Clinical Manifestations
  The clinical manifestations of GO can be fully explained in a mechanical sense from the increase in size of retro-ocular tissues: enlargement of extra-ocular muscles and retrobulbar fat is found in 46%, of muscles alone in 46%, and of fat alone in 8% (Forbes et al. 1986). The increased volume of retrobulbar tissues gives rise to an increase of retrobulbar pressure because of the bony cage of the orbit. The increased retrobulbar pressure interferes with the venous drainage of the orbit, resulting in periorbital edema, chemosis and redness of the conjunctiva. It may also cause herniation of fat through the orbital septum; periorbital swelling thus may be composed of edema or fat, which is difficult to distinguish by physical examination. The increased retrobulbar pressure pushes the globe forwards, and exophthalmos ensues. The average orbital volume is 26 ml (fat 12g, extra-ocular muscles 3.3g, lacrimal gland 0.65g, nerves and blood vessels 0.6g, fat-connective tissue residue 2.4g), and it has been calculated that a 4 ml increase of orbital volume results in a 6 mm increase of proptosis. The swelling of the extra-ocular eye muscles limit their movements, and may cause diplopia if impairment is asymmetrical. Severe exophthalmos prevents closure of the eyelids during sleep, and exposure keratitis may develop. Reduced blinking precludes normal tear drainage, and contributes to the risk of keratitis. In severe cases optic nerve dysfunction may occur, with manifestations of sight loss in 72%, visual field defects in 66% and disturbed colour vision in 64%. There may be direct compression of the optic nerve by marked swelling of the extra-ocular muscles in the apex of the orbit, and/or interference with the blood supply of the optic nerve by the elevated retrobulbar pressure. A very high retrobulbar pressure in the order of 17-40mmHg (normal 3-5mmHg) has indeed been measured in vivo in GO patients undergoing decompressive surgery because of optic neuropathy. These figures are higher than the values of 9-11mmHg measured in patients who underwent decompressive surgery because of disfiguring proptosis in the absence of optic nerve dysfunction. The development of exophthalmos mitigates the raised retrobulbar pressure and serves as a safeguard against the occurrence of optic nerve dysfunction; rightly it has been called nature's own decompression. When this mechanism fails, the patient is at risk for optic neuropathy. Why this mechanism fails, remains unknown. It has been hypothesized that this is due to the presence of rather firm connective tissue which will prevent nature's own decompression (Koornneef et al. 1994).


Table 1: Relative frequency of the clinical manifestations of GO classified according to the NO SPECS system in 90 consecutive untreated patients (Wiersinga et al. 1989).

NO SPECS classification of eye change

 class frequency 
No physical signs or symptoms class 0
Only signs (limited to upper lid retraction, stare and lid lag  class 1 
Soft tissue involvement (swollen eyelids, chemosis etc.)  class 2 90% 
Proptosis 3 mm or more in excess of uper normal limit* class 3  30% 
Extra-ocular muscle involvement (usually with diplopia) class 4  60% 
Corneal involvement class 5 9% 
Sight loss (due to optic nerve involvement) class 6 34% 

*upper normal limit is 20 mm in the Caucasian race, 18 mm in the Chinese race and 22 m in the Black race.


The clinical manifestation of GO can easily be memorized from the NO SPECS classification (Table 1). Classes 2-6 indicate orbital pathology. Class 2 and 4 are most prevalent. Although clinical examination revealed eye muscle involvement in 60% of the patients, CT of the orbit demonstrated enlarged eye muscles in 93%. The occurrence of exophthalmos is grossly underestimated since proptosis values of 21- 22 mm in a Caucasian patient are not recorded in this system (although it may signify marked protrusion of the eye, very relevant to the patient). Class 5 is largely preventable by the liberal use of artificial tears and the application of occlusive eye pads and eye ointments during nighttime. GO usually manifests itself as a bilateral eye disease, although slight asymmetry is not uncommon. Unilateral eye disease is seen in 14% of GO patients, which is difficult to explain in view of the systemic nature of Graves' disease. The distribution of age, sex and NO SPECS classes in patients with unilateral eye disease is similar to that in patients with bilateral eye disease, but the interval between the onset of thyroid and eye disease is much shorter in the patients with unilateral eye disease. Interestingly, in unilateral GO eye muscle enlargement in the fellow eye is observed on CT scan in appr. 50% (Wiersinga et al. 1989). Unilateral GO may thus represent an early stage of the disease, that as a rule already is or develops shortly afterwards into a bilateral disease. Bona fide cases of unilateral GO, which never develop into bilateral disease do, however, exist; the reason for this remains obscure, but local factors presumably related to the anatomy of the orbit might be involved (Figure 1).


Figure 1:



Unusual presentation of Graves' ophthalmopathy as unilateral 'malignant' eye disease. The male sex, advanced age and heavy smoking all predisposed this patient to the development of severe eye disease; note the absence of exophthalmos in this case of dysthyroid optic neuropathy.


Another unexplained phenomenon is the differential involvement of extra-ocular muscles: as evident from CT scanning, the inferior rectus muscle is enlarged in 60%, the medial rectus in 50%, the superior rectus in 40% and the lateral rectus in 22% (Wiersinga et al. 1989). The swollen inferior rectus muscle causes limitation of upward gaze (as the impaired motility has a restrictive nature and is caused by the inability to relax on attempted gaze in the opposite direction); because of its preferential involvement impaired elevation is four times as common as impaired abduction, adduction and depression combined.