Introduction

Anterior uveitis is inflammation involving the anterior uveal tract – the iris and the anterior part (pars plicata) of the ciliary body – and is the most common form of uveitis. Iritis refers to inflammation primarily involving the iris, and iridocyclitis to involvement of both the iris and anterior ciliary body; in practice these are interchangeable as they cannot be distinguished clinically.

Acute anterior uveitis (AAU) is the most common presentation, of which HLA-B27-related and idiopathic forms make up the largest proportion. Aetiology in these cases is uncertain, but may involve cross-reactivity with particular microbial antigens in genetically predisposed individuals. AAU can be a feature of a wide variety of ocular conditions such as trauma (including surgery), lens-related inflammation and herpes simplex infection, or can be secondary to inflammation elsewhere in the eye, such as bacterial keratitis and scleritis. AAU can also be the presenting clinical scenario, without accompanying intermediate or posterior uveitis, in a range of systemic conditions including chronic inflammatory disorders such as sarcoidosis.

Chronic anterior uveitis (CAU) is less common than AAU. It is more commonly bilateral, and associated systemic disease is more likely. Granulomatous inflammatory signs (see below) are often present.

Surveys of systemic associations of anterior uveitis vary in their findings; Table 11.1 lists important possibilities, but is not exhaustive.

The prognosis is usually good in most idiopathic and HLA-B27-related AAU provided management is adequate. Outcomes are more variable in CAU and in cases where there is an underlying ocular or systemic disorder.

Clinical features

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  Symptoms in AAU consist of the rapid onset of unilateral pain, photophobia, redness and watery discharge, sometimes preceded by mild ocular discomfort for a few days. Blurring of vision is related to severity. As recurrent disease is very common, especially with the idiopathic and HLA-B27-related types, there will often be a history of previous similar episodes. CAU may be of insidious or acute onset, and can be asymptomatic until the development of complications such as cataract.

  
  
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  Visual acuity is variably impaired depending on the severity of inflammation and the presence of complications. It is frequently only mildly reduced in AAU.

  
  
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  ‘Ciliary injection’ (perilimbal injection, ciliary flush or just ‘injection’) is circumcorneal conjunctival hyperaemia with a violaceous (purplish) hue due to involvement of deeper blood vessels ( Fig. 11.2A ), and is typically seen in anterior uveitis of acute onset. Ciliary injection is characteristically absent in some forms of CAU, and occasionally AAU.

  
  

  
  

  
  

  

  
  

  
  

  Signs of acute anterior uveitis. (A) Ciliary injection; (B) miosis; (C) anterior chamber cells in mild anterior uveitis; (D) hypopyon

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Miosis due to pupillary sphincter spasm ( Fig. 11.2B ) predisposes to the formation of posterior synechiae (see below).

  
  
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  Anterior chamber cells ( Fig. 11.2C ) are a dependable indicator of inflammatory activity. Grading (SUN Working Group) is performed by estimating the number of cells in a 1 mm by 1 mm slit beam field, employing adequate light intensity and magnification ( Table 11.2 ). This must be performed before pupillary dilatation, which can lead to shedding of pigment cells into the aqueous. Inflammatory cells are commonly also seen in the anterior vitreous.

  
  
  
  

  Table 11.2

  
  

  Standardization of Uveitis Nomenclature (SUN) Working Group grading of anterior chamber cells (1 mm by 1 mm slit beam)

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Grade	Cells in field
  0	<1
  0.5+	1–5
  1+	6–15
  2+	16–25
  3+	26–50
  4+	>50

   
  
  
  
  
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  Hypopyon ( Fig. 11.2D ) refers to a whitish purulent exudate composed of myriad inflammatory cells in the inferior part of the anterior chamber (AC), forming a horizontal level under the influence of gravity. Hypopyon is common in HLA-B27-associated AAU (see below), when a high fibrin content makes it immobile and slow to absorb. In patients with Behçet disease the hypopyon contains minimal fibrin and so characteristically shifts according to the patient’s head position.

  
  
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  Keratic precipitates (KP) are deposits on the corneal endothelium ( Fig. 11.3A ) composed of inflammatory cells such as lymphocytes, plasma cells and macrophages ( Fig. 11.3B ). They are usually concentrated inferiorly, often in a triangular pattern with the apex pointing up (Arlt triangle) under the influence of gravity and aqueous convection currents; a notable exception is Fuchs uveitis syndrome (FUS), in which they are diffusely distributed. Their characteristics indicate the probable type of uveitis: typically smaller in the non-granulomatous inflammation typical of AAU, and medium to large in (classically chronic) granulomatous inflammation in which cell types may include epithelioid and multinucleated cells. Large greasy-appearing granulomatous KP are said to have a ‘mutton fat’ appearance ( Fig. 11.3C ). KP are small to medium and adopt a star-shaped (‘stellate’ – Fig. 11.3D ) or filamentous morphology in FUS. KP usually resolve as acute inflammation subsides: long-standing non-granulomatous KP may become pigmented; granulomatous KP may become pigmented ( Fig. 11.3E ) and/or assume a ‘ground glass’ appearance. Endothelial dusting by numerous individual cells precedes the formation of true KP aggregates ( Fig. 11.3F ).

  
  

  
  

  
  

  

  
  

  
  

  Keratic precipitates (KP). (A) Highly magnified view of fresh KP in early anterior uveitis; (B) histology showing typical aggregate of inflammatory cells on the corneal endothelium; (C) large ‘mutton fat’ keratic precipitates; (D) stellate KPs in Fuchs uveitis syndrome; (E) old pigmented granulomatous KP; (F) endothelial cellular ‘dusting’ and early KP formation

  
  

  (Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology , Butterworth-Heinemann 2001 – fig. B)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Aqueous flare is haziness of the normally clear fluid in the anterior chamber, reflecting the presence of protein due to breakdown of the blood–aqueous barrier. Based on work in children with juvenile idiopathic arthritis-associated CAU, it is now thought that in most or all patients the presence of flare indicates active inflammation with a resultant higher risk of complications over the longer term. Flare may be graded clinically using a slit lamp to assess the degree of interference with visualization of iris and lens ( Table 11.3 ). When available, laser flare photometry gives greater objectivity.

  
  
  
  

  Table 11.3

  
  

  SUN Working Group slit lamp grading scheme for anterior chamber flare

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Grade	Description
  0	None
  1+	Faint
  2+	Moderate (iris and lens details clear)
  3+	Marked (iris and lens details hazy)
  4+	Intense (fibrin or plastic aqueous)

   
  
  
  
  
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  Fibrinous exudate in the anterior chamber ( Fig. 11.4 ) is common in severe AAU, and as with hypopyon is often seen with HLA-B27-related inflammation.

  
  

  
  

  
  

  

  
  

  
  

  Fibrinous exudate

  
  
  
  
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  Iris nodules : Koeppe nodules are located on the pupillary margin ( Fig. 11.5A ), and may be the site of posterior synechiae formation (see below). They can occur in both granulomatous and non-granulomatous anterior uveitis. Busacca nodules involve the iris stroma ( Figs 11.5B and C ) and are a feature of granulomatous uveitis. Yellowish nodules can develop from dilated iris vessels (roseolae) in syphilitic uveitis. Iris ‘pearls’ may be seen in lepromatous chronic anterior uveitis. Iris crystals (Russell bodies), thought to consist of immunoglobulin deposits, are a rare finding in some cases of chronic uveitis ( Fig. 11.5D ), including FUS.

  
  

  
  

  
  

  

  
  

  
  

  Iris nodules in anterior uveitis. (A) Koeppe nodules in Fuchs uveitis syndrome; (B) Busacca and Koeppe nodules; (C) very large nodule in sarcoid uveitis; (D) iris crystals (Russell bodies) in chronic syphilitic uveitis

  
  

  (Courtesy of C Barry – fig. A; C. Pavesio – figs B and C; S Chen – fig. D)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Posterior synechiae (PS) are inflammatory adhesions between the pupil margin and the anterior lens capsule ( Figs 11.6A and B ), and may be particularly likely to form at the location of a Koeppe nodule. They can develop rapidly, and to prevent their formation initial prophylaxis with a mydriatic agent is routine in all but very mild AAU. Once established, every attempt must be made to break PS ( Fig. 11.6C ) before they become permanent.

  
  

  
  

  
  

  

  
  

  
  

  Posterior synechiae. (A) Adhesions in active acute anterior uveitis; (B) extensive synechiae and pigment on the lens following severe acute anterior uveitis; (C) recently broken synechiae in a patient with HLA-B27-associated acute anterior uveitis

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Iris atrophy may offer useful diagnostic clues. Diffuse stromal atrophy is seen in FUS, and patchy or sectoral atrophy can occur in herpetic uveitis ( Fig. 11.7 ); both patterns may be seen in both simplex and zoster-related inflammation, though the latter is said to more commonly give a sectoral pattern.

  
  

  
  

  
  

  

  
  

  
  

  Extensive iris atrophy following herpes zoster ophthalmicus – predominantly sectoral pattern

  
  

  (Courtesy of C Barry)

  
  
  
  
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  Heterochromia iridis refers to a difference in colour between the iris of the two eyes, best seen in daylight. In the context of uveitis, heterochromia characteristically occurs in FUS; see also Table 11.6 .

  
  
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  Iris neovascularization (rubeosis iridis) can occur, particularly in chronic inflammation. The process tends to be less acute than with a primary vascular cause such as central retinal vein occlusion. Abnormal iris vessels are very common in FUS, but do not cause synechial angle closure. Iris neovascularization may also occur in posterior uveitis, particularly when retinal perfusion is compromised. New iris vessels may be difficult to differentiate from dilated normal vessels (sometimes called ‘pseudorubeosis’); normal vessels course radially in contrast to the irregular distribution of neovascularization. Fluorescein angiography may show leakage from new vessels, though this can also be seen with dilated normal vessels, particularly in the presence of active inflammation.

  
  
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  Intraocular pressure (IOP) may be reduced as the result of impairment of aqueous secretion by the ciliary epithelium, or elevated due to a variety of mechanisms (see ‘Inflammatory glaucoma’ in Chapter 10 ), including therapeutic steroids.

  
  
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  Posterior segment examination should always be performed to detect a masquerading cause of anterior uveitis (e.g. retinal detachment, tumour), primary intermediate or posterior segment inflammation, and complications of anterior uveitis such as cystoid macular oedema.

Investigation

Investigations are often negative, with no clear underlying cause determined in many patients. Rather than performing a battery of screening tests, investigation is tailored to each patient, directed by clinical features. Sometimes a likely cause may be obvious, such as severe anterior uveitis following intraocular surgery when endophthalmitis will lead the differential diagnosis list. In most cases, a careful review for systemic symptoms is essential to detect any clues to underlying disease, with referral to a specialist physician for further assessment where appropriate. Many associations of uveitis can present with a wide range of systemic features.

Investigation is generally not indicated in the following circumstances:

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  A single episode of unilateral mild/moderate (no hypopyon) non-granulomatous AAU with no ocular or systemic suggestion of underlying disease.

  
  
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  Typical clinical features of a specific entity for which investigation is not usually indicated (e.g. FUS).

  
  
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  A systemic diagnosis compatible with the clinical features (e.g. sarcoidosis) has already been confirmed.

Situations in which investigation of anterior uveitis is generally appropriate include:

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  Recurrent AAU.

  
  
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  Severe AAU.

  
  
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  Bilateral AAU.

  
  
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  Anterior uveitis that is persistent, chronic or resistant to treatment.

  
  
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  Granulomatous inflammatory signs (note that granulomatous conditions may give non-granulomatous AAU).

  
  
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  Associated intermediate or posterior uveitis.

  
  
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  Ocular or systemic clinical features suggesting underlying disease.

  
  
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  Some authorities advocate routine syphilis serology for all uveitis patients at first presentation; a history of high-risk sexual behaviour in particular must prompt this.

  
  
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  Repeating targeted previously negative investigations several years later is sometimes fruitful.

The following investigations should be considered:

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  HLA tissue typing (HLA-B27). The major histocompatibility complex (MHC) is a group of genes involved in white cell–antigen interaction and other immune functions, including the encoding of cell surface glycoproteins. In humans the MHC, found on chromosome 6, is called the human leukocyte antigen (HLA) system. HLA typing is used to determine organ transplantation compatibility and can also indicate predisposition to particular diseases. It has conventionally been performed by serological antigen identification, but increasingly involves analysis of DNA. HLA-B27 is a common (e.g. 6–8% of Caucasians in the USA, 0.5% of patients of Japanese ethnic origin) cell surface protein that presents peptides to T cells. The phenotype has a very strong association with acute anterior uveitis, ankylosing spondylitis and some other inflammatory conditions such as reactive arthritis (Reiter syndrome), psoriatic arthritis and arthritis in inflammatory bowel disease. It is present in 50% of patients with AAU who are otherwise fit and well, and 90% of patients with AAU who have an associated spondyloarthropathy, notably ankylosing spondylitis. Many HLA-B27 subtypes have been identified and their significance is subject to ongoing investigation. HLA types associated with ocular inflammatory disease are listed in Table 11.4 . HLA-B27 testing should be performed in any adult or child with recurrent or chronic non-granulomatous anterior uveitis.

  
  
  
  

  Table 11.4

  
  

  Examples of HLA associations with uveitis

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  HLA type	Associated disease
  HLA-B27	Recurrent acute anterior uveitis
  HLA-A29	Birdshot retinochoroidopathy
  HLA-B51 and HLA B5	Behçet syndrome
  HLA-B7 and HLA-DR2	(Presumed) ocular histoplasmosis syndrome
  HLA-DR4	Sympathetic ophthalmitis
  HLA-DR4	Vogt–Koyanagi–Harada syndrome

   
  
  
  
  
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  Syphilis serology

  
  
  
  
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    Treponemal antibody tests such as the ELISA (enzyme-linked immunosorbent assay) are highly sensitive and specific, but take around 3 months to become positive.

    
    
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    Non-specific titratable cardiolipin antibody tests such as the rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) are more commonly positive in early infection, and are used to help monitor disease activity; they become negative over time, typically in treated disease. False-positive results can occur.

    
    
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    Both categories of test should be performed when screening for ocular syphilis.

    
    
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    Clinical features suggesting a diagnosis of syphilis should prompt urgent referral to a physician specializing in infectious or sexually transmitted diseases.

  
  
  
  
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  Serum angiotensin-converting enzyme (ACE) : a non-specific test that indicates the presence of a granulomatous disease such as sarcoidosis, tuberculosis and leprosy. Elevation occurs in up to 80% of patients with acute sarcoidosis but may be normal during remissions. In children serum ACE levels tend to be higher and diagnostically less useful. Vigorous exercise can elevate ACE.

  
  
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  Lysozyme is a group of enzymes found in polymorphonuclear neutrophils and numerous secretions including tears. It has a strong antibacterial action, mediating breakdown of the bacterial cell wall. Serum lysozyme assay is generally slightly less sensitive and specific than serum ACE in the diagnosis of sarcoidosis, but performing both tests may increase sensitivity and specificity.

  
  
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  Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) : acute-phase reactants that are probably of limited value, but may be elevated in a range of systemic inflammatory disorders.

  
  
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  Complete blood count : leukocytosis may raise suspicion of infection and, exceptionally, haematological malignancy. Eosinophilia may occur in parasitic infection.

  
  
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  Lyme disease : serology may be considered, particularly in endemic areas. Serology for other infectious diseases such as brucellosis and leptospirosis can be requested if relevant risk factors are present (e.g. endemic region).

  
  
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  Antinuclear antibody (ANA) : limited use, except in children. In those with juvenile idiopathic arthritis (JIA) its presence is associated with a higher risk of CAU; cases of possible subclinical JIA have been reported in ANA-positive children with CAU.

  
  
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  Antineutrophil cytoplasmic antibody (ANCA) : limited use in anterior uveitis unless associated with scleritis and/or peripheral ulcerative keratitis, when cytoplasmic ANCA (c-ANCA) testing should be considered as evidence of Wegener granulomatosis.

  
  
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  Interferon-gamma release assay (e.g. QuantiFERON-TB Gold™) blood test for tuberculosis.

  
  
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  HIV serology : indicated for selected patients, usually those in whom an opportunistic infection has been diagnosed or is suspected.

  
  
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  Sacroiliac joint X-ray may show evidence of sacroiliitis in ankylosing spondylitis and other seronegative spondyloarthropathies.

  
  
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  Chest X-ray may show evidence of sarcoidosis or tuberculosis; a high level of suspicion for both of these treatable conditions (as well as syphilis) should always be adopted, particularly if inflammation is granulomatous.

  
  
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  Ocular imaging

  
  
  
  
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    B-scan ultrasonography, if the posterior segment view is compromised by very small pupils or opaque media.

    
    
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    Optical coherence tomography (OCT) may reveal posterior segment complications such as cystoid macular oedema and epiretinal membrane.

    
    
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    Fundus autofluorescence (FAF) may demonstrate suspected posterior segment pathology as the lesions of several inflammatory conditions, such as multiple evanescent white dot syndrome (MEWDS), which may give mild anterior chamber inflammation, are often shown more effectively than on clinical examination.

    
    
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    Fluorescein angiography (FA) is useful in some cases of anterior uveitis such as the confirmation or exclusion of suspected posterior segment pathology, e.g. vasculitis, white dot syndromes, or identifying macular ischaemia as the cause of reduced vision if no macular abnormality is visible on OCT.

    
    
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    Indocyanine green angiography (ICGA) is rarely indicated in anterior uveitis, but might be used to look for subtle associated choroidal pathology.

    
    
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    Ultrasound biomicroscopy (UBM) is particularly indicated in cases of hypotony, and may demonstrate pathology such as subtle choroidal effusion, cyclodialysis cleft and cyclitic membrane.

  
  
  
  
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  Aqueous tap : historically rarely performed in anterior uveitis, but viral causes are now recognized as being more frequent than previously realized. Herpesviruses (including cytomegalovirus) and rubella in particular should be considered in clinically suspicious cases, especially unexplained hypertensive uveitis and cases relatively unresponsive to topical steroids. An aqueous humour sample may be sent for polymerase chain reaction (PCR) analysis for evidence of viral genetic material, and for microscopy, culture and antibody assay; PCR may also help to exclude propionibacter infection in chronically inflamed pseudophakic eyes.

  
  
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  Iris biopsy is rarely performed.

  
  
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  Vitreous biopsy tends to be confined to the investigation of obscure posterior segment inflammation and suspected infectious endophthalmitis.

  
  
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  Conjunctival biopsy : sampling of tissue such as a suspected granuloma or infiltrative lesion is occasionally indicated.

  
  
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  Referral to a specialist physician with resultant further investigation. This is vital when systemic disease is suspected. For instance, if respiratory symptoms are present, a chest physician may arrange additional testing such as a high resolution computed tomography (CT) chest scan, a whole-body gallium scan (sarcoidosis), a purified protein derivative skin test for tuberculosis (negative test is a diagnostic indicator in sarcoidosis), and bronchoscopy with lavage/biopsy. Similarly neurological referral may lead to a cranial magnetic resonance imaging (MRI) and lumbar puncture, and gastroenterological referral to endoscopy.

Treatment

For patients with a treatable cause of inflammation such as an infection, specific treatment (see individual topics) is given either instead of or in addition to the general anti-inflammatory measures discussed below. Review frequency is set according to the severity and chronicity of inflammation; patients with severe inflammation may need to be seen within a day or two of initiating treatment. Those with mild recurrent idiopathic AAU may not need to be seen for several weeks after treatment is commenced.

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  Topical steroids

  
  
  
  
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    Prednisolone 1% or dexamethasone 0.1% is commonly utilized as a first choice. Other preparations, of varying availability geographically, include difluprednate 0.05% (may be administered at a lower frequency), loteprednol etabonate 0.2% and 0.5% (moderate to marked potency but a lower tendency to elevate IOP), betamethasone, prednisolone 0.5%, fluorometholone and rimexolone; the latter three are of moderate to lower potency. The selection of topical steroid preparation can be modified according to severity and other factors such as a known tendency to IOP elevation. Steroid ointment (e.g. betamethasone) may be instilled at bedtime to supplement the drops. Additional anti-inflammatory treatment (see below) is necessary in some cases.

    
    
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    Treatment of AAU initially involves instillation at a frequency appropriate to the severity of inflammation, typically starting with one drop hourly in moderate to severe cases. Once the inflammation is controlled the instillation frequency should be carefully tapered; a commonly adopted regimen might consist of:

    
    
    
    
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      one drop hourly for 3 days, then

      
      
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      every two hours for 3 days, then

      
      
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      four times a day for 1 week, then

      
      
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      three times a day for 1 week, then

      
      
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      twice a day for 1 week, then

      
      
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      once a day for 1 week and stop; treatment is often discontinued by 5–6 weeks.

    
    
    
    
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    Periodic review is undertaken as appropriate during the treatment course, with further assessment a week or two after cessation, following which the patient can be discharged but cautioned to re-attend urgently should symptoms recur.

    
    
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    Treatment of CAU is generally targeted at complete suppression of inflammation, with no anterior chamber cellular activity or flare – the latter is now thought to be an indicator of active inflammation in most or all cases. Even low-grade ongoing activity is associated with a greater incidence of complications that outweighs the risk of complications from treatment. Exacerbations are initially treated in the same way as AAU, though with more gradual tapering and typically a maintenance regimen; Fuchs uveitis syndrome is an exception to this approach.

    
    
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    Common complications of topical steroids include transient elevation of IOP in susceptible individuals (‘steroid responders’); long-term treatment may lead to permanent IOP elevation with glaucomatous damage. Cataract can be induced, but is less common than with systemic steroid administration; the risk increases with dose and duration of therapy. Corneal complications are uncommon; they include secondary infection with bacteria and fungi, recrudescence of herpes simplex keratitis, and corneal melting. Systemic side effects are rare with topical steroids, but may occur following prolonged administration, particularly in children, in whom measures to reduce systemic absorption such as medial canthal pressure and blotting away of overspill from the eyelids following instillation should be discussed.

  
  
  
  
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  Cycloplegic agents. These are used in AAU and in exacerbations of CAU to prevent the formation of posterior synechiae (PS), to break down recently formed synechiae and to promote comfort by relieving spasm of the pupillary and ciliary muscle. Commonly used anticholinergic agents in order of increasing potency and duration of action include cyclopentolate (duration 12–24 hours), homatropine and atropine (10–14 days). In the acute stage, phenylephrine 2.5% or 10% may be used to supplement anticholinergics and break PS. In mild or chronic anterior uveitis, a cycloplegic can be instilled at bedtime to prevent difficulties with accommodation during the day. In children, care should be taken to avoid systemic toxicity; a range of systemic adverse effects have occurred including seizures. Prolonged uniocular cycloplegia may induce amblyopia in the susceptible age group.

  
  
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  Mydricaine® No. 2. This is a preparation containing adrenaline and atropine that is used to try to break fresh PS when drops are ineffective; it also contains local anaesthetic to improve comfort. Constituent quantities vary according to manufacturer but 0.3 ml containing 0.12 mg adrenaline, 1 mg atropine and 6 mg procaine is typical. It is usually administered by subconjunctival injection; division between the four conjunctival quadrants may enhance the effect. An alternative to injection is insertion of a cotton pledget soaked in Mydricaine into the superior and inferior fornices for 5 minutes. Serious cardiovascular events have been reported following injection (a transient sinus tachycardia is common), and the patient should be monitored after injection. Mydricaine No. 1 is a paediatric version that may also be effective in adults.

  
  
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  Tissue plasminogen activator (TPA). In severe fibrinous anterior uveitis 12.5–25 µg of TPA in 0.1 ml injected into the anterior chamber (intracamerally) with a 30-gauge needle under topical anaesthesia will dissolve dense fibrinous exudate and may break down recently formed PS. Antiseptic precautions similar to those for intravitreal injection should be taken.

  
  
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  Subconjunctival steroid can be administered in severe cases or to patients in whom poor compliance is likely. For example, betamethasone sodium phosphate solution (4 mg in 1 ml) can be given alone or in a combined preparation with betamethasone acetate suspension for a sustained effect (e.g. Celestone, 6 mg in 1 ml).

  
  
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  Regional steroid injection. The use of an inferior approach (‘orbital floor’) or posterior sub-Tenon ( Fig. 11.8 ) injection of depot steroid preparations (e.g. triamcinolone acetonide, methylprednisolone acetate) is common in the treatment of posterior segment inflammation, but is generally reserved in anterior uveitis patients for the treatment of cases complicated by cystoid macular oedema (CMO), and for patients noncompliant with topical administration. Periocular injections may also be administered at the time of surgery, and may rarely be used to supplement systemic therapy or when systemic steroids are contraindicated. The peak action is at about four weeks, with a maximum duration of action of around 3 months. Complications include subconjunctival haemorrhage, globe penetration, refractory elevation of IOP (up to 25%), cataract, ptosis, eyelid haemorrhage, eyelid ischaemic necrosis, retrobulbar haemorrhage, subdermal fat atrophy, extraocular muscle paresis, optic nerve injury, retinal and choroidal vascular occlusion and cutaneous hypopigmentation; systemic adverse effects are rare but can occur. Table 11.5 gives injection procedures; there is no clear evidence of the superiority of one route over the other, but advocates suggest there may be a lower risk of ocular perforation, of raised IOP and of ptosis with the orbital floor approach. Utilizing a plastic intravenous cannula via a superior sub-Tenon route has been described and is thought to offer a lower risk of perforation.

  
  

  
  

  
  

  

  
  

  
  

  Posterior sub-Tenon steroid injection

  
  

  (Courtesy of C Pavesio)

  
  
  
  

  Table 11.5

  
  

  Procedure for inferior transseptal and posterior sub-Tenon regional steroid injection

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  

  Route	Technique
  Inferior transseptal (‘orbital floor’) injection	A topical anaesthetic such as tetracaine (amethocaine) is instilled to prevent stinging by the antiseptic agents The skin of the lower eyelid and maxillary area is cleaned with an antiseptic agent such as an alcohol swab or povidone-iodine 5% The vial containing the steroid is shaken 1 ml steroid (triamcinolone acetonide or methylprednisolone acetate 40 mg/ml) is drawn up into a 2 ml syringe and the drawing-up needle replaced with a 25-gauge 5/8 inch (16 mm) needle The patient is asked to maintain gaze straight ahead The needle is inserted through the skin (some practitioners inject via the conjunctiva), at approximately the junction of the outer third and inner two-thirds of the lower orbital rim, entering close to the bony margin whilst clearing the margin itself The needle is slowly advanced tangentially to (or, anatomy permitting, away from) the globe in similar fashion to a peribulbar local anaesthetic block up to the needle hub The skin may be indented to ensure the needle tip is sufficiently posterior to deposit the steroid away from the anterior subconjunctival area The tip may be felt to engage the bony orbital floor, and/or to pierce the orbital septum; as with the superior injection technique, the needle can be moved from side to side to ensure the sclera has not been engaged The plunger is slightly withdrawn and, if no blood enters the syringe, the full 1 ml is slowly injected and the needle carefully withdrawn Special care is required in a patient with a large eye (e.g. myopia) to avoid penetration of the globe
  Posterior sub-Tenon approach	A topical anaesthetic such as tetracaine (amethocaine) is instilled A small cotton pledget impregnated with tetracaine, lidocaine (lignocaine) 2% gel or an alternative is placed into the superior fornix at the site of injection for 2 minutes The vial containing the steroid is shaken 1 ml steroid (triamcinolone acetonide methylprednisolone acetate or 40 mg/ml) is drawn up into a 2 ml syringe and the drawing-up needle replaced with a 25-gauge 5/8 inch (16 mm) needle The patient is asked to look in the direction opposite to the superotemporal injection site The bulbar conjunctiva is penetrated with the tip of the needle, bevel towards the globe, slightly on the bulbar side of the fornix The needle is slowly inserted posteriorly, following the contour of the globe, keeping it as close to the globe as possible. In order not to penetrate the globe accidentally, wide side-to-side motions are made as the needle is being inserted and the limbus watched; movement of the limbus means that the sclera has been engaged When the needle has been advanced to the hub the plunger is slightly withdrawn and, if no blood enters the syringe, the full 1 ml is slowly injected A method utilizing a plastic intravenous cannula introduced via the same route following conjunctival incision and limited blunt dissection has been described

   
  
  
  
  
• •
  

  Intraocular steroids. Intravitreal triamcinolone acetonide (4 mg in 0.1 ml, i.e. one-tenth of the orbital dose) is occasionally used in anterior uveitis for CMO unresponsive to other forms of therapy (see Fig. 13.34E ), and rarely may be considered at the time of intraocular surgery in high risk anterior uveitis patients. Complications include elevation of IOP, cataract, endophthalmitis (sterile or infectious), haemorrhage, retinal detachment and pseudohypopyon ( Fig. 11.9 ). Slow-release intravitreal implants may occasionally be indicated.

  
  

  
  

  
  

  

  
  

  
  

  Pseudohypopyon formed by crystalline steroid following intravitreal triamcinolone injection

  
  

  (Courtesy of S Chen)

  
  
  
  
• •
  

  Systemic steroids are very rarely required for anterior uveitis but may be needed where the response to less aggressive treatment is inadequate. They are sometimes given as a short course prior to intraocular surgery as prophylaxis against worsening inflammation, having the advantage of rapid cessation of effect in comparison with depot peri- or intraocular steroid injection, but have major potential adverse effects.

  
  
• •
  

  Non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and tolmetin may be effective in CAU and can be used long-term under appropriate specialist physician supervision.

  
  
• •
  

  Antimetabolites such as methotrexate are generally not required in the treatment of anterior uveitis, though may be necessary in exceptional patients such as juvenile idiopathic arthritis-associated CAU when other measures fail to control inflammation, or as a steroid-sparing measure.

Introduction

Ankylosing spondylitis (AS) is characterized by inflammation, calcification and finally ossification of ligaments and capsules of joints with resultant bony ankylosis of the axial skeleton. It more commonly affects males, of whom 90% are HLA-B27-positive.

Systemic features

• •
  

  Presentation is commonly in the third to fourth decades with the insidious onset of pain and stiffness in the lower back or buttocks.

  
  
• •
  

  Spondyloarthritis causes progressive limitation of spinal movements; eventually the spine may become fixed in flexion ( Fig. 11.10A ). Spinal stenosis and fractures may occur.

  
  

  
  

  
  

  

  
  

  
  

  Ankylosing spondylitis. (A) Fixed flexion deformity of the spine; (B) sclerosis and bony obliteration of the sacroiliac joints

  
  

  (Courtesy of MA Mir, from Atlas of Clinical Diagnosis , Saunders 2003 – fig. A)

  
  

  
  

  

  
  
  
  
• •
  

  Enthesitis is characterized clinically by inflammation and pain at ligamentous attachments to bone.

  
  
• •
  

  Cardiac complications are rare.

  
  
• •
  

  Radiology of the sacroiliac joints shows juxta-articular osteoporosis in the early stages, followed by sclerosis and bony obliteration of the joint ( Fig. 11.10B ). Calcification of spinal ligaments gives rise to a ‘bamboo spine’. Radiological changes often predate clinical symptoms.

Ocular features

• •
  

  AAU is by far the most common ocular association, and occurs in about 25% of patients with AS; 25% of males with AAU will have AS. Either eye is frequently affected at different times but bilateral simultaneous involvement is rare. There is often no correlation between the severity and activity of eye and joint involvement. Chronicity occurs in a few patients. HLA-B27-positive ankylosing spondylitis patients tend to have worse disease across a range of parameters, including earlier onset and greater intensity of inflammation with an increased frequency of complications.

  
  
• •
  

  Other ocular features include scleritis, episcleritis, keratitis and mechanical ptosis.

Introduction

Reactive arthritis (ReA, also known as Reiter syndrome) is characterized by a triad of non-specific urethritis, conjunctivitis and arthritis. Around 75% of patients are positive for HLA-B27. A range of infective agents can trigger the syndrome, which develops in 1–3% of men after non-specific urethritis, and around 4% of individuals after enteric infections caused by a range of organisms including Shigella , Salmonella and Campylobacter . Chlamydia pneumoniae respiratory infection and others may also precede ReA.

Systemic features

• •
  

  Presentation is with the acute onset of malaise, with fever and dysuria 1–4 weeks after a linked infection in a patient aged between 20 and 40, with arthritis that may be preceded by conjunctivitis. A variety of other features may be present, though not always the defining triad.

  
  
• •
  

  Peripheral oligoarthritis is acute, asymmetrical and migratory; 2–4 joints tend to be involved, most commonly the knees, ankles and toes.

  
  
• •
  

  Spondyloarthritis affects about 50% of patients, manifesting with low back pain. This sometimes becomes chronic.

  
  
• •
  

  Enthesitis manifests with plantar fasciitis, Achilles tenosynovitis, bursitis and calcaneal periostitis; reactive bone formation in the latter may result in a calcaneal spur.

  
  
• •
  

  Mucocutaneous lesions include painless mouth ulceration, circinate balanitis and keratoderma blennorrhagica – skin lesions resembling psoriasis – involving the palms and soles ( Fig. 11.11 ).

  
  

  
  

  
  

  

  
  

  
  

  Keratoderma blennorrhagica in reactive arthritis (Reiter syndrome)

  
  
  
  
• •
  

  Genitourinary involvement includes cervicitis, prostatitis and epididymitis.

  
  
• •
  

  Aortitis occurs in 1–2%.

Ocular features

The eye is involved in 50% of cases with a urogenital inciting infection and 75% of enteric ReA syndrome.

• •
  

  Conjunctivitis is very common; it classically follows urethritis but precedes arthritis. The inflammation is usually mild, bilateral and mucopurulent with a papillary and/or follicular reaction. Spontaneous resolution occurs within 7–10 days and treatment is not required. Some patients develop peripheral corneal infiltrates.

  
  
• •
  

  AAU occurs in 20%.

  
  
• •
  

  Episcleritis sometimes occurs.

Introduction

Up to 40% of patients with psoriasis develop arthritis. The arthritis is more common in whites than other racial groups and affects both sexes equally. There is a first-degree family history in 40% or more, and many genetic markers have been identified.

Systemic features

• •
  

  Presentation of psoriatic arthritis is usually in middle age – later than skin features.

  
  
• •
  

  Skin. There are multiple types of psoriasis. Plaque-type, the most common form, is characterized by well-demarcated raised silvery inflamed plaques ( Fig. 11.12A ) on the scalp, trunk, arms and legs. Psoriatic erythroderma features widespread exfoliative skin changes with associated inflammation, and pustular psoriasis inflamed but non-infectious pustules limited or generalized in distribution.

  
  

  
  

  
  

  

  
  

  
  

  Psoriasis. (A) Skin plaques; (B) arthritis and severe nail dystrophy

  
  

  
  

  

  
  
  
  
• •
  

  Nail changes (dystrophy) include pitting, transverse depression and onycholysis ( Fig. 11.12B ).

  
  
• •
  

  Arthritis is typically asymmetrical and involves the distal interphalangeal joints (sausage digits). Some patients develop enthesitis.

Ocular features

AAU occurs in approximately 7%; conjunctivitis, marginal corneal infiltrates and secondary Sjögren syndrome may occur but are uncommon.

Introduction

Fuchs uveitis syndrome (FUS), also known as Fuchs heterochromic iridocyclitis or cyclitis (FHC), is a chronic non-granulomatous condition diagnosed at an average of 40 years old. There is no gender or racial predilection. The cause is uncertain, but there is evidence that implicates the rubella virus. Signs in toxoplasmosis can be similar, and T. gondii has also been suspected as a cause. It is possible that most of the anterior chamber activity is due to blood–aqueous barrier breakdown rather than inflammation.

Clinical features

Detection is often incidental; findings are usually unilateral (90–95%).

• •
  

  Symptoms. Gradual blurring due to cataract is a common presentation, as are persistent floaters; heterochromia (see next) may be noted.

  
  
• •
  

  Heterochromia iridis ( Table 11.6 ) is demonstrated most effectively in daylight; most commonly the affected eye is hypochromic ( Fig. 11.13A ). Its quality is determined by the relative degrees of atrophy of the stroma and posterior pigment epithelium. It may be absent or subtle, particularly in brown eyes. In blue eyes, stromal atrophy allows the posterior pigmented layer to show through and become the dominant pigmentation, so that the eye sometimes becomes hyperchromic.

  
  
  
  

  Table 11.6

  
  

  Causes of heterochromia iridis

  
  

  
  
  
  
  

  Hypochromic Idiopathic congenital Horner syndrome, particularly if congenital Waardenburg syndrome Hyperchromic Unilateral use of a topical prostaglandin analogue for glaucoma Oculodermal melanocytosis (naevus of Ota) Ocular siderosis Diffuse iris naevus or melanoma Sturge–Weber syndrome Hypo- or hyperchromic Fuchs uveitis syndrome Other chronic anterior uveitides

   
  
  

  
  

  
  

  

  
  

  
  

  Fuchs uveitis syndrome. (A) Left hypochromic heterochromia and cataract; (B) diffuse stellate keratic precipitates; (C) Koeppe nodules, stromal atrophy and prominent blood vessels including neovascularization; (D) band-like posterior pigment layer atrophy seen on retroillumination; (E) angle vessels and small peripheral anterior synechiae

  
  

  (Courtesy of C Pavesio – fig. B; C Barry – fig. C)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
• •
  

  Posterior synechiae are absent, except occasionally following cataract surgery.

  
  
• •
  

  Anterior chamber shows faint flare and usually only mild cellular activity, though exacerbations can sometimes be marked. The eye is virtually always white, even during exacerbations.

  
  
• •
  

  Keratic precipitates are characteristically stellate and grey–white in colour; they are located diffusely over the entire corneal endothelium ( Fig. 11.13B and see Fig. 11.3D ).

  
  
• •
  

  Iris nodules (30%) on the pupillary border (Koeppe – Fig. 11.13C and see Fig. 11.5A ) or occasionally in the stroma (Busacca). Tiny crystals (Russell bodies) may be present on the iris surface (see Fig. 11.5D ).

  
  
• •
  

  Iris atrophy is diffuse with loss of crypts; the iris appears smooth, with a prominent sphincter pupillae and sometimes blood vessels (see Fig. 11.13C ); pigment epithelial atrophy can be demonstrated by retroillumination ( Fig. 11.13D ).

  
  
• •
  

  Iris vessels. Fine irregular iris surface vessels (see Fig. 11.13C ) are commonly present.

  
  
• •
  

  Vitritis. Opacities in the anterior gel may be dense.

  
  
• •
  

  Cataract is extremely common; a posterior subcapsular morphology is seen initially.

  
  
• •
  

  Glaucoma is typically a later manifestation but is occasionally advanced at diagnosis. It develops in up to 60% of involved eyes. Several mechanisms are suspected.

  
  
• •
  

  Gonioscopy may show fine radial angle vessels or small irregular peripheral anterior synechiae ( Fig. 11.13E ); the vessels are typically the source of the haemorrhage sometimes seen on incision into the anterior chamber (Amsler sign).

  
  
• •
  

  Fundus : peripheral choroiditis foci/scarring have been reported. There may be an increased incidence of retinal dialysis. Macular oedema essentially does not occur, except following surgery.

Investigation

Diagnosis is clinical, though investigation may be necessary to exclude alternative conditions.

Treatment

• •
  

  Long-term monitoring is indicated to detect glaucoma and other complications.

  
  
• •
  

  Topical steroids may be used short-term for moderate/severe exacerbations, but are generally not thought to be helpful in the management of chronic low-grade inflammation.

  
  
• •
  

  Cataract surgery carries a higher risk of complications. Poor mydriasis and the possibility of postoperative hyphaema, increased inflammation, worsening of glaucoma control and zonular dehiscence should be taken into account. Preoperative topical or systemic steroids are used by some practitioners.

  
  
• •
  

  Glaucoma can be difficult to control medically. The place of laser trabeculoplasty is undefined, but is probably ineffective if PAS are present. Options include a glaucoma drainage device or trabeculectomy with mitomycin-C enhancement.

  
  
• •
  

  Pars plana vitrectomy may be considered for visually problematic vitreous opacification.

Introduction

Juvenile idiopathic arthritis (JIA) is by far the most common systemic disease associated with childhood anterior uveitis; the prevalence is about 1 : 1000. It is defined as arthritis of unknown aetiology that begins before the age of 16 years and persists for at least 6 weeks; up to 50% of children affected have persistently active disease after 10 years. It may result from exposure to one or more unknown antigens in genetically predisposed individuals.

Clinical features

• •
  

  Arthritis . JIA is classified by the International League of Associations for Rheumatology (ILAR, 2004 revision), according to the extent of joint involvement during the first 6 months:

  
  
  
  
  • ○
    

    Oligoarticular is the most common form. Four or fewer joints are involved, the knees most commonly, followed by the ankles and wrists. Girls are affected five times as often as boys, with a peak age of onset around 2 years. Some patients subsequently develop polyarthritis. About 75% of children are antinuclear antibody (ANA) positive, a strong risk factor for uveitis, which is common, affecting about 20% of children in this group.

    
    
  • ○
    

    Polyarticular (rheumatoid factor negative) affects five or more joints, typically both small and large joints symmetrically. The female : male ratio is about 3 : 1; the disease may commence at any age throughout childhood. Systemic features such as fever and rash may occur but are milder than in the systemic onset form (see below). About 40% of children are ANA-positive. Uveitis occurs in 5–10% of cases.

    
    
  • ○
    

    Polyarticular (rheumatoid factor positive) again affects five or more joints, and may resemble adult rheumatoid arthritis; there is a very low risk of uveitis.

    
    
  • ○
    

    Systemic, also known as Still (Still’s) disease. Systemic features such as fever, episodic erythematous maculopapular rash, lymphadenopathy and hepatosplenomegaly may precede arthritis. The disease occurs with equal frequency in boys and girls and may occur at any age throughout childhood. The majority are negative for ANA, and uveitis is rare.

    
    
  • ○
    

    Enthesitis-related, psoriatic and undifferentiated are three other forms under the ILAR classification; the first two have a relatively high risk of uveitis, risk in the latter is variable but often low.

  
  
  
  
• •
  

  Anterior uveitis is a key cause of morbidity in JIA. It is particularly common in oligoarticular JIA, and relatively frequent in several other types. Progression to blindness has been high in historical data but shows a declining trend in recent years associated with improved screening and management. Arthritis usually antedates the diagnosis of uveitis.

  
  
  
  
  • ○
    

    Presentation. The uveitis of JIA is particularly dangerous because it is invariably asymptomatic and must generally be detected by screening with slit lamp examination. Even during acute exacerbations with +4 aqueous cells, it is rare for patients to complain, although a few report an increase in vitreous floaters. Often uveitis may not be suspected until the parents recognize complications such as strabismus, or an abnormal appearance of the eyeball due to band keratopathy or cataract.

    
    
  • ○
    

    Injection is usually absent even in the presence of severe uveitis.

    
    
  • ○
    

    Inflammation is chronic and non-granulomatous. Both eyes are affected in 70%; when bilateral, the severity of inflammation is usually symmetrical. During acute exacerbations, the entire endothelium shows ‘dusting’ by many hundreds of cells, but hypopyon is absent.

    
    
  • ○
    

    Posterior synechiae are common in long-standing undetected cases.

    
    
  • ○
    

    Band keratopathy and cataract ( Fig. 11.14 ) are extremely common in severe cases.

    
    

    
    

    
    

    

    
    

    
    

    Band keratopathy, posterior synechiae and mature cataract in chronic anterior uveitis associated with juvenile idiopathic arthritis

    
    
    
    
  • ○
    

    Other serious complications include glaucoma (common), amblyopia, maculopathy (cystoid macular oedema, epiretinal membrane), cyclitic membrane and phthisis.

    
    
  • ○
    

    Prognosis. In about 10% the uveitis is mild, with never more than +1 aqueous cells, and persists for less than 12 months. About 15% of patients have one attack lasting less than 4 months, the severity of inflammation varying from +2 to +4 aqueous cells. In 50% of cases, the uveitis is moderate to severe and persists for more than 4 months, and in 25%, the uveitis is very severe, lasts for several years and responds poorly to treatment. The presence of complications at initial examination appears to be an important risk factor for the development of subsequent complications, regardless of therapy.

  
  

Investigation

• •
  

  Systemic diagnosis and management should be performed by a physician familiar with the management of JIA, typically a paediatric rheumatologist.

  
  
• •
  

  Antinuclear antibody (ANA). Positivity denotes an increased risk of uveitis.

  
  
• •
  

  HLA-B27 testing is useful in differential diagnosis (see above) and if present may indicate an increased risk of uveitis.

  
  
• •
  

  Rheumatoid factor. is also useful in differential diagnosis.

  
  
• •
  

  Screening. There has been a shift in recommendation towards long-term 3–4 monthly review intervals in all higher-risk categories. Review should continue in most cases until the age of 12 years.

  
  
  
  
  • ○
    

    Initial examination within 6 weeks of first diagnosis of JIA. Delayed early examination is an important cause of morbidity.

    
    
  • ○
    

    Visual symptoms or a suspicion of ocular signs (synechiae, cataract, band keratopathy) should lead to urgent ophthalmological referral and slit lamp examination within a week.

    
    
  • ○
    

    Initial 2-monthly examinations for 6 months may be considered for all newly diagnosed oligoarticular, psoriatic, polyarticular and enthesitis-related patients, regardless of ANA status, followed by 3–4 monthly intervals.

    
    
  • ○
    

    Polyarticular: every 3–4 months; some guidelines reduce the interval to 6-monthly after a number of years. Higher-risk factors that might be taken into account in deciding whether to alter the interval include the presence of ANA, onset before 7 years of age and female gender.

    
    
  • ○
    

    Systemic onset and polyarticular RF-positive patients: most authorities recommend at least an initial screening examination, with some guidelines suggesting annual review.

    
    
  • ○
    

    Missed appointments must be effectively detected and patients rebooked.

    
    
  • ○
    

    Information for parents should include an emphasis on the importance of compliance with screening, as well as the need to seek urgent advice should there be any cause for concern such as visual symptoms, ocular redness or clouding, or abnormal pupils.

    
    
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    Self-monitoring. At eventual discharge from screening, patients should be warned to self-monitor by checking the monocular vision at least once a week; the risk of uveitis has not entirely disappeared by this age. They should also attend an optometrist annually for an eye examination. Selected patients such as those with learning difficulties may require ongoing ophthalmological screening.

  
  
  
  
• •
  

  Differential diagnosis : investigations as appropriate. Particular considerations in children include:

  
  
  
  
  • ○
    

    Idiopathic juvenile chronic iridocyclitis: otherwise healthy patients with juvenile CAU; also generally asymptomatic until complications occur.

    
    
  • ○
    

    Other types of juvenile arthritis and uveitis including juvenile reactive arthritis, juvenile inflammatory bowel disease-associated arthritis.

    
    
  • ○
    

    Juvenile sarcoidosis: rare; pulmonary involvement is less common than in adults; may be granulomatous and involve the posterior segment.

    
    
  • ○
    

    Lyme disease usually presents with intermediate uveitis in conjunction with significant anterior uveitis.

    
    
  • ○
    

    Intermediate uveitis: 20% of all cases of paediatric uveitis.

    
    
  • ○
    

    Neonatal-onset multisystem inflammatory disease is a rare, idiopathic, chronic relapsing disease that predominantly involves the skin, joints and the central nervous system. About 50% of children develop recurrent anterior uveitis. The absence of posterior synechiae and no tendency to glaucoma and cataract formation are characteristic.

    
    
  • ○
    

    Masquerade syndromes such as anterior segment involvement by retinoblastoma.

    
    
  • ○
    

    Familial juvenile systemic granulomatosis (Blau syndrome), is a rare autosomal dominant disorder characterized by childhood onset of granulomatous disease of skin (panuveitis and multifocal choroiditis), eyes and joints.

  
  

Treatment

The aim of treatment should be the suppression of all active inflammation.

• •
  

  Topical steroids are effective in most cases (80%); acute exacerbations require very frequent instillation.

  
  
• •
  

  Mydriatic agents may be required for exacerbations to prevent synechiae formation. A relatively short-acting preparation such as cyclopentolate should be used and discontinued as early as possible, particularly in monocular treatment of younger children susceptible to the development of amblyopia.

  
  
• •
  

  Periocular steroids.

  
  
• •
  

  Oral steroids.

  
  
• •
  

  Non-steroidal anti-inflammatory drugs (NSAIDs).

  
  
• •
  

  Systemic immunosuppressive agents will be required in resistant cases (e.g. methotrexate, infliximab, adalimumab, ciclosporin) and should be managed by a specialist ophthalmologist, typically in collaboration with a paediatric rheumatologist. Doses required are often low.

Introduction

Ulcerative colitis (UC) is an idiopathic chronic relapsing inflammatory disease, involving the rectum and extending proximally to involve part or all of the large intestine. The disease is characterized by contiguous surface ulceration of the bowel mucosa with the development of crypt abscesses and pseudopolyps ( Fig. 11.15A ). Long-standing disease carries an increased risk of carcinoma of the colon. A genetic predisposition is thought to be important; inflammatory bowel disease is more common in patients with other autoimmune diseases such as ankylosing spondylitis, psoriasis and multiple sclerosis.

Ulcerative colitis. (A) Barium enema shows pseudopolyposis, lack of haustral markings and straightening of the ascending colon; (B) pyoderma gangrenosum

Systemic features

• •
  

  Presentation is in the second to third decades with bloody diarrhoea, lower abdominal cramps, urgency and tenesmus. Constitutional symptoms include tiredness, weight loss, malaise and fever.

  
  
• •
  

  Cutaneous lesions include oral aphthous ulceration, erythema nodosum and pyoderma gangrenosum ( Fig. 11.15B ).

  
  
• •
  

  Arthritis is typically asymmetrical and involves large joints of the legs; sacroiliitis and ankylosing spondylitis (AS) may develop in HLA-B27-positive patients.

  
  
• •
  

  Hepatic disease may be in the form of autoimmune hepatitis, sclerosing cholangitis and cholangiocarcinoma.

  
  
• •
  

  Thrombosis may affect both arteries and veins.

Ocular features

• •
  

  AAU occurs in about 5% and may coincide with exacerbations of colitis. As expected, uveitis is more common in patients with associated arthritis, AS and HLA-B27 positivity.

  
  
• •
  

  Other ocular features : conjunctivitis, episcleritis and scleritis may all be more common than in the general population.

Introduction

Crohn disease (CD) is an idiopathic chronic relapsing disease characterized by multifocal full-thickness granulomatous inflammation of the intestinal wall. It most frequently involves the terminal ileum and colon but in contrast to UC any area of the gastrointestinal tract, including the mouth, may be affected. There is strong evidence for a genetic aetiological component such as mutations in the CARD15 (previously NOD2 ) gene. Infective agents almost certainly play a role.

Systemic features

• •
  

  Presentation is typically in the second–third decades with abdominal pain and diarrhoea. Weight loss, fever, vomiting, oral aphthous ulceration and perirectal lesions such as abscesses and fistulae may occur.

  
  
• •
  

  Cutaneous lesions include erythema nodosum and pyoderma gangrenosum (see Fig. 11.15B ).

  
  
• •
  

  Anaemia is common.

  
  
• •
  

  Hepatic disease may occur.

  
  
• •
  

  Skeletal features include finger clubbing, acute peripheral arthritis, sacroiliitis and ankylosing spondylitis (especially if HLA-B27-positive).

Ocular features

AAU occurs in about 3%; dry eye, conjunctivitis and scleritis may be more common than in the general population.

Introduction

Whipple disease (intestinal lipodystrophy) is a rare chronic gastro­intestinal inflammatory condition caused by infection with the bacterium Tropheryma whipplei . It occurs mainly in white middle-aged men and when diagnosed (duodenal biopsy; DNA detection in blood, ocular and other fluids) can be cured with antibiotics.

Systemic features

Inflammatory bowel disease with malabsorption; joint, cardiac and central nervous system (CNS) involvement is common.

Ocular features

• •
  

  Uveitis. Keratitis, anterior uveitis , vitritis, retinitis with retinal haemorrhages, cotton-wool spots and potentially vascular occlusion, and multifocal choroiditis.

  
  
• •
  

  Neuro-ophthalmic manifestations can be varied, e.g. gaze palsy, nystagmus, ophthalmoplegia, papilloedema and optic atrophy. Oculomasticatory myorhythmia is characteristic.

Introduction

Tubulointerstitial nephritis and uveitis (TINU) is an uncommon disorder of immune origin characterized by a combination of acute tubulointerstitial nephritis and uveitis. It typically occurs in adolescent girls; renal disease usually precedes uveitis.

Systemic features

Presentation is with constitutional symptoms, proteinuria, anaemia, hypertension and renal failure. The response to systemic steroid therapy is good and renal function usually returns to normal within a few months without complication.

Ocular features

• •
  

  Bilateral non-granulomatous (occasionally granulomatous) anterior uveitis that usually responds well to topical steroids. Disc and macular oedema may occur. Many cases are relapsing and some require systemic steroids or immunosuppressive therapy.

  
  
• •
  

  Intermediate, posterior or panuveitis may occur.

Introduction

Intermediate uveitis (IU) is a chronic, relapsing disease of insidious onset in which, according to the SUN Working Group, the vitreous is the primary site of inflammation as determined clinically. It incorporates pars planitis, posterior cyclitis and hyalitis. The diagnosis is essentially clinical; IU may be idiopathic (at least half) or associated with a systemic disease, and systemic investigations are routinely performed, especially in the presence of suggestive findings and/or in older individuals. Pars planitis (PP) is the term used for a subset of IU in which there is snowbanking and/or snowball formation (see below), but only if the inflammation is idiopathic – that is, with no identifiable underlying infection or systemic disease – otherwise the term intermediate uveitis is reverted to. IU accounts for up to 15% of all uveitis cases and about 20% of paediatric uveitis. A minority of patients have a benign course, with spontaneous resolution within several years. In other patients the disease is more severe and prolonged with episodic exacerbations. IU associated with systemic disease has a variable course.

Clinical features

• •
  

  Symptoms. Presentation is with the insidious onset of blurred vision, often accompanied by vitreous floaters; there is usually no pain or redness. Though initial symptoms are often unilateral, objective findings are typically present asymmetrically in both eyes.

  
  
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  Visual acuity is variably affected depending on inflammatory activity and complications, particularly CMO. The disease may last as long as 15 years and preservation of vision will depend largely on control of macular disease. In follow-up of up to 4 years, 75% of patients maintain a visual acuity of 6/12 or better.

  
  
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  Anterior uveitis. In PP there may be a few cells and small scattered KP which occasionally have an inferior linear distribution. In other forms of IU, anterior uveitis and its associated findings such as PS can be more prominent, especially in children, and in sarcoidosis and Lyme disease.

  
  
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  Vitreous. Vitreous cells with anterior predominance ( Fig. 11.16A ) are universal, with vitreous condensation and haze ( Table 11.7 ) in more severe cases ( Fig. 11.16B ). Snowballs are whitish focal collections of inflammatory cells and exudate, usually most numerous in the inferior vitreous ( Fig. 11.17A ).

  
  

  
  

  
  

  

  
  

  
  

  Vitreous inflammatory activity. (A) Mild; (B) severe

  
  

  
  

  

  
  
  
  

  Table 11.7

  
  

  Grading of vitreous haze

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Haze severity	Grading
  Good view of nerve fibre layer (NFL)	0
  Clear disc and vessels but hazy NFL	+1
  Disc and vessels hazy	+2
  Only disc visible	+3
  Disc not visible	+4

   
  
  

  
  

  
  

  

  
  

  
  

  Intermediate uveitis. (A) Snowballs; (B) peripheral periphlebitis and snowballs; (C) inferior snowbanking and snowballs

  
  

  (Courtesy of CL Schepens, ME Hartnett and T Hirose, from Schepens’ Retinal Detachment and Allied Diseases , Butterworth-Heinemann, 2000 – fig. B)

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Peripheral periphlebitis ( Fig. 11.17B ) is common, particularly in MS. Careful examination of a normal fellow eye in apparently unilateral disease may reveal mild vascular sheathing.

  
  
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  Snowbanking ( Figs 11.17C ) is characterized by a grey–white fibrovascular and/or exudative plaque that may occur in any or all quadrants, but is most frequently found inferiorly.

  
  
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  Neovascularization may occur, particularly in the retinal periphery (often associated with snowbanks) and on the optic nerve head; the latter usually resolves when activity is controlled. This can sometimes lead to vitreous haemorrhage, retinal detachment and cyclitic membrane formation. Focal peripheral retinal vasoproliferative tumours (see Ch. 12 ) are uncommon. Vitreous haemorrhage is more common in children.

  
  
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  Optic disc swelling is common, especially in younger patients.

  
  
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  CMO occurs in up to half of patients and is the major cause of impaired visual acuity.

  
  
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  Macular epiretinal membrane formation is common.

  
  
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  Cataract can be caused by steroid treatment or by the inflammation itself; both are probably contributory in the majority of patients.

  
  
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  Glaucoma may occur in eyes with prolonged inflammation, particularly if receiving long-term steroid therapy.

  
  
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  Retinal detachment is generally uncommon, but as it can progress to hypotony and phthisis in advanced cases, prevention should be a major goal of management. The aetiology may be tractional, rhegmatogenous and occasionally exudative. Retinoschisis has also been described.

Investigation

Inflammatory markers such as ESR and/or CRP should be checked, together with a complete blood count, as they may raise suspicion of a systemic inflammatory process. OCT is key to excluding subtle CMO, and FA will help in assessing severity. Other investigations are targeted at the exclusion of an underlying cause as below.

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  Multiple sclerosis. Enquiry should be made in all patients about neurological symptoms, noting that IU may precede other symptoms of demyelination. MS should be suspected in patients aged 20–50; it is twice as common in women. Granulomatous AAU may occur. Cranial MRI imaging should be performed if any suspicion is raised.

  
  
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  Sarcoidosis. A review of systems should include respiratory function. Sarcoid-associated IU is relatively uncommon and as with MS may antedate the onset of systemic disease. The presence of associated granulomatous anterior uveitis should arouse suspicion. A serum ACE level and chest X-ray should be performed in all adult patients.

  
  
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  Lyme disease-associated IU is often associated with severe anterior uveitis. Serology should be performed if residence in or a visit to an endemic area is elicited.

  
  
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  Syphilis serology – treponemal and cardiolipin antibody tests – should be performed.

  
  
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  Tuberculosis is an uncommon association that may give respiratory symptoms and be demonstrated on chest X-ray. Tuberculin skin and/or blood (e.g. QuantiFERON™) testing should be performed prior to steroid treatment in the presence of any suspicion.

  
  
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  Other conditions that may give vitritis mimicking IU include Fuchs uveitis syndrome, intraocular lymphoma (older patients), Toxocara granuloma, Whipple disease, endogenous Candida endophthalmitis (risk factors such as IV drug use) and toxoplasmosis. These will commonly be suspected on the basis of the history and specific clinical findings.

Treatment

An identified infection or other underlying disease should be treated specifically, supplemented by anti-inflammatory measures below as appropriate. Many authorities aim to abolish all active inflammation regardless of whether vision has been affected; factors such as the presence of peripheral neovascularization may prompt earlier intervention.

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  Topical steroids do not reach the posterior segment in high concentrations so have only a limited role, and are used principally to treat any anterior uveitic component. It has been proposed that in mild intermediate uveitis a course of frequent topical steroid of a few weeks’ duration may exert some benefit and identify individuals at high risk of IOP elevation without committing to the extended action of depot injection.

  
  
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  Regional steroid injection. Orbital floor or posterior sub-Tenon injection as described for anterior uveitis. Depending on severity, injection is performed 4–6 times at intervals of 2–4 weeks, accompanied by careful IOP monitoring.

  
  
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  NSAID. If inflammation persists after regional injection, an agent such as naproxen 500 mg twice daily can be commenced.

  
  
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  Cryotherapy (double freeze–thaw) to the pars plana and retinal periphery under peribulbar anaesthesia can be highly effective if inflammation is steroid-resistant, and may be appropriate prior to systemic steroids. It can be associated with transiently increased vitritis and other complications including retinal detachment, cataract, vitreous and anterior chamber haemorrhage, epiretinal membrane formation and hypotony. A repeat application may be needed after several months. Some authorities reserve cryotherapy for peripheral neovascularization with haemorrhage.

  
  
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  Peripheral retinal laser adjacent to snowbanking and/or to ischaemic areas on FA is an alternative to cryotherapy, and may be as effective with a lower rate of complications.

  
  
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  Intraocular steroid. Intravitreal triamcinolone has shown benefit, but the effect is of relatively short duration. Slow-release implants have demonstrated promising results.

  
  
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  Systemic steroids. This modality is preferred over regional steroid by some practitioners if symptomatic inflammation is bilateral, though others prefer to avoid systemic steroids in most cases, proceeding directly to immunosuppressive chemotherapeutic agents. A large dose of 1–2 mg/kg/day is commenced, tapered slowly over months according to response. Familiarity with precautions to be taken, contraindications to and potential adverse effects of steroids is essential before prescribing; optimally steroids should be prescribed in conjunction with a specialist physician, such as a rheumatologist.

  
  
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  Immunosuppressive agents. Mycophenolate, methotrexate, tacrolimus, ciclosporin and others are alternatives in steroid-resistant inflammation or as steroid-sparing agents. One or more of these may be available as local sustained-release preparations in the near future.

  
  
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  Other agents demonstrating efficacy in refractory and other patients include interferon-beta (in MS-related IU), the anti-tumour necrosis factor infliximab, intravitreal bevacizumab and others.

  
  
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  Pars plana vitrectomy typically substantially reduces inflammatory intensity and recurrence, though the mechanism is imperfectly understood. It may be particularly indicated in patients with tractional retinal detachment, epiretinal membrane, refractory CMO, dense vitreous opacity, vitreous haemorrhage or substantial peripheral neovascularization.

  
  
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  Cataract and glaucoma are managed medically and surgically as indicated.