Treatment of Graves' ophthalmopathy

Treatment of Graves’ ophthalmopathy See page 949 The eye disease that occurs in some patients with Graves’ disease has always been perplexing. The ophthalmopathy tends to appear initially at the same time as the thyroid overactivity but sometimes arises independently. Its course is probably not directly affected by treatment of the thyroid condition, although this has been disputed. Graves’ ophthalmopathy is generally regarded an independent expression of the prevailing immune disturbance in patients with Graves’ disease, tending to become manifest at the time that autoimmune stimulation activates thyrotoxicosis but pursuing an independent course. The antigenic target of the immune response remains uncertain, and what determines the specificity of the reaction for the retro-orbital tissues is also unclear. The retro-orbital fibroblasts and the skeletal muscle of the extraocular muscles do not differ in such obvious ways from their counterparts at other sites that they stand out as immunological targets. Histological evidence suggests that the fibroblasts are the primary target, with exuberant elaboration of glycosaminoglycans producing the swelling of oculomotor muscles and expansion of the retro-orbital tissues.1 Similar doubts have surrounded the optimum treatment of Graves’ ophthalmopathy. Prummel and colleagues, who report in this issue, compared prednisone and local radiotherapy in Graves’ ophthalmopathy and found them to be equally effective. This observation is important because high-dose glucocorticoids are used more commonly than irradiation for primary therapy and they have serious side-effects. Although radiotherapy has been used in the management of Graves’ ophthalmopathy for many years,2 no previous controlled trial has compared its efficacy with that of steroids. One controlled study showed that combined treatment with orbital irradiation and glucocorticoids was better than treatment with glucocorticoids alone,3 but confirmation that radiotherapy is as effective as glucocorticoids provides justification for irradiation as a single treatment modality. I have two outstanding concerns. First, only patients with moderately severe Graves’ ophthalmopathy were included in the study. Since patients with sight-threatening ophthalmopathy (manifested by corneal involvement or loss of visual acuity) were excluded we cannot assume that radiotherapy is an alternative to high-dose glucocorticoids or decompressive surgery in such cases. The longer time required for response to radiotherapy in the less urgent situations described by Prummel et al indicates that radiotherapy has no immediate role in sight-threatening Graves’ ophthalmopathy. Second, I note the high rate of non-responders in both groups (about 50 %) and the incomplete nature of the response in the responders. That three-quarters of the patients

subsequently required decompressive or squint surgery indicates that neither prednisone nor radiotherapy achieved a satisfactory long-term outcome in most cases. The high frequency of decompressive surgery (approaching 40%) indicates that the researchers favour this approach to a greater extent than many other workers. As decompressive surgery has become more refined, this form of therapy is increasingly used in subjects with persistent, cosmetically disturbing proptosis (> 25 mm), as well as in the more urgent situation of sight-threatening

ophthalmopathy associated with compressive optic neuropathy.4,5 Overall, the findings of Prummel et al indicate that radiotherapy is preferable to high-dose glucocorticoids in moderate Graves’ ophthalmopathy which is not sightthreatening. However, most patients with Graves’ disease have milder forms of ophthalmopathy (or none at all), and require only symptomatic treatment with moisturising eye drops, and perhaps reduction of periorbital oedema that can be achieved by sleeping with the head of the bed elevated. For severe disease where sight is threatened, decompressive surgery is indicated at once or, if still required, after a short and carefully monitored trial of high-dose glucocorticoids; radiotherapy has a definite role in less urgent

cases.

Richard Larkins Department of Medicine, Royal Melbourne Hospital, Melbourne, Australia

1 2

Weetman AP. Thyroid-associated eye disease: pathophysiology. Lancet 1991; 338: 25-28. Donaldson SS, Bagshaw MA, Kriss JP. Supervoltage orbital radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab

1973; 37: 276-85. 3

4 5

Bartalena L, Marcocci C, Chiovato L, et al. Orbital cobalt irradiation combined with systemic corticosteroids alone. J Clin Endocrinol Metab 1983; 56: 1139-44. Bahn RS, Garrity JA, Gorman CA. Diagnosis and management of Graves’ ophthalmopathy. J Clin Endocrinol Metab 1990; 71: 559-63. Fells P. Thyroid-associated eye disease: clinical management. Lancet

1991; 338: 29-32.

Inhalational agents for

pulmonary

hypertension See page 961

Pulmonary hypertension is a serious primary disease and an important complication of various acute non-pulmonary diseases. Several treatments aimed at lowering pulmonary vascular tone have been triedl and may reduce mortality (eg, calcium channel blockers,22 nitroprusside,33 and prostacyclin4) but they remain controversial because they lower systemic vascular resistance and increase the shunt fraction, which leads to a fall in arterial oxygen tension.3-5 Considerable interest has therefore been focused on the inhalation of nitric oxide (NO).6 NO is thought to act in the smooth muscle of vessels: it stimulates production of cyclic

guanosine

monophosphate

(cGMP),

subsequent

alterations in intracellular calcium leading to relaxation of the vessel wall. Unlike other agents, NO inhalation reduces intrapulmonary shunting. The apparent lack of systemic effects may be due to avid binding of NO to haemoglobin. Concern over NO mainly relates to its toxicity in high concentrations and to difficulties in developing safe and effective delivery systems for the gas and for monitoring the inhaled concentration accurately. An exciting development is the report by Walmrath and colleagues in this issue showing that inhaled prostacyclin (epoprostenol) will correct pulmonary hypertension in patients with acute respiratory failure and do so without systemic effects. Given as an aerosol, prostacyclin produced effects analogous to those seen with NO; the shunt fraction decreased, arterial oxygen tension rose, and systemic blood pressure was not greatly altered. This observation, if confirmed, would mean that pulmonary hypertension can be treated effectively with an 941