Exp. Clin. Endocrinol. Vol. 97, No. 2/3, 1991, pp. 320-327
J. A. Barth, Leipzig
Institute of Endocrinology, University of Pisa, Italy
Glucocorticoid Therapy of Graves' Ophthalmopathy L. BARTALENA, C. MARoccI, F. BOGAZZI, GABRIELLA BRuN0-Bosslo and A. PINCHERA
Introduction Considerable evidence has accumulated indicating that Graves' ophthalmopathy is likely to be an autoimmune disorder, although its precise pathogenesis and its relationship with Graves' hyperthyroidism remain to be fully understood (Pinchera et al., 1989; Marcocci et al., 1989). The autoimmune and inflammatory' nature of Graves' ophthalmopathy has led to consider therapeutic approaches aimed at suppressing the immune response (glucocorticoids, immunosuppressant drugs), at removing its effec-
tors from the circulation (plasmapheresis), or at abating the inflammatory process (glucocorticoids, orbital radiotherapy) (see Jacobson and Gorman, 1984, for review). Among these methods, glucocorticoids have gained an established place in view of their immunosuppressive and anti-inflammatory actions. These include: i) Inhibition of hypersensitivity reactions, cell-mediated functions, and complement activation; ii) Interference with T and B lymphocytes' function and reduction of their number in the circulation; iii) Decrease in the recruitment of neutrophils, monocytes and macrophages into the inflamed area; iv) Inhibition of the function of immunocompetent cells at the site of inflammation; y) Interference in the liberation and action of effectors (prostaglandins, leukotrienes, interleukins etc.) (Baker and Tyrell, 1987); vi) Inhibition of the release of glycosaminoglycans (Jacobson and Gorman, 1984). In view of these multiple actions, glucocorticoids have been widely used for severe and active Graves' ophthalmopathy (see McConahey, 1984, for review). They have been administered either by systemic (oral and intravenous) or by local (retrobulbar and subconjunctival) route. Recently, we have also proposed the use of systemic glucocorticoids
for preventing progression of mild Graves' ophthalmopathy which may occur after radioiodine therapy of Graves' hyperthyroidism (Bartalena et al., 1989). Systemic Glucocorticoid Therapy
Although there are no significant differences as to the effects of the different oral glucocorticoid preparations, prednisone, prednisolone and methyiprednisolone are the most widely used steroids. In general, high doses, in excess of 60 mg prednisone/day,
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With 2 Figures
L.
BARTALENA et. al., Glucocorticoids for Graves' Ophthalmopathy
321
are required to achieve a substantial immunosuppressive effect (McConahey, 1984). Werner (1966) reported a dramatic improvement of ocular conditions in two patients given 100-140 mg prednisone, who had not responded to lower doses of the drug (45-50 mg/day). Thus, it would appear that glucocorticoid dose may be a crucial point to obtain favourable results. The association with either radiotherapy (Schaaf et al., 1989) or cyclosporine (Kalahy et al., 1986) would appear to be advantageous to reduce the
cumulative dose of administered glucocorticoids. Glucocorticoids need to be administered for prolonged periods of time (5-6 months) to abate the inflammatory process and also to reduce the possibility that the disease may flare upon drug withdrawal. The latter problem may be relevant, making it difficult to wean the patient from glucocor-
orbital radiotherapy, see below), we have noted 5 serious side effects: depressive psychosis, diabetic ketoacidosis, pemphigoid dermatitis, herpetic encephalitis, increased intraocular pressure. This finding underscores the need for a careful selection of patients entering this kind of treatment, and for their careful observation. The patients should be hospitalized during the first few weeks of treatment, when the highest doses of the drug are administered. Oral glucocorticoids have proven to be particularly effective on soft tissue changes, recently developed extraocular muscle restriction and optic neuropathy (Hoffenberg and Jackson, 1958; Evans et al., 1961; Brown et al., 1963; Werner, 1966; Day and Carroll, 1968; Mulherin, 1972; Apers et al., 1976; Yamamoto et al., 1982; Bartalena et al., 1983; Kahaly et al., Pinchera et al., 1987). Overall favourable responses have been obtained in approximately 60% of the patients submitted to this kind of treatment (Thble 1). The effects of treatment usually become manifest within few weeks, sometimes even earlier. The results of oral glucocorticoid therapy, as well as of other conservative treatments, are usually inversely related to the duration of treatment (Bartalena et al., 1983). Proptosis and longstanding extraocular muscle involvement are less likely to be favourably influenced by glucocorticoid therapy. Thble I
Overall effects of oral glucucorticoids on Graves' ophthalmopathy.
N. of patients
Favourable results
Author
Year
Hoffenberg
Mulherin
1958 1961 1963 1966 1968 1972
Apers Yamamoto Bartalenaa) Kahaly
1976 1982 1983 1986
1
1
12
4
20
Pincheraa)
1987
36
12 26
Total
133
Evans
Brown Werner
Day
5
2
13
6
19
10
2 10 2
2 10
13
7
) Associated with orbital radiotherapy.
1
81 (61)
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ticoids. The major drawbacks of oral glucocorticoid therapy reside in its possible side effects, which have been reported by several authors. In our own series of more than 300 patients given high dose oral glucocorticoids for Graves' ophthalmopathy (mostly combined with
Exp. Clin. Endocrinol. 97 (1991) 2/3
322
Recently, intravenous methyiprednisolone pulse therapy has been proposed by two groups (Nagayama et al., Kendall-Thylor et al., 1988) on the basis of the good results obtained by this therapeutic approach in other autoimmune disorders, such as autoimmune glomerulonephritis (Short et al., 1987). This modality of glucocorticoid administration [1 g methylprednisolone i.v. for 3 days in Nagayama et al.'s (1987) report, 0.5 g i.v. twice at 48-h intervals in Kendall.Taylor's (1988) paper] is claimed to provide favourable results
and to be devoid of significant side effects. It should, however, be noted that in both reports most patients received additional treatments (oral glucocorticoids, orbital radiotherapy). Furthermore, the lack of control groups and the small number of patients treated by this procedure call for caution in the acceptance of this method for the treatment of Graves' ophthalmopathy.
The potential side effects of systematically given glucocorticoids have led some researchers to evaluate the possibility to administer glucocorticoids locally, either subconjunctivally or into the retrobulbar space (Garber, 1966; Pinchera et al., 1967; Riley, 1972; Thomas and Hart, 1974; Trobe et al., 1978; Marocci et al., 1987). Depot preparations are used (e.g. methyiprednisolone acetate, 40 mg), and repeated administration (12-14 injections at 2-3 week intervals) is required. This approach is usually safe and no relevant adverse reactions have been observed in the different series. Unfortunately, locally administered glucocorticoids are less effective than systemic glucocorticoids, especially as far as proptosis and eye muscle dysfunction are concerned (Table 2). For this reason, overall results have been, with few exceptions (Garber, 1966; Thomas and Hart, 1974), less satisfactory than by the systemic route, overall favourable responses being observed in approximately 40% of patients (Table 3). This observation, along with Table 2 Effects of systemic and local glucocorticoids on eye manifestations of Graves' ophthalmopathy.
Soft tissues Proptosis Recent eye muscle involvement Optic neuropathy Risks Table 3
Systemic
Local
+++ + ++ ++
++
++
++
-
++
Overall effects of locally administered glucucorticoids on Graves' ophthalmopathy.
Author
Year
Garber Pinchera
1966 1967 1972 1974 1978 1987
Riley
Thomas 'TIobe
Marcocci')
Total
N. of patients
Favourable results
13
9
10
5
27
9
19
16
3
0
44
11
116
) Associated with orbital radiotherapy.
50 (43%)
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Local Glucocorticoid Therapy
L. BARTALENA et. al., Glucocorticoids for Graves' Ophthalmopathy
323
the frequently reported reluctance of the patient to receive frequent injections, suggests that the use of locally administered glucocorticoids should be limited to patients with contraindications to the systemic administration of the drug.
Glucocorticoids Combined with Orbital Radiotherapy
tion with systemic glucocorticoids (Fig. 1) might improve the results obtained by systemic glucocorticoids alone (Bartalena et al., 1983). Our results did show that, although, as expected, systemic glucocorticoids alone were also effective, the combined therapy achieved a higher rate of beneficial effects, as assessed on clinical grounds and by the variations of the ophthalmopathy index, the numerical score used to quantitate eye changes of Graves'
disease (Donaldson et al., 1973). In a subsequent randomized prospective study (Pinchera et al., 1987; Marocci et al., 1987) we showed that the use of orbital irradiation in combination with systemic glucocorticoids was more effective than combining orbital radiotherapy with retrobulbar glucocorticoids. Finally, we have recently carried out a third randomized prospective study comparing the effects of the combined therapy with those obtained by orbital radiotherapy alone (Marcocci et al., 199O) Again, the association of the two treatments produced more favorable results than orbital irradiation alone. These data, taken together, confirm the usefulness of glucocorticoids (particularly by the systemic route) and of orbital radiotherapy for the treatment of Graves' ophthalmopathy, but support the concept that the two treatments potentiate each other and should be preferably used in combination (Fig. 1).
Fig. I Orbital radiotherapy and systemic g ucocorticoids are established methods of treatment for Graves' ophthalmopathy, alone or in combination.
Glucocorticoids for Preventing Exacerbation of Ophthalmopathy Following Radioiodine Administration
It has been reported that Graves' ophthalmopathy may occur or worsen following thyroid surgery(Werner et al., 1967), radioiodine treatment (Kriss et al., 1967; Pequegnat et al., 1967; Hamilton et al., 1967; Jones et al., 1969; Vestergaard and Laurberg, 1989;
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Orbital radiotherapy, currently carried by high energy sources, is an established method of treatment for Graves' ophthalmopathy (Pinchera et al., 1984), usually considered as alternative to glucocorticoids (Kriss, 1984). In our Institution, we carried out a randomized prospective study to evaluate whether the combination of orbital irradia-
324
Exp. Clin. Endocrino!. 97 (1991) 2/3
01=0
0121
SC- GROUP
Fig. 2
01=0
0121
SC+ GROUP
Variations of ocu!ar conditions following radioiodine administration for hyperthyroidism due to
Graves' disease. SC-grouP: patients receiving radioiodine alone: SC+ group: patients receiving oral glucocorticoids concomitantly with radioiodine. The patients in each group were subdivided according to the presence (0! t) or absence (01 O) of mild ophtha!mopathy prior to radioiodine treatment. Increase and decrease were defined as changes of the ophthalmopathy index of at least 1 point.
Conclusions
The minority of patients who develop active and severe Graves' ophthalmopathy represent a difficult therapeutic problem (Utiger, 1989). No available treatment is entirely satisfactory, also due to the incomplete knowledge of the etiology and pathogenesis of the disease. With these limitations, glucocorticoids, though far from being the ideal form of therapy, still represent a keystone in the management of these patients, often producing favourable results, especially when the inflammatory components of the disease and optic neuropathy are prominent. The necessity of utilizing high doses of the drug for long periods of time requires an accurate follow-up of the patient and is associated with the risk of side effects. The association with orbital radiotherapy improves the results and may reduce the cumulative dose of glucocorticoids.
While high doses of glucocorticoids are to be given to manage severe ophthal-
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Karisson et al., 1989), or neck irradiation for nonthyroidal neoplastic diseases (Wasnich et al., 1973; Jackson et al., 1979). Other authors have failed to find any progression of ophthalmopathy after radioiodine (Gwinup et al., 1982; Sridama and De Groot, 1989). All the above findings were based on retrospective studies. In a randomized prospective study, we have recently demonstrated that radioiodine treatment of Graves' disease did produce an exacerbation of mild, preexisting ophthalmopathy in a relevant proportion of cases, but did not induce the occurrence of clinically apparent ophthalmopathy in patients with no eye involvement prior to therapy (Fig. 2) (Bartalena et al., 1989). The doses of glucocorticoids were much lower than those employed for severe ophthalmopathy (30-40 mg prednisone/day, initial dose) and, therefore, devoid of relevant side effects. The duration of treatment is also shorter (3-4 months). Thus, it would appear that the use of middle dose glucocorticoids may be advantageous for preventing exacerbation of eye disease caused by radioiodine (Bartalena et al., 1990).
L..BARTALENA et. al., Glucocorticoids for Graves' Ophthalmopathy
325
mopathy, lower doses of the drug are useful to prevent the exacerbation of mild preexisting ophthalmopathy which frequently follows radioiodine administration for Graves' hyperthyroidism. Acknowledgements. This study was supported in part by grants from the Ministero della Publica Istruzione (60%), Rome, Italy.
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rence of ophthalmopathy in Graves' disease. Acta Endocrinol. (Copenh.) 120 (1989) 473-478. MARCOCCI, C.; BARTALENA, L.; PANIcuccI, M.; MARc0NcINI, C.; CARTE!, E; CAVALLACCI, G.; L&rDAGA, M.; CAMPOBASSO, G.; BASCH!ERI, L.; PINCHERA, A.: Orbital cobalt irradiation combined with
NAGAYAMA, Y.; IzuM!, M.; K1Rwu&, T.; YOKOYAMA, N.; MORITA, S.; KAKEZONO, F.; OHTAKARA, S.;
MORIMYÏ-O, I.; OKAMCJrO, S.; NAGATAXI, S.: Treatment of Graves' ophthalmopathy with high-dose
intravenous methylprednisolone pulse therapy. Acta Endocrinol. (Copenh.) 116 (1987) 513-518. PEQUEGNAT, E. P.; MAYBERRY, W. M.; MCCONAHEY, W. M.; WYSE, E. P.: Large doses of radioiodide in Graves' disease: effect on ophthalmopathy and long-acting thyroid stimulator. Mayo Clin. Proc. 42(1967) 802-811. PINCHERA, A.; BARTALENA, L.; CHIOVATO, L.; MARcoccI, C.: Radiotherapy of Graves' ophthalmopathy. In: The Eye and Orbit in Thyroid Disease. Eds. GORMAN, C. A.; WALLER, R. R.; DYER, J. A., New York: Raven Press 1984, pp. 301-3 15. PINCHERA, A.; BARTALENA, L.; MARcocci, C.; CECCARELLI, P.; Cuccm, P.; VITTI, P.; MAJUOrTI, S.;
FENZI, G. E: Humoral autoimmunity in endocrine ophthalmopathy. Acta Endocrinol. (Copenh.) 121 (Suppi. 2) (1989) 112-116. PINCHERA, A.; LIBERTI, P.; STIRPE, M.; MARTINO, E.; FENZI, G. E; Gisso, L.; Rovis, L.; BASCHIERI, L.: Oftalmopatia basedowiana: problemi patogenetic e terapeutici. Atti XVII Giornate Reumatologiche, Acqui Terme, 1967, pp. 55-60. PINCHERA, A.; MARcoccI, C.; BARTALENA, L.; PANIcuccI, M.; MARCONCINI, C.; LEPRI, A.; CAVALLACCI, G.; CARTE!, E; LADDAGA, M.: Orbital cobalt radiotherapy and systemic or retrobulbar
corticosteroids for Graves' ophthalmopathy. Horm. Res. 26 (1987) 177-183. RILEY, F. C.: Discussion of paper by Ivy, H. K., Medical approach to ophthalmopathy of Graves' disease. Ma7o Clin. Proc. 47 (1972) 992. SCHAAF, L.; ROMINGER-SEYRICH, D.; GROSSMANN, E.; GEISSLER, W.; EGGSTEIN, M.; SElF, E J.:
Reduction by orbital radiation of cumulative doses of glucocorticoids in patients with Graves'-Basedow ophthalmopathy. In: Graves' Ophthalmopathy. Developments in Diagnostic Methods and Therapeutic Procedures. Eds. PICKARDT, C. R.; BOERGEN, K. P., Basel: Karger 1989,
pp. 155-158. SHORT, C. D.; SoloMoN, L. R.; GOKAL, R.; MALLICK, N. P.: Methylprednisolone in patients with
membraneous nephropathy and declining renal function. Q. J. Med. 247 (1987) 929-940. SRIDAMA, V.; DEGROOT, L. J.: 'Theatment of Graves' disease and the course of ophthalmopathy. Am.
J. Med. 87 (1989) 70-73. I. D.; HART, J. K.: Retrobulbar repository corticosteroid therapy in thyroid ophthalmopathy. Med. J. Aust. 2 (1974) 484-487. ThoMAs,
1ItOBE, J. D.; GLASER, J. S.; LAFLAMME, P.: Dysthyroid optic neuropathy. Arch. Ophthalmol. 96
(1978) 1199-1209. UTIGER, R. D.: Treatment of Graves' ophthalmopathy. N. Engl. J. Med. 321 (1989) 1403-1405 (Editorial). VESTERGAARD, H.; LAURBERG, P.: Radioiodine and aggravation of Graves' ophthalmopathy. Lancet ii (1989) 47 (Letter). WASNICH, R. D.; GRUMET, E C.; PAYNE, R. O.; Kiuss, J. P.: Graves' ophthalmopathy following ex-
ternal neck irradiation for nonthyroidal neoplastic disease. J. Clin. Endocrinol. Metab. 37 (1973)
703-713.
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[42] WERNER, S. C.: Prednisone in emergence treatment of malignant exophthalmos. Lancet i (1966)
1004-1007. L43] WERNER, S. C.; FREIND, C. R.; AIDA, M.: Graves' disease and total thyroidectomy: progression of severe eye changes and decrease in serum long acting thyroid stimulator after operation. N. Engl. J.
Med. 276 (1967) 132-138. [44] YAMAMmD, K.; SALID, K.; TArCAT, T.; Y05HIDA, S.: Treatment of Graves' ophthalmopathy by steroid
therapy, orbital radiation therapy, plasmapheresis and thyroxine replacement. Endocrinol. Jap. 29 (1982) 495-501. Author's address: Dr. L. BARTALENA, M. D.,
Downloaded by: Universite Laval. Copyrighted material.
Istituto di Endocrinologia, Università di Pisa, Viale di Tirreno 64, I-56018 Tirrenia-Pisa
J. A. Barth, Leipzig
Institute of Endocrinology, University of Pisa, Italy
Glucocorticoid Therapy of Graves' Ophthalmopathy L. BARTALENA, C. MARoccI, F. BOGAZZI, GABRIELLA BRuN0-Bosslo and A. PINCHERA
Introduction Considerable evidence has accumulated indicating that Graves' ophthalmopathy is likely to be an autoimmune disorder, although its precise pathogenesis and its relationship with Graves' hyperthyroidism remain to be fully understood (Pinchera et al., 1989; Marcocci et al., 1989). The autoimmune and inflammatory' nature of Graves' ophthalmopathy has led to consider therapeutic approaches aimed at suppressing the immune response (glucocorticoids, immunosuppressant drugs), at removing its effec-
tors from the circulation (plasmapheresis), or at abating the inflammatory process (glucocorticoids, orbital radiotherapy) (see Jacobson and Gorman, 1984, for review). Among these methods, glucocorticoids have gained an established place in view of their immunosuppressive and anti-inflammatory actions. These include: i) Inhibition of hypersensitivity reactions, cell-mediated functions, and complement activation; ii) Interference with T and B lymphocytes' function and reduction of their number in the circulation; iii) Decrease in the recruitment of neutrophils, monocytes and macrophages into the inflamed area; iv) Inhibition of the function of immunocompetent cells at the site of inflammation; y) Interference in the liberation and action of effectors (prostaglandins, leukotrienes, interleukins etc.) (Baker and Tyrell, 1987); vi) Inhibition of the release of glycosaminoglycans (Jacobson and Gorman, 1984). In view of these multiple actions, glucocorticoids have been widely used for severe and active Graves' ophthalmopathy (see McConahey, 1984, for review). They have been administered either by systemic (oral and intravenous) or by local (retrobulbar and subconjunctival) route. Recently, we have also proposed the use of systemic glucocorticoids
for preventing progression of mild Graves' ophthalmopathy which may occur after radioiodine therapy of Graves' hyperthyroidism (Bartalena et al., 1989). Systemic Glucocorticoid Therapy
Although there are no significant differences as to the effects of the different oral glucocorticoid preparations, prednisone, prednisolone and methyiprednisolone are the most widely used steroids. In general, high doses, in excess of 60 mg prednisone/day,
Downloaded by: Universite Laval. Copyrighted material.
With 2 Figures
L.
BARTALENA et. al., Glucocorticoids for Graves' Ophthalmopathy
321
are required to achieve a substantial immunosuppressive effect (McConahey, 1984). Werner (1966) reported a dramatic improvement of ocular conditions in two patients given 100-140 mg prednisone, who had not responded to lower doses of the drug (45-50 mg/day). Thus, it would appear that glucocorticoid dose may be a crucial point to obtain favourable results. The association with either radiotherapy (Schaaf et al., 1989) or cyclosporine (Kalahy et al., 1986) would appear to be advantageous to reduce the
cumulative dose of administered glucocorticoids. Glucocorticoids need to be administered for prolonged periods of time (5-6 months) to abate the inflammatory process and also to reduce the possibility that the disease may flare upon drug withdrawal. The latter problem may be relevant, making it difficult to wean the patient from glucocor-
orbital radiotherapy, see below), we have noted 5 serious side effects: depressive psychosis, diabetic ketoacidosis, pemphigoid dermatitis, herpetic encephalitis, increased intraocular pressure. This finding underscores the need for a careful selection of patients entering this kind of treatment, and for their careful observation. The patients should be hospitalized during the first few weeks of treatment, when the highest doses of the drug are administered. Oral glucocorticoids have proven to be particularly effective on soft tissue changes, recently developed extraocular muscle restriction and optic neuropathy (Hoffenberg and Jackson, 1958; Evans et al., 1961; Brown et al., 1963; Werner, 1966; Day and Carroll, 1968; Mulherin, 1972; Apers et al., 1976; Yamamoto et al., 1982; Bartalena et al., 1983; Kahaly et al., Pinchera et al., 1987). Overall favourable responses have been obtained in approximately 60% of the patients submitted to this kind of treatment (Thble 1). The effects of treatment usually become manifest within few weeks, sometimes even earlier. The results of oral glucocorticoid therapy, as well as of other conservative treatments, are usually inversely related to the duration of treatment (Bartalena et al., 1983). Proptosis and longstanding extraocular muscle involvement are less likely to be favourably influenced by glucocorticoid therapy. Thble I
Overall effects of oral glucucorticoids on Graves' ophthalmopathy.
N. of patients
Favourable results
Author
Year
Hoffenberg
Mulherin
1958 1961 1963 1966 1968 1972
Apers Yamamoto Bartalenaa) Kahaly
1976 1982 1983 1986
1
1
12
4
20
Pincheraa)
1987
36
12 26
Total
133
Evans
Brown Werner
Day
5
2
13
6
19
10
2 10 2
2 10
13
7
) Associated with orbital radiotherapy.
1
81 (61)
Downloaded by: Universite Laval. Copyrighted material.
ticoids. The major drawbacks of oral glucocorticoid therapy reside in its possible side effects, which have been reported by several authors. In our own series of more than 300 patients given high dose oral glucocorticoids for Graves' ophthalmopathy (mostly combined with
Exp. Clin. Endocrinol. 97 (1991) 2/3
322
Recently, intravenous methyiprednisolone pulse therapy has been proposed by two groups (Nagayama et al., Kendall-Thylor et al., 1988) on the basis of the good results obtained by this therapeutic approach in other autoimmune disorders, such as autoimmune glomerulonephritis (Short et al., 1987). This modality of glucocorticoid administration [1 g methylprednisolone i.v. for 3 days in Nagayama et al.'s (1987) report, 0.5 g i.v. twice at 48-h intervals in Kendall.Taylor's (1988) paper] is claimed to provide favourable results
and to be devoid of significant side effects. It should, however, be noted that in both reports most patients received additional treatments (oral glucocorticoids, orbital radiotherapy). Furthermore, the lack of control groups and the small number of patients treated by this procedure call for caution in the acceptance of this method for the treatment of Graves' ophthalmopathy.
The potential side effects of systematically given glucocorticoids have led some researchers to evaluate the possibility to administer glucocorticoids locally, either subconjunctivally or into the retrobulbar space (Garber, 1966; Pinchera et al., 1967; Riley, 1972; Thomas and Hart, 1974; Trobe et al., 1978; Marocci et al., 1987). Depot preparations are used (e.g. methyiprednisolone acetate, 40 mg), and repeated administration (12-14 injections at 2-3 week intervals) is required. This approach is usually safe and no relevant adverse reactions have been observed in the different series. Unfortunately, locally administered glucocorticoids are less effective than systemic glucocorticoids, especially as far as proptosis and eye muscle dysfunction are concerned (Table 2). For this reason, overall results have been, with few exceptions (Garber, 1966; Thomas and Hart, 1974), less satisfactory than by the systemic route, overall favourable responses being observed in approximately 40% of patients (Table 3). This observation, along with Table 2 Effects of systemic and local glucocorticoids on eye manifestations of Graves' ophthalmopathy.
Soft tissues Proptosis Recent eye muscle involvement Optic neuropathy Risks Table 3
Systemic
Local
+++ + ++ ++
++
++
++
-
++
Overall effects of locally administered glucucorticoids on Graves' ophthalmopathy.
Author
Year
Garber Pinchera
1966 1967 1972 1974 1978 1987
Riley
Thomas 'TIobe
Marcocci')
Total
N. of patients
Favourable results
13
9
10
5
27
9
19
16
3
0
44
11
116
) Associated with orbital radiotherapy.
50 (43%)
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Local Glucocorticoid Therapy
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323
the frequently reported reluctance of the patient to receive frequent injections, suggests that the use of locally administered glucocorticoids should be limited to patients with contraindications to the systemic administration of the drug.
Glucocorticoids Combined with Orbital Radiotherapy
tion with systemic glucocorticoids (Fig. 1) might improve the results obtained by systemic glucocorticoids alone (Bartalena et al., 1983). Our results did show that, although, as expected, systemic glucocorticoids alone were also effective, the combined therapy achieved a higher rate of beneficial effects, as assessed on clinical grounds and by the variations of the ophthalmopathy index, the numerical score used to quantitate eye changes of Graves'
disease (Donaldson et al., 1973). In a subsequent randomized prospective study (Pinchera et al., 1987; Marocci et al., 1987) we showed that the use of orbital irradiation in combination with systemic glucocorticoids was more effective than combining orbital radiotherapy with retrobulbar glucocorticoids. Finally, we have recently carried out a third randomized prospective study comparing the effects of the combined therapy with those obtained by orbital radiotherapy alone (Marcocci et al., 199O) Again, the association of the two treatments produced more favorable results than orbital irradiation alone. These data, taken together, confirm the usefulness of glucocorticoids (particularly by the systemic route) and of orbital radiotherapy for the treatment of Graves' ophthalmopathy, but support the concept that the two treatments potentiate each other and should be preferably used in combination (Fig. 1).
Fig. I Orbital radiotherapy and systemic g ucocorticoids are established methods of treatment for Graves' ophthalmopathy, alone or in combination.
Glucocorticoids for Preventing Exacerbation of Ophthalmopathy Following Radioiodine Administration
It has been reported that Graves' ophthalmopathy may occur or worsen following thyroid surgery(Werner et al., 1967), radioiodine treatment (Kriss et al., 1967; Pequegnat et al., 1967; Hamilton et al., 1967; Jones et al., 1969; Vestergaard and Laurberg, 1989;
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Orbital radiotherapy, currently carried by high energy sources, is an established method of treatment for Graves' ophthalmopathy (Pinchera et al., 1984), usually considered as alternative to glucocorticoids (Kriss, 1984). In our Institution, we carried out a randomized prospective study to evaluate whether the combination of orbital irradia-
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01=0
0121
SC- GROUP
Fig. 2
01=0
0121
SC+ GROUP
Variations of ocu!ar conditions following radioiodine administration for hyperthyroidism due to
Graves' disease. SC-grouP: patients receiving radioiodine alone: SC+ group: patients receiving oral glucocorticoids concomitantly with radioiodine. The patients in each group were subdivided according to the presence (0! t) or absence (01 O) of mild ophtha!mopathy prior to radioiodine treatment. Increase and decrease were defined as changes of the ophthalmopathy index of at least 1 point.
Conclusions
The minority of patients who develop active and severe Graves' ophthalmopathy represent a difficult therapeutic problem (Utiger, 1989). No available treatment is entirely satisfactory, also due to the incomplete knowledge of the etiology and pathogenesis of the disease. With these limitations, glucocorticoids, though far from being the ideal form of therapy, still represent a keystone in the management of these patients, often producing favourable results, especially when the inflammatory components of the disease and optic neuropathy are prominent. The necessity of utilizing high doses of the drug for long periods of time requires an accurate follow-up of the patient and is associated with the risk of side effects. The association with orbital radiotherapy improves the results and may reduce the cumulative dose of glucocorticoids.
While high doses of glucocorticoids are to be given to manage severe ophthal-
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Karisson et al., 1989), or neck irradiation for nonthyroidal neoplastic diseases (Wasnich et al., 1973; Jackson et al., 1979). Other authors have failed to find any progression of ophthalmopathy after radioiodine (Gwinup et al., 1982; Sridama and De Groot, 1989). All the above findings were based on retrospective studies. In a randomized prospective study, we have recently demonstrated that radioiodine treatment of Graves' disease did produce an exacerbation of mild, preexisting ophthalmopathy in a relevant proportion of cases, but did not induce the occurrence of clinically apparent ophthalmopathy in patients with no eye involvement prior to therapy (Fig. 2) (Bartalena et al., 1989). The doses of glucocorticoids were much lower than those employed for severe ophthalmopathy (30-40 mg prednisone/day, initial dose) and, therefore, devoid of relevant side effects. The duration of treatment is also shorter (3-4 months). Thus, it would appear that the use of middle dose glucocorticoids may be advantageous for preventing exacerbation of eye disease caused by radioiodine (Bartalena et al., 1990).
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mopathy, lower doses of the drug are useful to prevent the exacerbation of mild preexisting ophthalmopathy which frequently follows radioiodine administration for Graves' hyperthyroidism. Acknowledgements. This study was supported in part by grants from the Ministero della Publica Istruzione (60%), Rome, Italy.
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Istituto di Endocrinologia, Università di Pisa, Viale di Tirreno 64, I-56018 Tirrenia-Pisa
