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Fig. 2. Opposite contribution of extramusclar (a) and muscle (b) swelling of the retrobulbar tissues.

      De novo Adipogenesis

Orbital fibroblasts include a subpopulation of cells (preadipocytes and/or mesenchymal stem/stromal cells) which may differentiate into adipocytes [4–6]. De novo adipogenesis in orbital adipose/connective tissue is demonstrated by an increase in the “adipocyte-related immediate early gene” mRNAs, including the angiogenic inducer, followed by increased expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), adiponectin, leptin, and stearyl-CoA-desaturase [7]. In vitro, orbital fibroblasts differentiate into adipocytes when treated with PPAR-γ agonists, e.g., rosiglitazone, in keeping with the observations of GO progression in 1 patient [8] and mildly increased eye protrusion in type 2 diabetes patients [9] treated with pioglitazone.

      Increased Production of Glycosaminoglycans

Orbit connective/adipose tissue and extraocular muscles are particularly rich in GAGs, mainly chondroitin sulphate and hyaluronan (HA), an especially hydrophilic molecule. HA synthases are strongly expressed by orbital fibroblasts and upregulated in the presence of various cytokines. Furthermore, there are reports of undetectable hyaluronidase activity (the enzyme complex which degrades HA) in orbital fibroblasts in vitro [10], although the mRNA transcripts for all hyaluronidase isoforms have been detected in GO tissues ex vivo [11]. Enlargement of intraorbital tissues is largely accounted for by the accumulation of GAG and oedema within the connective tissue, both within and outside the muscles.

How Do the Pathological Changes Give Rise to the Clinical Manifestations?

Most of the signs and symptoms of GO result from local mechanical constraints due to the increased volume of intraorbital tissues. This is in keeping with the cat model of orbitopathy induced by ligation of the superior ophthalmic vein [12].

      Lid retraction, the most common ocular sign, may result from excessive sympathetic activity within Müller’s muscle as well as retraction of the levator muscle.

Proptosis results from the forward push of the globus. The degree of proptosis is correlated more with the volume of orbital fat than with the degree of muscle enlargement [13]. However, proptosis is also conditioned by the resilience of the periorbital fibrous tissue, mainly the sclera. Restriction of the forward displacement of the globus may limit the release of the intraorbital excess pressure and favour compression of the optic nerve with the risk of ischaemia and optic neuropathy. Chemosis and periorbital oedema are signs of inflammation or may result mainly from decreased venous drainage within the orbit due to increased volume of intraorbital tissues [14]. It is less easy to explain the abnormalities in the eye movements. In many but not all cases, restriction in eye ductions appear to strongly parallel the degree of muscle hypertrophy. In late stages, restriction of the eye movements results from the fibrotic changes that affect extraocular muscles. However, none of these account for unilateral or grossly asymmetrical forms of the disease.

      Additional manifestations may worsen the clinical presentation:

      •Excessive exposure of the cornea due to lid retraction and/or proptosis, especially in cases of lidlag, may lead to keratitis and, if not treated properly, to a cornea ulcer or even perforation. There is a risk of a central cornea ulcer when the Charles Bell phenomenon is impaired due to restriction of the upper duction.

      •Impairments in vision may result from optic neuropathy. However, an impression of visual impairment may have many other causes: keratitis, photophobia, orbital pain, excessive tearing, mild diplopia and severe lid oedema, which should be recognised as such. Dysthyroid optic neuropathy usually results from the compression of the optic nerve by the enlarged posterior segment of the rectus muscles at the orbital apex. Coronal imaging demonstrates the apical crowding resulting from muscle enlargement and the loss of the perinerve lining. In these cases, surgical decompression or glucocorticoids usually lead to visual recovery. Dysthyroid optic neuropathy may also result from stretching the optic nerve or ischaemia, a mechanism which is difficult to demonstrate.

What Triggers Graves’ Orbitopathy?

      So far, what really triggers GO – and indeed Graves’ hyperthyroidism (GH) itself – is unknown.

      Minimal symptoms/signs of GO are very common in GH as suggested by the presence of mild symptoms upon meticulous clinical examination and orbit imaging as well as the exaggerated increase in intraocular pressure in the upper gaze. However, full-blown GO is present in only 25–50% of the patients with GH.

      Therefore, there are two questions:

      1.What triggers GO?

      2.Why is GO more prominent or severe in some patients than in others?

      GO onset is not related to hyperthyroidism per se as it can precede,

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