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

tertiary referrals [1, 2, 44]. The prevalence of class III signs in the EUGOGO series of tertiary referrals was similar to an incidence cohort at 63% [1, 2, 44]. The prevalence of class IV signs depends on assessment method, but is between 40–60% [2, 44]. Class V signs are much less common and although 10–17% of patients will show punctuate staining, the incidence of sight-threatening ulceration was 2% a century ago, and is probably lower now [45]. Class VI affects around 5% of patients, and although it is generally thought to affect 10% of tertiary referrals, in the EUGOGO series 21% of patients had DON [2, 3, 44, 46].

How Are Signs of Severity Assessed?

A precise and consistent method is required when assessing the various signs of severity. One such method is described in principle below but can be found in more detail at www.eugogo.org. The order of NOSPECS has been used.

(I) Palpebral aperture (fig. 1): The vertical height of the eyelid in the midpupil position is noted after first stabilising the patient’s head position and fixation to reduce artefacts, and occluding the opposite eye if vertical strabismus is present. Both upper and lower eyelid positions are recorded relative to the respective limbus. Lateral flare is disregarded.

(II) Soft tissue involvement: Although soft tissue involvement indicates activity, the degree of soft tissue swelling also describes severity. The signs are assessed as described above and in figure 8.

(III) Proptosis: This is usually measured clinically using a Hertel exophthalmometer. Unfortunately, the numerous models available give significantly different readings and accuracy will depend on using the same instrument, and ideally the same observer [46]. An intercanthal distance is chosen to fit the instrument snugly against the lateral orbital margins at the level of the lateral canthi and prevent horizontal rotation, and the patient looks at the examiners eye being used to record the position of the corneal apex, i.e. the examiner’s right eye for patient’s left eye etc. The measurement is taken after aligning the reference points on the instrument (fig. 10). Proptosis is defined as a reading 2 mm greater than the upper limit of normal for that patient’s gender, age and race; however, despite many publications reporting normal ranges, the instruments on which they are based are not always described, and meaningful calibration has yet to be achieved [47–49]. It appears true that women have lower measurements than men, and children have lower measurements than adults, although these decline again with age. Asians have lower measurements than Caucasians who have lower measurements than Negros. Until normal ranges are reported for specified and calibrated instruments then the measured change in exophthalmometry is of greatest relevance to monitoring [50].

Table 4. Mean ocular excursions at all ages in degrees

Directions of gaze right eye (NB left eye is a mirror image around the vertical axis).

After Mourits et al. [53]* and Haggerty et al. [54]†.

The extraocular muscles may behave quite differently over the course of GO. Hence, uniocular fields of fixation (UFOF) are of value as they independently assess the limitation of excursions of each eye [26, 52–54]. The prism cover test and the field of binocular single vision (BSV) reflect changes in both eyes; however, each retains a valuable place in assessment, the first in planning for strabismus surgery, and the second as a useful way to monitor change. They remain useful when both eyes are abnormal, unlike the Hess-Lees screen [3]. BSV has been shown to be quantifiable and reproducible [55], and to correlate well with the functional deficit from the patient’s perspective [56]. UFOF are quantified in either 4 or 6 directions of gaze [53, 54] by using a bowl or arc perimeter, with mean excursions as shown in table 4. An age-related decline in excursions, especially elevation has been noted by some but not all studies [53, 54, 57].

(V) Corneal pathology: While minor corneal pathology requires slit lamp examination to detect punctate fluorescein staining, sight-threatening pathology is evident with simple torch examination. In this situation, the eyelids do not close gently to cover the cornea, which remains visible. The lower conjunctiva is generally red and if ulceration has developed, then a grey opacity or even an abscess will be seen in the inferior cornea. This constitutes an emergency.

(VI) Visual disturbance: Clinical assessments for DON comprise the following:

(a)Best corrected visual acuity of each eye, which is most accurately measured with a Logmar chart, although Snellen charts are more widely available.

(b)Colour vision. Testing in the blue/yellow axis is most likely to pick up early defects of DON; however red-green pseudo-isochromatic charts (e.g. Ishihara) are more readily available and remain very useful in this context

Fig. 11. Fundus showing choroidal folds.

[see below, ‘How do you decide whether a patient has dysthyroid optic neuropathy’]. Each eye is tested separately using a reading correction as required.

(c)Pupil responses are assessed by the swinging flashlight test for a relative afferent pupil defect. Artefacts can easily be produced if a consistent method is not followed, particularly in patients with manifest strabismus. The patient fixates on a distant target and care is taken to give both eyes equal stimulation with the same alignment to the visual axis while the light is moved between alternate eyes.

(d)Fundoscopy will detect abnormal swelling or pallor of the optic disc and the presence of choroidal folds (fig. 11) as well as giving valuable information on confounding pathology such as cataract and glaucoma. Choroidal folds are thought to develop when the eyeball is mechanically deformed by the secondary effects of enlarged rectus muscles in a restricted space. The folds are horizontal, and generally pass straight through the macula unlike retinal folds.

(e)Perimetry. This is reserved for eyes with suspicion of DON. Automated perimetry is most commonly used.

In addition to the above, the intra-ocular pressure is measured. High readings are commonly found in patients with orbital congestion [58], and although these may increase on upgaze in relation to a tight inferior rectus muscle, the reliability of this sign is poor [3].

How Reproducible Are These Assessments?

There are no peer-reviewed publications on the reproducibility of eyelid dimensions in GO although unpublished data from the author’s institution show that the intraclass correlation for palpebral aperture was good at 0.65. Eyelid dimensions in ptosis subjects have been found to be highly repeatable [59]; however, patients with GO frequently exhibit marked variability in upper eyelid positions and are likely to be more difficult to measure accurately.

Proptosis accuracy depends significantly on the model of exophthalmometer used together with technique. The Hertel exophthalmometer with straight footplates and a single mirror appears to be more accurate than other Hertel models [50], and although other types of exophthalmometer may be more reliable [60] they are much less commonly available. Reproducibility to within 2 mm is generally quoted [3, 47, 48] and unpublished data from the author’s institution showed the intraclass correlation to be 0.71 for exophthalmometry.

Both UFOF and BSV measurements show high levels of accuracy with UFOF repeatable to within 8 for single muscle measurement [54], and BSV fields accurate to within 4%.

The reproducibility of assessments for DON is unknown.

How Do You Decide Whether a Patient Has Dysthyroid

Optic Neuropathy?

There is no single test that will conclusively establish or refute the diagnosis of DON. Therefore the clinician has to be alert to the possibility of DON in all patients with active disease and look for it in particular when there are certain constellations of other GO features.

Although in theory any patient could develop DON during active GO, unless there is significant motility disturbance or extreme proptosis then they are essentially not at risk. To put it another way, for the optic nerve to be compromised, which is a secondary phenomenon, there has to be evidence of primary tissue involvement that could lead to this as described above ‘Can you give me a short mechanistic explanation for all these clinical manifestations?’. There are 2 scenarios: in the majority of patients DON is caused by very large muscles at the orbital apex (especially the medial rectus and inferior rectus) combined with sufficient tension in the anterior orbital septum that the orbit cannot self decompress. In such patients there may be little or no proptosis,

although it can still be moderately severe [23, 24, 61]. However, there should always be evidence of restricted motility, very often with a vertical tropia or esotropia [23, 62]. Ballottement of the globe is a crude test, but these patients will have tense rather than soft orbits. In the alternative scenario, there is such extreme proptosis from self-decompression of the orbit that there is no compression of the optic nerve, but rather it is stretched, as are the muscles. In some of these patients there is global restriction of motility. Although in one series this scenario accounted for 24% of DON [61], others have found it to be much less common [23, 24].

The typical presentation of DON is of a symptomatic patient with ocular surface discomfort or aching and evidence of muscle restriction. Soft tissue involvement is often not severe [23, 61, 63] although the CAS is often 4 [24]. The onset of DON is usually insidious, but symptoms of blurring, patchy visual loss or colour desaturation can be elicited from up to 80% of affected patients [23, 61]. Nevertheless, visual acuity is often well preserved, and a normal acuity does not exclude DON. DON is usually bilateral (70%) and therefore a relative afferent pupil defect is usually absent. Colour defects are present in most patients [23, 24] and although red-green pseudo-isochromatic colour plates (e.g. Ishihara) are thought to be less sensitive for detecting early DON, a recent study found them to be almost universally abnormal [24]. While 30–40% of eyes with DON may show disc swelling, all studies agree that 40–50% will appear normal. Visual field assessment will detect defects in most patients with other evidence of DON. These are commonly central paracentral and/or inferior [3]. It should be appreciated that these tests can show normal fluctuation and may be very misleading in patients with marked visual loss [64] or confounding pathology such as cataract, age-related maculopathy or glaucoma. Unfortunately, the age of patients at greatest risk of DON makes them more likely to show these confounding pathologies, and indeed a recent study showed confounding pathology in 28% [24]. This may make the signs of DON difficult to interpret.

So, how then can the diagnosis of DON be made with confidence? Recent evidence suggests that the signs with the greatest specificity for DON are impairment of colour perception and optic disc swelling [24]. These signs are least likely to be influenced by confounding pathology, provided the patient is not colour blind. A practical approach would be to diagnose DON on disc swelling alone, provided other causes for this have been excluded. In patients without disc swelling, DON should only be diagnosed when there are at least 2 other features of optic neuropathy: impaired acuity or colour vision, an afferent pupil defect or abnormal perimetry [3]. Patients without significant visual loss who have inconclusive evidence of DON, may not require treatment; however, they should be monitored very carefully.

Can Dysthyroid Optic Neuropathy Ever Be Present with

Normal Vision?

There is clear evidence that DON can be present with normal vision [3, 24]. In some patients, visual acuity of 1.0 may represent a reduction on their normal acuity, while others will truly have no objective reduction by the time DON is diagnosed. Indeed, 50–70% of eyes with DON have acuities of 0.5 or better [61, 65, 66].

Are Some Patients at Particular Risk?

There is a higher risk of DON in men, and in older patients of either gender. The mean age at presentation of DON is 56–57 years [23, 24] whereas for GO without DON it is 49 years [17, 23]. Other risk factors included diabetes mellitus which constitutes an additional 10-fold risk for DON [67]. Smoking is associated with a greater risk of more severe orbitopathy and may confer a higher risk for DON.

What Other Assessments Are Useful in Evaluating

Possible Dysthyroid Optic Neuropathy?

In addition to the clinical assessments described above, several ancillary tests can also help to identify DON. These include visual-evoked potentials, contrast sensitivity and imaging.

Abnormalities in both latency and amplitude of visual-evoked potentials can be supportive in the diagnosis of DON; however, several issues affect their value in practice. Firstly, they can be affected by thyroid dysfunction, which is frequently present at the time that DON develops [24]. In addition, many laboratories have no normal data for patients over 60 years old, making it hard to interpret findings in those who are already the most difficult to diagnose due to confounding pathology [3]. Hence, they should be interpreted with caution in patients with no other evidence of DON.

Contrast sensitivity, which measures spatial resolution at all levels of contrast, appears to be a sensitive indicator of DON [66]; however, it is less readily available and still subject to confounding pathologies.

Imaging has a very valuable place in supporting the diagnosis of DON. Coronal images on CT or MRI demonstrate apical crowding in the majority of patients. This is defined as the effacement of perineural orbital fat in the posterior orbit. The combination of apical crowding with evidence of fat herniation

through the superior orbital fissure seen on axial images is thought to have a specificity of 91% and sensitivity of 94% for DON [68]. Nugent et al. [69] noted mild or no apical crowding in 17% of DON, while 13% had severe apical crowding but no clinical evidence of DON. This emphasises the point that, as with evoked potentials and contrast sensitivity, DON should not be diagnosed from imaging alone. Stretching of the optic nerve is less easy to diagnose without both axial and sagittal images: the latter are not generally available with CT.

Should These Tests Be Performed in All Patients at Every Assessment?

It is not necessary to perform any of these additional tests in all patients at every assessment. They can be very valuable when there are features suspicious for DON as described above, and, if abnormal, they may be useful for monitoring response to treatment.

References

1Kendler DL, Lippa J, Rootman J: The initial clinical characteristics of Graves’ orbitopathy vary with age and sex. Arch Ophthalmol 1993;111:197–201.

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

3Dickinson 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 2001;55:283–303.

4Mourits 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.

5Khan JA, Doane JF, Whitacre MM: Does decompression diminish the discomfort of severe dysthyroid orbitopathy? Ophthal Plast Reconstr Surg 1995;11:109–112.

6Rubin PA, Watkins LM, Rumelt S, Sutula FC, Dallow RL: Orbital computed tomographic characteristics of globe subluxation in thyroid orbitopathy. Ophthalmology 1998;105:2061–2064.

7Saks ND, Burnstine MA, Putterman AM: Glabellar rhytids in thyroid-associated orbitopathy. Ophthal Plast Reconstr Surg 2001;17:91–95.

8Velasco e Cruz AA, Vagner de Oliveira M: The effect of Mullerectomy on Kocher sign. Ophthal Plast Reconstr Surg 2001;17:309–311.

9Bartley GB, Gorman CA: Diagnostic criteria for Graves’ ophthalmopathy. Am J Ophthalmol 1995;119:792–795.

10Koornneef L: Eyelid and orbital fascial attachments and their clinical significance. Eye 1988;2: 130–134.

11Frueh BR, Musch DC, Garber FW: Lid retraction and levator aponeurosis defects in Graves’ eye disease. Ophthalmic Surg 1986;17:216–220.

12Gilbard JP, Farris RL: Ocular surface drying and tear film osmolarity in thyroid eye disease. Acta Ophthalmol (Copenh) 1983;61:108–116.

13Vaidya B, Oakes EJC, Imrie H, Dickinson AJ, Perros P, Kendall-Taylor P, Pearce SHS: CTLA4 gene and Graves’ disease: association of Graves’ disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism. Clin Endocrinol 2003;58:732–735.

14Tellez M, Cooper J, Edmonds C: Graves’ ophthalmopathy in relation to cigarette smoking and ethnic origin. Clin Endocrinol 1992;36:291–294.

15de Juan E, Hurley DP, Sapira JD: Racial differences in normal values of proptosis. Arch Intern Med 1980;140:1230–1231.

16Tsai CC, Kau HC, Kao SC, Hsu WM: Exophthalmos of patients with Graves’ disease in Chinese of Taiwan. Eye 2006;20:569–573.

17Perros P, Crombie AL, Matthews JNS, 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 1993;38:367–372.

18Krassas GE, Segni M, Wiersinga WM: Childhood Graves’ ophthalmopathy: results of a European questionnaire study. Eur J Endocrinol 2005;153:515–521.

19Krassas GE, Gogakos A: Thyroid-associated ophthalmopathy in juvenile Graves’ disease: clinical, endocrine and therapeutic aspects. J Pediatr Endocrinol Metab 2006;19:1193–1206.

20Young LA: Dysthyroid ophthalmopathy in children. J Pediatr Ophthalmol Strabismus 1979;16: 105–107.

21Durairaj VD, Bartley GB, Garrity JA: Clinical features and treatment of Graves ophthalmopathy in pediatric patients. Ophthal Plast Reconstr Surg 2006;22:7–12.

22Trobe JD, Glaser JS, Laflamme P: Dysthyroid optic neuropathy: clinical profile and rationale for management. Arch Ophthalmol 1978;96:1199–1209.

23Neigel JM, Rootman J, Belkin RI, Nugent RA, Drance SM, Beattie CW, Spinelli JA: Dysthyroid optic neuropathy: the crowded orbital apex syndrome. Ophthalmology 1988;95:1515–1521.

24McKeag D, Lane C, Lazarus JH, Baldeschi L, Boboridis K, Dickinson AJ, Hullo A, Kahaly G, Krassas G, Marcocci C, Marino M, Mourits M, Nardi M, Neoh C, Orgiazzi J, Perros P, Pinchera A, Pitz S, Prummel MF, Sartini MS, Wiersinga WM: Clinical features of dysthyroid optic neuropathy: a European Group on Graves’ Orbitopathy (EUGOGO) survey. Br J Ophthalmol 2007;91:455–458.

25Mourits MP, Rose GE, Garrity JA, Nardi M, Matton G, Koorneef L: Surgical management of Graves’ ophthalmopathy; in Prummel MF (ed): Recent Developments in Graves’ Ophthalmopathy. London, Kluwer Academic Publishers, 2000, pp 133–169.

26Garrity JA, Terwee CB, Feldon SE, Wiersinga WM: Assessment of disease severity; in Prummel MF (ed): Recent Developments in Graves’ Ophthalmopathy. London, Kluwer Academic Publishers, 2000, pp 39–57.

27Mourits MP, Prummel MF, Wiersinga WM, Koornneef L: Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol 1997;47:9–14.

28Gorman CA: The measurement of change in Graves’ ophthalmopathy. Thyroid 1998;8:539–543.

29Gerding MN, Prummel MF, Kalmann R, Koornneef L, Wiersinga WM: The use of colour slides in the assessment of changes in soft-tissue involvement in Graves’ ophthalmopathy. J Endocrinol Invest 1998;21:459–462.

30Anderton LC, Neoh C, Walshaw D, Dickinson AJ: Reproducibility of clinical assessment in thyroid eye disease; in Abstract of the European Society of Ophthalmic, Plastic and Reconstructive Surgery, Paris, 2000, p 107.

31Gerding 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.

32Martins JRM, Furlanetto RP, Oliveira LM, Mendes A, Passerotti CC, Chiamolera MI, Rocha AJ, Manso PG, Nader HB, Dietrich CP, Maciel RMB: Comparison of practical methods for urinary glycosaminoglycans and serum hyaluronan with clinical activity scores in patients with Graves’ ophthalmopathy. Clin Endocrinol 2004;60:726–733.

33Gerding MN, Prummel MF, Wiersinga WM: Assessment of disease activity in Graves’ ophthalmopathy by orbital ultrasonography and clinical parameters. Clin Endocrinol 2000;52:641–646.

34Hiromatsu Y, Kojima K, Ishisaka N, Tanaka K, Sato M, Nonaka K, Nishimura H, Nishida H: Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy. Thyroid 1992;2:299–305.

35Just M, Kahaly G, Higer HP, Rösler HP, Kutzner J, Beyer J, Thelen M. Graves ophthalmopathy: role of MRI imaging in radiation therapy. Radiology 1991;179:187–190.

36Polito E, Leccisotti A: MRI in Graves orbitopathy: recognition of enlarged muscles and prediction of steroid response. Ophthalmologica 1995;209:182–186.

37Ohnishi T, Noguchi S, Murakami N, Tajiri J, Harao M, Kawamoto H, Hoshi H, Jinnouchi S, Futami S, Nagamachi S, Watanabe K: Extraocular muscles in Graves’ ophthalmopathy: usefulness of T2 relaxation time measurements. Radiology 1994;190:857–862.

38Prummel MF, Gerding MN, Zonneveld FW, Wiersinga WM: The usefulness of quantitative orbital magnetic resonance imaging in Graves’ ophthalmopathy. Clin Endocrinol 2001;54:205–209.

39Gerding MN, van der Zant FM, van Royen EA, Koorneef L, Krenning EP, Wiersinga WM, Prummel MF: Octreotide-scintigraphy is a disease-activity parameter in Graves’ ophthalmopathy. Clin Endocrinol 1999;50:373–379.

40Konuk O, Atasever T, Mehmet U, Ayvaz G, Yetkin I, Cakir N, Arslan M, Hasanreisoglu B: Orbital gallium-67 scintigraphy in Graves’ ophthalmopathy: a disease activity parameter that predicts the therapeutic response to immunosuppressive treatment. Thyroid 2005;15:358–363.

41Gerding MN, Prummel MF, Wiersinga WM: Assessment of disease activity in Graves’ ophthalmopathy by orbital ultrasonography and clinical parameters. Clin Endocrinol 2000;52:641–646.

42Terwee 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.

43Werner SC: Modification of the classification of the eye changes of Graves’ disease. Am J Ophthalmol 1977;83:725–727.

44Prummel MF, Bakker A, Wiersinga WM, Baldeschi L, Mourits MP, Kendall-Taylor P, Perros P, Neoh C, Dickinson AJ, Lazarus JH, Lane CM, Kahaly GJ, Pitz S, Orgiazzi J, Pinchera A, Marcocci C, Sartini MS, Rocchi R, Nardi M, Krassas GE, Halkias A: Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: the first European Group on Graves’ Orbitopathy experience. Eur J Endocrinol 2003;148:491–495.

45Burch HB, Wartofsky L: Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev 1993;14:747–793.

46Bartalena L, Wiersinga WM, Pinchera A: Graves’ ophthalmopathy: state of the art and perspectives. J Endocrinol Invest 2004;27:295–301.

47Mourits MP, Lombardo SHC, van der Sluijs FA, Fenton S: Reliability of exophthalmos measurement and the exophthalmometry value distribution in a healthy Dutch population and in Graves’ patients: an exploratory study. Orbit 2004;23:161–168.

48Sleep TJ, Manners RM: Interinstrument variability in Hertel-type exophthalmometers. Ophthal Plast Reconstr Surg 2002;18:254–257.

49Van den Bosch WA: Normal exophthalmometry values: the need for calibrated exophthalmometers. Orbit 2004;23:147–151.

50Vardizer Y, Berendschot TTJM, Mourits MP: Effect of exophthalmometer design on its accuracy. Ophthal Plast Reconstr Surg 2005;21:427–430.

51Bahn RS, Gorman CA: Choice of therapy and criteria for assessing treatment outcome in thyroidassociated ophthalmopathy. Endocrinol Metab Clin N Am 1987;16:391–407.

52Steel DHW, Hoh HB, Potts MJ, Harrad RA: Uniocular fields of fixation in thyroid eye disease. Eye 1995;9:348–351.

53Mourits MP, Prummel MF, Wiersinga WM, Koornneef L: Measuring eye movements in Graves’ ophthalmopathy. Ophthalmology 1994;101:1341–1346.

54Haggerty H, Richardson S, Mitchell KW, Dickinson AJ: A modified method for measuring uniocular fields of fixation: reliability in normal subjects and in patients with Graves’ orbitopathy. Arch Ophthalmol 2005;123:1–7.

55Sullivan TJ, Kraft SP, Burack C, O’Reilly C: A functional scoring method for the field of binocular single vision. Ophthalmology 1992;99:575–581.

56Fitzsimons R, White J; Functional scoring of the field of binocular single vision. Ophthalmology 1990;97:33–35.

57Clark RA, Isenberg SJ: The range of ocular movements decreases with ageing; in Transactions 25th Meeting European Strabismologicol Association. Jerusalem, 1986, pp 152–157.

58Kalmann R, Mourits MP: Prevalence and management of elevated intraocular pressure in patients with Graves’ orbitopathy. Br J Ophthalmol 1998;82:754–757.