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

mechanism for these effects of cigarette smoking are as yet unknown, but it is clear that smoking influences the risk, the severity and the response to treatment.

Gender and age both influence the severity of GO. Patients over the age of 60, particularly males, are at risk of developing severe disease and being male itself confers an increased risk [26].

Although there are as yet no direct data demonstrating genetic effects on the course of GO, it appears that the disease severity may be increased in association with certain genetic factors. The CTLA-4 gene is a susceptibility locus for Graves’ disease, and there appears to be a particularly strong association in patients who also have GO [27]; however, much more work is needed to clarify the role of genetic factors in GO.

References

1Marcocci C, Bartalena L, Bogazzi F, Panicucci M, Pinchera A: Studies on the occurrence of ophthalmopathy in Graves’ disease. Acta Endocrinol (Copenh) 1989;129:473–478.

2Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman C: Clinical features of Graves’ ophthalmopathy in an incidence cohort. Am J Ophthalmol 1996;121:284–290.

3Kendler DL, Lippa J, Rootman J: The initial clinical characteristics of Graves’ orbitopathy with age and sex. Arch Ophthalmol 1993;111:197–201.

4Marcocci C, Bruni-Bossio G, Manetti L, Tanda ML, Miccoli P, Iacconi P, Bartolomei MP, Nardi M, Pinchera A, Bartalena L: The course of Graves’ ophthalmopathy is not influenced by near total thyroidectomy: a case-control study. Clin Endocrinol (Oxf) 1999;51:503–508.

5Järhult J, Rudberg C, Larsson E, Selvander H, Sjövall K, Winsa B, Rastad J, Karlsson FA, the TEO Study Group: Graves’ disease with moderate-severe endocrine ophthalmopathy: long term results of a prospective, randomized study of total or subtotal thyroid resection. Thyroid 2005;15: 1157–1164.

6Tallstedt L, Lundell G, Torring O, Wallin G, Ljunggren JG, Blomgren H, Taube A: Occurrence of ophthalmopathy after treatment for Graves’ hyperthyroidism. The Thyroid Study Group. N Engl J Med 1992;326:1733–1738.

7Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A: Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 1998;338:73–78.

8Perros P, Anwar A, Toft AD: Evidence for a decline in the incidence and severity of thyroidassociated ophthalmopathy: twenty years experience of a large thyroid clinic. J Endocrinol 1996;148 (suppl):253.

9Karlsson AF, Westermark K, Dahlberg PA, Jansson R, Enoksson P: Ophthalmopathy and thyroid stimulation. Lancet 1989;ii:691.

10Prummel MF, Wiersinga WM, Mourits MP, Koornneef L, Berghout A, van der Gaag R: Effect of abnormal thyroid function on the severity of Graves’ ophthalmopathy. Arch Intern Med 1990;150:1098–1101.

11Tallstedt L, Lundell G, Blomgren H, Bring J: Does early administration of thyroxine reduce the development of Graves’ ophthalmopathy after radioiodine treatment? Eur J Endocrinol 1994;130: 494–497.

12Rundle FF: Management of exophthalmos and related ocular changes in Graves’ disease. Metabolism 1957;6:36–47.

13Hales IB, Rundle FF: Ocular changes in Graves’ disease. Quart J Med 1960;29:113–126.

14Perros P, Crombie AL, Kendall-Taylor P: Natural history of thyroid associated ophthalmopathy. Clin Endocrinol 1995;42:45–50.

15Wiersinga WM, Prummel MF: Therapeutic controversies: retrobulbar radiation in Graves’ ophthalmopathy. J Clin Endocrinol Metab 1995;80:345–347.

16Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R: Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol 1989;73:639–644.

17Dickinson AJ, Perros P: Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol (Oxf) 2001;55:283–303.

18Werner SC: Modification of the classification of the eye changes in Graves’ disease: recommendations of the ad hoc committee of the American Thyroid Association. J Clin Endocrinol Metab 1977;44:203–209.

19Bartalena L, Pinchera A, Marcocci C: Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev 2000;21:168–199.

20Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA: Long term follow-up of Graves’ ophthalmopathy in an incidence cohort. Ophthalmology 1996;103:958–962.

21Selva D, Chen C, King G: Late reactivation of thyroid orbitopathy. Clin Exp Ophthalmol 2004;32:46–50.

22Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF: Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol (Oxf) 2000;52:267–271.

23Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler N: Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 2006;91:3464–3470.

24Hagg E, Asplund K: Is endocrine opthalmopathy related to smoking? Br Med J 1987;295: 634–635.

25Mann K: Risk of smoking in thyroid-associated orbitopathy. Exp Clin Endocrinol Diabetes 1999;107(suppl 5):S164–S167.

26Perros P, Crombie AL, Matthews JN, Kendall-Taylor P: Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol (Oxf) 1993;38:367–372.

27Vaidya B, Kendall-Taylor P, Pearce SH: The genetics of autoimmune thyroid disease. J Clin Endocrinol Metab 2002;87:5385–5397.

Dr. Pat Kendall-Taylor The Barn

Newton Northumberland NE43 7UL (UK)

Table 1. Available ways of helping patients stop smoking and effectiveness

disease (or if alternative treatment modalities cannot be used, it should be combined with a short course of oral steroids).

Before considering immunosuppressive treatments, orbital radiotherapy or surgery, don’t forget simple ways of helping patients’ symptoms (see below, ‘What simple measures can help the eyes?’).

How Good Is the Evidence that Quitting Smoking Helps?

The association between smoking and GO is striking and has been confirmed by many studies. The risk of GO in smokers is increased 7- to 8-fold [2]. Furthermore, there is a dose-response relationship between number of cigarettes consumed per day and severity of the eye disease [3]. Patients who are current smokers have a less favourable response to treatment like radiotherapy or steroids [4, 5]. An association between smoking and progression of GO after radioiodine treatment has also been documented [4]. The risk of worsening GO is reduced drastically in patients who give up smoking [3]. So, although there are no studies that have directly assessed the effect of giving up smoking on GO, the evidence is highly suggestive that giving up smoking reduces the risk of GO becoming worse, and improves the chance of having a good response to treatment [6].

Does Thyroid Status Affect the Eyes?

Observational studies have found an association between severity of GO and both hypothyroidism and hyperthyroidism [7–10]. Hypothyroidism following radioiodine is associated with a risk of deterioration or emergence of new GO [11], and this effect can be at least partially prevented by maintaining

Table 2. Simple measures that may help patients with GO

euthyroidism [11, 12]. There is therefore convincing, albeit circumstantial, evidence that dysthyroidism is detrimental to the eyes.

What Simple Measures Can Help the Eyes?

Clinicians often forget that simple solutions can have a significant impact on symptoms (table 2).

Artificial tear drops or gels (administered 4–6 times daily) can alleviate the ocular surface symptoms (such as grittiness, excessive watering, photophobia) from reduced tear production and corneal exposure, which are both common features in patients with GO [13, 14].

Lubricant ointments prior to sleeping can help, particularly if surface symptoms are prominent on waking up. Taping the lids at night to prevent exposure keratopathy from lagophthalmos may also be an effective temporary measure, though if the orbitopathy is severe enough to require such measures, surgery needs to be considered.

A short course of weak corticosteroid (fluorometholone) or non-steroidal anti-inflammatory (ketorolac) eye drops can reduce the ocular symptoms and inflammatory signs especially when combined with intensive lubrication. The use of preservative free eye drops can help to avoid the allergic reactions, epithelial toxicity and chronic conjunctival inflammation produced by the preservatives and particularly benzalkonium chloride.

Several adrenergic blocking agents have been used topically and systemically to control eyelid retraction caused by increased sympathetic tone affecting Muller’s muscle. Topical guanethidine 2% has been found to control upper eyelid retraction in the majority of patients [15]. Unpredictable response, limited long-term effect, conjunctival hyperaemia, miosis and epithelial toxicity are the most frequently encountered complications responsible for the limited acceptability of this approach.

Spectacle correction of the induced refractive changes can improve visual acuity and sunglasses likewise can protect and minimise surface symptoms in response to wind or sunlight, and help some patients feel less self-conscious.

Patients with troublesome diplopia in the active stage should be considered for prisms before surgical correction can be applied. Monitoring and lowering intraocular pressure can reduce the chances of progression to glaucoma in some of those patients [16].

Diuretics and raising the head of the bed have been advocated as means of reducing the amount of periorbital edema, but objective evidence in favour of these measures is lacking and in the authors’ experience the former is ineffective and the latter poorly tolerated.

A sympathetic approach by the clinician and explanation of the various aspects of the disease and its treatment is appreciated by many patients. All patients can be reassured that with optimal management blindness (a dreaded fear by most patients with GO) is highly unlikely. The clinician should also encourage patients to be positive towards the disease. These basic strategies help to reduce the anxiety that many patients experience, and make life more tolerable, especially in the early days after diagnosis. Patient-led self-help groups also have an important role.

Is There a Place for Botulinum Toxin?

Botulinum toxin type A has been used to reduce lid retraction by injecting it into the levator complex of the upper lid through the skin or conjunctiva in both the active and inactive stage of the disease [17]. Similarly, it can be used to reduce the amount of diplopia by injecting into the appropriate extraocular muscles which also has a significant lowering effect on intraocular pressure [18]. The relief is temporary lasting for less than 12 weeks but often appreciated by patients and has a role until the eye disease is sufficiently inactive for lid and eye muscle surgery. Botulinum toxin has been successfully used for chemical denervation of the overactive corrugator supercilii and treatment of glabellar lines in patients with GO [19]. This was the first FDA-approved cosmetic application of botulinum toxin.

How Do You Define Mild, Moderately Severe, and

Very Severe Graves’Orbitopathy?

Although different clinicians with experience in managing GO are likely to classify the severity of individual patients similarly, agreeing on a definition that may be applicable to all patients is difficult [20]. This is because GO manifests in many different ways and in the same individual some features may be mild while others are severe. Furthermore, the symptoms experienced by patients of similar disease severity may be vastly different. Nonetheless, classifying patients into different categories of disease severity is useful and a guide to whether treatments are justified or not.

Patients with ‘mild’ disease are usually defined as those with minimal lid changes, little or no proptosis, absent or intermittent diplopia and no impairment of optic nerve function. Such cases usually do not require immunosuppressive or surgical treatment as the potential risks of such currently available therapies outweigh the benefits.

Sight-threatening disease refers to cases where there is evidence of DON and/or corneal breakdown and urgent treatment is required to prevent blindness.

‘Moderate to severe’ GO are cases that fall between the mild and sightthreatening severe categories. Such cases may benefit from immunosuppressive therapies and/or surgery.

Can You Give a Simplified Overall Management Scheme?

Patients with mild disease should be managed initially conservatively, focusing on simple measures, addressing their smoking habit and maintaining euthyroidism (fig. 1). The majority of such cases (about 2/3) will improve spontaneously over the following 3–6 months [21]. In special circumstances specific treatment may be justified, although the benefits will be marginal. If no specific treatment is administered, such patients should be monitored every few months to ensure that the disease does not deteriorate. Once the disease has reached its inactive stage, rehabilitative surgery may need to be considered.

Sight-threatening disease needs to be treated urgently. If sight is not threatened, treatment is not mandatory, but should be given serious consideration. Deciding whether to treat and with what modality depends on assessment of disease activity [22, 23]. During the active phase of GO, immunosuppression with steroids, orbital irradiation, or the combination of the two, are likely to be beneficial. If the disease is inactive rehabilitative reconstructive surgery has a major role. In the most severe of cases multiple treatments are required. These need to be planned carefully and in an appropriate sequence. For best results,

New diagnosis of GO

Yes Is there doubt about the diagnosis? No

Diagnostic tests

Diagnosis of GO confirmed

(orbital imaging) Sight-threatening GO?

Consider medical treatments

Consider surgical treatments (decompression before eye muscle surgery, before lid surgery)

Fig. 1. Overall management plan for patients with GO.

steroid therapy with or without orbital irradiation is administered until the disease becomes inactive. If medical treatment does not reverse the features of dysthyroid optic neuropathy, or is poorly tolerated, surgical orbital decompression must be considered sooner rather than later. The presence of significant proptosis which is unacceptable to the patient or troublesome corneal exposure due to proptosis are also indications for surgical decompression. Eye muscle surgery to correct diplopia should follow orbital decompression as new strabismus can occur after surgical decompression [24]. The final stage is lid lengthening to correct retraction followed by cosmetic blepharoplasty [25, 26].

References

1Wiersinga WM, Perros P, Kahaly GJ, Mourits MP, Baldeschi L, Boboridis K, Boschi A, Dickinson AJ, Kendall-Taylor P, Krassas GE, Lane CM, Lazarus JH, Marcocci C, Marino M, Nardi M, Neoh C, Orgiazzi J, Pinchera A, Pitz S, Prummel MF, Sartini MS, Stahl M, von Arx G: Clinical assessment of patients with Graves’ orbitopathy: the European Group on Graves’ Orbitopathy recommenda-

tions to generalists, specialists and clinical researchers. Eur J Endocrinol 2006;155: 387–389.

2Prummel MF, Wiersinga WM: Smoking and risk of Graves’ disease. J Am Med Assoc 1993;269: 479–482.

3Pfeilschifter J, Ziegler R: Smoking and endocrine ophthalmopathy: impact of smoking severity

and current vs. lifetime cigarette consumption. Clin Endocrinol (Oxf) 1996;45:477–481.

4Bartalena 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.

5Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, Steuhl P, Esser J: Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J

Ophthalmol 2003;87:773–776.

6Krassas GE, Wiersinga W: Smoking and autoimmune thyroid disease: the plot thickens. Eur J

Endocrinol 2006;154:777–780.

7Prummel MF, Wiersinga WM, Mourits MP, Koornneef L, Berghout A, van der Gaag R: Amelioration of eye changes of Graves’ ophthalmopathy by achieving euthyroidism. Acta Endocrinol (Copenh) 1989;121(suppl 2):185–189.

8Prummel MF, Wiersinga WM, Mourits MP, Koornneef L, Berghout A, van der Gaag R: Effect of abnormal thyroid function on the severity of Graves’ ophthalmopathy. Arch Intern Med 1990;150: 1098–1101.

9Kim JM, LaBree L, Levin L, Feldon SE: The relation of Graves’ ophthalmopathy to circulating

thyroid hormone status. Br J Ophthalmol 2004;88:72–74.

10Karlsson F, Westermark K, Dahlberg PA, Jansson R, Enoksson P: Ophthalmopathy and thyroid stimulation. Lancet 1989;ii:691.

11Tallstedt L, Lundell G, Blomgren H, Bring J: Does early administration of thyroxine reduce the development of Graves’ ophthalmopathy after radioiodine treatment? Eur J Endocrinol 1994;130: 494–497.

12Perros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J: A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active Graves’ ophthalmopathy. J Clin Endocrinol Metab 2005;90:5321–5323.

13Eckstein AK, Finkenrath A, Heiligenhaus A, Renzing-Kohler K, Esser J, Kruger C, Quadbeck B, Steuhl KP, Gieseler RK: Dry eye syndrome in thyroid-associated ophthalmopathy: lacrimal expression of TSH receptor suggests involvement of TSHR-specific autoantibodies. Acta Ophthalmol Scand 2004;82:291–297.

14Gilbard JP, Farris RL: Ocular surface drying and tear film osmolarity in thyroid eye disease. Acta Ophthalmol (Copenh) 1983;61:108–116.

15Haddad HM: Lid retraction therapy with a guanethidine solution. Arch Ophthalmol 1989;107:169.

16Cockerham KP, Pal C, Jani B, Wolter A, Kennerdell JS: The prevalence and implications of ocular hypertension and glaucoma in thyroid-associated orbitopathy. Ophthalmology 1997;104: 914–917.

17Uddin JM, Davies PD: Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology 2002;109:1183–1187.

18Kikkawa DO, Cruz RC Jr, Christian WK, Rikkers S, Weinreb RN, Levi L, Granet DB: Botulinum A toxin injection for restrictive myopathy of thyroid-related orbitopathy: effects on intraocular pressure. Am J Ophthalmol 2003;135:427–431.

19Carruthers JA, Lowe NJ, Menter MA, Gibson J, Nordquist M, Mordaunt J, Walker P, Eadie N: A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002;46: 840–849.

20Bartalena L, Pinchera A, Marcocci C: Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev 2000;21:168–199.

21Perros P, Crombie AL, Kendall-Taylor P: Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf) 1995;42:45–50.

22Wiersinga WM, Prummel MF: Graves’ ophthalmopathy: a rational approach to treatment. Trends Endocrinol Metab 2002;13:280–287.

23Bartalena L, Marcocci C, Tanda ML, Piantanida E, Lai A, Marino M, Pinchera A: An update on medical management of Graves’ ophthalmopathy. J Endocrinol Invest 2005;28:469–478.

24Abramoff MD, Kalmann R, de Graaf ME, Stilma JS, Mourits MP: Rectus extraocular muscle paths and decompression surgery for Graves orbitopathy: mechanism of motility disturbances. Invest Ophthalmol Vis Sci 2002;43:300–307.

25Fenton S, Kemp EG: A review of the outcome of upper lid lowering for eyelid retraction and complications of spacers at a single unit over five years. Orbit 2002;21:289–294.

26Shorr N, Seiff SR: The four stages of surgical rehabilitation of the patient with dysthyroid ophthalmopathy. Ophthalmology 1986;93:476–483.

27West R, McNeill A, Raw M: Smoking cessation guidelines for health professionals: an update. Health Education Authority. Thorax 2000;55:987–999.

Dr. P Perros

Department of Endocrinology, Level 6, Freeman Hospital Freeman Road

Newcastle upon Tyne NE7 7DN (UK)

Tel. 44 191 213 7245, Ext. 26245, Fax 44 191 2231249, E-Mail petros.perros@ncl.ac.uk