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

146

therapeutic effect of Octreotide LAR was seen. In the second multicenter trial conducted in France [48], a SS analogue (16 weeks of long-acting release formulation of Octreotide-LAR) was administered in 26 of 51 patients with active and moderate GO. The CAS was slightly reduced for patients treated with Octreotide-LAR, nevertheless no significant differences were noted vs. placebo (n 25). Also, no treatment effect was observed for the primary end point (preventing deterioration of the disease). Orbital MRI revealed no significant changes of the eye muscle volume. This was associated with non-significant differences in class 3 grades, opening of the upper lid, the difference in ocular pressure in primary position and in upgaze, as well as in the involvement of extraocular muscles. Although Octreotide-LAR slightly and significantly reduced proptosis, the inference and overall conclusion of this study is that the drug was not suitable to mitigate activity of moderate GO. A third trial from Taiwan [49] randomly including the largest number (n 60) of patients with active and moderately severe GO showed that 20 mg of Lanreotide® given intramuscularly every 2 weeks had absolutely no effect on the CAS and clinical course of the disease. Finally, the last study [50] involving a lower number of subjects with GO (n 29) showed that those (n 14) receiving Sandostatin LAR® 20 mg intramuscularly only had a slight and clinically irrelevant decrease of CAS and lid fissure, thus further questioning the role and efficacy of the SS analogs in moderately severe GO. One candidate explanation for this very low therapeutically answer might be that both Octreotide and Lanreotide have a high affinity for the SS receptor two only, a low affinity for the receptors three and five, and an almost absent affinity for the receptors one and four. This is unfortunate in view of the expression of all five subtypes of the SS receptors in orbital fibroblasts and lymphocytes of GO patients. Finally, the high costs of this treatment must also be taken into account.

What Should You Do if Steroids Fail?

The success rate of systemic steroid treatment averages 50–75% and heavily relies on activity and duration of GO as well as on steroid dosage. For those patients not responding to steroids, alternative schemes may be offered (fig. 3). Presence of diplopia and/or impaired motility of the eye muscles are a clear indication for performing Rx alone or in combination with either intravenous steroid pulses if severe orbital inflammation is present or with a low dose of steroids (starting dose of 0.20–0.25 mg/kg BW/day) for moderate cases. The oral prednisolone dose should be tapered weekly and the steroid therapy may be stopped after termination of Rx. Severe reduction of visual acuity and/or development of optic neuropathy makes a decompression surgery mandatory. On the other hand,

strongly recommended (recommendation A) in this stage of the disease and are actually regarded as the first-line treatment worldwide. With respect to orbital Rx, the cited trials (table 3) have also proven the beneficial effect of Rx regarding a clinically relevant amelioration of motility disturbances of the eye muscles. Thus, this treatment is evidence-based recommended (recommendation B) in subjects with active GO and impaired motility only. The combination of the standard treatments steroids and Rx in the early stage of active GO with impaired motility is strongly evidence-based recommended (recommendation A) and, as cited before (table 4), has proven to be superior to either monotherapy. In contrast, the studies involving SS analogs did not show a relevant clinical improvement in those receiving these drugs (table 6). Therefore, SS analogs are evidence-based not recommended (recommendation D) in severe GO. Finally, in subjects with active and moderately severe GO, either not answering to prednisone or presenting a relapse after a course of intravenous steroids, a few controlled studies have proven that additional administration of non-steroid immunosuppressants, e.g. cyclosporine, is more effective that monotherapy with prednisolone alone (table 5). Thus, this combined therapy can fairly be recommended (recommendation C) since it may both decrease the activity and inflammation of the orbital connective tissue as well as reduce the rate of relapses of GO.

Acknowledgments

The most valuable help of Anna Katharina Ponto, Medical Fellow of the Thyroid Research Laboratory, Department of Medicine I, Gutenberg University Hospital, in extensively reviewing the corresponding literature and subsequently excellently preparing the tables is greatly appreciated.

References

1Stemberger K, Kahaly GJ, Pitz S: Update on thyroid eye disease. Compr Ophthalmol Update 2006;7:287–298.

2Terwee CB, Prummel MF, Gerding MN, Kahaly GJ, Dekker FW, Wiersinga WM: Measuring disease activity to predict therapeutic outcome in Graves’ ophthalmopathy. Clin Endocrinol 2005;62: 145–155.

3Kahaly GJ: Imaging in thyroid-associated orbitopathy. Eur J Endocrinol 2001;145:107–118.

4Kahaly GJ: Recent developments in Graves’ ophthalmopathy imaging. J Endocrinol Invest 2004;27: 254–258.

5Kahaly GJ, Bang H, Berg W, Dittmar M: Alpha-fodrin as a putative autoantigen in Graves’ oph-

thalmopathy. Clin Exp Immunol 2005;140:166–172.

6Abalkhail S, Doi SAR, Al-Shoumer KAS: The use of corticosteroids versus other treatments for

Graves’ ophthalmopathy: a quantitative evaluation. Med Sci Monitor 2003;9:CR477–CR483.

7Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A, Pinchera A: Use of corticosteroids to prevent progression of Graves’ ophthalmopathy after radioiodine therapy for hyperthyroidism. N Engl J Med 1989;321:1349–1352.

8Kahaly GJ, Petrak F, Hardt J, Pitz S, Egle UT: Psychosocial morbidity of Graves’ orbitopathy. Clin

Endocrinol 2005;63:395–402.

9Tehrani M, Krummenauer F, Mann WJ, Pitz S, Dick HB, Kahaly GJ: Disease-specific assessment

of quality of life after decompression surgery for Graves’ ophthalmopathy. Eur J Ophthalmol 2004;14:193–199.

10Marcocci C, Bartalena L, Panicucci M, Marconcini C, Cartei F, Cavallacci G, Laddaga M, Campobasso G, Baschieri L, Pinchera A: Orbital cobalt irradiation combined with retrobulbar or systemic corticosteroids for Graves’ ophthalmopathy: a comparative study. Clin Endocrinol 1987;27:33–42.

11Prummel MF, Mourits MP, Blank L, Berghout A, Koornneef L, Wiersinga WM: Randomized double-blind trial of prednisone versus radiotherapy in Graves’ ophthalmopathy. Lancet 1993;342: 949–954.

12Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell’Unto E, Bartolomei MP, Nardi M, Martino E, Pinchera A: Cigarette smoking and treatment outcomes in Graves’ ophthalmopathy. Ann Intern Med 1998;129:632–635.

13Kahaly GJ, Pitz S, Hommel G, Dittmar M: Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 2005;90:5234–5240.

14Macchia PE, Bagattini M, Lupoli G, Vitale M, Vitale G, Fenzi G: High-dose intravenous corticosteroid therapy for Graves’ ophthalmopathy. J Endocrinol Invest 2001;24:152–158.

15Kauppinen-Mäkelin R, Karma A, Leinonen E, Löyttyniemi E, Salonen O, Sane T, Setälä K, Viikari J, Heufelder A, Välimäki M: High dose intravenous methylprednisolone pulse therapy versus oral prednisone for thyroid-associated ophthalmopathy. Acta Ophthalm Scan 2002;80: 316–321.

16Ebner R, Devoto MH, Weil D, Bordaberry M, Mir C, Martinez H, Bonelli L, Niepomniszcze H: Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone. Br J Ophthalmol 2004;88:1380–1386.

17Weissel M, Hauff W: Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease. Thyroid 2000;10:521.

18Marino M, Morabito E, Brunetto MR, Bartalena L, Pinchera A, Marcocci C: Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 2004;14:403–406.

19Salvi M, Vannuchi G, Sbrozzi P, Bottari del Castello A, Carnevali A, Fargion S, Beck-Peccoz P: Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto’ s thyroiditis: case report. Thyroid 2004;14:631–634.

20Le Moli R, Baldeschi L, Saeed P, Regensburg N, Mourits MP, Wiersinga WM: Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves’ ophthalmopathy. Thyroid 2007;17:357–360.

21Kahaly GJ, Rösler HP, Kutzner J, Pitz S, Müller-Forell W, Beyer J, Mann WJ: Radiotherapy for thyroid-associated orbitopathy. Exp Clin Endocrinol Diab 1999;107:201–207.

22Kahaly GJ, Gorman CA, Kal HB, Mourits MP, Pinchera A, Tan S, Prummel MF: Radiotherapy for Graves’ ophthalmopathy; in Prummel MF (ed): Recent Developments in Graves’ Ophthalmopathy. Boston, Kluwer Academic Publishers, 2000, pp 115–131.

23Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB: Radiotherapy for Graves’ orbitopathy: randomised placebo-controlled study. Lancet 2000;355: 1505–1509.

24Prummel MF, Terwee CB, Gerding MN, Baldeschi L, Mourits MP, Blank L, Dekker FW, Wiersinga WM: A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves’ ophthalmopathy. J Clin Endocrinol Metab 2004;89:15–20.

25Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL, Earle JD, Forbes GS, Kline RW, Bergstralh EJ, Offord KP, Rademacher DM, Stanley NM, Bartley GB: A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves’ ophthalmopathy. Ophthalmology 2001;108:1523–1534.

26Kahaly GJ, Rösler HP, Pitz S, Krummenauer F, Hommel G: Radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab 2001;86:2327–2328.

27Kahaly GJ, Rösler HP, Pitz S, Hommel G: Lowversus high-dose radiotherapy for Graves’ ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab 2000;85:102–108.

28Wakelkamp IMMJ, Tan H, Saeed P, Schlingenmann RO, Verbraak FD, Blank LECM, Prummel MF, Wiersinga WM: Orbital irradiation for Graves’ ophthalmopathy: is it safe? A long-term follow-up study. Ophthalmology 2004;111:1557–1562.

29Marcocci C, Bartalena L, Rocchi R, Marino M, Menconi F, Morabito E, Mazzi B, Mazzeo S, Sartini MS, Nardi M, Cartei F, Cionini L, Pinchera A: Long-term safety of orbital radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab 2003;88:3561–3566.

30Bartalena 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.

31Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A: Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves’ ophthalmopathy is more effective than radiotherapy alone: results of a prospective randomized study. J Endocrinol Invest 1991;14: 853–860.

32Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell’Unto E, Rocchi R, Barbesino G, Mazzi B, Bartolomei MP, Lepri P, Cartei F, Nardi M, Pinchera A: Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab 2001;86:3562–3567.

33Ng CM, Yuen HKL, Choi KL, Chan MK, Yuen KT, Ng YW, Tiu SC: Combined orbital irradiation and systemic steroids compared with systemic steroids alone in the management of moderate-to- severe Graves’ ophthalmopathy: a preliminary study. Hong Kong Med J 2005;11:322–330.

34Ohtsuka K, Sato A, Kawaguchi S, Hashimoto M, Suzuki Y: Effect of steroid pulse therapy with and without orbital radiotherapy on Graves’ ophthalmopathy. Am J Ophthalmol 2003;135: 285–290.

35Kahaly GJ, Schrezenmeir J, Krause U, Schweikert B, Meuer S, Muller W, Dennebaum R, Beyer J: Ciclosporin and prednisone vs. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest 1986;16:415–422.

36Kahaly GJ, Schrezenmeir J, Schweikert B, Müller W, Krause U, Beyer J: Remission-maintaining effect of cyclosporine in endocrine ophthalmopathy. Transplant Proc 1986;18:844–846.

37Kahaly GJ, Yuan JP, Krause U, Hülbusch K, Beyer J: Ciclosporin and thyroid-stimulating immunoglobulins in endocrine orbitopathy. Res Exp Med 1989;189:355–362.

38Kahaly GJ, Moncayo R, Bemetz U, Krause U, Beyer J, Pfeifer EF: Eye muscle antibodies in endocrine exophthalmos. Horm Metab Res 1989;12:137–141.

39Prummel 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.

40Kazatschkine MD, Kaveri SV: Advances in immunology: immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747–755.

41Kahaly GJ, Pitz S, Muller-Forell W, Hommel G: Randomized trial of intravenous immunoglobulins versus prednisolone in Graves’ ophthalmopathy. Clin Exp Immunol 1996;106:197–202.

42Antonelli A, Saracino A, Alberti B, Canapicchi R, Cartei F, Lepri A, Laddaga M, Baschieri L: High-dose intravenous immunoglobulin treatment in Graves’ ophthalmopathy. Acta Endocrinol 1992;126:13–23.

43Baschieri L, Antonelli A, Nardi S, Alberti B, Lepri A, Canapicchi R, Fallahi P: Intravenous immunoglobulin versus corticosteroid in treatment of Graves’ ophthalmopathy. Thyroid 1997;7: 579–585.

44Perros P, Weightman DR, Crombie AL, Kendall-Taylor P: Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol 1990;122:8–12.

45Kahaly GJ, Lieb W, Müller-Forell W, Mainberger M, Beyer J, Vollmer J, Staiger C: Ciamexone in endocrine orbitopathy. Acta Endocrinol 1990;122:13–21.

46Kung AW, Michon J, Tai KS, Chan FL: The effect of somatostatin versus corticosteroid in the treatment of Graves’ ophthalmopathy. Thyroid 1996;6:381–384.

47Dickinson AJ, Vaidya B, Miller M, Coulthard A, Perros P, Baister E, Andrews CD, Hesse L, Heverhagen JT, Heufelder AE, Kendall-Taylor P: Double-blind, placebo-controlled trial of

octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2004;89:5910–5915.

48Wemeau JL, Caron P, Beckers A, Rohmer V, Orgiazzi J, Borson-Chazot F, Nocaudie M, Perimenis P, Bisot-Locard S, Bourdeix I, Dejager S: Octreotide (long-acting release formulation) treatment in patients with Graves’ orbitopathy: clinical results of a four-month, randomized, placebocontrolled, double-blind study. J Clin Endocrinol Metab 2005;90:841–848.

49Chang TC, Liao SL: Slow-release Lanreotide in Graves’ opthalmopathy: a double-blind randomized, placebo-controlled clinical trial. J Endocrinol Invest 2006;29:413–422.

50Stan MN, Garrity JA, Bradley EA, Woog JJ, Bahn MM, Brennan M, Bryant SC, Achenbach SJ, Bahn RS: Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of Graves’ ophthalmopathy. J Clin Endocrinol Metab 2006;91:4817–4824.

Prof. George J. Kahaly

Department of Medicine I, Gutenberg University Hospital Langenbeckstrasse 1

DE–55131 Mainz (Germany)

Tel. 49 6131 17 3768, Fax 49 6131 17 3460, E-Mail gkahaly@mail.uni-mainz.de

Fig. 1. Axial (a) and coronal (b) CT scans of an 86-year-old man with DON showing apical compression of the optic nerve with apical crowding. Axial (c) and coronal (d ) CT scans of the same patient, 2 days following bilateral medial wall and medial floor orbital decompression.

Which Symptoms Should Alert Me?

Visual dimming is often so insidious that the patient will be unaware of it until late in the clinical course. Such patients may complain of ‘foggy’ or ‘blurred’ vision which persists after blinking (so is not caused by tear film disruption), and after closing one eye (so is not caused by diplopia). Some patients can read 20/20 and have no visual complaints [9]. Light sensitivity (in the absence of corneal lesions) or dimming of colours should also alert the clinician to the possibility of DON. Orbital ache and gaze-evoked pain are not specific, but should alert the clinician in the presence of restriction of elevation ( 30 ) [8].

Fig. 2. Axial T2-weighted MRI scan showing optic nerve stretch with tenting of the posterior globe in severe thyroid eye disease.

Appearance of inconstant (gaze-evoked) diplopia or constant diplopia in the primary position or reading should also warn the clinician, because diplopia has been reported in almost 50% of DON patients [2, 8].

What Are the Ophthalmological Signs of

Dysthyroid Optic Neuropathy?

Normal visual acuity does not preclude an optic neuropathy. But, in presence of a dyschromatopsia, and particularly of a relative afferent pupillary defect (RAPD), optic nerve dysfunction should always be ruled out. Many reports indicate that visual loss is similar in both eyes in about 40% of DON patients [8]; in this condition a RAPD will not be detectable [9]. Presence of active inflammatory signs and symptoms (CAS 3) has been observed in the majority of DON patients, but is not absolutely required for the diagnosis of DON [8]. The optic disc may be swollen in 30% [9] to 56% [8], rarely pale or may appear perfectly normal associated with or without retinal venous congestion (table 1).