Classification^[1][2]

The condition can be classified in various ways:

Anatomical

A common classification is by anatomical location of the pathology:

• Anterior uveitis refers to an inflammation of the iris (hence its previous name, still used by many, iritis). It may also be referred to as iridocyclitis (iris + ciliary body involvement) or anterior cyclitis (anterior portion of ciliary body affected) depending on the exact structures involved.
• Intermediate uveitis affects the vitreous and posterior part of the ciliary body; hence, may be called pars planitis, posterior cyclitis or hyalitis, the latter referring to the anterior portion of the vitreous.
• Posterior uveitis describes an inflammation of the choroid which may be referred to as choroiditis or chorioretinitis if the retina is also involved. It may also affect the retinal blood vessels, giving rise to retinal vasculitis. Posterior uveitis is further defined as being focal, multifocal or diffuse, depending on the nature of the inflammatory lesions seen on the fundus.
• Panuveitis indicates inflammation throughout the uveal tract and is an indication of serious disease.

Onset, duration, course^[3]

The onset may be sudden or insidious and the duration is defined as acute when less than three months or chronic when greater than three months. The course can be acute, recurrent (repeated episodes separated by periods of inactivity of ≥3 months' duration) or chronic (relapses occur in <3 months after discontinuing treatment.

Aetiology

This may be classified into:

• Inflammatory - due to autoimmune disease.
• Infectious - caused by known ocular and systemic pathogens.
• Infiltrative - secondary to invasive neoplastic processes (sometimes referred to as masquerade syndromes).
• Injurious - due to trauma.
• Iatrogenic - caused by surgery, inadvertent trauma, or medication (eg rifabutin, cidofovir).^[1]
• Inherited - secondary to metabolic or dystrophic disease.
• Ischaemic - caused by impaired circulation.
• Idiopathic - a category used when thorough evaluation has failed to find an underlying cause.

There are also some ocular syndromes that may give rise to anterior uveitis (eg Posner-Schlossman syndrome, Fuchs' heterochromic cyclitis, Schwartz' syndrome).^[4] Sympathetic ophthalmia (sometimes referred to as sympathetic ophthalmitis or sympathetic uveitis) is a rare form of bilateral panuveitis. It is a specific type of uveitis in response to trauma to one of the eyes. For further information, see separate article Sympathetic Ophthalmia.

Presenting clinical features^[5][6]

A new system based on a number of presenting clinical features is being proposed by the International Uveitis Study Group. These criteria include:

• Location of inflammation.
• Anterior chamber cells.
• Anterior chamber flare.
• Vitreous cells (present or absent).
• Vitreous haze.

Pathophysiology

In many cases - particularly anterior disease - the aetiology of uveitis is idiopathic.^[2] There are a number of situations that can predispose an individual to uveitis (see 'Aetiology', above) and the mechanisms leading to this inflammatory response depend on the underlying trigger. So, for example, trauma may result in a combination of microbial contamination and accumulation of necrotic products at the site of injury, giving rise to inflammation. In autoimmune conditions, the mechanism may be a hypersensitivity reaction involving immune complex deposition within the uveal tract. It is beyond the remit of this record to go into the detailed pathophysiology for each underlying cause of uveitis but you can read more about this in the references.^[7]

Regardless of the aetiology and mechanism leading to the inflammation, the eye's ultimate response is the same, characterised by classic signs seen on slit-lamp examination (see 'Signs', below). These can be summarised as the presence of inflammatory cells in the anterior chamber, vitreous or posteriorly, depending on the location of the inflammatory response. Other pathological changes found in uveitis include:

• Anterior chamber flare - severely inflamed vessels become leaky and protein gets out, so clouding the normally clear aqueous. As the slit-lamp beam of light is shone through this, it appears hazy and the beam is dispersed - hence, the term flare. This is a marker of severe inflammation.
• Synechiae - these are adhesions of the iris to the cornea (anterior synechiae) or to the lens (posterior synechiae) which develop as a result of the inflammatory process.
• Keratic precipitates (KPs) - these are another finding in anterior uveitis: inflammatory cells clump together on the posterior (endothelial) part of the cornea, giving rise to the appearance of little white spots known as keratic precipitates (KPs). When KPs appear large and granular or greasy, the uveitis is said to be granulomatous. This suggests sarcoidosis or tuberculosis as an underlying cause.^[1]
• Retinal lesions - these may develop and may be single, multifocal, disseminated or diffuse. The type or distribution may be a pointer to the aetiology.

Epidemiology

• Uveitis is a relatively common condition; it is thought to account for 10% of blindness in people of working age in the Western world.^[3] The existence of self-resolving forms means that the true incidence is unknown.
• Although uveitis is regarded as a disease of adults of working age (mean: 20-50 years),^[7] an American study found that the incidence of uveitis in the elderly was substantially higher than previously thought. Anterior uveitis, the most common form in this age group, had a mean incidence of 243.6 cases per 100,000 persons per year.^[8]
• The epidemiology of uveitis varies with both age and geographical location.
• Racial predisposition to uveitis is related to the patient's underlying systemic disease (eg HLA-B27 positivity in Caucasians, Behçet's disease in individuals of Mediterranean origin, etc.).
• Acute anterior uveitis is the most common type of uveitis in the UK.^[3]

Presentation^[7]

It is important to take a detailed history and, if the history suggests systemic symptoms, a full physical examination,^[3] as there may be signs relating to one of the many associated systemic diseases.^[4] Immunosuppression is an important fact to note, as these individuals are at particular risk of infection-related uveitis.

Symptoms

• Acute anterior uveitis presents as a progressive (over a few hours/days) unilateral, painful red eye, with blurred vision and photophobia. There may be excess tear production and an accompanying headache is common. Not all of these symptoms may be present at the start of an attack.^[3]
• Chronic anterior uveitis presents as recurrent episodes, with less acute symptoms. Patients may find that one symptom predominates (this tends to be blurred vision) and they tend to get very good at spotting this early.
• Posterior uveitis causes gradual visual loss, usually bilateral, often associated with floaters. There is occasional photophobia, but little or no discomfort or redness.

Some types of uveitis are more insidious and may be asymptomatic (eg that associated with juvenile idiopathic arthritis).^[3]

Signs

Anterior uveitis:

• Visual acuity in the affected eye is often reduced.
• The pupil may be abnormally shaped or of a different size to the unaffected eye.
• Direct photophobia (shining a light directly into the affected eye) and consensual photophobia (shining a light into the unaffected eye) may be demonstrated. This helps to exclude uveitis from conjunctivitis, in which consensual photophobia is absent.^[7]
• Injection around the corneal limbus (edge of the cornea) is characteristic and referred to as circumlimbal injection. This can be fairly localised but, as the uveitis progresses, the entire conjunctiva may appear red to the naked eye.
• The predominant signs are seen in the anterior chamber (the space bound by the cornea and iris and filled with aqueous humor). These are best demonstrated with a slit-lamp microscope. A slit lamp is used to shine a beam at an angle of 30-40° on the cornea and the area is inspected with the microscope. The beam should be narrowed to about 1 mm and put on its brightest setting.
• The characteristic sign is the presence of cells in the aqueous humour. As you shine the slit-lamp beam through the anterior chamber, the appearance is of a shaft of light shining through darkness with bits of dust floating through it. Ophthalmologists grade the severity of the uveitis by the number of cells seen, ranging from 0 (no cells seen) to +4 (>50 cells seen).
• The aqueous humour is normally clear but in anterior uveitis it may become cloudy, giving the appearance of a 'flare' (see 'Pathophysiology', above). This appears rather like a shaft of light shining through a darkened, smoky room. Flare is also graded from 0 (no flare) to +4 (fibrin deposition).
• Other findings may include synechiae and keratic precipitates.

A full dilated examination is mandatory on presentation, to exclude posterior segment disease/complications.^[1]

Intermediate uveitis:^[9]

• This is often manifested by the presence of inflammatory cells in the vitreous (the clear gel which fills the bulk of the globe, just behind the posterior chamber), best seen with a slit lamp and following dilation of the pupil. If you do have access to a slit lamp, get the patient to look just past you and focus in through the pupil, past the iris. The cells can be seen as little specks crossing the clear orange-red background of the fundus.
• The term pars planitis refers to a subset of idiopathic intermediate uveitis in which there is a snowball or snowbank effect. Clumps of white cells form the globular yellow-white 'snowballs' in the inferior peripheral vitreous and yellow-white exudates band to form 'snowbanks'.

Posterior uveitis:^[7]

• Inflammatory lesions may be seen on the retina or choroid. They may look yellow when fresh, whilst older ones have a more distinct edge and a whitish appearance.
• Inflammation of the retinal blood vessels (retinal vasculitis) may occur, signified amongst other things, by fluffy white perivascular deposits.^[10]
• Oedema of the optic nerve may be another feature.
• The inflammation may 'spill over' anteriorly and give rise to cells in the vitreous.

Differential diagnosis

Any cause of a red eye should be included in the differential diagnosis.

Investigations

A first episode of unilateral nongranulomatous acute uveitis can be diagnosed by history and clinical examination alone and does not need laboratory investigation.^[10] Imaging may be helpful where there is posterior disease in order to assess site or severity of posterior inflammation. Fundus fluorescein angiography and optical coherence tomography (OCT) are the commonly used techniques, the latter being particularly helpful because it is a non-invasive test that only takes a few minutes to perform in clinic.

If history and examination are normal but the uveitis is granulomatous, recurrent or bilateral, further investigations are necessary to hunt for underlying causes. The exact nature of the investigation is guided by clinical suspicion. So, for example, a history of weight loss and unexplained diarrhoea might prompt a search for inflammatory bowel disease. It is tempting to run off a list of 'routine' bloods and a CXR but the value of doing this untargeted screen is not clear^[3] and investigates the patient unnecessarily with the risk of coming up with a confused clinical picture.^[10] The role of some investigations (eg HLA-B27 status) remains controversial. Laboratory tests on a sample of aqueous (anterior chamber) or vitreous (posterior part of the globe) may be helpful where infection or malignancy is suspected.

Associated diseases^[7]

Uveitis is thought to be caused by an immune reaction. The underlying trigger varies according to genetic and environmental factors.^[3] About 50% of cases of uveitis are idiopathic. The remainder may be associated with a number of conditions. There are specific conditions associated with subcategories of uveitis (anterior, intermediate, posterior and panuveitis), each with their own (long) lists of differentials. A selection of the more common associations is presented here but full lists can be obtained in the Internet and further reading section, below.^[1][7][10]. About 50% of patients with acute anterior uveitis are HLA-B27 positive. Nongranulomatous disease can be associated with:

• Sacroiliitis
• Ankylosing spondylitis
• Reiter's syndrome
• Psoriasis
• Inflammatory bowel disease
• Sarcoidosis
• Behçet's disease
• Juvenile idiopathic arthritis

It is worth noting that the only group of patients currently screened for uveitis is children with juvenile idiopathic arthritis. Some infections are associated with anterior uveitis and this is thought to be due to an immune reaction to the organism. They include herpes simplex and herpes zoster. Granulomatous anterior and posterior uveitis are associated with:

• Toxoplasmosis - the most common association with posterior disease.
• Cytomegalovirus.
• Herpes simplex virus.
• Herpes zoster virus.
• Tuberculosis.
• Syphilis.
• In AIDS:
  • Cytomegalovirus
  • Human syncytial virus
  • Cryptococcus
  • Candida

Non-infectious causes of posterior disease include:

• Behçet's disease
• Sacroiliitis (usually bilateral)
• Lymphoma
• Vogt-Koyanagi-Harada disease

Posterior uveitis may also be associated with autoimmune retinal vasculitis.

Management

General principles^[3]

If uveitis is suspected, immediate specialist referral is appropriate to confirm diagnosis and facilitate treatment. Delay in appropriate management can lead to the development of significant complications and irreversible loss of vision. Exact treatment is determined by the type of uveitis (anterior versus posterior), whether the uveitis is secondary to an infection or not and whether it is likely to threaten sight. All patients with anterior disease and most with intermediate or posterior disease require treatment. For patients with systemic disease, a collaborative approach between ophthalmologists and other specialities is important.

Steroid therapy and cycloplegia^[3]

The immune response is thought to be responsible in part for the destructive inflammatory reaction seen in uveitis and so steroids are usually used to suppress this. Prednisolone 1% eye drops are the first-line treatment for the management of uveitis. The typical approach is a tapering course of steroid drops (these may be needed hourly, including overnight). Steroid ointment may also be prescribed for treatment overnight.

In more severe cases or posterior disease, systemic therapy may be required. As with topical treatment, systemic corticosteroids are started at high doses and tapered. Periocular steroid injections may be considered where the disease is severe or where there is cystoid macular oedema. Intravitreal implants may be used with chronic uveitis but they have been associated with secondary cataract and glaucoma. Intravitreal injections have also been tried in chronic disease and have been found to result in improvement of visual acuity but the effect is temporary and so not useful in the long term.

Topical steroids should normally only be prescribed by a specialist, as they can cause corneal ulceration when the diagnosis is herpes simplex infection, steroid glaucoma and, on prolonged use, steroid cataract. However, when the patient has had multiple recurrences over many years and becomes very familiar with their condition, they may be issued with topical steroids to start immediately when the symptoms occur, to avoid delay in treatment between onset of symptoms and specialist review.

Dilating drops are additionally used to relieve the spasmodic pain of the iris in anterior disease and to break any synechiae. Although there is no evidence to support their use, this is standard practice in the UK.^[3] Cyclopegics such as cyclopentolate 1% or atropine 1%^[7] are prescribed but this is best done by a specialist, as this treatment is contra-indicated in narrow angle glaucoma. Cyclopentolate is usually preferred, as it is much shorter acting than atropine. When using cyclopegics, the patient should be warned that the pupil will appear large and they will have a temporary problem with vision in the eye in which the drops have been administered. Cycloplegia can also exacerbate photophobia on particularly bright days.

Adjunctive therapy

• Secondary causes should be treated as appropriate. Where there is an infection, this needs to be treated as a priority.^[3] (See separate Chorioretinal Inflammation article for more details about treatment of ocular toxoplasmosis.)
• Ongoing research is looking at the use of immune modulators such as tumour necrosis factor alpha-blockers (eg etanercept, infliximab) and the interleukin-2 receptor blockers.^[10] Limitations of use include cost and methods of delivery. A number of studies on less invasive sustained ocular drug delivery systems, including episcleral implants, nanospheres, and cyclodextrin particles are being conducted.^[11] Interferon alfa may also have potential in treating refractory sight-threatening uveitis from a variety of causes.^[12]
• Azathioprine has been found to be useful in steroid-resistant autoimmune uveitis.^[13] Ciclosporin and tacrolimus have also been investigated in RCTs and have been associated with control of ocular inflammation and preservation or restoration of sight. However, currently immunosuppressive treatment has not been licensed for uveitis.
• There may be a role for the family of anti-vascular endothelial growth factor drugs (eg ranibizumab [Lucentis®] which is currently used for 'wet' age-related macular degeneration) in managing chronic, non-infective uveitis but these drugs are not yet licensed for this use.^[3] Furthermore, any intravitreal injection carries a small inherent risk of complications (including sight loss) in itself.

Surgery

Removal of the vitreous may be necessary when persistent floaters severely impede visual acuity.^[10] Surgery is only considered in a small proportion of patients with severe or intractable disease or where a diagnostic vitreous sample is required (eg to diagnose infection or malignancy). Other reasons for surgery include removal of a secondary cataract or for preservation of vision in uveitic glaucoma.^[3]

Monitoring the disease^[4]

This is almost entirely by clinical examination but some investigations provide a useful adjunct. Optical coherence tomography (OCT) is very helpful in looking for macular causes of worsening vision, particularly where slit-lamp view is not good. Fluorescein angiography is helpful where retinal vascular involvement needs to be assessed. Visual fields are also helpful for monitoring optic nerve damage. Furthermore, if the patient is on systemic corticosteroids, it is worth keeping an eye on their weight, BP, BMs and performing urinalysis. Blood tests may also be necessary for other immunosuppressive agents.

Complications

Visual loss as a result of:^[3]

• Cystoid macular oedema (swelling of the macula) - this is the leading cause of visual loss in the UK along with secondary cataract formation.
• Secondary cataract.
• Glaucoma - either secondary to steroid treatment or to the inflammatory process itself.
• Vitreous opacities (inflammatory debris or haemorrhage).
• Retinal detachment.
• Neovascularisation of the retina, optic nerve, or iris.
• Macular ischaemia, vascular occlusions and optic neuropathy - can be complications of posterior uveitis.

Posterior synechiae^[7] - these are a common complication of anterior uveitis; if numerous, they can cause blockage of the aqueous flow, leading to a rise in intra-ocular pressure, and can complicate cataract operations

Prognosis

Anterior uveitis is sometimes a self-limiting condition and, in the UK, usually has a good visual outcome (a study found that 91% of these patients retain normal vision).^[3] The factors which cause spontaneous resolution in some patients and complications in others are unclear.^[14] One study of acute uveitis comparing 119 HLA-B27-positive patients and 35 HLA-B27-negative patients found no significant difference in complications between the two groups.^[15] Relapse after a first episode of acute anterior uveitis is probably more common than previously thought - a recent study suggested an incidence of about 24% per person-year, this occurring more commonly in the younger patient age group (18-35 year-olds).^[16] The prognosis of chronic granulomatous uveitis depends on the cause and whether the underlying condition is recognised and treated early enough. Outcomes have been improved by the use of immune modulators in previously refractory cases.^[17]