Intraocular Inflammation

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10 Intraocular Inflammation

Miles Stanford, David Spalton

Signs of Uveitis

Causes of Uveitis

Anterior Uveitis

Intermediate Uveitis

Posterior Uveitis

White Dot Syndromes

Masquerade Syndromes

The uveal tract consists of the iris, ciliary body and choroid lying in continuity; inflammation in this tract is known as uveitis. Uveitis can be classified according to the principal site of inflammation as anterior uveitis, intermediate uveitis (a subgroup of which is pars planitis), posterior uveitis or panuveitis. Because the uveal tract is continuous, severe inflammation in one part may be accompanied by signs of overspill inflammation in another. For example, a severe anterior uveitis (iritis) may be accompanied by a cellular infiltrate in the anterior vitreous (some ophthalmologists would term this an iridocyclitis). Conversely, posterior uveitis may be accompanied by signs of inflammation in the anterior chamber; furthermore, diseases included under the umbrella of posterior uveitis often have significant retinal signs.

The onset of uveitis may be acute or chronic, defined as inflammation continuing for more than 3 months. Acute inflammation produces pain, redness and photophobia and sometimes blurring of vision, depending on the degree of haze within the ocular media. Chronic inflammation occurs in a whiter eye, but clinical appearances may change with time so that acute symptoms may be followed by chronic uveitis and vice versa. Granulomatous uveitis is differentiated from the nongranulomatous type by the appearance of the keratic precipitates (KPs). In granulomatous uveitis, KPs have a large pale greasy appearance (mutton fat KP) and the eye is generally not particularly red. Mutton fat KP used to be taken to indicate that the uveitis was caused by a systemic granulomatous disease such as sarcoidosis or tuberculosis but this clinical distinction is blurred as many of these patients have no detectable underlying systemic disease. Furthermore, there is often considerable overlap in the appearance of KPs with granulomatous diseases such as sarcoidosis sometimes presenting with nongranulomatous KPs whereas nongranulomatous diseases such as multiple sclerosis can present with granulomatous KPs.

Whilst uveitis is often thought of as a distinct entity, a secondary uveitis frequently plays an important role in many other ocular diseases such as corneal infection, scleritis and ocular trauma or in surgery, where it is responsible for many postoperative complications. Uveitis produces visual loss through cataract or loss of clarity of the ocular media, glaucoma, hypotony from defective secretion of aqueous humour, retinal or choroidal destruction, macular oedema or neovascularization.

The eye has a number of particularly unusual immunological features. The avascularity of the cornea, vitreous and lens and the physiological blood–aqueous and blood–retina barriers normally isolate the eye from the general immune system. There is no intraocular lymphatic drainage, so that any ocular immune response must be mediated through the blood. The immune privilege enjoyed by the eye is maintained by active immunosuppression. Resident support cells in the retina such as astrocytes and Müller cells also have a role in immune surveillance being able to present antigen, to phagocytose and to participate in healing and scarring.

Anterior and posterior uveitis appear to be entirely different diseases. Anterior uveitis is associated with a wide variety of systemic stimuli (e.g. ankylosing spondylitis, urethritis, inflammatory bowel disease) in which the initial immune event appears to be extraocular and then becomes targeted on the eye; circumstantial evidence suggests a role for autoimmune cross-reactivity between bowel flora and ocular antigens. Posterior uveitis is thought to be an example of an organ-specific disease mediated by T cells reactive to one or more specific antigens derived from the retina. The discovery that a retinal protein (S antigen) could induce a retinochoroiditis has led to great advances in the understanding of the mechanisms of posterior uveitis in experimental animals although the application to human disease has so far been disappointing. Several other retinal proteins such as rhodopsin, opsonin and interphotoreceptor retinol binding protein have also been found to be uveitogenic.

SIGNS OF UVEITIS

Inflammation within the eye causes damage to the vascular endothelium of the intraocular vessels with consequent breakdown of the blood–ocular barriers and exudation of leucocytes and proteins into the eye. The signs of this process within the eye will depend on the region most affected, the rapidity of onset, its severity and duration.

Fig. 10.1 Ciliary injection is seen here in its classical form as a dusky red circumlimbal vasodilatation in the area around the cornea where the ciliary and scleroconjunctival circulations anastomose. Its degree reflects the acuteness and severity of inflammation in the anterior uveal tract. With very severe inflammation the whole of the bulbar conjunctiva can be involved and the appearances may be difficult to distinguish from the diffuse appearance of conjunctival inflammation.

By courtesy of Dr J Krachmer.

Fig. 10.2 Cells in the anterior chamber are a sign of active inflammation within the eye. The cells are leucocytes that circulate in the convection currents present within the anterior chamber. In the slit-lamp beam they have an appearance similar to that of particles of dust in a sunbeam. They are best seen by a narrow high-intensity beam directed obliquely across the anterior chamber.

Fig. 10.3 A flare within the aqueous humour is the result of a raised protein concentration from breakdown of the blood–aqueous barrier together with locally synthesized immunoglobulin. It defines the slit-lamp beam within the anterior chamber rather like a car headlight cutting through a foggy night. Cells usually accompany flare but flare often persists for some time after the cells have disappeared indicating persistent vascular damage rather than active inflammation.

Fig. 10.4 Severe vascular damage, usually seen with really acute inflammation, infection or following surgery will allow even the largest plasma proteins to exude into the aqueous humour. Such exudation is manifested by fibrin, which clots in the anterior chamber to produce the ‘plastic’ uveitis so typical of HLA-B27-associated acute anterior uveitis.

Fig. 10.5 Cells within the anterior chamber circulate through the aqueous humour to agglutinate and become deposited on the corneal endothelium. They are then known as keratic precipitates (KPs) and are one of the classical signs of anterior uveitis. KPs are typically deposited in the inferior quadrant of the cornea, probably because of gravity and convection currents within the aqueous humour. They vary in distribution and number and also in size, colour and shape.

Fig. 10.6 With resolution of the uveitis with treatment or time the KPs will disappear. Chronic KPs tend to become more pigmented, as in this patient. These are typical mutton fat KPs; note the whiteness of the eye.

Fig. 10.7 Pathologically KPs consist of a mixture of neutrophils, macrophages and lymphocytes. Neutrophils predominate in newly formed KPs, whereas macrophages and lymphocytes are deposited later.

Fig. 10.8 A massive leucocytic response with an acute anterior uveitis can lead to cells precipitating as a hypopyon. This is typical of HLA-B27 positive anterior uveitis but is also seen with other causes of severe anterior uveitis such as Behçet’s disease. Hypopyon may also be the presenting sign of retinoblastoma in children, ocular lymphoma and bacterial or fungal endophthalmitis.

Fig. 10.9 Posterior synechiae are adhesions between the pupillary margin and anterior lens surface; they always reflect a previous anterior uveitis. Pupillary dilatation retracts the iris from contact with the anterior lens capsule and prevents their formation. This is one of the aims of mydriasis in the treatment of uveitis which will sometimes break weak adhesions to leave tell-tale pigment on the lens. Ring adhesions will seclude the pupil and prevent aqueous humour flowing anteriorly, causing iris bombé (see Ch. 8).

Fig. 10.10 Prolonged and severe inflammation in the anterior chamber produces a cyclitic membrane which can also occlude the pupil.

Fig. 10.11 Iris nodules are granulomas. These are known as Busacca nodules when they are in the stroma. At the pupillary margin they are known as Koeppe nodules; posterior synechiae often form at these positions.

Fig. 10.12 Nodules within the peripheral iris stroma can be seen in this patient with a granulomatous uveitis due to sarcoid.

Fig. 10.13 Posterior uveitis produces a cellular vitreous infiltration, analogous to anterior chamber infiltration, but because of the viscosity and structure of the vitreous gel the cells tend to circulate less and persist for longer. Vitreous cells are sometimes distributed more locally, for instance over a focus of chorioretinitis or over the ciliary body. Cells may be distributed as a mass of single cells or accumulate as larger clusters known as ‘snowballs’; they can also be seen as retrohyaloid precipitates on a detached posterior vitreous face. Persistent vitreous inflammation leads to collapse and vitreous detachment with a hazy gel filled with debris.

Fig. 10.14 Macular oedema can be seen with posterior uveitis of any type or severity; it is the most common cause of visual loss, although mild degrees can be compatible with normal visual acuity. Depending on the duration and severity of inflammation, the oedema resolves with the uveitis leaving a normal macula or progresses to permanent retinal damage. Macular oedema is often difficult to visualize ophthalmoscopically unless the macula is viewed stereoscopically with a fundus lens (see Ch. 1). Fluorescein angiography can be very useful in its assessment. In mild cases leakage will be seen from the parafoveal retinal capillaries; in more established cases there is pooling of fluorescein within the intraretinal cystoid spaces, giving a petalloid appearance to the angiogram. This patient with mild posterior uveitis had an acuity of 20/60, biomicroscopy showed macular thickening and fluorescein angiography shows marked macular oedema. Optical coherence tomography (OCT) clearly shows the intraretinal cystic spaces and macular thickening.

CAUSES OF UVEITIS

Anatomically uveitis can be classified into anterior uveitis, intermediate uveitis (a subgroup of which is pars planitis), posterior uveitis or panuveitis, although many patients often defy these strict anatomical divisions. For convenience of diagnosis, treatment and prognosis it is necessary to know whether uveitis has a systemic association, is due to an infectious disease or is idiopathic, in which case it can be subdivided further into syndromes with specific morphological characteristics. On this basis some type of diagnostic label can be given to about 70 per cent of cases. Other conditions such as neoplasia or infection can masquerade as uveitis.

ANTERIOR UVEITIS

ACUTE ANTERIOR UVEITIS

Acute anterior uveitis (AAU) is the most common type of uveitis with an incidence of about 15 per 100000 population per year. About 50 per cent of patients are HLA-B27 positive compared with about 8 per cent of the normal population. However, other factors are important in the pathogenesis, as 25 per cent of patients with ankylosing spondylitis (more than 90 per cent of whom are HLA-B27 positive) will suffer an attack of anterior uveitis during their lifetime compared with only 1 per cent of a normal population with HLA-B27. Being HLA-B27 positive correlates with uniocular involvement, increased severity and joint disease, especially in men but otherwise there are no special features that distinguish HLA-B27-positive from HLA-B27-negative patients. Common systemic associations of AAU are ankylosing spondylitis, psoriatic arthropathy and Reiter’s syndrome, all also linked to HLA-B27. There are many other associations of AAU but these are uncommon and, in the absence of any systemic signs or symptoms, it is reasonable to restrict the investigation of a new patient to a blood count and chest radiography. More extensive investigations should be reserved for patients with symptoms of systemic disease or an atypical course.

Ankylosing spondylitis

About 50 per cent of Caucasian patients who are HLA-B27 positive will have some signs of ankylosing spondylitis. Young adult males are predominantly affected with a male:female ratio of 3:1. Attacks of anterior uveitis occur acutely, usually in one eye and are not related to exacerbations of joint disease, its severity or any other known predisposing factor. The attacks usually subside over 4–6 weeks with treatment and with prompt treatment do not tend to cause residual ocular damage. Most patients can expect several attacks of acute anterior uveitis in either eye before the disease burns out in later life but the degree to which any one patient is affected is extremely variable. There is evidence that immune cross-reactivity to bowel flora may have a pathogenetic role.

Fig. 10.15 About 50 per cent of HLA-B27-positive patients will have evidence of ankylosing spondylitis which is seen in its earliest form in the sacroiliac joints. There is sclerosis of the periarticular bone with narrowing and irregularity of the joint space, progressing eventually to ankylosis. Similar changes are seen in the spine.

Fig. 10.16 This patient has the typical kyphoscoliotic posture of ankylosing spondylitis. He has had a total hip replacement for ankylosis of the joint. Note the swelling of the right knee and the deformity of the feet.

Reiter’s syndrome

This syndrome is a triad of arthritis, urethritis or dysentery, and acute anterior uveitis. Typically a seronegative (i.e. rheumatoid factor negative) arthritis affecting large peripheral joints such as the knees and the sacroiliac joints follows a few weeks after bacterial dysentery or a nonspecific urethritis. Conjunctivitis and uveitis occur in 30–50 per cent of patients. Other systemic features are plantar fasciitis and keratoderma blennorhagica on the penis, palms or soles of the feet. Aortic incompetence is a rare late complication. Males are usually affected; HLA-B27 is virtually always present and there is evidence that the disease is related to chlamydial genital infection if it follows a nonspecific urethritis. Partial manifestations of the syndrome are common. In most patients the uveitis recovers over a few weeks but the arthritis can progress to chronic joint destruction.

Fig. 10.17 Typical keratoderma blennorhagica of the penis.

Herpes zoster ophthalmicus

Keratitis (see Ch. 4) and anterior uveitis are common features of herpes zoster ophthalmicus and may occur independently of each other. It is said that keratitis and uveitis are particularly frequent if the vesicles appear along the side of the nose, the cutaneous distribution of the nasociliary nerve that also innervates the iris and pupil but this is not invariably so.

The uveitis is frequently subacute in onset and is often associated with keratitis. It may persist for many months. Sector atrophy of the iris is commonly seen and is due to an occlusive vasculitis of the iris vessels; retroillumination of the iris shows sectorial translucency to advantage. Corneal anaesthesia is commonly present and persists. Ocular nerve palsies and optic neuritis are occasionally seen and post-herpetic neuralgia can be disabling in a minority of patients. Oral antiviral agents should be given in the acute vesicular cutaneous stage of the disease. The rash heals more quickly with less post-herpetic neuralgia and a lower incidence of ocular involvement. The severity of the cutaneous disease does not necessarily correlate with the degree of severity of ocular involvement. Herpes zoster in young patients may indicate an underlying systemic immunosuppressive illness such as human immunodeficiency virus (HIV) infection or malignancy.

Fig. 10.18 Herpes zoster ophthalmicus with involvement of the nasociliary nerve along the lateral border of the nose. Cutaneous lesions may vary in severity from confluent vesicles to the occasional punctate lesion.

Fig. 10.19 Sectorial iris atrophy following herpes zoster uveitis. Retroillumination of the iris would show loss of iris pigment epithelium.

CHRONIC ANTERIOR UVEITIS

Juvenile idiopathic arthritis

Juvenile idiopathic arthritis can be divided into three main subtypes according to the presenting pattern of joint disease. These are the systemic, polyarticular and pauciarticular types. Ocular involvement is seen most commonly in the latter group, particularly in girls, and especially if antinuclear antibodies are present. HLA-DR5 carries an increased risk of ocular involvement. Occasionally the uveitis may precede joint symptoms by up to 2 years. Conversely development of uveitis after 5 years of joint disease is unusual. Typically the ocular disease is bilateral and the eye is completely white and painless. Accordingly there is a need to screen such children on a regular basis, particularly those at high risk. Visual loss occurs from band keratopathy, glaucoma or cataract. Many patients can be treated by topical or local steroid orbital injections; methotrexate is useful to control both the arthritis and eye disease without the problems of growth retardation from systemic steroids. Cataract surgery is frequently required; IOL implantation remains highly controversial in these children and at present is probably best avoided. Secondary glaucoma is a serious complication that responds poorly to standard medical treatment; surgical drainage with antimetabolites has considerably improved the prognosis.

Fig. 10.20 This little girl aged 4 years with pauciarticular disease has a swollen right knee on which she cannot weight bear.

By courtesy of Dr B Ansell.

Fig. 10.21 Typical features of chronic anterior uveitis in juvenile idiopathic arthritis. There is a moderately advanced band keratopathy with posterior synechiae and a dense cataract. There is no conjunctival injection.

By courtesy of Mr J Kanski.

Fuchs’ heterochromic cyclitis

This is a distinctive entity with many features not seen with other forms of uveitis. Small diffuse KPs are scattered over the whole of the corneal endothelium with a fluffy or feathery appearance of their border in contrast to the well circumscribed and inferiorly sited KPs seen with other types of uveitis. The eye is white and posterior synechiae do not form. The iris has a characteristic moth-eaten appearance and becomes de-pigmented, showing a bluish tinge in Caucasian patients. This depigmentation is not as obvious in heavily pigmented eyes where iris stromal atrophy is the hallmark. Heterochromic cyclitis is usually unilateral although bilateral cases rarely occur and are more difficult to diagnose. Glaucoma may develop and is associated with a fine neovascularization of the iris and angle (see Ch. 8). Cataracts are common and are hastened by steroid therapy; the benefit of steroids in this condition is unproven. Histopathological examination of iris specimens shows stromal atrophy with loss of pigment, hyalinization of blood vessel walls, proliferation of vascular endothelial cells and patchy loss of pigment epithelium. There is an inflammatory cell infiltrate of eosinophils, mast cells, lymphocytes and plasma cells; Russell bodies (immunoglobulins) are present. Recent evidence suggests that the condition is due to persistent localized rubella viral infection.

Fig. 10.22 The right eye of this patient is normal but the left shows stromal atrophy consistent with Fuchs’ heterochromic cyclitis. The left iris has a slightly bluish tinge. Note the peripheral iridectomy from previous glaucoma surgery.

Fig. 10.23 In African Caribbean patients, heterochromia is not seen and iris stromal atrophy is the hallmark. Superficial nodules can be seen on the stromal surface in some patients.

Fig. 10.24 This photograph shows the typical KPs of Fuch’s heterochromic cyclitis. These cover the whole of the endothelial surface and have ‘spidery’ margins. A stringy cellular infiltrate can often be seen in the vitreous.

By courtesy of Mr K Barton.

INTERMEDIATE UVEITIS

This usually affects young adults. It is usually bilateral and starts insidiously. Patients have white eyes and present with floaters from vitreous debris or blurred vision of gradual onset from macular oedema. Most cases have no apparent aetiology, but there is a well recognized association with multiple sclerosis and similar findings may occasionally be seen in patients with sarcoidosis. Anterior segment inflammation is minimal. A cellular vitreous infiltrate is always present in the anterior vitreous gel, together with snowballs (accumulations of cells), which are usually seen inferiorly in the peripheral vitreous gel. A low-grade peripheral periphlebitis is sometimes present. A ‘snowbank’ is a massive infiltrate that is sometimes seen inferiorly over the inferior pars plana and peripheral retina by scleral indentation; these patients are said to have pars planitis. The snowbank is composed of collagen, fibroblasts and astrocytes with an inflammatory cell infiltrate. It is sometimes associated with fibroglial membranes and neovascularization. Macular oedema and mild optic disc swelling are common. Neovascularization of the optic disc or peripheral retina may occur in some eyes. Most patients have a good visual prognosis with the disease burning out over a number of years. The most common cause of visual loss is macular oedema and occasionally vitreous haemorrhage or retinal detachment (from an associated posterior vitreous detachment). In some patients intermediate uveitis is associated with multiple sclerosis which may either precede or succeed the diagnosis of ocular inflammation.

Fig. 10.25 A mild snowbank can be seen over the scleral indent.

By courtsey of Dr R J Josephberg.

Fig. 10.26 This 42-year-old man presented with uniocular symptoms but had bilateral signs. The optic disc is normal but there is a trace of macular oedema with wrinkling of the internal limiting membrane causing blurring of vision. There was a low-grade vitreous cellular infiltrate, ‘snowballs’ within the gel inferiorly and periphlebitis of the equatorial retinal veins. The patient was systemically well and all investigations were normal.

POSTERIOR UVEITIS

Posterior uveitis is less common than anterior uveitis but has a more serious visual prognosis. In all but the mildest cases, orbital or systemic steroids or immunosuppressive drugs are required to control the intraocular inflammation. A diagnostic label can be given to about 70 per cent of patients with posterior uveitis; the remaining patients have an entirely idiopathic and nonspecific intraocular inflammation. It is extremely important to recognize those cases with an infectious or neoplastic cause as specific therapy may be required.

SYSTEMIC DISEASES ASSOCIATED WITH POSTERIOR UVEITIS

Multiple sclerosis

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