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C-42116

Systemic associations and uveitis management

A concise overview of the presenting signs and symptoms of uveitis and its association with systemic conditions is provided in the article. Equipment and techniques for clinical assessment are also covered along with the risks and benefits of different treatment regimes, and long-term prognosis.

Introduction

Uveitis is a potentially sight- threatening inflammatory condition of the eye that affects the uveal tract and adjacent structures. The incidence of uveitis varies from 14 to 52.4 per 100,000 with an overall prevalence around the world of 0.73%.1,2 It occurs most frequently in the 20-50 year age group but approximately 5-10% of uveitis cases occur in children under 16 years of age.3 Once considered a single disease entity, it is now known that there are many causes of uveitis including autoimmune disorders, infections, vasculitis, malignancy, and exposure to toxins. A systemic underlying cause is present in 20% of uveitis cases and early recognition of any systemic association is important, as uveitis may be one of the first signs of a serious underlying systemic disorder.3 Approximately 50% of uveitis, however, is idiopathic in nature.3

table 1

Although many cases of uveitis resolve rapidly, a significant number of patients develop persistent disease with inflammatory damage to ocular structures resulting in severe visual impairment. The main causes of sight loss in uveitis are cystoid macular oedema, cataract and glaucoma.4 Acute anterior uveitis is the most common subtype of uveitis and carries the best visual outcome, with a worse visual prognosis seen in patients with posterior and panuveitis.4

Permanent visual loss from uveitis can result from late detection with delayed treatment; poor control of the inflammation; cumulative damage from recurrent episodes; secondary glaucoma and side effects of treatment.4 Rapid identification, prompt management and early treatment is, therefore, essential.

Classification of uveitis 

Subtypes of uveitis can be described according to anatomical classification (see Table 1: Anatomic classification of uveitis. Adapted from IUSG and SUN classifications5,6), clinical classification (see Table 2: Clinical classification of uveitis. Adapted from the International Uveitis Study Group7), or endogenous/exogenous classification, where exogenous includes external injury and infection and endogenous includes systemic disease, prior infection and idiopathic uveitis.

table 2

Patient history and clinical presentation

Ocular and systemic patient history

A detailed patient history is required to identify recurrent episodes of uveitis, determine whether the clinical course of the uveitis is acute or chronic, and to help identify any associated systemic conditions. Previous eye surgery or trauma also needs to be noted. Family history is not usually relevant in uveitis but the inheritance of human leukocytic antigen (HLA)-B27 is an exception and familial cases of Behçet’s disease, sarcoidosis and multiple sclerosis have been reported.8

Uveitis in childhood is suggestive of juvenile chronic arthritis, whereas uveitis in young adults is more likely to be associated with HLA-B27-related diseases such as anklyosing spondylitis.9 The elderly,however, are more predisposed to masquerading syndromes such as lymphoma.9 Some racial groups are more prone to certain types of uveitis. For example, sarcoidosis is more prevalent in black ethnic groups and a high prevalence of Behçet’s disease has been reported in the Middle East and Asia, especially in Japan.9,10

Details of recent travel, contact with animals, occupation and previous vaccinations may all be relevant.

figure 1A systematic approach is recommended for undertaking a detailed medical history including details of any prior, recent or concurrent infections and asking questions regarding the respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal,dermatological and neurological systems. Table 3 shows some of the systemic clinical features of disorders associated with uveitis.


Signs and symptoms

Anterior uveitis

Patients usually present with pain, photophobia and lacrimation in one or both eyes and there may be a decrease in vision ranging from mild to severe. Unilateral anterior uveitis is typical in HLA-B27-related disease, herpetic infections and Fuchs’ uveitis syndrome. Corneal involvement may be present in herpetic disorders.

Signs of anterior uveitis may include circumcorneal injection,fine keratic precipitates, cells and flare in the anterior chamber, irregular pupil margin and posterior synechiae. Severe inflammation and the presence of hypopyon is highly suggestive of diseases associated with HLA-B27 and Behçet’s disease, although diabetes is an important cause of severe anterior segment disease in the middle-aged group.9 Iris nodules and ‘mutton fat’ keratic precipitates are a feature of granulomatous disease such as sarcoidosis, tuberculosis (TB) or syphilis (see Figure 1: Large mutton fat keratic precipitates in sarcoidosis) and sectorial iris atrophy is common in herpetic infections.

figure 2HLA-B27-related and idiopathic uveitis are frequently associated with a low IOP but raised IOP can be found in toxoplasmosis, sarcoidosis and herpetic infections.9 Peripheral anterior synechiae and posterior synechiae may cause secondary glaucomatous complications.

Cells in the anterior chamber are sometimes a ‘spillover’ from inflammation deeper within the eye. A full, bilateral, dilated examination is required in all cases of anterior uveitis to exclude posterior segment disease, particularly if the visual acuity is less than 6/9.11

Intermediate uveitis

Teenagers or young adults may report a gradual onset of floaters and blurred vision. Intermediate uveitis accounts for approximately 3–15% of uveitis cases,8 and is usually bilateral. Cells seen within the vitreous may coalesce to form ‘snowballs’ or inferior ‘snow- banking’. Cystoid macular oedema (CMO) occurs in 25% of cases,11 and other findings may include neovascularisation involving the peripheral retina or optic disc, periphlebitis and optic disc swelling. Mild anterior uveitis can also be present.

The majority of cases of intermediate uveitis are idiopathic but systemic diseases which may be associated with intermediate uveitis include sarcoidosis, syphilis, multiple sclerosis, Behçet’s disease and Lyme disease.12,13 Intermediate uveitis usually follows a chronic course lasting years with sub- acute exacerbations and low-grade remissions requiring long-term, periodic follow-up.11

Posterior uveitis

Figure 3Symptoms are related to the locality of the retinal and/or choroidal involvement (see Figures 2–4. Figure 2: White dot syndrome – multifocal choroiditis. Figure 3: A single chorioretinal granuloma in association with periphlebitis in tuberculosis. Figure 4: Retinal vasulitis in sarcoidosis). Peripheral inflammatory changes give rise to floaters and inflammatory changes at the posterior pole and cause decreased central vision. Retinitis is characterised by white lesions with indistinct borders, whereas choroidal lesions may appear as yellow nodules with more distinct borders, being both present in some cases.14 Periphlebitis and venous sheathing may be present in sarcoidosis and multiple sclerosis. A combination of arterial and venous vasculitis occurs in Behçet’s disease, syphilis, toxoplasmosis and acute retinal necrosis. Chorioretinal scars are associated with toxoplasmosis and sarcoidosis. Toxoplasmosis is the most common cause of posterior uveitis.8

Imaging methods and investigations 

Although optometrists are not directly involved with requesting investigations, in practice it is useful to know what is involved. 

Few laboratory tests or investigations can diagnose unequivocally the cause of uveitis in the absence of suggestive history or clinical findings, but they may be indicated when there is a clinical suspicion of systemic conditions (see Table 4: Investigations for systemic conditions causing uveitis). Chest X-ray, serum angiotensin converting enzyme (ACE) and syphilis serology are initial investigations required for intermediate and posterior uveitis and for anterior uveitis that is recurrent, aggressive, bilateral or poorly responsive to treatment. Chronic inflammation will also require investigation. Additional investigations are requested if indicated by the history or clinical signs such as Lyme disease serology or a QuantiFERON Gold blood test for TB. Baseline blood pressure, blood glucose, full blood count, urea and electrolytes, and liver function tests are requested to monitor side effects of systemic treatment.

figure 4Occasionally a CT or MRI head scan is required when demyelination, lymphoma or neurosarcoidosis is suspected. An aqueous or vitreous tap may be necessary in cases of suspect infective uveitis, such as acute retinal necrosis or endophthalmitis.

HLA-B27-associated acute anterior uveitis (AAU) accounts for 50% of all patients with anterior uveitis in the Western world,15 and systemic diseases associated with HLA-B27 include anklyosing spondylitis, reactive arthritis, psoriatic arthropathy and inflammatory bowel disease. Opinions differ but patients are not usually tested for HLA-B27 for first attacks of typical unilateral AAU without supporting evidence of an associated systemic condition. A positive HLA test has no direct relevance in managing the ocular condition.

Fluorescein angiography (FA) is useful for assessing the degree of vasculitis in posterior uveitis and differentiating between ischaemic and inflammatory neovasularisation. Indocyanine green angiography (ICA) complements FA in being superior at choroidal imaging and optical coherence tomography (OCT) has virtually replaced FA in detecting and monitoring macular oedema.

Treatment regimes

The aim of uveitis treatment is to alleviate patient symptoms, control inflammation and preserve vision. Early aggressive use of topical steroids is the mainstay of treatment for the majority of non- infectious acute anterior uveitis. Topical steroids are instilled at high doses initially (usually hourly) and then gradually tapered over six to eight weeks depending on the response to treatment. Stopping treatment abruptly may cause recurrence of the inflammation.

table 3Prednisolone acetate 1% is generally the first-choice topical steroid for use in AAU. One of the well-known side effects of topical steroids is raised intraocular pressure, as well as cataract formation and an increased susceptibility to infection.

Some topical steroids, such as rimexolone 1% and loteprednol etabonate 0.5%, are reported to have less of a tendency to raise IOP but are not as effective in reducing inflammation.16,17 Topical hypotensive agents can be used concurrently with topical steroids, although prostaglandin analogues are generally avoided as they may exacerbate the inflammatory response.18,19

A long-acting mydriatic is required in the early stages of treatment in AAU to break down or prevent posterior synechiae and also to reduce pain by immobilising the inflamed iris and ciliary body.9 Such mydriatics include atropine 1%, instilled twice a day, or cyclopentolate 1% three times a day. Attempts to break posterior synechiae should be made at the first visit using topical mydriatics and a warm compress if necessary.

Anterior uveitis that is refractory to topical steroids may require a subconjunctival injection of steroid, such as betamethasone, which is usually administered with subconjunctival mydricaine, a preparation used to achieve mydriasis and cycloplegia in severe inflammation. In rare cases of recalcitrant anterior uveitis, systemic steroids are used.

Sight-threatening intermediate and/or posterior uveitis requires treatment. Clinical features indicating treatment include severe vitritis, CMO, optic disc swelling,vasculitis and retinal/choroidal lesions involving the macula or optic nerve head.8,9 Systemic steroids, such as prednisolone, are usually the first-line of choice but it is important that infection and neoplasia (such as lymphoma) are excluded before treatment is started.

Local steroid injections (periocular or intravitreal) are useful in controlling vitritis and chronic CMO and can be considered in unilateral disease or when high-dose systemic steroids are contraindicated.11 The steroid that is typically used in these injections is triamcinolone.9,11 Formation of cataract and the development of glaucoma are major side effects and steroid injections should not be administered to known steroid responders or to patients who have untreated infectious conditions such as syphilis, Lyme disease, toxoplasmosis or TB. The potentially serious side effects of oral steroids such as susceptibility to infection, gastric ulceration, and raised blood pressure, makes them undesirable for long-term use in high doses. Steroid-sparing immunosuppressive agents such as methotrexate, mycophenolate, azathioprine or ciclosporin can be introduced to reduce or replace steroid treatment. They are often prescribed in conjunction with a rheumatologist or immunologist and require regular monitoring with blood tests, as they can affect the kidneys, liver and white blood cell count.

table 4Biologics are monoclonal antibodies that are targeted against specific cells or chemical signs in the immune system and several are widely used in the management of rheumatologic diseases. Recent studies have demonstrated that anti–TNF-αbiologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease.20,21 These agents tend to be supplied on a named patient basis and application for funding is usually required.

Conclusion 

Uveitis is one of the leading causes of preventable blindness in developed countries which makes it crucial that practising optometrists recognise the signs and symptoms of anterior, intermediate and posterior forms of uveitis in order to refer patients expediently and prevent visual loss from delayed treatment.

AAU often responds quickly to treatment with steroids and mydriatic eye drops with no lasting adverse effect on vision and frequently no identifiable cause. However, some varieties of uveitis can be severe, sight threatening and difficult to treat. Patients with uveitis have an increased risk of developing cataract and glaucoma, both of which can be challenging to manage, particularly in the presence of active uveitis. Chronic anterior uveitis may also lead to CMO or corneal band keratopathy.

Uveitis can be a manifestation of a number of systemic diseases, some of which may require investigation and treatment in their own right. Recent advances in the treatment of uveitis include the development of new biologic drugs and some additional immunosuppressive agents. New methods for delivering existing medications have also been developed such as direct intravitreal delivery of a range of therapeutic agents including antibiotics, antivirals, antifungals and sustained release mechanisms for intravitreal delivery of steroids.22 Risks and benefits of all drugs must be addressed before commencement.

Chronic anterior uveitis, first episodes of AAU and all cases of intermediate and posterior uveitis need to be referred by optometrists in practice, with same day referral if there is a reduction in vision, severe pain or raised intraocular pressure. Therapeutically qualified optometrists in practice are now able to reinstate uveitic therapy for second and subsequent episodes of acute anterior recurrent uveitis, with routine referral at the third episode for medical investigations.23 Therapeutically-qualified optometrists working within hospital acute referral clinics are able to investigate and prescribe for more complex cases under the supervision of an ophthalmologist. Close collaboration with general practitioners and other specialties such as rheumatology, dermatology and immunology is beneficial for the management of uveitis with associated systemic conditions.

About the author 

Alison Weston BSc, FCOptom, Dip CLP, DipGlauc, Dip TP(IP), is deputy head of optometry at Leeds Teaching Hospitals NHS Trust with special interests in contact lenses, corneal disorders, glaucoma and uveitis. She examines for the College of Optometrists in the pre-registration scheme and is a current member of the independent prescribing common final assessment panel and the clinical management guidelines review panel. 

Images courtesy of Teifi James and Professor Nicholas Jones. 

References

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  17. Pavesio C, Decory HH (2008) Treatment of ocular inflammatory conditions with loteprednol etabonate. Br J Ophthalmol 92: 455-9
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