3-1997

Graves' opthalmopathy

Wilmar M. Wiersinga MD, Amsterdam, The Netherlands

Introduction

Graves' ophthalmopathy (GO) or thyroid-associated ophthalmopathy (TAO) is one of the remaining enigmas in thyroidology, for the basic scientist as well as for the clinician. For, its immunopathogenesis is incompletely understood and its management can be rather difficult. The last ten years have witnessed considerable progress as quite a few basic and clinical studies have clarified many relevant issues, providing a scientific basis for the proposed immunopathogenesis and for the outline of a treatment plan. Nevertheless, there are remaining controversies in both areas which are currently heavily debated. This simply might indicate that the definitive evidence is still not sufficient to answer questions like: what is the responsible autoantigen? is GO a T- or B-cell mediated disease? what is the most appropriate treatment of Graves' hyperthyroidism that will not harm the eyes? what is the role of immunosuppressive treatment? It is thus timely to review in a concise manner what is known on GO, what is not known, and what is disagreed upon.

Clinical Manifestations

The clinical manifestations of GO can be fully explained in a mechanical sense from the increase in size of retro-ocular tissues: enlargement of extra-ocular muscles and retrobulbar fat is found in 46%, of muscles alone in 46%, and of fat alone in 8% (Forbes et al. 1986). The increased volume of retrobulbar tissues gives rise to an increase of retrobulbar pressure because of the bony cage of the orbit. The increased retrobulbar pressure interferes with the venous drainage of the orbit, resulting in periorbital edema, chemosis and redness of the conjunctiva. It may also cause herniation of fat through the orbital septum; periorbital swelling thus may be composed of edema or fat, which is difficult to distinguish by physical examination. The increased retrobulbar pressure pushes the globe forwards, and exophthalmos ensues. The average orbital volume is 26 ml (fat 12g, extra-ocular muscles 3.3g, lacrimal gland 0.65g, nerves and blood vessels 0.6g, fat-connective tissue residue 2.4g), and it has been calculated that a 4 ml increase of orbital volume results in a 6 mm increase of proptosis. The swelling of the extra-ocular eye muscles limit their movements, and may cause diplopia if impairment is asymmetrical. Severe exophthalmos prevents closure of the eyelids during sleep, and exposure keratitis may develop. Reduced blinking precludes normal tear drainage, and contributes to the risk of keratitis. In severe cases optic nerve dysfunction may occur, with manifestations of sight loss in 72%, visual field defects in 66% and disturbed colour vision in 64%. There may be direct compression of the optic nerve by marked swelling of the extra-ocular muscles in the apex of the orbit, and/or interference with the blood supply of the optic nerve by the elevated retrobulbar pressure. A very high retrobulbar pressure in the order of 17-40mmHg (normal 3-5mmHg) has indeed been measured in vivo in GO patients undergoing decompressive surgery because of optic neuropathy. These figures are higher than the values of 9-11mmHg measured in patients who underwent decompressive surgery because of disfiguring proptosis in the absence of optic nerve dysfunction. The development of exophthalmos mitigates the raised retrobulbar pressure and serves as a safeguard against the occurrence of optic nerve dysfunction; rightly it has been called nature's own decompression. When this mechanism fails, the patient is at risk for optic neuropathy. Why this mechanism fails, remains unknown. It has been hypothesized that this is due to the presence of rather firm connective tissue which will prevent nature's own decompression (Koornneef et al. 1994).

Table 1: Relative frequency of the clinical manifestations of GO classified according to the NO SPECS system in 90 consecutive untreated patients (Wiersinga et al. 1989).

NO SPECS classification of eye change	class	frequency
No physical signs or symptoms	class 0
Only signs (limited to upper lid retraction, stare and lid lag	class 1
Soft tissue involvement (swollen eyelids, chemosis etc.)	class 2	90%
Proptosis 3 mm or more in excess of uper normal limit*	class 3	30%
Extra-ocular muscle involvement (usually with diplopia)	class 4	60%
Corneal involvement	class 5	9%
Sight loss (due to optic nerve involvement)	class 6	34%

*upper normal limit is 20 mm in the Caucasian race, 18 mm in the Chinese race and 22 m in the Black race.

The clinical manifestation of GO can easily be memorized from the NO SPECS classification (Table 1). Classes 2-6 indicate orbital pathology. Class 2 and 4 are most prevalent. Although clinical examination revealed eye muscle involvement in 60% of the patients, CT of the orbit demonstrated enlarged eye muscles in 93%. The occurrence of exophthalmos is grossly underestimated since proptosis values of 21- 22 mm in a Caucasian patient are not recorded in this system (although it may signify marked protrusion of the eye, very relevant to the patient). Class 5 is largely preventable by the liberal use of artificial tears and the application of occlusive eye pads and eye ointments during nighttime. GO usually manifests itself as a bilateral eye disease, although slight asymmetry is not uncommon. Unilateral eye disease is seen in 14% of GO patients, which is difficult to explain in view of the systemic nature of Graves' disease. The distribution of age, sex and NO SPECS classes in patients with unilateral eye disease is similar to that in patients with bilateral eye disease, but the interval between the onset of thyroid and eye disease is much shorter in the patients with unilateral eye disease. Interestingly, in unilateral GO eye muscle enlargement in the fellow eye is observed on CT scan in appr. 50% (Wiersinga et al. 1989). Unilateral GO may thus represent an early stage of the disease, that as a rule already is or develops shortly afterwards into a bilateral disease. Bona fide cases of unilateral GO, which never develop into bilateral disease do, however, exist; the reason for this remains obscure, but local factors presumably related to the anatomy of the orbit might be involved (Figure 1).

View figure 1

Another unexplained phenomenon is the differential involvement of extra-ocular muscles: as evident from CT scanning, the inferior rectus muscle is enlarged in 60%, the medial rectus in 50%, the superior rectus in 40% and the lateral rectus in 22% (Wiersinga et al. 1989). The swollen inferior rectus muscle causes limitation of upward gaze (as the impaired motility has a restrictive nature and is caused by the inability to relax on attempted gaze in the opposite direction); because of its preferential involvement impaired elevation is four times as common as impaired abduction, adduction and depression combined.

Epidemiology

A recent population-based cohort study in Olmsted County, Minnesota has provided reliable epidemiological data (Bartley et al. 1995). The overall age-adjusted incidence rate of GO for women was 16.0 cases and for men 2.9 cases per 100,000 population per year. Incidence rates exhibited an apparent bimodal peak (in the age groups 40 to 44 years and 60 to 64 years in women, and 45 to 49 years and 65 to 69 years in men). Male sex and older age (over 60 years) are associated with more severe ophthalmopathy (Kendler et al. 1993; Perros et al. 1993). The reason for these associations is unknown, but smoking behaviour might be involved. In a case-control study it was found that smoking greatly increased the risk for GO (odds ratio 7.7, 95% CI 4.3 to 13.7); patients with Graves' hyperthyroidism without eye changes were also more often smokers than control subjects (odds ratio 1.9, 95% CI 1.1 to 3.2). Among the patients with GO smokers had more severe eye disease than nonsmokers (Figure 2).

View figure 2

GO is usually but not invariably associated with Graves' hyperthyroidism. In our own series of 125 consecutive GO patients Graves' hyperthyroidism was present in 77%, hypothyroidism in 2%, and euthyroidism in 20% (Wiersinga et al. 1988). In the patients with euthyroid GO thyroid abnormalities (like a blunted TRH test, failure to suppress radioiodine thyroidal uptake with T3, thyroid autoantibodies) are found in 89%, and hyperthyroidism develops subsequently in 14% (Burch and Wartofsky 1993). As evident from pooled data of 842 patients with both GO and Graves' hyperthyroidism, the eye disease becomes manifest before hyperthyroidism in 19.6%, concurrent with hyperthyroidism in 39.4%, and after hyperthyroidism in 41.0% (Burch and Wartofsky 1993). It follows that autoimmune thyroid disease is present in the vast majority if not all GO patients. Conversely, it has been argued that the vast majority if not all patients with Graves' hyperthyroidism also have GO. This view is based on evidence for subclinical GO in Graves' hyperthyroidism without apparent eye disease, encompassing a shift to higher proptosis values in this group compared to healthy subjects, an abnormal increase in intraocular pressure on upgaze in 61%, and enlarged extra-ocular eye muscles on ultrasound or CT scan in 70-100%.

Diagnosis

The diagnosis of GO is usually straightforward, especially when the typical eye changes occur in the setting of Graves' hyperthyroidism. It must be realized, however, that none of the eye changes is specific for GO: similiar manifestations are encountered in a wide variety of other orbital disorders (like pseudotumor orbitae, orbital myositis, Wegener's granulomatosis, sarcoidosis, tumors, arteriovenous malformations). The diagnosis might be difficult in patients with atypical presentations, like in euthyroid GO or unilateral GO. In euthyroid GO (or "ophthalmic Graves' disease") the finding of thyroid autoantibodies or an abnormal thyroid regulation provides circumstantial evidence for GO. Although GO is the most common cause of unilateral exophthalmos, it is mandatory to perform orbital imaging in cases of unilateral eye disease to exclude other orbital disorders, especially tumours. Using CT or MRI the typical enlargement of the belly of the extra-ocular muscles in GO is nicely visualized. In the absence of a gold standard or a specific immunologic test GO essentially remains a clinical diagnosis.

It is recommended that the eye changes of GO are assessed as follows:

Severity of the Eye Disease

This can be done according to the NO SPECS classification which serves as an ingenious memory aid for the clinical examination. Quantitative measurements should be recorded whenever possible to enable objective assessment (Pinchera et al. 1992) including:

Eyelids: measurement of lid aperture and of the position of the eyelids in relation to the corneoscleral limbus (e.g. lid fissure measures 14 mm, upper lid is retracted 2 mm while lower lid is retracted 1 mm from the limbus).
Proptosis: exophthalmometer measurements in mm.
Extra-ocular muscles: quantitative measurement of eye movements (e.g. by Hess chart or a modified perimeter) (Mourits et al. 1994); presence or absence of single binocular vision with or without prisms in the central 30° of the visual fields.
Cornea: presence or absence of exposure keratitis assessed with rose bengal or fluorescein.
Optic nerve: measurement of visual acuity, with additional measurement of visual fields, color vision and visual evoked response in suspected cases. Because many patients do not complain of reduced visual acuity, the clinician should remain alert on the existence of optic neuropathy and should ask specifically for grayish vision and for blurred vision (blurred vision that does not disappear after blinking or after covering of one eye is suspicious).

Activity of the Eye Disease

Disease activity may be evaluated by recording changes over time in the objective measurements described above. Disease activity at one time may be assessed by assigning 1 point for the presence of each of the following signs and symptoms: spontaneous retrobulbar pain, pain on eye movements, eyelid erythema, conjunctival injection, chemosis, swelling of the caruncle, and eyelid edema or fullness. The sum of these points defines the clinical activity score (range 0-7) (Mourits et al. 1989).

Orbital Imaging

CT or MRI scans provide accurate information on the extent of eye muscle enlargement. Successive coronal sections are particularly useful to evaluate extension of the swollen eye muscles into the apex of the orbit with encroachment on the optic nerve: such "apical crowding" is a risk factor for the development of optic neuropathy (Nugent et al. 1988) (Figure 3). Imaging techniques also appear useful to assess activity of the eye disease: a long T2 relaxation time in eye muscles and orbital fat on MRI (Just et al. 1991), a low internal eye muscle reflectivity on A-mode ultrasonography (Prummel et al. 1993), and a high orbital uptake on octreoscan (Postema et al. 1994) all indicate active disease. Their accuracy in predicting outcome of immunosuppression remains to be determined in prospective trials (vide infra).

View figure 3

Patient Self-Assessment

How patients themselves perceive their illness and treatment results, is what really matters. Nevertheless, there is a paucity of studies reporting self-assessment scores, and these are urgently required. There is a need for a disease-specific questionnaire, with separate items pertaining to appearance (like peri-orbital swelling and exophthalmos) and to functional impairments (like double vision and sight loss).

Pathogenesis

Histological examination of retrobulbar tissues in patients with severe and active GO shows excessive amounts of hydrophilic glycosaminoglycans (GAG's, predominantly hyaluronic acid) and marked infiltration with immunocompetent cells (macrophages and T lymphocytes, and a few B cells). The enlargement of the extra-ocular muscles is accounted for by excessive amounts of GAG's and fluid in the proliferating perimysial and interstitial connective tissue; the muscle fibers themselves are apparently intact (Weetman 1991; Heufelder 1995). In later stages of the disease fibrosis is observed and muscle cell damage may be encountered.

The mononuclear cell infiltrate in orbital tissues is predominantly composed of CD4+ and CD8+ T cells. Recognition of an antigen by a T-cell receptor on a CD4+ (helper) T cell stimulates the T cell to release cytokines which can activate either specific cytotoxic (CD8+) T cells or autoantibody-producing B cells. A variety of cytokines (in particular IFN-g, TNF-a and IL-1a) has been found in orbital tissues of GO patients, either in frozen sections or in primary cultures of orbital fibroblasts. The observed cytokine expression varies, probably as a function of disease activity. The few available studies in a limited number of patients suggest a Th-1 cytokine profile (cellular immunity) in the early stages; a Th-2 cytokine profile (humoral immunity) might be involved in propagating the disease (de Carli et al. 1993; Grubeck- Loebenstein et al. 1994; McLachlan et al. 1994; Heufelder 1995). Cytokines apparently are important mediators of the immune reponse as they induce expression of major histocompatibility complex class II molecules, heatshock proteins and adhesion molecules in retroorbital fibroblasts and endothelial cells. Furthermore several cytokines stimulate proliferation and GAG production of retro-orbital fibroblasts. The orbital fibroblast is peculiar in that fibroblasts taken from other parts of the body do not always respond to these cytokines in the same manner. T lymphocytes may recognize specific target antigens in the orbit. Indeed, retobulbar T cells from GO patients recognized in a MHC-class I restricted manner autologous retroorbital fibroblasts, but not eye muscle extracts! (Grubeck-Loebenstein et al. 1994). Homing of T cells to the orbit might be facilitated by the expression of HLA-DR and adhesion molecules in endothelial cells and fibroblasts (again, this was not observed in extra-ocular muscle fibers). Taken together, these studies have led to the widely accepted view that the orbital fibroblast is the primary target of the auto-immune attack in the orbit, and not the muscle cell. The proposed immunopathogenesis of GO is nicely depicted in Figure 4 derived from Weetman (1991), emphasizing the role of T cells. A clinical argument against a role of B cells is that no convincing evidence has been reported so far for the occurrence of neonatal Graves' ophthalmopathy - in contrast to neonatal thyrotoxicosis caused by the placental transfer of TSH receptor-stimulating antibodies.

View figure 4

The remaining unresolved question is which orbital autoantigen is involved. Graves' hyperthyroidism and GO are closely related disorders, and the epidemiological data strongly suggest that the two belong to the same disease entity. It thus comes natural to look for an antigen that is shared between the thyroid and the orbit. An obvious candidate is the TSH-receptor. There has been a flurry of papers in the last few years which claim or deny the presence of full length or splice variants of TSH-R mRNA in orbital tissues. Of interest is a recent paper reporting expression of the full length TSH-R at mRNA and at protein level in human orbital tissue (Spitzweg et al. 1997). This is not to say that the TSH-R is the link between the autoimmune reaction in the thyroid and the orbit; this is far from established. It could be that specific T cells recognize the orbital TSH-R. It could be that TSH-R antibodies or a specific subset bind to the orbital TSH-R (still requiring explanations for the occurrence of euthyroid GO and the poor relation between TSH-R stimulating antibodies and GO). It could also be that another antigen is involved: the field is still open, but starts to narrow.

Another unresolved issue is why only a minority of Graves' patients get the clinical manifestations of GO. This might be due to still unidentified genetic factors, but environmental factors like smoking are almost certainly involved. Why smoking increases the risk of GO, is unclear. The response of orbital fibroblasts to cytokines is enhanced when cultured under hypoxic conditions. A recent abstract reports lower serum concentrations of IL -1 receptor antagonist (IL-1RA) in smokers than in nonsmokers with GO (Hofbauer et al. 1996). The implication is that lowering the levels of the receptor antagonist IL-1RA favours the pro- inflammatory action of the receptor agonist IL-1a. Smoke seems really to get into your eyes!

Thyroid Management

The question is whether or not it matters for the eyes if the patient is not euthyroid. The answer seems to be yes, it does matter. In patients with both Graves' hyperthyroidism and GO the ophthalmopathy was more severe in those who had still an abnormal thyroid function despite antithyroid treatment (Prummel et al. 1990). Subsequent normalization of thyroid function was associated with a slight amelioration of eye signs, especially in classes 2 and 4 of the NO SPECS system (Prummel et al. 1989). Meticulous control of thyroid function in GO is thus important.

Next one may ask whether or not it matters for the eyes how the patient is made euthyroid, by antithyroid drugs, by surgery, or by radioactive iodine. This topic is the subject of much controversy (Gorman 1995). An often quoted large retrospective study found similar outcomes for all three treatment modalities (Sridama and DeGroot 1989). However, the study is biased in several ways: the groups differ in age, sex and severity of the eye disease, the prevalence of class 4 eye signs is surprisingly low, and the long time interval between thyroid treatment and outcome of the eyes suggests that the natural history of the eye disease rather than any specific effect of thyroid treatment has been studied. Data from prospective, preferably randomized trials provide in general more conclusive evidence. In a Swedish study Graves' hyperthyroid patients were randomized to receive antithyroid drugs, subtotal thyroidectomy, or 131I (Tallstedt et al. 1992). Worsening or development of GO was observed in 12.3% of patients treated with methimazole, in 14% after surgery, and in 33% after 131I. The authors conclude that a pretreatment serum T3 value of greater that 5nmol/l or 131I treatment are both risk factors for GO. The study has been criticized because the patients receiving 131I (in half of them more than one treatment was required!) were allowed to develop hypothyroidism before thyroxine was given, whereas thyroxine was administered routinely to the surgical and medical groups. Subsequent studies indeed have shown that prevention of the rise of TSH has a beneficial effect in this respect (Kung et al 1994; Tallstedt et al. 1994). The appealing explanation for the development of GO after 131I therapy is release of shared thyroid-orbit antigens from the radiation-damaged thyroid; in support of this hypothesis are the sustained elevations of TSH-R stimulating antibodies after radioiodine but not after surgery or during antithyroid drug treatment. A recent Italian study (reported so far only in abstract form) randomized Graves' hyperthyroid patients to receive 131I, 131I + prednisone, or anti-thyroid drugs (Bartalena et al. 1995). Developing or worsening of GO was observed in 15.3%, 0% and 2.7% respectively. The results again imply 131I as a risk factor for GO. It should be realized that the eye changes after radioiodine are usually mild (and limited to class 2 and 4) and transient in nature. The findings should thus not be construed as an argument against 131I therpy in patients without eye changes. In patients with active GO it seems, however, prudent to refrain from 131I therapy, or to administer 131I in combination with a short course of steroids. Our own policy is to continue antithyroid drugs preferably in combination with thyroxine until the eye treatment has been completed.

Very recently there has been a renewed surge of interest in performing total thyroidectomy in Graves' hyperthyroidism in order to get rid of all thyroid antigens and thereby hopefully to prevent the development of GO (Winsa et al. 1995). Its claimed superiority has to be validated in future prospective trials, both in terms of efficacy and safety.

Eye Management

A liberal use should be made of artificial tears and supportive measures like dark glasses and prisms: many symptoms are thus relieved in a simple manner. A further management plan can be laid out according to disease severity:

In mild eye disease one may opt to wait and see in view of spontaneous improvement in a large proportion of patients (Perros et al 1995).
In very severe eye disease ("malignant" GO, optic neuropathy) steroids are preferred because their efficacy and rapid reponse. Intravenous pulses of methylprednisolone (e.g. 1 gram on three successive days weekly for 2 weeks) followed by oral prednisone is an attractive scheme. If no improvement in optic nerve function is seen after two weeks, urgent decompressive surgery is required.
In moderately severe eye disease immunosuppressive treatment is usually given. The mainstay of immunosuppression has been high doses of oral steroids, but retrobulbar irradiation (20 Gy delivered in ten daily doses of 2 Gy over a two-week period) has similar efficacy as oral steroids but is devoid of the many side effects of steroids (Prummel et al. 1993). Cyclosporin-A as monotherapy is not very effective, but potentiates the effect of low-dose steroids; it can be considered when irradiation is contraindicated like in diabetic patients (Polak and Wijngaarde 1995). Other immunosuppressive treatment modalities such as intravenous immunoglobulins and subcutaneous octreotide (table 2) are laborious and very expensive; their response rate is in the same order (around 65%) as steroids and irradiation (Wiersinga 1996). Retrobulbar irradiation has thus been advocated as the first choice. A recent abstract reports similar response rates of 20 Gy and 10 Gy (Kahaly et al. 1996).

Table 2: Efficacy and side effects of immunosuppression in Graves' ophthalmopathy

Immunosuppression	Efficacy	Side Effects	Remarks*
Pharmacologic
glucocorticoids	++	++	mainstay of immunosuppression
cyclosporine A	±	+	RCT, limited application
intravenous immunoglobulin	+	±	RCT, very expensive
azathioprine	-	-	RCT, not indicated
ciamexone	-	-	RCT, not indicated
cyclophosphamide	±	±	no RCT
subcutaneous octreotide	+	±	limited data, expensive
Nonpharmacologic
acupuncture	-	-	RCT, not indicated
plasmapheresis	±	±	no RCT, steroids needed to prevent rebound effect
retrobular irradiation	+	-	RCT, contraindicated in diabetes mellitus

*RCT, randomized clinical trial

The efficacy of immunosuppression is good for relief of pain and improvement of visual acuity, moderate for improvement of appearance and correction of extra-ocular muscle dysfunction, and poor for reduction of proptosis. It follows that immunosuppression seldom cures the eye disease, and full restoration of eye function and appearance usually requires several surgical procedures. The results of rehabilitative surgery, however, can be lost when the eye disease is still active; it is therefore performed when the disease has been stable for six months. The main advantage of immunosuppression is thus inactivation of the inflammation of orbital tissues, thereby permitting corrective surgery at an earlier time. The efficacy of immunosuppression can be enhanced by combination therapy (like irradiation plus steroids). Alternatively, immunosuppression might be restricted to those patients who are likely to respond; age, sex, duration nor severity of GO, however, reliably predict outcome.

The notion that patients with the same degree of severity of their eye disease can or cannot respond to immunosuppression has led us to hypothesize that disease activity is the main determinant of outcome of immunosuppression. This is illustrated in Figure 5. In the natural history of GO the early dynamic phase is characterized by an initial stage of ingravescence followed by a stage of remission with some - usually incomplete - regresion of eye signs; the dynamic phase may last from several months to a few years. The eye disease then enters a static phase in which the ocular findings do not change very much. Immunosuppression will not be effective in the static (fibrotic) phase; in contrast, much benefit may be expected if given in the dynamic phase when active inflammation is present. We propose that the natural history of GO is also characterized - besides Rundle's curve of disease severity - by a curve depicting disease activity. As illustrated in Figure 5, disease activity might have predictive value, useful in the selection of patients who are likely to respond to immunosuppression. How can disease activity be assessed? A variety of methods have been proposed including a clinical activity score (Mourits et al. 1989). T2 relaxation time on MRI (Just et al. 1991), internal eye muscle reflectivity on ultrasound (Prummel et al. 1993), orbital octreoscan (Postema et al. 1994; Moncayo et al. 1997) and urinary glycosaminoglycans (Kahaly et al. 1990). The validation of these parameters as reliable indicators of disease activity must be derived indirectly (because biopsies of retrobulbar tissues are seldom feasible) from their accurate prediction of outcome of immunosuppression. The results of such studies are eagerly awaited. Management of GO according to disease activity (Table 3) has the advantage that immunosuppression will be only applied in patients who are likely to respond, and that patients with inactive disease might proceed directly to surgery.

View figure 5

Table 3: Management of Graves' opthalmopathy according to disease activity

In any stage
	maintain euthyroidism
	protect cornea (liberal use of artificial tears)
	dark glasses and prisms as required
In active stage
	retrobulbar irradiation (not in diabetic patients)
	steroids (for optic neuropathy)
	urgent orbital decompression (in "malignant" GO with steroids failure)
In inactive stage
	rehabilitative surgery in the following sequence:
	orbital decompression (for disfiguring proptosis)
	eye muscle surgery (for double vision)

Wilmar M. Wiersinga

Wilmar M. Wiersinga MD is Professor of Endocrinology and Head of the Department of Endocrinology and Metabolism of the Academic Medical Center at the University of Amsterdam, The Netherlands. He worked as a research fellow with Professors I.J. Chopra and D. Solomon at the UCLA. He organized several International Thyroid Symposia with the Amsterdam Thyroid Club, and chaired the local organizing committees of the 1994 EFES and 1996 ETA meetings in Amsterdam. He is past president of the Dutch Endocrine Society, and was member of the Council for Medical Sciences of the Netherlands Organization of Scientific Research. Current research interests are Graves' ophthalmopathy, nontoxic goiter, amiodarone and thyroid hormones, and nonthyroidal illness. Presently he serves as member of the Executive Committee of the European Thyroid Association and as Continental Editor of Clinical Endocrinology.