With few exceptions, favorable effects of orbital radiotherapy are observed in approximately 60% of cases, especially on soft tissue inflammatory changes, recent extraocular muscle involvement, and optic neuropathy. Recently, one study by Mourits et al.(10) confirmed the effectiveness of irradiation, although mainly confined to extraocular muscle motility. Another paper by Gorman et al. (11) reported substantially unfavorable results, although biases in patients’ selection may have influenced the results.

Orbital radiotherapy is usually well tolerated. It may be associated with a transient exacerbation of inflammatory eye signs and symptoms, but this is unlikely to occur if glucocorticoids are concomitantly administered. Cataract is a possible complication of irradiation to the lens, but fractionation of the dose should maintain the radiation exposure of the lens below the threshold dose for radiation-induced cataract. Radiation retinopathy is an extremely rare complication of radiotherapy. A major concern relates to the possibility that orbital radiotherapy may be carcinogenic. To date, no case of secondary tumor following orbital radiotherapy for GO has been reported in the literature. Nevertheless, it seems prudent to avoid irradiation in young patients.

Orbital Radiotherapy Combined with

Glucocorticoids

Orbital radiotherapy and systemic glucocorticoids can be used for GO either alone or in combination. In addition to these synergistic effects, the combined regimen exploits the more prompt effects of glucocorticoids and the more sustained action of irradiation. The inclusion of glucocorticoids prevents radiation-associated transient exacerbation of ocular manifestations, while the inclusion of orbital radiotherapy probably reduces the prevalence of recurrences of eye disease, which is not infrequently observed when glucocorticoids are withdrawn. Thus, we suggest that this combined therapeutic