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

Wiersinga WM, Kahaly GJ (eds): Graves’ Orbitopathy: A Multidisciplinary Approach. Basel, Karger, 2007, pp 66–77

Diagnosis and Differential Diagnosis

of Graves’Orbitopathy

Maarten P. Mourits

Department of Ophthalmology, Academic Medical Center – AMC,

University of Amsterdam, Amsterdam, The Netherlands

Can You Give an Overall Scheme for the Diagnosis of Graves’Orbitopathy?

The diagnosis of Graves’ orbitopathy (GO) is based on (1) the presence of eye signs and symptoms, (2) the presence of thyroid auto-immunity, and (3) the exclusion of an alternative diagnosis. None of the eye signs are specific for GO. It is the bilateral symmetric nature of the orbitopathy in a patient known to have Graves’ hyperthyroidism which makes the diagnosis straightforward in most patients. However, GO may precede the onset of Graves’ hyperthyroidism. In those patients, laboratory evidence of existing thyroid auto-immunity might favour GO as the cause of the eye changes. Euthyroidism does not exclude GO and the same holds true for (predominantly) unilateral eye changes occurring in as much as 15% [1] of all GO patients. Indeed, GO is the most frequent cause of unilateral proptosis. In such cases, it is prudent to perform orbital imaging to exclude other diseases.

Which Clinical Findings Are Helpful in Making a

Diagnosis of Graves’Orbitopathy?

Clinical symptoms found in GO are eyelid swelling, eyelid retraction, proptosis, eye muscle restriction, corneal staining and decreased visual acuity. During the active state of the disease additional symptoms are redness of the

Fig. 1. Patient with lower lid swelling due to GO.

Table 1. Differential diagnosis of soft eyelid swelling

1 Infection of dermis (impetigo, erysipelas) or adnexae (chalazion)

2 Toxic (chemical or bacterial toxins)

3 Auto-immune disease (Graves’ orbitopathy, dermatomyositis)

4 Allergic (urticaria, angioneurotic, eczematous, contact allergy, medicine-induced, bites) 5 Static (orbital tumor, heartfailure)

6 Metabolic (myxedema, nephrotic syndrome)

7 Miscellaneous (blepharochalazis syndrome, haemorrhage)

lids and conjunctiva, chemosis and caruncula swelling. GO is at least 3 times more common in females than in males [2].

Eyelid swelling (fig. 1) is a very common finding in patients with GO, but it is often hard to say if and to what extent the swelling is caused by the orbitopathy and what is the contribution of age, smoking habits, general condition, etc. Moreover, eyelid swelling may fluctuate over the day. Strict criteria for a definition of eyelid swelling do not exist and therefore the prevalence of eyelid swelling in GO is unknown. Eyelid swelling in GO is caused by edema and fat increase and is thus easily distinguishable by palpation from swelling by firm lesions. However, differentiation from other forms of soft eyelid swelling may be difficult (table 1). The von Graefe’s sign (1864), a dissociation of the movements of the eyelid and the globe showing sclera above the cornea in downgaze, can be considered a precursor of frank retraction and can be used to track down GO.

In the absence of other symptoms, eyelid swelling may be overlooked as an initial sign of GO and surgery to correct the eyelid swelling (e.g. blepharoplasty)

Fig. 2. Patient with unilateral upper lid retraction in mild GO.

Table 2. Differential diagnosis of eyelid retraction

1 Physiological in newborns

2 Some degree of retraction might be physiological in adults 3 Thyrotoxicosis (by pure sympathetic stimulation)

4 Graves’ orbitopathy (by a combination of factors)

5 Scarring after inflammation, trauma or surgery (e.g. after blepharoplasty) 6 In case of unilateral ptosis of the other eye (Hering’s law)

7 Marcus-Gunn phenomenon

8 Parinaud’s syndrome and midbrain disease

9 Myostatic paresis of Parkinsonism (by muscular rigidity)

10Hepatic cirrhosis (also by muscular rigidity)

11Sympathomimetic drugs

may then easily result into a undesired situation such as an inability to close the eyes. An attempt has been made to monitor eyelid swelling by repeated photographs taken under standardized circumstances [3].

In most individuals with their heads in the primary position, the upper eyelids cover the cornea at the 12 o’clock position for 0–1.5 mm, whereas the lower lids just touch the corneal limbus at the 6 o’clock position [4].

Eyelid retraction (fig. 2) is present when, in the absence of staring, these criteria are not fulfilled and a band of white sclera between limbus and eyelid margin is visible [5]. In contrast to what is often thought, not proptosis, but eyelid retraction is the most frequent symptom assessed in GO (occurring in up to 70%) [6], but it is certainly not pathognomonic for GO. Eye lid retraction is seen in many other conditions (table 2).

Proptosis ( exophthalmos) is present when the distance between the vortex of the cornea and the anterior surface of the bony lateral orbital rim is above the upper limit of normal found in a healthy population. Exophthalmometry values are race and gender dependent and show a wide range in healthy individuals. Attempts have been made to define pathologic exophthalmometry values [7, 8]. In GO, proptosis is caused by an increase of extraocular muscle (EOM) size and of orbital fat. Moreover, in contrast to some other causes of proptosis, such as for instance swelling of the lacrimal gland, the proptosis is axial in nature. However, the list of conditions causing axial proptosis is long (table 3) and the presence of axial proptosis alone is therefore insufficient to make a diagnosis of GO. Nevertheless, it is important to realise that the most common cause of both unilateral and bilateral proptosis is GO [2]. The prevalence of proptosis in patients with GO in our series is 60% [1]. Proptosis may be absent in patients with GO and especially in those with dysthyroid optic nerve compression, in whom spontaneous orbital decompression resulting in forward displacement of the globe did not occur.

Pseudoproptosis refers to appearance of proptosis in the absence of axial displacement of the globe. Well-known pitfalls are high myopia, buphthalmos, eyelid retraction, and contralateral enophthalmos.

Eyeball motility restriction, sometimes causing diplopia, in GO is caused by tethering of the inflamed EOMs. Because the inferior and medial rectus muscles are often involved, elevation and less often abduction limitation results. In more severe cases these restrictions may lead to frank hypoor esotropia. Attempts to elevate the eyes in GO may cause an aqueous outflow restriction by compression of the globe by the opposing inelastic EOMs resulting in a transient intraocular pressure rise [9]. This phenomenon can be used to assess even mild forms of GO. Enlarged, restrictive EOMs are also found in patients with orbital myositis or metastasis to EOM’s.

Corneal stippling or ulceration is seen in any condition, in which there is inability to close or to moisten the cornea. In GO, this phenomenon is now considered a secondary one due to proptosis and eyelid retraction.

Decreased visual acuity in GO is found in patients with corneal involvement and/or compression of the optic nerve. Its prevalence is 5% of untreated GO patients.

The above clearly shows that no single symptom or sign is pathognomonic for GO. However, the combination of eyelid retraction and proptosis must raise a high suspicion for GO. One should realize, however, that the absence of proptosis and retraction does not exclude GO and that eyelid swelling and/or acquired diplopia warrants an investigation for GO.

Can One Make a Diagnosis of Graves’Orbitopathy Based on Medical History and Clinical Picture Alone?

There is a close temporal relationship between the onset of GO and of Graves’ thyroid disease (GTD). In almost 80% of patients, GO and GTD develop concomitantly, that is within a period of 18 months [10, 11]. GO sometimes precedes GTD, more often manifests shortly after GTD. GO can be present in the absence of thyroidal disease and is then called ophthalmic or euthyroid Graves’ disease [12, 13], although more sensitive tools show that in almost all patients orbitopathy and thyroid disease co-exist. GO is an autoimmune disorder and thus occurs often in patients with other auto-immune disorders such as myasthenia and impetigo. Apart from these general aspects of the medical history, eye complaints can help to make a diagnosis of GO. GO patients may complain about changed looks (swollen eyelids, popping eyes), retrobulbar discomfort, tearing, grittiness, double and blurred vision.

Combining elements of the medical history with the clinical picture leads to a diagnosis of GO in the majority of cases. However, carefulness is required, because for instance a 50-year-old woman with hyperthyroidism and popping eyes might suffer from hyperthyroidism plus bilateral orbital non-Hodgkin lymphoma. Therefore, before a diagnosis of GO can be made, mimicking diseases have to be excluded.

Do We Always Need to Order Thyroid Autoantibodies and Thyroid Function Tests?

At present, no definitive laboratory tests to demonstrate GO exist. However, elevated serum concentrations of TBII (TSH-binding inhibitory immunoglobulins) and TPO (thyroperoxidase) antibodies are commonly elevated in GO. Depending on the assay used elevated TBII are seen in more than 95% of patients with Graves’ disease [14]. Especially in euthyroid patients, TPO antibodies and TBII are important to make a diagnosis of GO. TBII are found elevated in more than 90% of patients with euthyroid GO. TBII are found to correlate with disease severity and activity of GO [15, 16] and have prognostic

significance for the course of GO [17]. The course of GO is influenced by the thyroid status. Normalization of hyperor hypothyroidism ameliorates the orbitopathy to a certain extent [18]. Therefore, it is our opinion that TSH and free T4 [to assess hyperor (subclinical) hypothyroidism], in some cases T3 (to assess subclinical hyperthyroidism or T3 toxicosis) and TBII plus TPO antibodies should be known of each patient in whom GO is suspected.

Which Imaging Technique Is Best to Make a Diagnosis of

Graves’Orbitopathy and Is Imaging Always Requested?

Among orbitologists around the world there is no doubt that the best way to detect GO by imaging is making a coronal (for assessment of EOM swelling) and axial CT scan (for assessment of apical crowding) of the orbits and paranasal sinuses. CT scanning is fast, only few 1.5 mm slices are required and no contrast enhancing is needed. Orbital CT scans clearly show the globe, the optic nerve, the EOMs, the lacrimal gland, the paranasal sinuses and the bony structures. Enlarged superior ophthalmic veins and abnormal structures can also be seen easily. The irradiation burden of a series of orbital CT scans is no more than 30 mGy. In contrast, MRI scans require considerable scanning time and show bony structures less clearly, which is a disadvantage when used for possible orbital decompression planning. Echography of the orbital contents is a fast method, but cannot be used to demonstrate swelling of the superior rectus muscle and deep orbital structures. Both CT and MRI scans show enlargement of the EOMs, apical crowding and stretching of the optic nerve and tenting of the posterior globe when present. The presence of fat increase is deducted when there is proptosis in the absence of EOM swelling or a pathological orbital space occupying lesion. More accurate assessment of fat will become available, when orbital volumes can be measured and compared to standard values [19]. In GO, the inferior rectus muscle is involved most frequently (fig. 3), followed by the medial rectus and the superior rectus/levator complex. The lateral rectus and superior oblique participate only in more severe forms. Swelling of the lateral rectus in the absence of swelling of the other EOMs points to other diseases than GO such as orbital myositis [see below, Which are the most frequent conditions mimicking Graves’ orbitopathy?]. Scans are not only made to demonstrate eye muscle enlargement, but also to exclude other pathologies causing axial proptosis such as benign and malignant tumors (e.g. intraconal cavernous haemangioma and non-Hodgkin lymphoma).

Imaging in GO is not always necessary. In patients with mild orbitopathy in whom the diagnosis is straightforward, there is no need for scanning. Apart from for academic purposes (e.g. follow-up after immunomodulatory

Fig. 3. Enlarged inferior rectus muscle in a patient with GO shown on coronal CT scan.

interventions), imaging is required in doubtful cases to exclude any other pathology and/or to plan orbital decompression.

Which Are the Most Frequent Conditions Mimicking

Graves’Orbitopathy?

The most frequent diseases mimicking GO are orbital meningioma, orbital myositis, caroticocavernous fistula and non-Hodgkin lymphoma, which will be discussed briefly.

Orbital Meningioma

Orbital meningioma occurs frequently in middle aged women. There are two common forms:

(1)Sphenoid wing meningioma, causing hyperostosis of the larger sphenoid wing resulting in axial protrusion of the globe.

(2)Optic nerve sheet meningioma, causing visual obscurations prior to

reduced visual acuity and axial proptosis.

In addition to their proptosis, these patients usually have some degree of ptosis in stead of retraction. Diagnosis is based on CT scan or better on contrast enhanced MRI scans (fig. 4a–c).

Orbital Myositis and ‘Pseudotumour Orbitae’

Orbital myositis (fig. 5) is an idiopathic non-infectious inflammation of one or more EOMs belonging to the group of aspecific acute or subacute inflammatory orbital diseases, which were called pseudotumour in the past.

Fig. 4a–c. Clinical presentation of a patient with an orbital meningioma, and CT scans of patients with sphenoid wing and optic nerve sheet meningioma. Arrow showing hyperostosis of the greater wing of the sphenoid wing on axial CT scan (b). Arrow showing tubular swelling around the optic nerve leaving the optic nerve untouched (tram-track phenomenon), typical presentation of optic nerve sheet meningioma (c).

Aspecific inflammatory orbital diseases present as space occupying lesions anywhere in the orbit (fig. 6) and have inflammatory signs as seen in active GO. Unlike in GO, pain is usually the most important reason for the patient to seek doctor’s advice. When located within an EOM, the condition is called orbital

Fig. 5. CT scan of a patient with an orbital myositis (red arrow). Note thickened muscle tendon of external rectus (blue arrow).

Fig. 6. CT scan of an idiopathic inflammatory orbital inflammation (pseudotumor orbitae, red arrow): ill-defined mass near levator/superior rectus complex.

myositis. In contrast to GO, these diseases are seen at all ages and typically respond well to a course of prednisone. Orbital myositis can ‘jump’ from one muscle to another (in the same or the contralateral orbit). Several clinical and imaging qualities (table 4) distinguish orbital myositis from GO.

Table 4. Differentiation between GO and orbital myositis

Fig. 7. Corkscrew dilated episcleral vessels (arrow) in a patient with an acquired AV fistula.

Caroticocavernous Fistula

Pathological communications between the arterious and venous systems in the cavernous sinus can cause axial proptosis, so called corkscrew dilated episcleral vessels (fig. 7) and enlargement of all EOMs due to congestion. A traumatic and arteriosclerotic form are distinguished, the latter sometimes hold for GO. The presence of the episcleral vessels and a severely enlarged superior ophthalmic vein seen on orbital scans makes the diagnosis. Localisation of the pathologic communication can be assessed with angiographic investigations.