Ординатура / Офтальмология / Учебные материалы / Эндокринная офтальмопатия - мультидисциплинарный подход 2007

Fig. 1. Caleb Parry.

Fig. 2. Robert Graves.

Fig. 3. Karl Adolph von Basedow.

(Graves’ acropachy). For the same reason ‘endocrine ophthalmopathy’ is a misnomer, because ‘endocrine’ suggests the cause of the disease to be a change in hormone levels and ‘ophthalmopathy’ suggests an ophthalmic and not a primary orbital disease. What’s in a name? As long as we do not fully understand this ‘one of the most puzzling syndromes in ophthalmology’ [4], it seems not entirely unfair to call the disease after the person who not only described it for the first time in modern times, but also personally realized the importance of publishing his observations. Therefore, in this book, we speak about Graves’ disease, Graves’ thyroid disease, Graves’ orbitopathy, Graves’ dermopathy and Graves’ acropachy as a sign of esteem and for the sake of convenience.

Various Eye Signs Carry Specific Names: Are They Still Relevant?

Several famous clinicians of the 19th and early 20th century have done meticulous observations in patients with Graves’ disease. In a time when hard evidence for a diagnosis was often lacking, their signs may possibly have been of great importance. Table 1 has been conceived from Duke-Elder’s famous

System of Ophthalmology [4].

As shown in the chapter by Mourits [pp. 66–77], a diagnosis of GO nowadays rarely is a clinical problem and although one can assess these classical signs in many patients, modern diagnosis is based on other grounds.

Table 1. Eye signs of GO according to late 19th and early 20th century physicians

How Did Old Theories Explain the Relationship between

Hyperthyroidism and Proptosis?

The following explanations for proptosis in GO have been given:

–weakness of the EOMs (Cooper, 1849)

–contraction of smooth muscle in the orbit/sympathetic stimulation (Bernard, 1852)

–cardiac neurosis (Filehne, 1879)

–vascular congestion (Von Graefe, 1857; Moebius, 1891; Fründ, 1911)

–edema and fatty infiltration of the orbit (Pochin and Rundle, 1944)

–edema as the result of hydrophilic mucopolysaccharides (Ludwig et al., 1950).

Until recent times, exophthalmos (syn: proptosis; syn: protrusion) has been generally accepted as a significant feature of diffuse toxic goitre, as a sign of thyrotoxicosis [4]. However, this hypothesis could not explain why proptosis persisted or even increased after control of the thyrotoxicosis, nor why some patients had proptosis in the absence of hyperor hypo-thyroidism. So two types of proptosis were distinguished: a mild form as an expression of thyrotoxicosis (which may have been only lid retraction appearing as proptosis – a condition which is called pseudoproptosis) and a malignant form, that could co-occur with thyroid disease. Means (1945) divided Graves’ disease into three types: thyrotoxicosis with and without ophthalmopathy and (Graves’)

ophthalmopathy with hyper-, hypoand euthyroidism [4]. Pochin and Rundle hypothesized that this exophthalmos varied in severity following a definite cycle depending on pituitary activity.

After the discovery of the thyroid-stimulating hormone (TSH), secreted by the anterior lobe of the pituitary gland, at the beginning of the 20th century by Loeb and Basset (1928), over-secretion of TSH was considered the cause of Graves’ disease and GO. Destruction of the pituitary gland by irradiation was advocated for severe proptosis. However, this theory could not hold when it became clear that in the absence of TSH over-secretion, the proptosis could increase. Next, exophthalmos-producing substance (EPS) was considered the cause of proptosis in GO as it caused proptosis in certain species of fish. However, this fish exophthalmos basically differs from the one in man. Adams, Purves and McKenzie (1956–1958) identified long-acting thyroid stimulator (LATS) or thyroid-stimulating antibody in sera of patients who had undergone pituitary ablation and they believed to have found the substance causing proptosis. LATS is found in 80% of patients with untreated thyrotoxicosis, but severe exophthalmos has been described in patients without detectable LATS. So the etiological role of LATS remains unclear. Today we have arguments that the susceptibility to develop Graves’ disease has genetic determinants and that the course of the disease is influenced by exogeneous factors [5, 6].

Which Are Rundle’s Contributions to Our Understanding of Graves’Orbitopathy?

In a series of publications lasting from 1944 until 1960, Rundle and coworkers from Sydney are to be credited for a number of remarkable statements:

–‘the ocular manifestations have emerged as one of the most troublesome features of Graves’ disease’

–‘to women of any age, disfigurement of conspicuous eye signs causes acute mental suffering’

–‘purely descriptive notes will not provide a reliable guide during treatment’. Measuring is knowing must have been one of Rundle’s credos. He first

measured proptosis, eye movements (e.g. ductions) and lid apertures according to fixed rules on a monthly frequency during 18 months in a cohort of patients [7]. A subset of these patients has been examined by the same observer using identical assessing tools after 15 years [8]. From these observations the – what we now call – ‘Rundle’s curve’ is derived [see fig. 2, p. 80, chapter by KendallTaylor]. Rundle assessed that untreated GO runs a course of increasing severity reaching a plateau phase (dynamic phase) followed by a mostly incomplete recessing of symptoms (static phase). He thus concluded that GO to a certain

extent is self-limiting. He acknowledged that ‘the rate and extent of protrusion and recession, and the incidence of ophthalmoplegia, and therefore of paralytic lid retraction, vary widely (months to years)’. Most patients, however, reach their peak relatively early in the course of Graves’ disease and exophthalmos had usually reached its maximum by the time the patient was referred for treatment. In contrast to recent publications [9], no long-term follow-up recurrences were seen. In eyes, static after a year or two, measurements of proptosis 15 years later generally showed little or no change. Nevertheless, ‘eye signs had become slight or absent’, thanks to a decrease of lid width and an improvement of motility. Already in his early reports, Rundle warns not to correct surgically residual stigmata of the disease before at least 2 years after the peak have been passed. Rundle, therefore, should be honored also as a pioneer of the concept of disease activity and the subsequent treatment implications. But he made more seminal contributions. In a paper from 1945, he writes: ‘The average volume of the orbit is approximately 27 cc in males and 24 cc in females. In both sexes normally some 70 percent of the cavity is occupied by retrobulbar and peribulbar structures. The average weight of these structures is 19 g, made up of eye muscles 3.3 g, lacrimal gland 0.65 g, and fibro-fatty residue 15 g. The seven extrinsic eye muscles thus account for approximately 20 percent of the tissue bulk and the fibro-fatty residue and lacrimal gland for 80 percent. The capacity of the orbit can be simply determined by plugging its cavity with plasticine, and then determining the volume of plasticine so used, by water displacement. The degree of orbital filling may be expressed as the ratio between the bulk of orbital tissues (excluding the eyeball and optic nerve) and the capacity of the orbit. There is a linear relationship between the degree of orbital filling and the Hertel exophthalmometer reading. It may be calculated from the regression line relating orbital filling to the exophthalmometer reading that a marked exophthalmos of 6 mm would result from 20 percent increase (4 cc) in bulk of the orbital contents. The average protrusion of the eye in thyrotoxic patients of approximately 2 mm would result from a 6.6 percent increase in orbital filling’[10].

Rundle also notes ‘Strands of adipose tissue cells lie between the fibres of the extrinsic eye muscles in both normal and thyrotoxic subjects. The quantity of such adipose tissue is increased in thyrotoxicosis by about 85 percent. No droplets of fat could be demonstrated within the muscle fibres. Comparison of the mean average diameter of the fat globules in eye muscles from normal and thyrotoxic subjects shows the diameter to be decreased in thyrotoxicosis, suggesting that there is proliferation and development of new fat cells. Since in patient with exophthalmos the fat-free weight of the extrinsic muscles is increased, the adipose tissue cannot be simply a fatty replacement of degenerated muscle fibres, but must represent new tissue increasing the total bulk of muscles’ [10]. Rundle suggests there is proliferation of adipose tissue cells throughout the

Fig. 4. Fat content of eye muscles and other skeletal muscles in thyrotoxic and wasted cases, plotted against the normal fat content of each muscle; each point is based on the mean value for the group of subjects, lines are drawn to fit points for eye muscles. LPS Levator palpebrae superioris; SR superior rectus; MR medial rectus; IR inferior rectus; LR lateral rectus; SO superior oblique; IO inferior oblique; Tonque sample from midline; Infra-hyoid sample from sterno-hyoid; Rectus abdominis sample from level of umbilicus. By courtesy of the Editor, Clinical Science.

orbit, and continues ‘It is remarkable that this proliferation of fat occurs in the orbit despite the fact that thyrotoxics coming to post-mortem are generally wasted. Eleven of the 17 thyrotoxic subjects examined by Rundle and Pochin were wasted, four severely. In wasted controls there is marked loss of fat from the extrinsic muscles and residual orbital tissue’ (fig. 4). It is only in the last decade that the mechanism behind orbital adipogenesis has been partially classified (see below).

Table 2. Criteria for clinical evaluation of effects of orbital irradiation

Which Are Kriss’Contributions to the Management of Graves’Orbitopathy?

Treatment results in a disease with a presentation as protean as GO are hard to evaluate. For instance, how would we score the outcome of a treatment when motility has improved and at the same time proptosis has increased? Kriss and co-workers [11, 12] faced with this problem evaluating the outcome of retrobulbar irradiation, introduced criteria for clinical evaluation of effects of orbital irradiation, which can be used for medical treatment modalities as well (table 2). This concept has been altered into major and minor criteria for the outcome of treatment by Bartalena et al. [13], which in a modified way is used in present studies. Kriss has (co-)authored in almost 30 studies on Graves’ disease and developed theories about the origin of the orbitopathy and dermopathy in Graves’ disease. In particular, he injected radiolabelled thyroglobulin into the thyroid gland and was able to follow the location of radoactivity, which finally ended up in the orbit. The observation was interpreted as evidence for a direct connection between the thyroid gland and the orbit [12].

When Was Evidence-Based Medicine Incorporated

in Graves’Orbitopathy?

Till the 1980s interpretation of studies on Graves’ disease was flawed by the facts that evaluation of treatment outcome was done in incomparable (e.g. hyperand euthyroid, active and stable) patients, in individuals receiving several therapies at the same time (e.g. radiotherapy and prednisone), whereas no fixed endpoint or sharp outcome measures of the study had been defined. More importantly, the natural course of the disease was disregarded and no control

group was used. For these reasons, results were often conflicting. The group of Pinchera, Pisa, Italy, tackled most of these shortcomings in their study in 1983, in which orbital cobalt irradiation combined with systemic corticosteroids was compared with systemic corticosteroids alone [13]. Next came Kahaly’s group from Mainz, comparing prednisone and cyclosporine in 1986 [14], followed by the Pisa group again (1987) and the Amsterdam group of Wiersinga in 1989 [15].

References

1Parry CH: Collections from the Unpublished Medical Writings of the Late Caleb Hillier Parry. London, Underwoods, 1825, vol 2, pp 111–124.

2Graves RJ: Newly observed affection of the thyroid gland in females. Lond Med Surg J 1835;7:516–520.

3Basedov CA: Exophthalmos durch hypertrophie des Cellgewebes in der Augenhohle. Wochenschr Ges Heilk 1840;6:197–120.

4Duke-Elder S, MacFaul PA: Orbital involvement in general disease; in Duke-Elder S (ed): System of Ophthalmology, vol XVIII, part II. London, Henry Kimpton, 1974, pp 935–968.

5Hall R, Owen SG, Smart GA: Evidence for genetic predisposition to formation of thyroid autoan-

tibodies. Lancet 1960;ii:187–188.

6Krassas GE, Wiersinga W: Smoking and autoimmune thyroid disease: the plot thickens. Eur J Endocrinol 2006;154:777–880.

7Rundle FF: Management of exophthalmos and related ocular changes in Graves’ disease. Metabolism1957;6:36–48.

8Hales JB, Rundle FF: Ocular changes in Graves’ disease: a long-term follow-up study. Q J Med 1960;29:113–126.

9Kalman R, Mourits MP: Late recurrence of unilateral graves orbitopathy on the contralateral side. Am J Ophthalmol 2002;133:727–729.

10Rundle FF: Eye signs of Graves’ disease. Clin Sci 1945;5:177–197.

11Donaldson SS, Bagshaw MA, Kriss JP: Supervoltage orbital radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab 1973;37:276–285.

12Kriss JP, Konishi J, Herman M: Studies on the pathogenesis of Graves’ ophthalmopathy (with some related observations regarding therapy). Rec Prog Horm Res 1975;31:533–560.

13Bartalena L, Marcocci C, Chiovato L, Laddaga M, Lepri G, Andreani D, Cavallacci G, Baschieri L, Pinchera A: Orbital cobalt irradiation combined with systemic corticosteroids for Graves’ ophthalmopathy: comparison with systemic corticosteroids alone. J Clin Endocrinol Metab 1983;56: 1139–1144.

14Kahaly G, Schrezenmeir J, Krause U, Schweikert B, Meuer S, Muller W, Dennebaum R, Beyer J: Ciclosporin and prednisone v. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest 1986;16:415–422.

15Prummel MF, Mourits MP, Berghout A, Krenning EP, van der Gaag R, Koornneef L, Wiersinga WM: Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N Engl J Med 1989;321:1353–1359.

Prof. Dr. Maarten P Mourits

Department of Ophthalmology, Academic Medical Center – AMC University of Amsterdam, Meibergdreef 9

NL–1105 AZ Amsterdam (The Netherlands)

Tel. 31 20 566 3518, Fax 31 20 566 9053, E-Mail m.p.mourits@amc.uva.nl

Author Index

254

Subject Index

255