Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

INTRODUCTION

Anterior uveitis is described as inflammation of the iris and/or anterior ciliary body and is characterised by a perilimbal injection termed ciliary congestion, keratic precipitates (KPs) on the posterior corneal surface, cells and flare in the anterior chamber, posterior synechiae, and peripheral anterior synechiae.

Anterior uveitis is the most common form of uveitis, accounting for 50–92% of total uveitis cases in western studies and 28–50% of all uveitis cases in other parts of the world, including Asia.1-3 While in studies conducted in primary health care centres, anterior uveitis represented up to 92% of the total cases, tertiary referral centre based studies place their incidence at 30-50% of all uveitis cases.4 It most commonly affects young patients aged between 20 and 50 years and is relatively uncommon both in children and old patients.5

Anterior uveitis is usually characterised as granulomatous or non-granulomatous depending on the nature and character of keratic precipitates. Non-granulo- matous uveitis is characterised by very fine aggregates of inflammatory cells on the posterior corneal surface that appear like dust (Figure 1) which are predominantly composed of neutrophils and some lymphocytes. Fibrinous clotting or hypopyon may occur in severe anterior non-granulomatous uveitis.

Any KPs larger than dust or that can be individualised characterise the uveitis as a granulomatous anterior uveitis. Some of these KPs are small and can be called “microgranulomatous” as in Fuchs’ uveitis. Others are large and greasy and are called ‘muttonfat’ KPs composed of macrophages and giant cells.

Figure 1: Very fine regular keratic precipitates (KPs) appearing as dust on the posterior corneal surface on slit-lamp examination characterising anterior non-granulomatous uveitis

The distinction between non-granulomatous and granulomatous uveitis is important and useful in orienting the work-up and differential diagnosis of uveitis, although a granulomatous uveitis may initially present as non-granulomatous.

Anterior non-granulomatous uveitis can be further divided into various specific aetiologic entities (Table 1).

HLA-B27 ASSOCIATED ACUTE

ANTERIOR UVEITIS

EPIDEMIOLOGY AND PATHOGENESIS

HLA-B27 associated acute anterior uveitis (AAU) is defined as anterior segment intraocular inflammation

Table 1: Causes of anterior non-granulomatous uveitis

Non-Infectious Causes

HLA-B27 acute anterior uveitis (AAU)

–Isolated

–Associated with systemic disease: Ankylosing spondylitis

Reiter’s syndrome (Reactive arthritis) Psoriatic arthritis

Inflammatory bowel diseases Undifferentiated spondyloarthropathies

Juvenile idiopathic arthritis Behçet’s disease

Tubulointerstitial nephritis and uveitis (TINU) syndrome Kawasaki disease

Lens-induced uveitis Medication-induced uveitis Traumatic uveitis

Infectious Causes

Leptospirosis

Rickettsioses

Viral diseases

Poststreptococcal syndrome uveitis

Idiopathic Uveitis

occurring in association with the HLA-B27 antigen. HLA-B27 AAU is the most common identifiable cause of anterior uveitis seen in as high as 18–32% of all anterior uveitis cases in western countries.2,6,7 However, it accounts for only 4–13% of all anterior uveitis cases in other parts of the world, including Asia.3,8 This discrepancy probably reflects racial differences in the frequency of HLA-B27 in the general population (8–10% in western population and 1–6% in Asians).8 It is estimated that the lifetime cumulative incidence of AAU is approximately 0.2% in the general population which increases to 1% in the HLA-B27-positive individuals.9 HLA-B27 AAU may occur in the absence of associated systemic disease (isolated HLA-B27 AAU). However, 30-90% of patients with HLA-B27 AAU have an associated systemic disease.10

These systemic diseases, called seronegative spondyloarthropathies, are a group of disorders that share many clinical, pathologic, and immunogenetic features. They include ankylosing spondylitis, Reiter’s syndrome (Reactive arthritis), psoriatic arthritis, inflammatory bowel diseases, and undifferentiated spondyloarthropathies (Table 1). The term seronegative delineates these diseases from rheumatoid arthritis, as most patients with rheumatoid arthritis have a positive test for rheumatoid factor.

Both genetic and environmental factors are critically important in the pathogenesis of HLA-B27 associated diseases. The association between the antigen HLA-B27 and its spectrum of HLA-B27- associated systemic diseases and AAU remains one of the strongest HLA-disease associations.11,12 However, HLA-B27 may be a necessary but not a sufficient genetic predisposing factor to the disease. HLA-B27 associated anterior uveitis represents a multifactorial disease that occur in genetically predisposed persons and are triggered by unknown environmental factors. There is considerable epidemiological, clinical, and experimental evidence of association of HLA-B27 AAU with bacterial triggers such as Chlamydia trachomatis and the gram negative enterobacteria, including Klebsiella, Salmonella, Yersinia, etc.13-15

CLINICAL FEATURES

HLA-B27 AAU is characterised by a clear male preponderance, with most patients aged between 20 and 40 years at onset of the disease. Inflammation is typically sudden in onset and associated with significant perilimbal hyperaemia and symptoms of pain, photophobia, epiphora, and blurred vision. Typical cases are unilateral but involvement of contralateral eye may occur with subsequent attacks. Uveitis is typically non-granulomatous and is characterised by dusty KPs and significant cellular and protein extravasation into the aqueous humour. Inflammation may be severe enough to cause fibrinous exudation in the anterior chamber that contributes to the formation of posterior synechiae, or hypopyon (Figures 2-4). Characteristically each episode lasts for 4-6 weeks. However, there is a high tendency for recurrences in either eye with a mean number of 0.6– 3.3 attacks per patient, per year of follow-up.10,12,16

HLA-B27 AAU may be associated with potentially sight-threatening ocular complications, including posterior synechiae, cataract, and ocular hypertension. Posterior segment complications, such as cystoid macular oedema in about 16%, vitritis, and papillitis, may also occur. Therefore, a systematic fundus examination, complemented in selected cases with fluorescein angiography and optical coherence tomography, is recommended in patients with HLAB27 AAU.

Figure 3: A 32-year-old man presented with a 7-day history of pain, redness and photophobia in his right eye. It was his first attack. Slit lamp examination showed circumcorneal ciliary congestion, posterior synechiae, and hypopyon. There were 4+ cells in the anterior chamber. The patient was found to be HLAB27 positive without associated systemic disease. Treatment with topical betamethasone and mydriatics resulted in complete resolution of intraocular inflammation

Although the overall visual prognosis of patients with HLA-B27 AAU, either with or without associated systemic disease, is relatively good, it tends to be worse than that of patients with HLA-B27 negative AAU.12

ASSOCIATED SYSTEMIC DISEASES

HLA-B27 AAU may be isolated or associated with a systemic disease.

Figure 4: A 26-year-old man presented with a 5-day history of pain, redness and photophobia in his right eye. It was his first attack. Slit lamp examination showed circumcorneal cilliary congestion, posterior synechiae, and hypopyon. There were very fine KPs overall on the endothelium not appearing on the photograph. There was 3+ reaction in the anterior chamber. Systemic evaluation led to a diagnosis of HLA-B27 nongranulomatous AAU without associated systemic disease. The patient was treated with topical betamethasone and mydriatics, with subsequent resolution of inflammation in 6 weeks

The seronegative spondyloarthropathies are by far the most common systemic diseases associated with AAU and HLA-B27 AAU. About 23-37% of AAU patients have an associated seronegative spondylarthropathy and 30-90% of patients with HLA-B27- positive AAU have an associated systemic disease .10, 12

The association of AAU and these systemic diseases is clinically relevant for both the ophthalmologist and the rheumatologist. A routine rheumatologic evaluation is recommended for all cases of HLA-B27 AAU, especially when there are systemic symptoms, to detect a previously unknown spondyloarthropathy. On the other hand, all patients with established HLA-B27-associated systemic disease should be warned of possible ocular involvement and advised to see an ophthalmologist for the development of AAU in case of ocular symptoms.

Ankylosing Spondylitis

Ankylosing spondylitis (AS) is by the far the most common seronegative spondyloarthropathy known to be associated with AAU. The relative risk for developing AS is 100 times more frequent in HLA-B27 antigen positive individuals compared to HLA-B27 negative subjects. The disease is 2.5-3 times more common in males.17-19 Moreover females usually have a milder form of disease. Patients may be totally asymptomatic or present with back pain and morning stiffness. The disease involves first the sacroiliac joint resulting in sclerotic changes, narrowing of joint space and later its complete obliteration. In advanced stages, patients develop a fused spine starting from the lumbar region, which severely limits the range of movements.17

Ocular involvement presents typically as AAU with clinical features similar to that described above (Figures 5A and B). AAU may be the first symptom of a systemic disease, preceding the onset of other clinical manifestations, or it may be the clinical manifestation that completes the clinical picture of the systemic disease.10, 19 Nearly 10-20% patients develop posterior segment involvement in form of diffuse vitritis and cystoid macular oedema.20 The severity of uveitis does not correlate with the severity of spondylitis.

Although AAU is the most common ocular manifestation in AS, conjunctivitis and scleritis may occasionally occur.

Reiter’s Syndrome (Reactive Arthritis)

Reiter’s syndrome (RS) is a form of reactive arthritis seen commonly in young males and is characterised by a clinical triad of non-specific urethritis, arthritis, and conjunctivitis. Reactive arthritis usually begins one to four weeks after a genitourinary or gastrointestinal

Figures 5A and B: A 62-year-old old man presented with a 7- day history of photophobia, blurred vision, pain, and redness in his left eye. In the past history, he had similar attacks. (A) Ocular examination of left eye revealed circumcorneal congestion, posterior synechiae with fibrin in pupillary area. There was 3+ reaction in the anterior chamber. (B) Systemic examination revealed HLA-B27 positivity and advanced ankylosing spondylitis involving the axial skeleton. The patient was treated with topical steroids and mydriatics for ocular disease and referred to rheumatologist for ankylosing spondylitis (Courtesy Dr Carl P Herbort, Lausanne, Switzerland)

tract infection. Causative organisms include Chlamydia, Ureaplasma, Shigella, etc.

The arthritis is typically oligoarticular and preferentially involves the joints of the lower extremities. Urethritis classically is a sterile variant; although Chlamydia and Ureaplasma have been isolated in many patients with reactive arthritis.21 Other non-ocular manifestations include oral ulcers, circinate balanitis (painless erythematous lesion of the glans penis), keratoderma blennorrhagicum (hyperkeratotic lesions on the palms of the hand or the soles of the feet), plantar fasciitis, and tenosynovitis. About 20% patients also develop sacroiliitis and ascending spinal disease similar to AS.

The ocular manifestations of RS are characterised by conjunctivitis in nearly 50% of the patients and AAU in 3-12% of the cases. The AAU is usually mild, unilateral, and non-granulomatous, but recurrent episodes often affect the other eye (Figure 6).21,22

Other less common ocular manifestations of reactive arthritis include punctate subepithelial and anterior stromal keratitis, episcleritis, and scleritis.

Optic disc oedema, retinal oedema, and retinal vasculitis have been rarely reported in reactive arthritis.23

Psoriatic Arthritis

Psoriasis is a skin disease characterised by typical dry looking scaly lesions seen particularly on the extensor surface of the knees. These lesions are caused by hyperproliferation of the epidermis. Psoriatic arthritis (PA) is seen in around 20% of the patients and is asymmetric and usually involves the distal joints too. Many patients have associated pitting of the nails.24 Ocular involvement is characterised by non-granulo- matous bilateral anterior uveitis with a prolonged course seen in 7-20% of patients with PA.23 In certain cases, the uveitis may be clinically indistinguishable from other HLA-B27 associated diseases.25 Other eye lesions in PA may occur, including conjunctivitis, episcleritis, and scleritis.

Inflammatory Bowel Diseases

Both ulcerative colitis and Crohn’s disease are associated with anterior uveitis in around 2-11% of the cases, although the involvement is more common with Crohn’s disease than ulcerative colitis. Inflammation

Figure 6: A 46-year-old man presented with a 7-day history of photophobia, blurred vision, pain, and redness in his right eye. In the past history, he had one similar attack. Ocular examination revealed slight congestion, and posterior synechiae. There was 3+ reaction in the anterior chamber. There were dusty KPs on the posterior corneal surface not visible on the photograph. Patient gave a history of recurrent attacks of urethritis. Systemic examination revealed urethritis along with ocular signs. He was treated with topical steroids and mydriatics successfully and referred to physician for systemic disease

is usually insidious in onset, bilateral, recurrent or chronic, and nongranulomatous, with moderate cells and flare.26, 27 The predisposing factors include male sex, axial arthritis and presence of HLA-B27 antigen. In nearly 50% of the cases the diagnosis of uveitis precedes the diagnosis of inflammatory bowel disease. Other ocular findings in inflammatory bowel diseases include posterior uveitis, intermediate uveitis, retinal vasculitis, optic neuritis, episcleritis, scleritis, keratitis, conjunctivitis, and orbital disease.23

Undifferentiated Spondyloarthropathy

This condition is diagnosed in patients with spondyloarthropathy that does not fall into one of the categories mentioned above. Uveitis may occur in both eyes simultaneously and may be chronic. Vitritis, retinal vasculitis, and exudative retinal detachment may also occur.

TREATMENT

The mainstay of therapy for HLA-B27 AAU is topically applied corticosteroids (prednisolone acetate,

dexamethasone, betamethasone).12 This therapy is relatively easily administrated by compliant patients, without significant systemic adverse effects, and usually effective if given in sufficient quantity. The frequency of instillation of corticosteroids (every < 1 hour-6 hours, followed by gradual tapering) depends primarily on the intensity of the inflammation; the more severe the inflammation, the more frequent the dosage. Steroid ointments are a practical alternative to frequent dosing when use of the latter is impossible (during sleep). On occasion, AAU is severe enough to require periocular injection of corticosteroids (hydrosoluble corticosteroids or triamcinolone acetonide, 40 mg) or rarely oral steroids (prednisone, prednisolone). Ocular adverse effects of either topical or periocular corticosteroids mainly include ocular hypertension and cataract.

Topical corticosteroids less likely to provoke rise in intraocular pressure (IOP) include rimexolone and lodeprednol etabonate. They are less effective than prednisolone acetate and dexamethasone, but may be a good choice for patients who are steroid responders and who have mild to moderate AAU requiring steroid therapy for several weeks.

The concomitant use of mydriatic/cycloplegic drops (tropicamide, cyclopentolate, phenylephrine, homatropine, or atropine) reduces pain from ciliary spasm and helps break or prevent posterior synechiae in promptly treated patients.

Very rarely HLA-B27 AAU may be refractory to topical, injected, or even systemic corticosteroids, requiring immunosuppressive therapy to control inflammation and prevent or reduce the risk of ocular complications and subsequent visual impairment.

Prompt initiation of treatment at the time of recurrence of AAU may shorten the duration of the attack, prevent complications, and improve the visual prognosis. Patients with HLA-B27 AAU associated with spondyloarthropathy require concomitant management by the rheumatologist for their systemic disease.

JUVENILE IDIOPATHIC ARTHRITIS

ASSOCIATED UVEITIS

CLASSIFICATION

Juvenile idiopathic arthritis (JIA) is defined as an arthritis of unknown cause of at least 6 weeks duration starting before the patient’s 16th year of life. JIA was known as juvenile chronic arthritis or juvenile rheumatoid arthritis in the past. It has been classified by type of onset into oligoarticular, polyarticular, and systemic JIA (Table 2).23 Most of the publications regarding JIA uveitis refer to this classification.

Recently, the International League against Rheumatism has defined seven subgroups of JIA according to certain clinical and immunological criteria.28 Categories include oligoarthritis, rheumatoid factor (RF) negative polyarthritis, RF-positive polyarthritis, systemic arthritis, psoriatic arthritis, enthesitis-related arthritis, and undefined arthritis. Obviously, the proposed new classification require further evaluation to be definitively adopted by ophthalmologists.

FREQUENCY AND RISK FACTORS

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children. Together with

intermediate uveitis of the pars planitis type, it is the most common identifiable cause of childhood anterior uveitis in western countries (41-67%).23 However, the proportion of uveitis due to JIA is lower in other parts of the world, including the mediterranean region.29

Risk factors for JIA-associated uveitis are young age (< 7 years), female sex, antinuclear antibody positivity, rheumatoid factor seronegativity, and oligoarticular onset. About 20% of children with oligoarticular JIA and 5% of children with the polyarticular JIA develop anterior uveitis. Uveitis usually occur several years after joint inflammation, but it may occasionally precede arthritis.

CLINICAL FEATURES

In contrast to other anterior uveitis entities, the onset of JIA-associated uveitis is usually asymptomatic until damage to intraocular structures becomes substantial. It is typically insidious in onset, chronic, bilateral anterior uveitis, with sometimes remitting course.30 In majority of the cases, uveitis is non-granulomatous with flare and cells in the anterior chamber, and fine KPs localised in the inferior part of the corneal endothelium (Arlt’s triangle) (Figure 7).

Granulomatous KPs and iris nodules may rarely be present. Anterior vitreous cells may be present in severe uveitis.

Posterior synechiae and pupillary fibrin membrane

Figure 7: A 12-year-old girl presented with a 6-week history of blurring of vision bilaterally. She had been diagnosed with antinuclear antibody positive oligoarticular juvenile idiopathic arthritis. Ocular examination revealed mild ciliary congestion, posterior synechiae, and band shaped keratopathy (white area on cornea with calcium-free zone in the centre)

Figures 8A and B: A 10-year-old girl presented with a 6-month history of blurring of vision bilaterally. She had been diagnosed with antinuclear antibody positive oligoarticular juvenile idiopathic arthritis. She gave a history of repeated attacks of redness in both eyes. (A) Ocular examination of the right eye revealed posterior synechiae and pigment in pupillary area with nasal and temporal band shaped keratopathy. (B) Ocular examination of the left eye revealed posterior synechiae with fibrotic membrane and pigment in pupillary area (shown in figure) as well as temporal and nasal band-shaped keratopathy. She was already on immunosuppressive agents for her systemic disease

are seen in some cases (Figures 8A and B). Band shaped keratopathy, cataract, and glaucoma are frequent complications of JIA, seen in 41%, 42% and 19% patients, respectively (Figure 9). Severe uveitis can rarely result in cystoid macular oedema, epiretinal membranes, retinal detachment, ciliary body atrophy, cyclitic membrane, hypotony and phthisis bulbi leading to extremely poor prognosis. The development of these complications is related to the severity of

Figures 9A and B: Band shaped keratopathy in patient with long-standing oligoarticular juvenile idiopathic arthritis and chronic anterior uveitis. Before treatment (A). After chelation with EDTA and scraping (B) (Courtesy Dr Carl P Herbort, Lausanne, Switzerland)

uveitis at the onset of the disease.23

DIAGNOSIS

Most patients already have a diagnosis of JIA upon presentation to an ophthalmologist. Routine ocular examination is mandatory to detect and treat JIAassociated anterior uveitis early (Table 3).31

If a diagnosis of JIA is not present, other causes of uveitis must be ruled out using clinical and laboratory testing.23 Ocular sarcoidosis in children may closely mimic uveitis in JIA. Antinuclear antibodies positivity, characteristic distribution of involved joints, and chronic, anterior non-granulomatous uveitis can help diagnose JIA.

Table 3: Recommendations for ocular screening in juvenile idiopathic arthritis patients

High risk: followed every 3-4 months

Oligoarticular or polyarticular disease with onset before 7 years of age and antinuclear antibody (ANA) positive

Moderate risk: followed every 6 months

–Oligoarticular or polyarticular disease with onset before 7 years of age and ANA negative

–Oligoarticular or polyarticular disease with onset at 7 years of age or older (irrespective of ANA status)

Low risk: followed every year

Systemic onset disease

Anterior uveitis associated with the spondyloarthropathies can also occasionally occur in children and is characterised by sudden onset of anterior uveitis, unilateral involvement, limited course, and good visual prognosis if treated promptly and aggressively.

Other non-infectious or infectious diseases can be differentiated from JIA-associated anterior uveitis on the basis of history, systemic signs and symptoms, and results of ancillary tests.

TREATMENT

The JIA associated uveitis is a challenge because of its chronic nature. However due to advances in management and early diagnosis, the blindness rate has been reduced to less than 6%.32,38 Treatment should be initiated promptly with a trial of topical potent corticosteroids (up to every half hour and then tapered to the minimum) to control the inflammation. Mydriatic/ cycloplegic drops should be added to break or prevent posterior synechiae. Periocular corticosteroid injection may be given in cases refractory to topical corticosteroids. Clinicians should be aware of side effects of local corticosteroid therapy, especially cataract and elevation of intraocular pressure. Systemic corticosteroids may be used only for short-term control of a severe attack. However, their long-term use is not suggested due to the untoward side effects. If longterm quiescence cannot be achieved with low-dose steroids, immunosuppressive therapy is indicated even in the absence of sight-threatening complications or visual loss. Methotrexate is most commonly used drug probably it is prescribed by paediatric rheumatologist for systemic disease. Other immunosuppressants,

including azathioprine, cyclosporine A, mycophenolate mophetil, and alkylating agents may be used in refractory cases. Recently, TNF alpha inhibitors were found to be of benefit in the treatment of JIA associated uveitis.31, 33

Chelation therapy using ethylenediaminetetraacetic acid (EDTA) is the simplest and effective option for band shaped keratopathy. Recently excimer laser has been used to remove calcium by phototherapeutic keratectomy. Management of cataract involves two different approaches, including34 pars plana lensectomy and vitrectomy and phacoemulsification with or without intraocular lens implantation. Positive results have been published for both techniques. However, the eye should be free of inflammation for at least 3 months prior to the surgery. The control of elevated intraocular pressure can be tried initially with medical therapy including both topical and oral drugs. However, more than 50% of the patients who develop glaucoma, will eventually require filtration surgery.33, 35

OTHER NON-INFECTIOUS NONGRANULOMATOUS ANTERIOR UVEITIS

BEHÇET’S DISEASE

Bilateral panuveitis, frequently associated with retinal vasculitis and retinitis, is the most common ocular presentation of Behçet’s disease (BD).

Acute anterior uveitis may rarely be the only ocular manifestation of BD (11%).36 Inflammation is always non-granulomatous. There may be a hypopyon (12%) that shows smooth layer and shifts freely with head positioning. Fibrinous reaction is uncommon.

TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS (TINU) SYNDROME

TINU is a distinct clinicopathologic entity, occurring mainly in children and young adults, more often females. It is characterised by acute tubulointerstitial nephritis accompanied or followed by bilateral anterior acute non-granulomatous uveitis, which tends to be recurrent and resistant to treatment.37

KAWASAKI DISEASE

Kawasaki disease is a systemic disease of unknown cause affecting children and adolescents. Its major

Figure 10: Slit lamp photograph showing lens-induced anterior non-granulomatous uveitis in a 75-year-old woman with hypermature cataract

features are protracted fever, cervical lymph node swelling, strawberry tongue, palmar erythema, erythematous rash, and bilateral conjunctival injection. A self-limited, non-granulomatous anterior uveitis is very common, particularly in the early stages of the disease.38

LENS-INDUCED UVEITIS

Anterior uveitis may occur after trauma or cataract surgery and in cases associated with mature or hypermature cataract (Figure 10).39

The anterior chamber usually shows dense flare and abundant cells. KPs may be non-granulomatous at the early stage. Hypopyon or pseudohypopyon (lens material) may be seen. The IOP is usually elevated.

Once the lens material is completely removed from the eye, the inflammation resolves.

MEDICATION-INDUCED UVEITIS

Anterior non-granulomatous uveitis has been associated with a number of topical and systemic medications, and may also occur after vaccination and the use of other substances.40 Inflammation may range from mild to severe, and it always resolves after cessation of the medication and the institution of topical steroid treatment.

TRAUMATIC UVEITIS