Dov Hersh
Dr. Dov Hersh is an oculoplastic and ophthalmic surgeon based in Sydney, Australia. Dr Hersh undertook his comprehensive ophthalmic training at Sydney Eye Hospital and advanced oculoplastics subspecialty training at Bristol and Moorfields Eye Hospitals, UK. Dr Hersh is a clinical associate lecturer at Sydney University, Australia, and is an accredited investigator in a number of multinational oculoplastic clinical trials studying novel treatments for orbital inflammatory and thyroid eye disease. Prior to his medical career, Dr Hersh gained a B Com, specializing in IT. He has established telemedicine projects in developing countries.
Geoffrey E. Rose
Geoffrey Rose graduated BSc Pharmacology, MBBS, and MRCP. His postgraduate ophthalmic training culminated in award of FRCS in 1985 and FRCOphth at its foundation in 1988. In 1990, the University of London granted an MS doctorate for corneal research and, in 2004, a Doctor of Science in Ophthalmology and Ophthalmic Surgery.
Professor Rose was appointed consultant to Moorfields Eye Hospital, London, in 1990 and is also a Senior Research Fellow of the NIHR Biomedical Research Centre of the Institute of Ophthalmology. He served as the British Council member of the European Society of Ophthalmic Plastic and Reconstructive, is a Past-President of the British Oculoplastic Surgical Society, and is President of the European Society of Oculoplastic and Reconstructive Surgeons.
Idiopathic orbital inflammatory disease (IOID) is, realistically, an open-ended non-diagnosis in which a definite cause has not been found for the inflammation. The perceptive physician should, however, be aware that “inflammation is a tissue response and not a diagnosis”, and that orbital inflammation can occur alongside almost any pathological process – such as ischemia, exposure to noxious substances (e.g. foreign bodies, or keratin from dermoid cysts), infections or malignancies. Irrespective of the underlying aetiology, inflammation will show a clinical improvement with systemic steroids, and it is therefore unwise to regard a “steroid response” as a diagnostic confirmation of IOID [1].
Inflammation accounts for about 5 % of orbital disease, affects all ages, and is a frequent reason for orbital biopsy [2]. Although “benign” on histopathological grounds, orbital inflammatory disease (OID) may have a clinically aggressive course that can endanger the globe, extraocular muscles and optic nerve. OIDs may be solely orbital, with no identified systemic abnormalities (termed “idiopathic OID”, IOID), or associated with systemic inflammatory or sclerosing diseases, such as sarcoidosis or IgG4 sclerosing disease. IOID is an “umbrella” term commonly used to encompass dacryoadenitis, myositis and diffuse orbital soft-tissue inflammation for which no cause is found and, as our understanding of the mechanisms of inflammation improves, it is likely that the number of “idiopathic” presentations will decline.
The “classic” presentations of dacryoadenitis, myositis and diffuse OID are not mutually exclusive, and they can have significant overlap, as well as the inflammation spilling over to include scleritis or uveitis – particularly when associated with a systemic inflammatory disorder. OID can present in a hyperacute fashion (e.g. acute myositis) or as a subacute or chronic process. By taking a thorough history, particularly the temporal sequence of symptoms in relation to the patient’s age, a tailored list of differential diagnosis for the OID can be formed; the differential diagnosis should further guide the clinical examination and relevant investigations, this often including biopsy (and sometimes re-biopsy) to assist the clinician in reaching a likely diagnosis and detecting threat to life or vision.
Several conditions may present with OID (Table 27.1), and it is imperative to exclude these before assigning a diagnosis of presumed IOID; “IOID” should always be considered as a temporary diagnosis. The astute physician will repeatedly reconsider the “non-diagnosis” (of IOID) and remain vigilant for later development of an orbital or systemic cause – particularly if the condition worsens during or after treatment.
Table 27.1
Various orbital conditions that may present with orbital inflammation
Orbital inflammatory disease associated with systemic inflammatory conditions |
Thyroid-associated eye disease |
Neoplasms |
Lymphoma and other lymphoproliferative disorders |
Rhabdomyosarcoma |
Choroidal malignant melanoma with extrascleral spread |
Metastatic disease |
Congenital malformations |
Dermoid cyst |
Lymphangioma |
Carotico-cavernous fistula |
Histiocytosis |
Langerhans cell histiocytosis |
Erdheim–Chester syndrome |
Infectious diseases |
Bacterial orbital cellulitis |
Tuberculosis |
Syphilis |
Viral disease |
Primary infection (e.g. mumps dacryoadenitis) |
Secondary reactivation (e.g. herpes zoster) |
Trauma and/or occult orbital foreign body |
Systemic Inflammatory Conditions Associated with Orbital Inflammation
Several systemic inflammatory disorders have been associated with OID (Table 27.2), and the importance of detecting a systemic association is threefold. Firstly, if screening tests reveal an underlying systemic inflammatory disorder, it might be important to check for associated structural disease (e.g. retroperitoneal fibrosis in IgG4 disease). Secondly, OID associated with certain systemic inflammatory markers (ANCA-associated vasculitis being one such condition) can have a more protracted course and will often require more aggressive treatment for disease control [3]. Thirdly, development of novel biological agents (e.g. rituximab and anti-TNFα drugs) increases the prospect of targeted immunosuppression for specific diseases; clinical immunologists and rheumatologists have a leading role in exploring targeted treatments for systemic inflammation, and this work appears to be applicable to OID with underlying systemic aetiology – an example being the use of rituximab in the treatment of systemic ANCA-associated vasculitis [4].
Table 27.2
Systemic associations of orbital inflammatory disease
Sarcoidosis |
ANCA-associated vasculitis |
IgG4-related disease |
Systemic lupus erythematosus |
Crohn’s disease |
Churg–Strauss syndrome |
Polyarteritis nodosa |
Scleroderma |
Sarcoidosis is a chronic multisystem granulomatous inflammation that mainly affects the respiratory tract, skin and eyes, and the histopathology is characterised by non-caseating compact granulomas, asteroid bodies and Schaumann bodies. It is commoner in women and Afro-Caribbean people, with ocular involvement in up to a half of patients [5]. The commonest systemic manifestation is hilar lymphadenopathy and pulmonary fibrosis. Ophthalmic involvement includes conjunctival nodules, uveitis, chronic dacryoadenitis or more rarely optic neuropathy, myositis or fat infiltration. Skin disease may present as erythema nodosum, and much rarer manifestations include neurosarcoid and uveoparotid fever. Prior to treatment, serum angiotensin-converting enzyme (ACE) titres and calcium may be raised.
ANCA-associated vasculitis or granulomatous polyangiitis (previously known as Wegener’s granulomatosis) is a necrotising granulomatous inflammation affecting predominantly small vessels. Typically the upper airway, lungs and kidneys are most affected, but periocular disease may affect a half of patients, and there can be a form of disease limited only to the eyes and/or orbit. Ophthalmic manifestations include conjunctivitis, scleritis, keratitis and retinal vasculitis, and the orbital disease can include aggressively fibrosing OID, dacryoadenitis, myositis or nasolacrimal duct obstruction. Tissues with significant disease activity usually display zonal granulomas, vasculitis and fibrinoid necrosis. Antibodies against proteinase 3 (PR3) or c-ANCA antibodies are highly (90 %) sensitive and specific for disseminated disease, but are positive in only about one-third of those with solely ophthalmic disease. With systemic involvement, ANCA-associated vasculitis has a significant morbidity and mortality and should be treated aggressively using a multidisciplinary approach [3].
Immunoglobulin G4-related disease (IgG4-RD) is a recently recognised systemic inflammatory disorder with diffuse tissue infiltration by IgG4-positive plasma cells on a background of fibrosis; elevated serum concentrations of IgG4 are also found in 60–70 % of patients. IgG4-RD has been linked to autoimmune pancreatitis, Mikulicz’s disease, hepatic inflammatory pseudotumours, tubulo-interstitial nephritis, interstitial lung disease, retroperitoneal fibrosis and Hashimoto’s thyroiditis [6]. Orbital IgG4-RD manifest mainly as sclerosing dacryoadenitis that may be bilateral, or as a more diffuse inflammation; the tissues show widespread IgG4-positive plasma cells, dense fibrosis and, for the lacrimal gland, loss of acini. Certain forms of IgG4-RD – for example, pancreatitis or sclerosing cholangitis – have been associated with a higher incidence of non-Hodgkin’s lymphoma: to date there is no clear evidence linking orbital IgG4-RD and periocular lymphoma [7], but physicians should be aware of possible emergence of such a link.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune collagen disease in which various autoantibodies (ENA, ANA) trigger a type 3 hypersensitivity reaction, resulting in occlusive vasculitis and fibrinoid necrosis. Ophthalmic complications include OID, Sjogren’s syndrome, interstitial keratitis, scleritis and occlusive retinal vasculitis, and systemic manifestations include glomerulonephritis, pericarditis, malar rash and constitutional inflammatory symptoms (fevers, arthralgias, fatigue). Serological investigations include anti-nuclear antibodies (ANAs), double-stranded DNA (dsDNA) and extractable nuclear antigens (ENAs) that are all >90 % specific.
Crohn’s disease, a progressive chronic granulomatous enteritis with frequent extra-intestinal complications, is most commonly associated with uveitis, episcleritis or, more rarely, myositis [8]. Patients with orbital myositis should be questioned about persistent gastrointestinal symptoms (diarrhoea, abdominal pain/cramping or faecal blood and mucus) and about any family history of Crohn’s disease.
Churg–Strauss syndrome is a necrotising vasculitis with asthma, hypereosinophilia and multisystem vasculitis. Complications include myocarditis, coronary arteritis, granulomatous pneumonia, gastroenteritis, mononeuritis multiplex and atopy, and ophthalmic involvement include OID, ischemic optic neuropathy and retinal artery occlusion due to vasculitis. Classic histological findings are necrotizing arteritis, eosinophilic infiltration and extravascular granulomas, with laboratory evaluation showing raised serum IgE titre and p-ANCA antibodies. Early institution of therapy can reduce both systemic and ophthalmic complications [9].
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