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Chapter 11 Uveitis

INTRODUCTION 402
CLINICAL FEATURES 402
Acute anterior uveitis 402
Chronic anterior uveitis 404
Posterior uveitis 406
SPECIAL INVESTIGATIONS 406
Indications 406
Skin tests 407
Serology 407
Enzyme assay 408
HLA tissue typing 409
Imaging 409
Radiology 410
Biopsy 410
PRINCIPLES OF TREATMENT 410
General principles 410
Mydriatics 410
Topical steroids 411
Periocular steroid injection 411
Intraocular steroids 411
Systemic steroids 412
Antimetabolites 412
Calcineurin inhibitors 413
Biological blockers 413
INTERMEDIATE UVEITIS 413
UVEITIS IN SPONDYLOARTHROPATHIES 415
HLA-B27 and spondyloarthropathies 415
Ankylosing spondylitis 416
Reiter syndrome 416
Psoriatic arthritis 416
UVEITIS IN JUVENILE ARTHRITIS 416
Juvenile idiopathic arthritis 416
Familial juvenile systemic granulomatosis syndrome 420
UVEITIS IN BOWEL DISEASE 420
Ulcerative colitis 420
Crohn disease 420
Whipple disease 422
UVEITIS IN RENAL DISEASE 422
Tubulointerstitial nephritis and uveitis (TINU) 422
IgA glomerulonephritis 422
SARCOIDOSIS 422
BEHÇET SYNDROME 426
TOXOPLASMOSIS 429
Introduction 429
Toxoplasma retinitis 430
TOXOCARIASIS 433
MISCELLANEOUS PARASITIC UVEITIS 436
Onchocerciasis 436
Cysticercosis 438
Diffuse unilateral subacute neuroretinitis 439
Choroidal pneumocystosis 440
UVEITIS IN ACQUIRED IMMUNODEFICIENCY SYNDROME 441
Introduction 441
HIV microangiopathy 442
Cytomegalovirus retinitis 442
Progressive retinal necrosis 444
MISCELLANEOUS VIRAL UVEITIS 445
Acute retinal necrosis 445
Herpes simplex anterior uveitis 445
Varicella zoster anterior uveitis 445
Congenital rubella 446
Subacute sclerosing panencephalitis 447
FUNGAL UVEITIS 447
Presumed ocular histoplasmosis syndrome 447
Cryptococcosis 449
Endogenous fungal endophthalmitis 449
Coccidioidomycosis 450
BACTERIAL UVEITIS 450
Tuberculosis 450
Syphilis 451
Lyme disease 452
Brucellosis 454
Endogenous bacterial endophthalmitis 454
Cat-scratch disease 456
Leprosy 456
WHITE DOT SYNDROMES 457
Multiple evanescent white dot syndrome 457
Acute idiopathic blind spot enlargement syndrome 458
Acute posterior multifocal placoid pigment epitheliopathy 458
Multifocal choroiditis and panuveitis 459
Punctate inner choroidopathy 460
Serpiginous choroidopathy 461
Progressive subretinal fibrosis and uveitis syndrome 461
Acute macular neuroretinopathy 462
Acute zonal occult outer retinopathy  463
PRIMARY STROMAL CHOROIDITIS 464
Vogt–Koyanagi–Harada syndrome 464
Sympathetic ophthalmitis 465
Birdshot retinochoroidopathy 467
MISCELLANEOUS ANTERIOR UVEITIS 469
Fuchs uveitis syndrome 469
Lens-induced uveitis 469
MISCELLANEOUS POSTERIOR UVEITIS 471
Acute retinal pigment epitheliitis 471
Acute idiopathic maculopathy 472
Acute multifocal retinitis 473
Solitary idiopathic choroiditis 473
Frosted branch angiitis 473
Idiopathic retinal vasculitis, aneurysms and neuroretinitis syndrome 473
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Introduction

Anatomical classification

The uvea is the vascular layer of the eye and comprises the iris, ciliary body and choroid (Fig. 11.1).

1 Uveitis, by strict definition implies an inflammation of the uveal tract. However, the term is commonly used to describe many forms of intraocular inflammation involving not only the uvea but also the retina and its vessels.
2 Anterior uveitis may be subdivided into:
• Iritis in which the inflammation primarily involves the iris.
• Iridocyclitis in which both the iris and the pars plicata of the ciliary body are involved.
3 Intermediate uveitis is defined as inflammation predominantly involving the pars plana, the peripheral retina and the vitreous.
4 Posterior uveitis involves the fundus posterior to the vitreous base.
• Retinitis with the primary focus in the retina.
• Choroiditis with the primary focus in the choroid.
• Vasculitis which may involve veins, arteries or both.
5 Panuveitis implies involvement of the entire uveal tract without a predominant site of inflammation.
6 Endophthalmitis implies inflammation, often purulent, involving all intraocular tissues except the sclera.
7 Panophthalmitis involves the entire globe, often with orbital extension.
image

Fig. 11.1 Anatomical classification of uveitis

Anterior uveitis is the most common, followed by posterior, intermediate and panuveitis.

Definitions

1 Onset may be sudden or insidious.
2 Duration of an attack may be either limited, if 3 months or less in duration, or persistent, if longer.
3 Acute uveitis describes the course of a specific uveitis syndrome characterized by sudden onset and limited duration.
4 Chronic uveitis describes persistent inflammation characterized by prompt relapse (in less than 3 months) after discontinuation of therapy.
5 Recurrent uveitis is characterized by repeated episodes of uveitis separated by periods of inactivity without treatment lasting at least 3 months.
6 Remission refers to inactive disease for at least 3 months after discontinuation of treatment.
7 Resistant
• To steroids if there is no clinical improvement despite 2 weeks of treatment with maximal dose.
• To immunosuppressives if there is no clinical improvement despite 3 months of treatment.

Clinical features

Acute anterior uveitis

Anterior uveitis is the most common form of uveitis. Acute anterior uveitis (AAU) is the most common form of anterior uveitis, accounting for three-quarters of cases. It is characterized by sudden onset and duration of 3 months or less. It is easily recognized due to the severity of symptoms which will force the patient to seek medical attention.

1 Presentation is typically with sudden onset of unilateral pain, photophobia and redness, which may be associated with lacrimation. Occasionally patients may notice mild ocular discomfort a few days before the acute attack when clinical signs are absent.
2 Visual acuity is usually good at presentation except in eyes with severe hypopyon.
3 External examination shows ciliary (circumcorneal) injection which has a violaceous hue (Fig. 11.2A).
4 Miosis due to sphincter spasm (Fig. 11.2B) may predispose to the formation of posterior synechiae unless the pupil is pharmacologically dilated.
5 Endothelial dusting by a myriad of cells is present early and gives rise to a ‘dirty’ appearance (Fig. 11.2C). True keratic precipitates (KP) usually appear only after a few days and are usually non-granulomatous (see below).
6 Aqueous cells indicate disease activity and their number reflects disease severity (Fig. 11.2D). Grading of cells is performed with a 2 mm long and 1 mm wide slit beam with maximal light intensity and magnification. This must be performed before mydriasis because in normal eyes cells and pigment clumps may develop after pupillary dilatation. Table 11.1 shows the grading system.
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• Improvement of inflammation is defined as either a two-step decrease in the level of activity or a decrease to ‘inactive’.
• Worsening is defined as either a two-step increase in the level of activity or an increase to the maximum grade.
7 Anterior vitreous cells indicate iridocyclitis.
8 Aqueous flare reflects the presence of protein due to a breakdown of the blood–aqueous barrier (see Fig. 11.2D). Flare may be graded by laser interferometry using a flare meter or clinically by observing the degree of interference in the visualization of iris using the same settings as for cells (Table 11.2).
9 Aqueous fibrinous exudate typically occurs in HLA-B27-associated AAU (Fig. 11.2E).
10 Hypopyon is a feature of intense inflammation in which cells settle in the inferior part of the anterior chamber (AC) and form a horizontal level (Fig. 11.2F).
• In AAU associated with HLA-B27 the hypopyon has a high fibrin content which makes it dense, immobile and slow to absorb.
• In patients with Behçet syndrome the hypopyon has minimal fibrin and therefore shifts according to the patient’s head position and may disappear quickly.
• Hypopyon associated with blood may occur in herpetic infection and in eyes with associated rubeosis iridis.
11 Posterior synechiae may develop quickly (Fig. 11.3A) and must be broken down before they become permanent (Fig. 11.3B).
12 Low intraocular pressure (IOP) may occur as a result of reduced secretion of aqueous by the ciliary epithelium. Occasionally the intraocular pressure may be elevated (hypertensive uveitis) as in herpetic uveitis and Posner–Schlossman syndrome.
13 Fundus examination is usually normal, but should always be performed to exclude ‘spillover’ anterior uveitis associated with a posterior focus, notably toxoplasmosis and acute retinal necrosis.
14 Duration. With appropriate therapy the inflammation tends to completely resolve within 5–6 weeks.
15 The prognosis is usually very good. Complications and poor visual prognosis are related to delayed or inadequate management. Steroid-induced hypertension may occur but glaucomatous damage is uncommon.
image

Fig. 11.2 Signs of acute anterior uveitis. (A) Ciliary injection; (B) miosis; (C) endothelial dusting by cells; (D) aqueous flare and cells; (E) fibrinous exudate; (F) hypopyon

(Courtesy of JS Schuman, V Christopoulos, DK Dhaliwal, MY Kahook and RJ Noecker, from Lens and Glaucoma in Rapid Diagnosis in Ophthalmology, Mosby 2008 – fig. D).

Table 11.1 Grading anterior chamber cells

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

Table 11.2 Grading of aqueous flare

Description Grade
Nil 0
Just detectable +1
Moderate (iris and lens details clear) +2
Marked (iris and lens details hazy) +3
Intense (fibrinous exudate) +4
image

Fig. 11.3 Posterior synechiae. (A) Early synechiae formation in active acute anterior uveitis; (B) extensive synechiae and pigment on the lens following a severe attack of acute anterior uveitis

Chronic anterior uveitis

Chronic anterior uveitis (CAU) is less common than the acute type and is characterized by persistent inflammation that promptly relapses, in less than 3 months, after discontinuation of treatment. The inflammation may be granulomatous or non-granulomatous. Bilateral involvement is more common than in AAU.

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1 Presentation is often insidious and many patients are asymptomatic until the development of complications such as cataract or band keratopathy. Because of the lack of symptoms patients at risk of developing CAU should be routinely screened; this applies particularly in patients with juvenile idiopathic arthritis.
2 External examination usually shows a white eye. Occasionally the eye may be pink during periods of severe exacerbation of inflammatory activity.
3 Aqueous cells vary in number according to disease activity but even patients with numerous cells may have no symptoms.
4 Aqueous flare may be more marked than cells in eyes with prolonged activity and its severity may act as an indicator of disease activity (contrary to previous teaching).
5 KP are clusters of cellular deposits on the corneal endothelium composed of epithelioid cells, lymphocytes and polymorphs (Fig. 11.4A). Their characteristics and distribution may indicate the probable type of uveitis.
• Large KP in granulomatous disease have a greasy (‘mutton-fat’) appearance. They are often more numerous inferiorly and may form in a triangular pattern with the apex pointing up (Arlt triangle – Fig. 11.4B). This is the result of gravity and normal convection flow of aqueous.
• Resolved mutton-fat KP leave behind a ground-glass appearance (ghost KP), which is evidence of previous granulomatous inflammation (Fig. 11.4C).
• Long-standing non-granulomatous KP may become pigmented and less dense centrally (Fig. 11.4D).
6 Dilated iris vessels (pseudorubeosis) are occasionally seen in long-standing cases and resolve with treatment.
7 Iris nodules typically occur in granulomatous disease.
• Koeppe nodules are small and situated at the pupillary border (Fig. 11.5A).
• Busacca nodules involve the iris stroma (Fig. 11.5B).
• Large pink nodules are characteristic of sarcoid uveitis (Fig. 11.5C).
8 Iris atrophy that is sectoral occurs characteristically in herpes simplex and herpes zoster (see Fig. 11.44). Diffuse iris atrophy occurs in Fuchs uveitis syndrome (see Fig. 11.75D).
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9 The duration is prolonged and in some cases the inflammation may last for many months or even years. Remissions and exacerbations of inflammatory activity are common and it is difficult to determine when the natural course of the disease has come to an end.
10 The prognosis is guarded because of complications such as cataract, glaucoma and hypotony.
image

Fig. 11.4 Keratic precipitates. (A) Aggregate of inflammatory cells on the corneal endothelium; (B) large ‘mutton-fat’ keratic precipitates; (C) ‘ghost’ keratic precipitates; (D) old pigmented keratic precipitates

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

image

Fig. 11.5 Iris nodules in granulomatous anterior uveitis. (A) Koeppe nodules; (B) Busacca nodules; (C) very large nodule in sarcoid uveitis

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

Posterior uveitis

Posterior uveitis encompasses retinitis, choroiditis and retinal vasculitis. Some lesions may originate primarily in the retina or choroid but often there is involvement of both (retinochoroiditis and chorioretinitis).

1 Presentation varies according to the location of the inflammatory focus and the presence of vitritis. For example a patient with a peripheral lesion may complain of floaters whereas a patient with a lesion involving the macula will predominantly complain of impaired central vision.
2 Retinitis may be focal (solitary), multifocal, geographic or diffuse. Active lesions are characterized by whitish retinal opacities with indistinct borders due to surrounding oedema (Fig. 11.6A). As the lesion resolves, the borders become better defined.
3 Choroiditis may also be focal, multifocal, geographic or diffuse. It does not usually induce vitritis in the absence of concomitant retinal involvement. Active choroiditis is characterized by a round, yellow nodule (Fig. 11.6B).
4 Vasculitis may occur as a primary condition or as a secondary phenomenon adjacent to a focus of retinitis. Both arteries (periarteritis) and veins (periphlebitis) may be affected although venous involvement is more common. Active vasculitis is characterized by yellowish or grey-white, patchy, perivascular cuffing (Fig. 11.6C) that may be associated with haemorrhage. Quiescent vasculitis may leave perivascular scarring, which should not be mistaken for active disease.
image

Fig. 11.6 Signs of posterior uveitis. (A) Retinitis; (B) choroiditis; (C) vasculitis

Special investigations

Indications

1 Not indicated
• Single attack of mild unilateral AAU without suggestion of a possible underlying disease.
• A specific uveitis entity such as sympathetic ophthalmitis and Fuchs cyclitis.
• When a systemic diagnosis compatible with the uveitis is already apparent such as Behçet disease or sarcoidosis.
2 Indications
• Granulomatous inflammation.
• Recurrent uveitis.
• Bilateral disease.
• Systemic manifestations without a specific diagnosis.
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• Confirmation of a suspected ocular picture which depends on the test result as part of the criteria for diagnosis such as HLA-A29 testing for birdshot chorioretinopathy.

Skin tests

1 Tuberculin skin tests (Mantoux and Heaf) involve the intradermal injection of purified protein derivative of M. tuberculosis.
a Positive result is characterized by the development of an induration of 5–14 mm with 48 hours (Fig. 11.7A).
b Negative result usually excludes TB, but may also occur in patients with advanced consumptive disease.
c Weakly positive result does not necessarily distinguish between previous exposure and active disease. This is because most individuals have already received BCG (Bacille Calmette–Guérin) vaccination and will therefore exhibit a hypersensitivity response.
d Strongly positive result (induration > 15 mm) is usually indicative of active disease since this level of response is not expected after long exposure to the vaccine (Fig. 11.7B).
2 Pathergy test (increased dermal sensitivity to needle trauma) is a criteria for the diagnosis of Behçet syndrome, but the results vary and it is only rarely positive in the absence of systemic activity. A positive response is the formation of a pustule following pricking of the skin with a needle (Fig. 11.7C).
3 Lepromin test involves intradermal injection of an extract of leprosy bacilli. It differs from the tuberculin test because it becomes positive after several weeks. It is strongly positive in tuberculoid leprosy and negative in lepromatous leprosy.
image

Fig. 11.7 Skin tests in the investigation of uveitis. (A) Positive tuberculin skin reaction; (B) strongly positive tuberculin skin reaction; (C) positive pathergy test in Behçet syndrome

(Courtesy of U Raina – fig. A; B Noble – fig. C)

Serology

Syphilis

Because of the variable presentation serology should be performed in all patients with uveitis who require investigation. Serological tests rely on detection of nonspecific antibodies (cardiolipin) or specific treponemal antibodies.

1 Non-treponemal tests such as rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) are best used to diagnose primary infection, monitor disease activity or response to therapy based on titre. The patient’s serum is mixed with commercially prepared carbon-like cardiolipin antigen (Fig. 11.8A). The results may be negative in up to 30% of patients with documented syphilitic uveitis. They also tend to become negative 6–18 months after therapy.
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2 Treponemal antibody tests are highly sensitive and specific and more useful to prove past infection, as well as active secondary or tertiary forms of clinical infection. The fluorescent treponemal antibody absorption test (FTA-ABS) and the more specific microhaemagglutination Treponema pallidum test (MHA-TP) are most commonly used. The antibody in the patient’s serum binds to bacteria and is visualized by a fluorescent dye (Fig. 11.8B). The result cannot be titrated and is either positive (reactive) or negative (non-reactive). A positive result always remains positive (serological scar).
3 Dark-ground microscopy of exudate from a mucocutaneous lesion is reliable if positive.
image

Fig. 11.8 Serological tests for syphilis. (A) Rapid plasma regain (RPR) for syphilis showing clumping of the antigenic particles (left) after 4 minutes; (B) positive fluorescent treponema antibody test (FTA-ABS) for syphilis

(Courtesy of Mims, Dockrell, Goering, Roitt, Wakelin and Zuckerman, from Medical Microbiology, Mosby 2004)

Toxoplasmosis

1 Dye test (Sabin-Feldman) utilizes live organisms which are exposed to the patient’s serum complement. The cell membranes of the organisms are lysed in the presence of the specific anti-toxoplasma IgG, and as consequence the organisms fail to stain with methylene blue dye. This test remains the gold standard for the diagnosis of toxoplasmosis.
2 Immunofluorescent antibody tests utilize dead organisms exposed to the patient’s serum and antihuman globulin labelled with fluorescein. The results are read using a fluorescent microscope (Fig. 11.9A).
3 Haemagglutination tests involve the coating of lysed organisms on to red blood cells which are then exposed to the patient’s serum; positive sera cause the red cells to agglutinate (Fig. 11.9B).
4 Enzyme-linked immunosorbent assay (ELISA) involves binding of the patient’s antibodies to an excess of solid phase antigen (Fig. 11.9C). This complex is then incubated with an enzyme-linked second antibody. Assessment of enzyme activity provides measurement of specific antibody concentration. The test can also be used to detect antibodies in the aqueous which are more specific than those in the serum, and is useful in other conditions such as cat-scratch fever and toxocariasis. Any positive titre, even in undiluted serum, is significant in the presence of a fundus lesion compatible with toxoplasmic retinitis. Reactivation of ocular disease alone will have no impact on the titre.
image

Fig. 11.9 Serological tests for toxoplasmosis. (A) Positive immunofluorescent antibody test; (B) haemagglutination test; (C) ELISA test showing positive (yellow-brown) and negative wells

Enzyme assay

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1 Serum angiotensin-converting enzyme (ACE) is a non-specific test which indicates the presence of a granulomatous disease such as sarcoidosis, tuberculosis and leprosy. Elevation of ACE occurs in up to 80% of patients with acute sarcoidosis but may be normal during remissions. The normal serum level in adults is 32.1 ± 8.5 IU. In children the levels tend to be higher and diagnostically less useful. In patients with suspected neurosarcoid ACE can be measured in the cerebrospinal fluid. ACE may also be elevated in other conditions such as tuberculosis, lymphoma and asbestosis.
2 Lysozyme assay has good sensitivity but less specificity than ACE in the diagnosis of sarcoidosis but performing both tests seems to increase sensitivity and specificity.

HLA tissue typing

Table 11.3 HLA type and systemic disease

HLA type Associated disease
B27 Spondyloarthropathies, particularly ankylosing spondylitis
A29 Birdshot chorioretinopathy
B51 Behçet syndrome
HLA-B7 and HLA-DR2 POHS and APMPPE

Imaging

1 Fluorescein angiography (FA) is useful in the following circumstances.
• Evaluation of retinal vasculitis.
• Diagnosis of macular disease, particularly cystoid macular oedema (CMO) and choroidal neovascularization (CNV).
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• Demonstrating macular ischaemia as the cause of visual loss rather than CMO.
• Differentiation between inflammatory and ischaemic causes of retinal neovascularization.
• Diagnosis of specific uveitis entities that have characteristic features on FA (e.g. acute posterior multifocal placoid pigment epitheliopathy and Harada disease).
2 Indocyanine green angiography (ICGA) is better suited for evaluating choroidal disease because the dye does not readily leak out of choroidal vessels which are better visualized through the RPE. ICGA is able to detect non-perfusion of the choriocapillaris and provide information regarding inflammation affecting the choroidal stroma.
3 Optical coherence tomography (OCT) is useful in detecting complications such as macular oedema, epiretinal membranes and subretinal fluid. It is also useful in delineating the anatomical layer of the inflammatory focus.

Radiology

1 Chest X-ray is frequently requested to exclude tuberculosis and sarcoidosis.
2 Sacroiliac joint X-ray is helpful in the diagnosis of a spondyloarthropathy in the presence of symptoms of low back pain and uveitis.
3 CT and MR of the brain and thorax may be appropriate in the investigation of sarcoidosis, multiple sclerosis and primary intraocular lymphoma. A thorax MR scan may clarify any doubts regarding the presence of hilar lymphadenopathy.

Biopsy

Histopathology still remains the gold standard for definitive diagnosis of many conditions. Biopsies of the skin or other organs may establish the diagnosis of a systemic disorder associated with the ocular manifestations, such as sarcoidosis. However, intraocular structures are relatively inaccessible to this procedure without running the risk of significant morbidity.

1 Conjunctival and lacrimal gland biopsy may useful for the diagnosis of sarcoidosis but only in the presence of clinically apparent disease.
2 Aqueous samples for polymerase chain reaction (PCR) may occasionally be useful in the diagnosis of viral retinitis.
3 Vitreous biopsy, apart from its well-established role in infectious endophthalmitis, can also be used for the diagnosis of other infectious conditions by obtaining samples for culture and PCR. It is also used for the diagnosis of intraocular lymphoma.
4 Retinal and choroidal biopsies may be useful in the following situations.
• Diagnosis not established.
• No response to therapy.
• Further deterioration despite therapy.
• Exclusion of malignancy or infection.

Principles of treatment

General principles

Treatment of immune-mediated uveitis involves predominantly the use of anti-inflammatory and immunosuppressive agents. Antibiotic therapy for infectious diseases will be discussed in the specific sections. It is important to keep in mind that drugs used to treat uveitis have potential side-effects, and this should always be weighed against the decision to treat. Also, it must be emphasized that the use of systemic therapy should be carried out in conjunction with a physician who is competent to deal with complications associated with both the underlying disease and the therapy.

Mydriatics

Preparations

1 Short-acting
a Tropicamide (0.5% and 1%) has a duration of 6 hours.
b Cyclopentolate (0.5% and 1%) has a duration of 24 hours.
c Phenylephrine (2.5% and 10%) has a duration of 3 hours but no cycloplegia.
2 Long-acting
a Homatropine 2% has a duration of up to 2 days.
b Atropine 1% is the most powerful cycloplegic and mydriatic with a duration of up to 2 weeks.

Indications

1 To promote comfort by relieving spasm of the ciliary muscle and pupillary sphincter, usually with atropine or homatropine, although it is usually unnecessary to use these agents for more than 1–2 weeks. Once the inflammation shows signs of subsiding, a short-acting preparation can be used.
2 To break down recently formed posterior synechiae with intensive topical mydriatics (atropine, phenylephrine) or subconjunctival injection of Mydricaine® (adrenaline, atropine and procaine) in eyes that do not respond to drops. A subconjunctival injection (0.5 mL) can be divided into the four quadrants for maximal effect. A transient sinus tachycardia occurs in about 20% of patients. A good alternative to injection is to insert a cotton pledget soaked in Mydricaine into the superior and inferior fornices for 5 minutes. Tissue plasminogen activator (25 µg in 0.05 mL) injected into the anterior chamber (intracamerally) with a 25-gauge needle will dissolve fibrinous exudate and help break down persistent fresh posterior synechiae.
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3 To prevent formation of posterior synechiae following control of acute inflammation by using a short-acting mydriatic that allows some mobility of the pupil but prevents formation of synechiae in the dilated position. In mild chronic anterior uveitis, the mydriatic can be instilled at bedtime to prevent difficulties with accommodation during the day. In young children, constant uniocular atropinization may induce amblyopia.

Topical steroids

Indications

1 Treatment of AAU is usually relatively straightforward.
• Initial therapy involves instillation either hourly or even more frequently according to severity of inflammation.
• Once the inflammation is controlled the frequency should be carefully tapered to 2-hourly, followed by 3-hourly, then four times a day and eventually reduced by one drop a week. The drops are often discontinued altogether by 5–6 weeks.
2 Treatment of CAU is more difficult because long-term therapy is often required with the risk of complications such as cataract and steroid-induced elevation of intraocular pressure.
• Exacerbations are initially treated in the same way as acute anterior uveitis. If the inflammation is controlled with no more than +1 aqueous cells, the rate of instillation can be gradually further reduced by one drop/month.
• The classical teaching that only cellular reaction in the anterior chamber represents active inflammation has been challenged. Flare is caused by chronic break-down of the blood–aqueous barrier, but the intensity of the flare can also indicate an active process, which may respond to therapy.
• Following cessation of treatment, the patient should be re-examined within a short time to ensure that the uveitis has not recurred.

Complications

1 Elevation of IOP is common in susceptible individuals (‘steroid responders’), but long-term exposure to topical steroids may eventually result in glaucoma in many patients.
2 Cataract can be induced by both systemic and, less frequently, topical steroid administration. The risk increases with dose and duration of therapy.
3 Corneal complications, which are uncommon, include secondary infection with bacteria and fungi, recrudescence of herpes simplex keratitis, and corneal melting, which may be enhanced by inhibition of collagen synthesis.
4 Systemic side-effects are rare, but may occasionally occur following prolonged administration, particularly in children.

Periocular steroid injection

1 Advantages over topical administration
• Therapeutic concentrations behind the lens may be achieved.
• Water-soluble drugs, incapable of penetrating the cornea when given topically, can enter the eye trans-sclerally when given by periocular injection.
• A prolonged effect can be achieved with ‘depot’ preparation such as triamcinolone acetonide (Kenalog) or methylprednisolone acetate (Depomedrone).
2 Indications
• In unilateral or asymmetrical intermediate or posterior uveitis, periocular injections should be considered as first-line therapy to control inflammation and macular oedema.
• In bilateral posterior uveitis either to supplement systemic therapy or when systemic steroids are contraindicated.
• Poor compliance with topical or systemic medication.
• At the time of surgery in eyes with uveitis.
3 Complications
• Globe penetration.
• Elevation of IOP, which with depot preparations may be refractory.
• Ptosis.
• Subdermal fat atrophy.
• Extraocular muscle paresis.
• Optic nerve injury.
• Retinal and choroidal vascular occlusion.
• Cutaneous hypopigmentation.
4 Technique
a A topical anaesthetic such as tetracaine is instilled.
b A small cotton pledget impregnated with amethocaine (or equivalent) is placed into the superior fornix at the site of injection for 2 minutes.
c The vial containing the steroid is shaken.
d 1.5 mL steroid is drawn up into a 2-mL syringe and the drawing-up needle replaced with a 25-gauge 5/8 inch (16 mm).
e The patient is asked to look away from the site of injection; most frequently inferiorly when the injection is being given superotemporally.
f The bulbar conjunctiva is penetrated with the tip of the needle, bevel towards the globe, slightly on the bulbar side of the fornix.
g 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!
h When the needle has been advanced to the hub and cannot be inserted any further (Fig. 11.10), the plunger is slightly withdrawn and, if no blood has entered the syringe, 1 mL is injected.
i Alternatively, some practitioners prefer orbital floor injection via the skin or conjunctiva, due to a perceived lower risk of ocular perforation.
image

Fig. 11.10 Technique of posterior sub-Tenon steroid injection

(Courtesy of C Pavésio)

Intraocular steroids

1 Injection
• Triamcinolone acetonide (4 mg in 0.1 mL) is an option in the treatment of posterior uveitis and CMO unresponsive to other forms of therapy.
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• It produces rapid resolution of CMO lasting about 4 months and may be used to determine reversibility of visual loss due to CMO.
• Injections may be used following surgery on eyes with uveitis when other forms of prophylaxis are not appropriate.
• Complications include elevation of IOP, cataract, endophthalmitis (sterile or infectious), haemorrhage and retinal detachment.
2 Slow-release implants appear to be useful in patients with posterior uveitis who do not respond to, or are intolerant to, conventional treatment.
• The implant, either a biodegradable insert or a slow-release reservoir (fluocinolone acetonide, dexamethasone), is implanted via a pars plana incision.
• The steroid is continuously released for 18 months–3 years and this may obviate the use of long-term systemic steroids.
• Complications are similar to those of intravitreal triamcinolone injection.

Systemic steroids

1 Preparations
a Oral prednisolone 5 or 25 mg tablets are the main preparations.
b Intravenous infusion of methylprednisolone 1 g/day, repeated for 2 to 3 days is an option in severe disease.
2 Indications
• Intermediate uveitis unresponsive to posterior sub-Tenon injections.
• Sight-threatening posterior or panuveitis, particularly with bilateral involvement.
• Rarely, anterior uveitis resistant to topical therapy.
• Occasionally prior to intraocular surgery as prophylaxis against worsening inflammation.
3 Contraindications
• Poorly controlled diabetes is a relative contraindication.
• Peptic ulceration.
• Osteoporosis.
• Active systemic infection.
• Psychosis on previous exposure to steroids.
4 General rules of administration
• Start with a large dose and then reduce.
• The starting dose of prednisolone is 1–2 mg/kg/day given in a single morning dose, after breakfast.
• A high level is maintained until a clinical effect is seen, followed by a slow taper over several weeks to avoid reactivation.
• Doses of 40 mg or less for 3 weeks or less do not require gradual reduction.
• Doses of more than 15 mg/day are unacceptable long-term so that the use of a steroid-sparing agent has to be considered. A common cause of failure of treatment is sub-optimal dosage.
5 Side-effects depend on the duration and dose of administration.
a Short-term therapy may cause dyspepsia, mental changes, electrolyte imbalance, aseptic necrosis of the head of the femur and, very rarely, hyperosmolar hyperglycaemic non-ketotic coma.
b Long-term therapy may cause a Cushingoid state, osteoporosis, limitation of growth in children, reactivation of infections such as TB, cataract and exacerbation of pre-existing conditions such as diabetes and myopathy. Rarely, systemic steroids may cause severe ocular hypertension in children, even when administered only for several days.

Antimetabolites

Indications

1 Sight-threatening uveitis, which is usually bilateral, non-infectious, reversible and has failed to respond to adequate steroid therapy.
2 Steroid-sparing therapy in patients with intolerable side-effects from systemic steroids or those with chronic relapsing disease requiring a daily dose of prednisolone of more than 10 mg. Once a patient has been started on an immunosuppressive drug and the appropriate dose ascertained, treatment should continue for 6–24 months, after which gradual tapering and discontinuation of medication should be attempted over the next 3–12 months. However, some patients may require long-term therapy for control of disease activity.

Azathioprine

1 Indications are chronic conditions such as Behçet syndrome and Vogt–Koyanagi–Harada syndrome. Because the drug takes several weeks to take effect it is not appropriate for acute conditions.
2 Dose and route
• Starting daily dose is 1–3 mg/kg (50 mg tablets) once daily or in divided doses.
• After 1–2 weeks the dose is doubled.
• If appropriate control of inflammation is achieved the dose of other drugs (e.g. steroids, ciclosporin and tacrolimus) can be tapered.
• Azathioprine is usually stopped only after the disease has been inactive for over 1 year and the daily steroid dose is under 7.5 mg.
3 Side-effects include bone marrow suppression, hepatotoxicity and nausea.
4 Monitoring involves a complete blood count, initially weekly and then every 4–6 weeks, and liver function tests every 12 weeks.

Methotrexate

1 Indications are mainly as a steroid-sparing agent in patients with uveitis associated with sarcoidosis and juvenile idiopathic arthritis. It is more convenient to use than azathioprine because of weekly administration.
2 Dose and route
• Adult 10–25 mg weekly orally or intramuscularly.
• Children required a higher dose (up to 30 mg) since the clearance of the drug is increased.
• Folic acid at 2.5–5 mg/day is administered to reduce bone marrow toxicity.
3 Side-effects including bone marrow suppression, hepatotoxicity, acute pneumonitis (hypersensitivity reaction) are the most serious, but rarely occur with low-dose therapy. Less severe adverse effects include nausea, vomiting, mouth ulcers and alopecia.
4 Monitoring involves a full blood count and liver function tests every 1–2 months. Patients must be warned to abstain from alcohol.

Mycophenolate mofetil

1 Indications. A good alternative to azathioprine in unresponsive or intolerant patients, though it is not recommended in children.
2 Dose and route is 1–2 g daily orally.
3 Side-effects include gastrointestinal disturbance and bone marrow suppression.
4 Monitoring involves a full blood count initially weekly for 4 weeks and then monthly.

Calcineurin inhibitors

Ciclosporin

1 Indications. This is the drug of choice for Behçet syndrome, and may also be used in other conditions, namely intermediate uveitis, birdshot retinochoroidopathy, Vogt–Koyanagi–Harada syndrome, sympathetic ophthalmitis and idiopathic retinal vasculitis.
2 Dose and route is 2.5–7 mg/kg daily orally.
3 Side-effects include nephrotoxicity, hyperlipidaemia, hepatotoxicity, hypertension, hirsutism and gingival hyperplasia. Poorly controlled hypertension and renal disease are relative contraindications.
4 Monitoring involves blood pressure, and renal and liver function tests every 6 weeks.

Tacrolimus

1 Indications. An alternative to ciclosporin in intolerant or unresponsive patients.
2 Dose and route is 1–0.25 mg/kg daily orally.
3 Side-effects include hyperglycaemia, neurotoxicity and nephrotoxicity; these are more common than with ciclosporin.
4 Monitoring involves blood pressure, renal function tests and blood glucose, initially weekly and then less frequently.

Biological blockers

The exact indications and efficacy of these drugs in the treatment of uveitis are largely unknown although there are several clinical trials currently in progress. The two main groups are:

1 Interleukin receptor antagonists such as daclizumab and anakinra.
2 Tumour necrosis factor alpha antagonists such as infliximab and adalimumab.

Intermediate uveitis

Overview

Intermediate uveitis (IU) is an insidious, chronic, relapsing disease in which the vitreous is the major site of inflammatory signs. The condition may be idiopathic or associated with a systemic disease (see below). Pars planitis (PP) is a subset of IU in which there is ‘snowbanking’ and/or ‘snowball’ formation. IU accounts for up to 15% of all uveitis cases and about 20% of paediatric uveitis. The diagnosis is essentially clinical, and investigations are carried out to exclude a systemic association, especially in the presence of suggestive findings and in older individuals. The exact age of onset of IU may be difficult to determine, since an extended period may elapse before patients become symptomatic.

Diagnosis

1 Presentation is with the insidious onset of blurred vision often accompanied by vitreous floaters. The initial symptoms are usually unilateral, but the condition is typically bilateral and often asymmetrical. Careful examination of the apparently normal eye may reveal minor abnormalities of the peripheral retina, such as vascular sheathing or localized vitreous condensations.
2 Anterior uveitis
• In PP there may be a few cells and small scattered KP which occasionally have a linear distribution in the inferior cornea.
• In the other forms of IU, anterior uveitis can be severe, especially in patients with sarcoidosis and Lyme disease.
3 Vitreous
• Vitreous cells with anterior predominance are universal.
• Vitreous condensation and haze in more severe cases. Table 11.4 shows the grading of vitreous haze.
• Vitreous snowballs are usually most numerous in the inferior peripheral vitreous (see Fig. 11.11B).
4 Posterior segment
• Peripheral periphlebitis is common, particularly in patients with MS (Fig. 11.11A).
• Snowbanking is characterized by a grey-white fibrovascular plaque which may occur in all quadrants, but is most frequently inferior (Fig. 11.11B).
• Neovascularization may occur on the ‘snowbank’ (Fig. 11.11C) or the optic nerve head; the latter usually resolves when inflammatory activity is controlled.
• Subtle disc oedema may be seen, especially in young patients.

Table 11.4 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
image

Fig. 11.11 Posterior segment signs in intermediate uveitis. (A) Peripheral periphlebitis and a few snowballs inferiorly; (B) inferior snowbanking and snowballs; (C) severe snowbanking, neovascularization and inferior retinal detachment

(Courtesy of CL Schepens, ME Hartnett and T Hirose, from Schepens’ Retinal Detachment and Allied Diseases, Butterworth-Heinemann, 2000 – figs A and C)

Course

• A minority of patients have a benign course, which may not require treatment, with spontaneous resolution within several years.
• In other patients the disease is more severe and prolonged with episodes of exacerbations that tend to become progressively worse.
• IU associated with systemic diseases has a variable course depending on the disease and its severity.
• The disease may last as long as 15 years and preservation of vision will depend on control of macular disease. In follow-up of up to 4 years, 75% of patients have a visual acuity of 6/12 or better.

Complications

• CMO occurs in 30% of cases and is the major cause of impaired visual acuity.
• Macular epiretinal formation is common.
• Cataract and glaucoma may occur in eyes with prolonged inflammation, particularly if requiring long-term steroid therapy.
• Peripheral retinal vasoproliferative tumours are uncommon.
• Retinal detachment is uncommon, but may occur in advanced cases (see Fig. 11.11C). The detachment may be tractional, rhegmatogenous and occasionally exudative; retinoschisis has also been described.
• Vitreous haemorrhage may occur from the snowbank or disc new vessels, particularly in children with PP.

Treatment

1 Medical. Initial treatment involves topical steroids or posterior periocular steroid injections. Further options in unresponsive cases include systemic steroids and immunosuppressive agents. Intermediate uveitis associated with multiple sclerosis (see below) may respond to interferon beta.
2 Vitrectomy may be beneficial for CMO as well as the inflammatory process itself. It may therefore be considered following failure of systemic steroids to control CMO but prior to the use of immunosuppressive agents. Other indications for vitrectomy include tractional retinal detachment, severe vitreous opacification, non-resolving vitreous haemorrhage and epiretinal membranes.
3 Cryotherapy is now seldom used but may be considered for peripheral exudative retinal detachments associated with telangiectatic vessels and vasoproliferative tumours.
4 Laser photocoagulation of the peripheral retina is useful in eyes with neovascularization of the vitreous base.

Systemic associations

1 Multiple sclerosis-associated IU may precede or antedate the diagnosis of demyelination. MS should be suspected in females in the 3rd–4th decades especially if they are carriers of HLA-DR15 (a suballele of HLA-DR2). Other causes of neurological concomitants of uveitis include: Vogt–Koyanagi–Harada syndrome, Behçet syndrome, AIDS, primary CNS lymphoma, herpes virus infections, syphilis, acute posterior multifocal placoid pigment epitheliopathy and Whipple disease.
2 Sarcoidosis-associated IU is relatively uncommon and may antedate the onset of systemic disease. The presence of associated granulomatous anterior uveitis should arouse suspicion.
3 Lyme disease-associated IU is often associated with severe anterior uveitis. Visits to endemic areas and a history of a tick bite should be elicited, and the diagnosis confirmed by serology.
4 Tuberculosis is an uncommon association.

Differential diagnosis

Chronic conditions which produce vitritis, or peripheral retinal changes mimicking IU include the following:

1 Fuchs uveitis syndrome may be associated with severe vitreous inflammation but it is usually unilateral, not associated with CMO and manifests characteristic anterior segment findings.
2 Primary intraocular lymphoma may also present with vitritis but the infiltrate is more homogeneous and ‘snow-balls’ are absent.
3 A peripheral toxocara granuloma may resemble snowbanking and be associated with mild vitritis but is invariably unilateral.
4 Other conditions
• Amyloidosis may produce vitreous opacities (see Ch. 17) without vasculitis or CMO.
• Whipple disease may be associated with vitritis without snowballs.
• Endogenous candida endophthalmitis may be associated with snowballs.
• Toxoplasmosis may give dense vitritis that can obscure the focus of retinitis.

Uveitis in spondyloarthropathies

HLA-B27 and spondyloarthropathies

A strong association exists between HLA-B27 and spondyloarthropathies; the prevalence of HLA B-27 is as follows:

• 6–8% of the Caucasian population of the USA.
• 50% of patients with AAU who are otherwise fit and well.
• 90% of patients with AAU who have an associated spondyloarthropathy, most notably ankylosing spondylitis.
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The AAU associated with HLA-B27 is typically unilateral, severe, recurrent and associated with a higher incidence of posterior synechiae. A fibrinous exudate in the anterior chamber is common. Patients who do not carry HLA-B27 tend to have a more benign course with fewer recurrences.

Ankylosing spondylitis

1 Definition. 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 typically affects males, of whom 90% are HLA-B27 positive; some patients also have inflammatory bowel disease (enteropathic arthritis).
2 Presentation is in the 3rd–4th decades with insidious onset of pain and stiffness in the lower back or buttocks.
3 Signs
a Spondyloarthritis causes progressive limitation of spinal movements and eventually the spine may become fixed in flexion (Fig. 11.12A).
b Enthesopathy is characterized by inflammation and pain at ligamentous attachments to bone.
4 Radiology of the sacroiliac joints reveals juxta-articular osteoporosis in the early stages, followed by sclerosis and bony obliteration of the joint (Fig. 11.12B). Calcification of spinal ligaments gives rise to a ‘bamboo spine’. Radiological changes often predate clinical symptoms.
5 AAU occurs in about 25% of patients with AS; conversely, 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. In a few patients with many recurrent attacks the inflammation may become chronic.
image
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Fig. 11.12 Spondyloarthropathies. (A) Fixed flexion deformity in ankylosing spondylitis; (B) sclerosis and bony obliteration of the sacroiliac joints in ankylosing spondylitis; (C) circinate balanitis in Reiter syndrome; (D) keratoderma blenorrhagica in Reiter syndrome; (E) psoriasis; (F) arthritis of the fingers and severe nail dystrophy in psoriatic arthritis

(Courtesy of MA Mir, from Atlas of Clinical Diagnosis, Saunders 2003 – fig. A; RT Emond, PD Welsby and HA Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003 – fig. C)

Reiter syndrome

1 Definition. Reiter syndrome (RS), also referred to as reactive arthritis, is characterized by the triad of (a) non-specific (non-gonococcal) urethritis, (b) conjunctivitis and (c) arthritis. About 85% of patients are positive for HLA-B27.
2 Pathogenesis. RS develops in 1–3% of men after non-specific urethritis, up to 4% of persons after enteric infections caused by Shigella, Salmonella and Campylobacter, and in a higher proportion of patients with Yersinia enteric infections. Post-dysenteric RS affects males and females equally, whereas post-venereal RS is more common in men.
3 Presentation is in the 3rd–4th decades with non-specific urethritis, conjunctivitis and arthritis occurring within a short period of each other, classically a month after dysentery or sexual intercourse.
4 Signs
a Peripheral arthritis is acute, asymmetrical and migratory. Two to four joints tend to be involved, most commonly the knees, ankles and toes.
b Spondyloarthritis affects about 30% of patients with severe chronic RS and is related to the presence of HLA-B27.
c Enthesopathy causes plantar fasciitis, Achilles tenosynovitis, bursitis and calcaneal periostitis; reactive bone formation in the latter may result in a calcaneal spur.
d Mucocutaneous lesions include painless mouth ulceration, circinate balanitis (Fig. 11.12C), keratoderma blenorrhagica involving the palms and soles (Fig. 11.12D) and nail dystrophy.
e Genitourinary involvement causes cystitis, cervicitis, prostatitis, epididymitis and orchitis.
5 AAU occurs in up to 12% patients but is higher in carriers of HLA-B27.
6 Conjunctivitis is very common and usually follows the urethritis by about 2 weeks and precedes the arthritis. The inflammation is usually mild, bilateral and mucopurulent with a papillary or follicular reaction. Spontaneous resolution occurs within 7–10 days and treatment is not required. Some patients develop peripheral corneal infiltrates.

Psoriatic arthritis

1 Definition. About 7% of patients with psoriasis develop arthritis. Psoriatic arthritis affects both sexes equally and is associated with an increased prevalence of HLA-B27 and HLA-B17.
2 Presentation: 3rd–4th decades.
3 Signs
a Skin
• Plaque psoriasis (most common) is characterized by well-demarcated, salmon-pink areas covered with thick, silvery plaques (Fig. 11.12E).
• Flexural psoriasis is characterized by non-scaly pink lesions usually affecting the groin and perineum.
b Nail dystrophy is characterized by pitting, transverse depression and onycholysis (Fig. 11.12F).
c Arthritis is typically asymmetrical and involves the distal interphalangeal joints (see Fig. 11.12F) although some patients may develop ankylosing spondylitis.
4 AAU occurs in approximately 7% of arthritis patients.
5 Other ocular manifestations which are uncommon include conjunctivitis, marginal corneal infiltrates and secondary Sjögren syndrome.

Uveitis in juvenile arthritis

Juvenile idiopathic arthritis

Overview

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Juvenile idiopathic arthritis (JIA) is an inflammatory arthritis of at least 6 weeks’ duration occurring before the age of 16 years when all other causes, such as infection, metabolic disorders or neoplasms have been excluded. Females are affected more commonly by a ratio of 3 : 2. JIA is by far the most common disease associated with childhood anterior uveitis. It should be emphasized that JIA is not the same as juvenile rheumatoid arthritis (JRA); the former is negative for rheumatoid factor whereas the latter is positive; JRA is the same disease as rheumatoid arthritis except that it occurs before the age of 16 years.

Arthritis

1 Presentation is based on the onset and the extent of joint involvement during the first 6 months; three types of presentation are recognized.
a Pauciarticular onset JIA involves four or fewer joints and accounts for about 60% of cases.
• Girls are affected five times as often as boys, with a peak age of onset around 2 years.
• The arthritis involves the knees most commonly (Fig. 11.13A), although the ankles and wrists may also be affected.
• Some patients in this subgroup remain pauciarticular, others subsequently develop a polyarthritis.
• About 75% of children are antinuclear antibody (ANA) positive.
• Uveitis is common in this group and affects about 20% of children.
• Risk factors for uveitis are early onset of JIA and ANA positivity.
b Polyarticular onset JIA affects five or more joints and accounts for a further 20% of cases.
• Girls are affected about three times as often as boys and the disease may commence at any age throughout childhood.
• The arthritis involves both small and large joints symmetrically (Fig. 11.13B).
• Systemic features such as fever and rash are mild or absent.
• About 40% of children are ANA positive.
• Uveitis occurs in about 5% of cases.
c Systemic onset JIA accounts for about 20% of cases.
• The disease occurs with equal frequency in boys and girls and may occur at any age throughout childhood.
• Systemic features include a high remittent fever, transient maculopapular rash (Fig. 11.13C), generalized lymphadenopathy, hepatosplenomegaly and serositis.
• Initially, arthralgia or arthritis may be absent or minimal and a minority of patients subsequently develop progressive polyarthritis.
• The vast majority are negative for ANA.
• Uveitis does not occur.
• The term ‘Still disease’ is reserved for patients in this subgroup.
image

Fig. 11.13 Juvenile idiopathic arthritis. (A) Monoarticular disease affecting a knee; (B) severe polyarticular disease; (C) maculopapular rash in systemic-onset disease; (D) band keratopathy and mature cataract in associated chronic anterior uveitis

Anterior uveitis

1 Presentation is invariably asymptomatic; the uveitis is frequently detected on routine 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. In the greater majority of patients, arthritis antedates the diagnosis of uveitis although rarely ocular involvement may precede joint disease by several years. Often uveitis may not be suspected until the parents recognize complications such as strabismus, or an abnormal appearance of the eye due to band keratopathy or cataract.
2 Signs
• Inflammation is chronic and non-granulomatous.
• Both eyes are affected in 70%; it is unusual for unilateral uveitis to become bilateral after more than a year.
• When bilateral, the severity of inflammation is usually symmetrical.
• The eye is usually white even in the presence of severe uveitis.
• 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.
3 Prognosis
• In about 10% of cases 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.
• In 25% of cases, the uveitis is very severe, lasts for several years and responds poorly to treatment. In this subgroup, band keratopathy occurs in 40% of patients, cataract in 30% (Fig. 11.13D) and secondary glaucoma in 15%.
• Other serious complications include phthisis and amblyopia.
• The presence of complications at initial examination appears to be an important risk factor for the development of subsequent complications, regardless of therapy.
4 Treatment with topical steroids is usually effective; acute exacerbations require very frequent instillation. Poor responders to topical administration may benefit from periocular injections. Low-dose methotrexate is useful for steroid resistance.
5 Screening. Because the onset of intraocular inflammation is invariably asymptomatic, it is extremely important to regularly screen children at risk for at least 7 years from the onset of arthritis or until the age of 12 years. The frequency of slit-lamp examination is governed by the following risk factors.
• Systemic onset = not required.
• Polyarticular onset = every 9 months.
• Polyarticular onset + ANA = every 6 months.
• Pauciarticular onset = every 3 months.
• Pauciarticular onset + ANA = every 2 months.

Differential diagnosis

1 Idiopathic juvenile chronic iridocyclitis. Whilst JIA is the most common systemic association of CAU in children, many patients with juvenile CAU are otherwise healthy. The majority of patients are also girls. As the onset of intraocular inflammation is frequently insidious and asymptomatic, most cases are not diagnosed until visual acuity is reduced from cataract or the parents notice a white patch on the cornea caused by band keratopathy. In a small number of cases the uveitis is detected by chance.
2 Other types of juvenile arthritis and uveitis
a Juvenile AS is uncommon and typically affects boys around the age of 10 years. Early diagnosis may be difficult, because in children the disease frequently presents with peripheral lower limb arthritis and radiological evaluation of the sacro-iliac joints is usually not helpful during the early stages. Just like adults, some children develop AAU.
b Juvenile Reiter syndrome is very rare and is invariably post-dysenteric. A few cases of acute anterior uveitis have been reported.
c Juvenile psoriatic arthritis is relatively uncommon and is characterized by asymmetrical involvement of both large and small joints in association with skin lesions and nail pitting. Chronic anterior uveitis is uncommon.
d Juvenile bowel-associated arthritis is rare. Joint involvement is usually mild and affects large joints in association with either ulcerative colitis or Crohn disease. Anterior uveitis, which may be acute or chronic, has been reported in a few patients.
3 Juvenile sarcoidosis is rare and less frequently associated with pulmonary involvement than in adults. It typically manifests with skin, joint and eye disease. Chest radiographs are therefore of less diagnostic value in children. Serum angiotensin-converting enzyme may also be misleading because children have higher normal values than adults. When uveitis is confined to the anterior segment it can be confused with JIA-associated uveitis. Unlike JIA-associated uveitis, however, it may also be granulomatous and also involve the posterior segment.
4 Lyme disease usually presents with intermediate uveitis in conjunction with significant anterior uveitis.
5 Intermediate uveitis accounts for 20% of all cases of paediatric uveitis and is frequently bilateral. The inflammation primarily involves the vitreous and anterior uveitis is usually insignificant.
6 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.
7 Masquerade syndromes, most notably anterior segment involvement by retinoblastoma (see Fig. 12.33D), which typically affects older children.

Familial juvenile systemic granulomatosis syndrome

Familial juvenile systemic granulomatosis (Blau syndrome), is a rare AD disorder characterized by childhood onset of granulomatous disease of skin, eyes and joints but absence of pulmonary disease.

1 Systemic features, which develop in the 1st decade, include painful cystic joint swelling which may progress to flexion contractures (camptodactyly), and an intermittent perioral rash.
2 Ocular manifestations include panuveitis and multifocal choroiditis. Complications include cataract, band keratopathy and CMO.
3 Differential diagnosis includes early-onset sarcoidosis and JIA.

Uveitis in bowel disease

Ulcerative colitis

1 Definition. Ulcerative colitis 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 diffuse surface ulceration of the mucosa with the development of crypt abscesses and pseudopolyps (Fig. 11.14A). Patients with long-standing disease carry an increased risk of developing carcinoma of the colon.
2 Presentation is in the 2nd–3rd decades with bloody diarrhoea, lower abdominal cramps, urgency and tenesmus. Constitutional symptoms include tiredness, weight loss, malaise and fever.
3 Extra-intestinal manifestations
a Mucocutaneous lesions include oral aphthous ulceration, erythema nodosum and pyoderma gangrenosum (Fig. 11.14B).
b Arthritis is typically asymmetrical and involves large joints of the legs; sacroiliitis and AS may develop in HLA-B27 positive patients.
c Hepatic disease may be in the form of autoimmune hepatitis, sclerosing cholangitis and cholangiocarcinoma.
d Thromboses may affect both arteries and veins.
4 AAU occurs in about 5% of patients and may synchronize with exacerbations of colitis. As expected, uveitis is more common in patients with associated AS.
image
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Fig. 11.14 Inflammatory bowel disease. (A) Barium enema in ulcerative colitis shows pseudopolyposis, lack of haustral markings and straightening of the ascending colon; (B) pyoderma gangrenosum in ulcerative colitis; (C) barium enema in Crohn disease shows a stricture in the descending colon; (D) perianal abscess and fistula in Crohn disease

(Courtesy of CD Forbes and WF Jackson, from Color Atlas and Text in Clinical Medicine, Mosby 2003 – fig. D)

Crohn disease

1 Definition. Crohn disease (regional ileitis) is an idiopathic chronic relapsing disease characterized by multifocal, full-thickness, non-caseating granulomatous inflammation of the intestinal wall. It most frequently involves the ileocaecal region but any area of the bowel, including the mouth, may be affected. Complications include stricture formation (Fig. 11.14C), perirectal abscesses and fistulae (Fig. 11.14D), and liver disease.
2 Presentation is in the 2nd–3rd decades with fever, weight loss, diarrhoea and abdominal pain.
3 Extra-intestinal manifestations
a Mucocutaneous involvement includes glossitis, aphthous ulceration, erythema nodosum, pyoderma gangrenosum and psoriasis.
b Skeletal features include finger clubbing, acute peripheral arthritis, sacroiliitis and ankylosing spondylitis.
4 AAU occurs in about 3% of patients.
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Whipple disease

1 Definition. Whipple disease (intestinal lipodystrophy) is a rare, chronic, bacterial infection with Tropheryma whipplei that primarily involves the gastrointestinal tract and its lymphatic drainage. It occurs mostly in white middle-aged men. Jejunal biopsy shows infiltration of small intestinal mucosa by ‘foamy’ macrophages which stain with periodic acid-Schiff. Electron microscopy shows small rod-shaped bacilli within the macrophages.
2 Presentation is with weight loss, arthralgia, diarrhoea and abdominal pain.
3 Extra-intestinal manifestations involve the CNS, lungs, heart, joints and eyes.
4 Uveitis in the form of vitritis, retinitis, retinal haemorrhages and cotton wool spots, and multifocal choroiditis may occur with or without concomitant CNS disease.
5 Neuro-ophthalmic involvement may cause gaze palsy, nystagmus, ophthalmoplegia, papilloedema and optic atrophy.

Uveitis in renal disease

Tubulointerstitial nephritis and uveitis (TINU)

1 Definition. Tubulointerstitial nephritis and uveitis (TINU) is an uncommon oculorenal disorder of immune origin characterized by a combination of idiopathic acute tubulointerstitial nephritis and uveitis. It typically occurs in adolescent girls. Renal disease usually precedes uveitis.
2 Presentation is with constitutional symptoms, proteinuria, anaemia, hypertension and renal failure. The response to systemic steroid therapy is good and the condition resolves within a few months.
3 AAU is usually anterior, bilateral, non-granulomatous, and responds well to topical steroids. Some cases become chronic and relapsing and may require immunosuppressive therapy. Intermediate uveitis, posterior uveitis and disc oedema may also occur.

IgA glomerulonephritis

1 Definition. IgA glomerulonephritis is a relatively common disease in which IgA is found in the glomerular mesangium.
2 Presentation is usually in the 3rd–5th decades with recurrent haematuria which may be associated with upper respiratory tract infection, lethargy and muscle pains; renal failure ensues in 20% of cases.
3 AAU is uncommon.

Sarcoidosis

Definition

Sarcoidosis is a T-lymphocyte-mediated non-caseating granulomatous inflammatory disorder of unknown cause. It is most common in colder climates, although it more frequently affects patients of African descent than Caucasians. The clinical spectrum of disease varies from mild single-organ involvement to potentially fatal multisystem disease which can affect almost any tissue. The tissues most commonly involved are the mediastinal and superficial lymph nodes, lungs, liver, spleen, skin, parotid glands, phalangeal bones and the eye.

Presentation

1 Acute-onset sarcoidosis presents in young patients in one of the following ways:
a Löfgren syndrome is characterized by erythema nodosum (Fig. 11.15A) and bilateral hilar lymphadenopathy (Fig. 11.15B), often accompanied by fever, anorexia and arthralgia.
b Heerfordt syndrome (uveoparotid fever) is characterized by uveitis, parotitis, fever and cranial nerve palsy, usually the seventh nerve (Fig. 11.15C).
2 Insidious-onset disease typically presents during the 5th decade with pulmonary involvement resulting in cough and dyspnoea, together with extrapulmonary manifestations.
image

Fig. 11.15 Sarcoidosis. (A) Erythema nodosum; (B) bilateral hilar lymphadenopathy; (C) seventh nerve palsy; (D) lupus pernio; (E) lacrimal gland enlargement

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

Pulmonary disease

Stage 1 manifests bilateral asymptomatic hilar lymphadenopathy (see Fig. 11.15B); spontaneous resolution occurs within 1 year in most cases.
Stage 2 consists of stage 1 and diffuse parenchymal reticulonodular infiltrates; spontaneous resolution occurs in the majority.
Stage 3 is characterized by reticulonodular infiltrates alone; spontaneous resolution is less common.
Stage 4 manifests pulmonary fibrosis which may result in progressive dyspnoea, pulmonary hypertension and cor pulmonale.

Skin lesions

The skin is involved in about 25% of patients by one of the following:

1 Erythema nodosum is characterized by tender erythematous plaques typically involving the knees and shins (see Fig. 11.15A) and occasionally the thighs and forearms.
2 Granulomatous scattered papules, plaques or nodules.
3 Lupus pernio consists of indurated, violaceous lesions involving exposed parts of the body such as the nose, cheeks, fingers and ears (Fig. 11.15D).
4 Granulomatous deposits in long-standing scars or tattoos.

Other manifestations

1 Neurological disease affects 5–10% of patients. The most common lesion is unilateral facial nerve palsy (see Fig. 11.15C); less common manifestations include seizures, meningitis, peripheral neuropathy and psychiatric symptoms.
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2 Arthritis in chronic sarcoidosis is typically symmetrical and may involve both small and large joints. In children the presentation can be very similar to JIA because arthropathy tends to be more prominent than pulmonary disease.
3 Bone cysts typically involve the digits and are associated with swelling.
4 Renal disease in the form of nephrocalcinosis, hypercalciuria and calculi.
5 Miscellaneous manifestations include lymphadenopathy, granulomatous liver disease, splenomegaly and cardiac arrhythmias.

Investigations

1 Chest radiographs are abnormal in 90%.
2 Biopsy
• Lungs give the greatest yield (90%) even in asymptomatic patients with normal chest radiograms.
• Conjunctiva is positive in about 70% of patients with granulomatous inflammation in the form of nodules, which resemble those of follicular conjunctivitis.
• Lacrimal glands are positive in 25% of un-enlarged and 75% of enlarged glands (Fig. 11.15E).
• Superficial lymph node or skin lesion.
3 Enzyme assay for serum angiotensin-converting enzyme (ACE) and lysozyme as already described.
4 Bronchoalveolar lavage shows a raised proportion of activated T-helper lymphocytes. Sputum examination may also show increased CD4/CD8 ratios.
5 Pulmonary function tests reveal a restrictive lung defect with reduced total lung capacity and are very useful for monitoring disease activity and the need for systemic therapy.
6 Mantoux test is negative in most patients; a strongly positive reaction to one tuberculin unit makes the diagnosis of sarcoidosis highly unlikely.

Ocular features

Uveitis is the most common and may be in the form of anterior, posterior or intermediate. Other manifestations include KCS, conjunctival nodules, and rarely, orbital and scleral lesions.

1 AAU typically affects patients with acute-onset sarcoid.
2 CAU, typically granulomatous (see Figs 11.4B and 11.5), tends to affect older patients with chronic pulmonary disease.
• Iris nodules may be very large (Fig. 11.16A).
• The trabecular meshwork may show nodules (Fig. 11.16B) and tent-shaped peripheral anterior synechiae.
3 Intermediate uveitis with snowballs (Fig. 11.16C) or string-like opacities is uncommon and may antedate systemic disease. The presence of associated granulomatous anterior uveitis should arouse suspicion.
4 Periphlebitis
• Yellowish or grey-white perivenous sheathing that may also involve the optic nerve head (Fig. 11.17A).
• Occlusive periphlebitis is uncommon (Fig. 11.17B).
• Perivenous exudates referred to as ‘candlewax drippings’ (en taches de bougie) are typical of severe sarcoid periphlebitis (Fig. 11.17C).
5 Choroidal infiltrates are uncommon and vary in appearance:
• Multiple small pale-yellow infiltrates, which may have a ‘punched-out’ appearance, and are often most numerous inferiorly are the commonest (Fig. 11.18A).
• Multiple large confluent infiltrates which may have amoeboid margins are less common (Fig. 11.18B).
• Solitary choroidal granulomas are the least common (see Fig. 11.6B).
6 Multifocal choroiditis (Fig. 11.18C) carries a guarded visual prognosis because it may cause loss of central vision as a result of secondary CNV which may be peripapillary or associated with a chorioretinal scar.
7 Retinal granulomas are small discrete yellow-white lesions (Fig. 11.18D).
8 Peripheral retinal neovascularization may develop secondary to retinal capillary dropout. In black patients it may be mistaken for proliferative sickle-cell retinopathy.
9 Optic nerve involvement may take the following forms:
• Focal granulomas, which do not usually affect vision.
• Papilloedema due to CNS involvement may occur in the absence of other ocular manifestations.
• Persistent disc oedema is a frequent finding in patients with retinal or vitreous involvement (see Fig. 11.17B).
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10 Treatment of anterior uveitis is with topical and/or periocular steroids. Posterior uveitis often requires systemic steroids and occasionally immunosuppressive agents such as methotrexate, azathioprine and ciclosporin.
image

Fig. 11.16 Ocular sarcoidosis (A) Large iris nodules; (B) nodular involvement of the trabecular meshwork; (C) snowballs

(Courtesy of J Salmon – fig. A)

image

Fig. 11.17 Periphlebitis in sarcoidosis. (A) Periphlebitis with involvement of the optic nerve head; (B) occlusive periphlebitis and disc oedema; (C) ‘candlewax’ drippings

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. A; C Pavésio – fig. B; P Morse – fig. C)

image

Fig. 11.18 Choroidal and retinal involvement in sarcoidosis. (A) Small peripheral choroidal granulomas; (B) confluent choroidal infiltrates; (C) multifocal choroiditis; (D) multiple small retinal granulomas

Table 11.5 Differential diagnosis of posterior segment sarcoid

1 Small choroidal lesions
• Multifocal choroiditis with panuveitis
• Birdshot chorioretinopathy
• Tuberculosis
2 Large choroidal infiltrates
• Metastatic tumour
• Large cell lymphoma
• Harada disease
• Serpiginous choroidopathy
3 Periphlebitis
• Tuberculosis
• Behçet syndrome
• Cytomegalovirus retinitis

Behçet syndrome

Overview

Behçet syndrome (BS) is an idiopathic, multisystem disease characterized by recurrent episodes of orogenital ulceration and vasculitis which may involve small, medium and large veins and arteries. The disease typically affects patients from the eastern Mediterranean region and Japan and is strongly associated with human leucocyte antigen (HLA) B51 in different ethnic groups; it is not clear whether the HLA-B51 itself is the pathogenic gene related to BS or some other gene is in linkage disequilibrium. The peak age of onset of BS is in the 3rd decade, although rarely it presents in childhood or old age; males are affected more frequently than females.

Diagnostic criteria

1 Recurrent oral ulceration characterized by painful minor or major aphthous (Fig. 11.19A) or herpetiform ulcerative lesions that have recurred at least three times in a 12-month period.
2 Plus at least two of the following:
• Recurrent genital ulceration (Fig. 11.19B).
• Ocular inflammation.
• Skin lesions include erythema nodosum, folliculitis, acneiform nodules or papulopustular lesions.
• Positive pathergy test, which is characterized by the formation of a pustule after 24–48 hours at the site of a sterile needle prick (see Fig. 11.7C).
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Fig. 11.19 Behçet syndrome. (A) Major aphthous ulceration; (B) genital ulceration; (C) superficial thrombophlebitis; (D) dermatographia

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

Additional features

1 Major vascular complications
• Aneurysms of the pulmonary and/or systemic arterial system.
• Coronary artery disease, cardiomyopathy and valvular disease.
• Venous thrombosis which may involve superficial (Fig. 11.19C) or deep veins, the vena cava, portohepatic vein and cerebral sinuses.
2 Arthritis occurs in 50% of patients. It is typically mild and involves a few large joints, particularly the knees.
3 Skin hypersensitivity demonstrated by the formation of erythematous lines following stroking of the skin (dermatographia – Fig. 11.19D).
4 Gastrointestinal ulceration is uncommon and may involve the oesophagus, stomach or intestines.
5 Neurological manifestations occur in 5% of patients and mainly involve the brainstem although meningoencephalitis and spinal cord disease may also occur.
6 Other uncommon manifestations include glomerulonephritis and epididymitis.

Ocular features

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Ocular complications occur in up to 95% of men and 70% of women. Eye disease typically occurs within 2 years of oral ulceration, but rarely the delay may be as long as 14 years. Conversely, ocular inflammation is the presenting manifestation in about 10% of cases. Ocular disease is usually bilateral and typically presents during the 3rd–4th decades.

1 AAU, which may be simultaneously bilateral and frequently associated with a transient mobile hypopyon in a relatively white eye (‘cold hypopyon’ – Fig. 11.20A). It usually responds well to topical steroids.
2 Retinitis may take the following forms:
• Transient, white, superficial infiltrates (Fig. 11.20B) that heal without scarring may be seen during the acute stage of the systemic disease.
• Diffuse retinitis similar in appearance to a virus-induced lesion.
3 Retinal vasculitis may involve both veins and arteries and result in occlusion (Fig. 11.20C). Vascular leakage may give rise to diffuse retinal oedema, CMO and disc oedema.
4 Vitritis, which may be severe and persistent, is universal in eyes with active disease.
5 End-stage disease is characterized by optic atrophy, vascular occlusion and gliotic sheathing (Fig. 11.20D) but the vitreous is remarkably clear by this stage.
6 Other manifestations, which are uncommon, include conjunctivitis, conjunctival ulcers, episcleritis, scleritis and ophthalmoplegia from neurological involvement.
image

Fig. 11.20 Ocular Behçet syndrome. (A) Hypopyon in a white eye; (B) retinal infiltrates; (C) occlusive vasculitis; (D) end-stage disease

(Courtesy of A Dick – fig. C)

Treatment of posterior uveitis

1 Systemic steroids may shorten the duration of an inflammatory episode but an additional agent is usually required.
2 Azathioprine does not act rapidly enough in acute disease but is suitable for long-term therapy.
3 Ciclosporin is effective and rapidly acting but is associated with nephrotoxicity, particularly at doses higher than 5 mg/kg/day; relapses after cessation often limit its use.
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4 Subcutaneous interferon alfa is very effective for mucocutaneous lesions and may also be used to treat ocular disease resistant to high dose steroids. Side-effects are dose-dependent and include flu-like symptoms, hair loss, itching and depression.
5 Biological blockers such as infliximab show promise in treating retinal vasculitis.

Differential diagnosis

Differential diagnosis in patients with suggestive ocular findings but lack of classical systemic manifestations should include the following:

1 Recurrent anterior uveitis with hypopyon may occur in spondyloarthropathies. However, the uveitis is not usually simultaneously bilateral and the hypopyon is not mobile because it is frequently associated with a fibrinous exudate. In BS uveitis is frequently simultaneously bilateral and the hypopyon shifts with gravity as the patient changes head position.
2 Retinal vasculitis may be associated with sarcoidosis. However, sarcoid vasculitis involves only veins in a segmental manner and is rarely occlusive. In contrast, BS usually affects both arteries and veins, is diffuse, frequently occlusive and is associated with vitritis, which is uncommon in sarcoid-related vasculitis.
3 Retinal infiltrates similar to those in BS may be seen in viral retinitis such as acute retinal necrosis. However, in viral retinitis the infiltrates eventually coalesce. Multiple retinal infiltrates also occur in idiopathic acute multifocal retinitis (see Fig. 11.79) in which the clinical course is more favourable.

Toxoplasmosis

Introduction

Pathogenesis

Toxoplasmosis is caused by Toxoplasma gondii, an obligate intracellular protozoan. It is estimated to infest at least 10% of adults in northern temperate countries and more than half of adults in Mediterranean and tropical countries. The cat is the definitive host and intermediate hosts include mice, livestock and humans (Fig. 11.21). The parasite exists in the following forms:

1 Sporozoites are contained within an oocyst (sporocyst) and result from sexual reproduction of the organisms with the intestinal mucosa of the cat. They are excreted in the faeces and spread to intermediate hosts.
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2 Bradyzoites are relatively inactive and are contained within tissue cysts (Fig. 11.22A) that most commonly develop in the brain, eye, heart, skeletal muscles and lymph nodes. They may lie dormant for many years without provoking an inflammatory reaction.
3 Tachyzoites (trophozoites) are the proliferating active form responsible for tissue destruction and inflammation following rupture of the wall of a cell containing bradyzoites (Fig. 11.22B).
image

Fig. 11.21 Life cycle of Toxoplasma gondii

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Fig. 11.22 Toxoplasma gondii. (A) Tissue cysts containing bradyzoites; (B) release of tachyzoites (arrow) following rupture of the cell wall

(Courtesy of J Harry – fig. A; RT Emond, PD Welsby and HA Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003 – fig. B)

Mode of human infection

1 Ingestion of undercooked meat (lamb, pork, beef) containing bradyzoites of an intermediate host.
2 Ingestion of sporocysts following inadvertent contamination of hands when disposing of cat litter trays and then subsequent transfer on to food. Infants may also become infected by eating dirt (pica) containing sporocysts. It is likely that water contamination plays an important role in the transmission of the disease in rural areas.
3 Transplacental spread of the parasite (tachyzoite) can occur if a pregnant woman becomes infected.

Congenital toxoplasmosis

Toxoplasmosis is transmitted to the fetus through the placenta when a pregnant woman becomes infected. If the mother is infected before pregnancy, the fetus will be unscathed.

1 Severity of involvement of the fetus is dependent on the duration of gestation at the time of maternal infection. For example, infection during early pregnancy may result in stillbirth, whereas if it occurs during late pregnancy it may result in convulsions, paralysis, hydrocephalus (Fig. 11.23A) and visceral involvement.
2 Manifestations
• Intracranial calcification seen on CT (Fig. 11.23B).
• However, just as in the acquired form, most cases of congenital systemic toxoplasmosis are subclinical. In these children, bilateral healed chorioretinal scars may be discovered later in life, either by chance or when the child is found to have defective vision.
• Infections occurring towards the end of the second trimester usually result in disease that can be detected at birth such as macular scars (Fig. 11.23B), while those occurring later in the third trimester may result in normal examination at birth, but the appearance of ocular or neurological symptoms in the future.
• The risk of disease later in life can be modified by early recognition of the transmission and long-term therapy.
3 Serological tests as previously described.
image

Fig. 11.23 Congenital toxoplasmosis. (A) Hydrocephalus and right anophthalmos; (B) axial CT shows cerebral calcification; (C) macular scar

(Courtesy of M Szreter – fig. A; R T Emond, P D Welsby and H A Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003 – fig. B)

Acquired toxoplasmosis

1 Immunocompetent patients may have the following manifestations:
a Subclinical is the most frequent.
b Lymphadenopathic syndrome, which is uncommon and self-limiting, is characterized by cervical lymphadenopathy, fever, malaise and pharyngitis.
c Meningoencephalitis, characterized by convulsions and altered consciousness, occurs in a minority of patients.
d The exanthematous form, resembling a rickettsial infection, is the rarest.
2 In immunocompromised patients the disease may be life-threatening. The most common manifestation in AIDS patients is an intracerebral space-occupying lesion which resembles a cerebral abscess on MR.

Toxoplasma retinitis

Pathogenesis

Toxoplasmosis is the most frequent cause of infectious retinitis in immunocompetent individuals. Reactivation at previously inactive cyst-containing scars is the rule in the immunocompetent, although a small minority may represent new infection. Most quiescent lesions will have been acquired postnatally. Recurrent episodes of inflammation are common and occur when the cysts rupture and release hundreds of tachyzoites into normal retinal cells. Recurrences usually take place between the ages of 10 and 35 years (average age 25 years).

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Clinical features

The diagnosis of toxoplasma retinitis is based on a compatible fundus lesion and positive serology for toxoplasma antibodies (see ‘Investigations’). Any antibody titre is significant because in recurrent ocular toxoplasmosis, no correlation exists between the titre and the activity of retinitis.

1 Presentation is with unilateral sudden onset of floaters, visual loss and photophobia.
2 Signs
• ‘Spill-over’ anterior uveitis, which may be granulomatous and resemble Fuchs syndrome, is common.
• Solitary inflammatory focus near an old pigmented scar (‘satellite lesion’) (Fig. 11.24A).
• Multiple foci are uncommon (Fig. 11.24B).
• Severe vitritis may greatly impair visualization of the fundus, although the inflammatory focus may still be discernible (‘headlight in the fog’ appearance) (Fig. 11.24C).
3 Atypical features that may occur particularty in immunocompromised individuals are the following:
• Extensive confluent areas of retinitis that may be bilateral and difficult to distinguish from a viral retinitis.
• Inflammatory focus not associated with a pre-existing scar implying that the infestation has been newly acquired and disseminated to the eye from extraocular sites.
4 The rate of healing is dependent on the virulence of the organism, the competence of the host’s immune system and (especially) the size of the lesion. In uncompromised hosts healing occurs within 6 to 8 weeks (Fig. 11.25A-C) although vitreous opacities take longer to resolve. The inflammatory focus is replaced by a sharply demarcated atrophic scar which becomes progressively pigmented starting at the edges, producing a hyperpigmented border. Resolution of anterior uveitis is a reliable sign of posterior segment healing. After the first attack, the mean recurrence rate within 3 years is about 50% and the average number of recurrent attacks per patient is 2.7. In elderly patients the course may be progressive and should be differentiated from viral retinitis and lymphoma.
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Fig. 11.24 Active toxoplasma retinitis. (A) Typical ‘satellite’ lesion adjacent to an old scar; (B) two small foci; (C) severe vitreous haze and ‘headlight in the fog’ appearance

(Courtesy of C Pavésio – figs B and C)

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Fig. 11.25 Progression of toxoplasma retinitis. (A) Mild fluffy haze adjacent to an old scar at presentation; (B) after 2 weeks the area of retinitis is larger and denser; (C) after 7 weeks the retinitis has nearly resolved.

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Complications

Nearly 25% of eyes develop visual loss as a result of the following:

1 Common
• Direct involvement of the macula (Fig. 11.26A).
• Secondary optic nerve head involvement due to a juxtapapillary lesion (Fig. 11.26B).
2 Uncommon
• Primary optic nerve head involvement may mimic anterior ischaemic optic neuropathy.
• Occlusion of a major blood vessel by the inflammatory focus (Fig. 11.27A and B).
• Choroidal neovascularization (Fig. 11.27C and D).
• Serous retinal detachment (Fig. 11.27E and F).
• Tractional retinal detachment secondary to organization of severe vitreous opacification.
• Macular oedema.
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Fig. 11.26 Common complications of toxoplasma retinitis. (A) Scar at the fovea and a fresh lesion involving the papillomacular bundle; (B) juxtapapillary lesion involving the optic nerve head

image

Fig. 11.27 Uncommon complications of toxoplasma retinitis. (A) Periarteritis resulting in branch retinal artery occlusion; (B) FA shows extensive non-perfusion at the posterior pole; (C) choroidal neovascularization adjacent to an old scar; (D) FA shows corresponding hyperfluorescence; (E) serous macular detachment; (F) FA shows hyperfluorescence due to pooling of dye

(Courtesy of C Pavésio – figs A, B, E and F; P Gili – figs C and D)

Treatment

1 Aims
• To reduce the duration and severity of acute inflammation.
• To lessen the risk of permanent visual loss by reducing the size of the eventual retinochoroidal scar.
• To reduce the risk of recurrences.
2 Indications. There is lack of evidence that treatment with antibiotics achieves any of the above aims although adjunctive corticosteroids may diminish the duration and severity of inflammation. Despite these reservations treatment may be considered for the following vision-threatening lesions:
• A sight-threatening lesion involving the macula, papillomacular bundle, optic nerve head or a major blood vessel.
• Very severe vitritis, because of the risk of vitreous fibrosis and tractional retinal detachment.
• In immunocompromised patients all lesions should be treated irrespective of location or severity.
3 Regimen. There is no universally agreed therapeutic regimen. Systemic prednisolone (1 mg/kg) is given initially and tapered according to clinical response, but should always be used in conjunction with a specific anti-toxoplasma agent, most frequently pyrimethamine combined with sulfadiazine. Systemic steroids should be avoided or used with extreme caution in the immunocompromised.
a Pyrimethamine (Daraprim) is administered as a loading dose of 50 mg followed by 25–50 mg daily for 4 weeks in combination with oral folinic acid 5 mg (mixed with orange juice) three times a week to prevent thrombocytopenia, leucopenia and folate deficiency. Weekly blood counts should be performed. In AIDS pyrimethamine is avoided because of possible pre-existing bone marrow suppression and the antagonistic effect of zidovudine when the drugs are combined.
b Sulfadiazine 1 g q.i.d. for 3–4 weeks is usually given in combination with pyrimethamine. Side-effects of sulphonamides include renal stones, allergic reactions and Stevens–Johnson syndrome.
c Other systemic options include clindamycin, spiramycin, tetracyclines, atovaquone, azithromycin and clarithromycin.
d Topical steroids may be given for anterior uveitis but periocular depot injections are contraindicated as they may lead to uncontrolled progression.

Toxocariasis

Pathogenesis

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Toxocariasis is caused by an infestation with a common intestinal ascarid (roundworm) of dogs called Toxocara canis (Fig. 11.28A). About 80% of puppies between the ages of 2 and 6 months are infested with this worm. Human infestation is by accidental ingestion of soil or food contaminated with ova shed in dogs’ faeces. Very young children who eat dirt (pica) or are in close contact with puppies are at particular risk of acquiring the disease. In the human intestine, the ova develop into larvae which penetrate the intestinal wall and travel to various organs, such as the liver, lungs, skin, brain and eyes (Fig. 11.28B). When the larvae die, they disintegrate and cause an inflammatory reaction followed by granulation. Clinically, human infestation can take one of the following forms:

1 Visceral larva migrans (VLM) is caused by severe systemic infection which usually occurs at about the age of 2 years. The clinical features, which vary in severity, include a low-grade fever, hepatosplenomegaly, pneumonitis, convulsions and rarely, death. The blood shows leucocytosis and marked eosinophilia.
2 Ocular toxocariasis differs markedly from VLM because it involves otherwise healthy individuals who have a normal white cell count with absence of eosinophilia. A history of pica is less common, and the average age at presentation is considerably older (7.5 years) compared with VLM (2 years). ELISA can be used to determine the level of serum antibodies to T. canis. When ocular toxocariasis is suspected, exact ELISA titres should be requested, including testing of undiluted serum. Any positive titre is consistent with, but not necessarily diagnostic of, toxocariasis. It must therefore be interpreted in conjunction with the clinical findings. A positive titre does not therefore exclude the possibility of retinoblastoma. Ocular toxocariasis may present as one of the following clinical forms.
image

Fig. 11.28 Toxocara canis. (A) Adult worms from dog faeces; (B) larva in tissues surrounded by an inflammatory reaction

(Courtesy of CA Hart and P Shears, from Color Atlas of Medical Microbiology, Mosby 2004 – fig. B)

Chronic endophthalmitis

1 Presentation is between the ages of 2 and 9 years with leukocoria (Fig. 11.29A), strabismus or unilateral visual loss.
2 Signs
• Anterior uveitis and vitritis.
• In some cases, there may be a peripheral granuloma.
• The peripheral retina and pars plana may be covered by a dense greyish-white exudate, similar to the snowbanking seen in pars planitis (Fig. 11.29B).
3 Ultrasonography may be useful in establishing the diagnosis in eyes with hazy media and in excluding other causes of leukocoria (Fig. 11.29C).
4 Treatment with steroids, either periocular or systemic, may be used to reduce the inflammatory activity.
5 Prognosis in most cases is very poor and some eyes eventually require enucleation. The main causes of visual loss are tractional retinal detachment and hypotony with phthisis bulbi, the latter caused by separation of the ciliary body from the sclera by contraction of a cyclitic membrane (Fig. 11.29D).
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Fig. 11.29 Chronic toxocara endophthalmitis. (A) Leukocoria; (B) peripheral exudation and vitreoretinal traction bands; (C) ultrasonography shows a vitreoretinal traction band; (D) a pathological specimen shows an inflammatory mass and total retinal detachment

(Courtesy of N Rogers – figs A and C; S Lightman – fig. B; J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. D)

Posterior pole granuloma

1 Presentation is typically with unilateral visual impairment between the ages of 6–14 years.
2 Signs
• Absence of intraocular inflammation.
• Round, yellow-white, solid granuloma which varies between one to two disc-diameters in size in the posterior fundus (Fig. 11.30A).
• Associated findings include vitreoretinal traction bands and localized tractional retinal detachment (Fig. 11.30B).
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Fig. 11.30 Toxocara granuloma. (A) Juxtapapillary granuloma: (B) posterior pole granuloma associated with a localized tractional retinal detachment; (C) peripheral granuloma with a vitreous band extending to the disc

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. A)

Peripheral granuloma

1 Presentation is usually in adolescence or adult life with visual impairment from distortion of the macula or retinal detachment. In uncomplicated cases, the lesion may remain undetected throughout life.
2 Signs
• Absence of intraocular inflammation.
• A white hemispherical peripheral granuloma in any quadrant of the fundus that may be associated with a vitreous band extending to the disc causing ‘dragging’ (Fig. 11.30C).
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Miscellaneous parasitic uveitis

Onchocerciasis

Pathogenesis

Onchocerciasis or river blindness is caused by infestation with the parasitic helminth Onchocerca volvulus. The normal vector is the black fly Simulium spp., an obligate intermediate host, which breeds in fast flowing water. Larvae are transmitted when the fly bites to obtain blood, which then mature into adult worms that produce millions of microfilariae over years (Fig. 11.31). Wolbachia (a rickettsia) lives symbiotically in the coat of the microfilaria in a fashion similar to mitochondria and are important for fertility of the female filarial worm. Onchocerciasis is endemic in West, Central and East Africa, with small foci in central and South America, Sudan and Yemen. Infecting nearly 18 million people most of whom are asymptomatic but with an estimated 270 000 blind and half a million visually impaired. The disease is especially severe in savannah areas.

image

Fig. 11.31 Life cycle of Onchocerca volvulus

Systemic features

1 Signs
• The most common early manifestation is pruritus which is followed by a maculopapular rash often involving the buttocks and extremities (Fig. 11.32A).
• Chronic lesions are characterized by focal areas of hypo- and hyperpigmentation on the shins (‘leopard’ skin – Fig. 11.32B).
• With time the skin may become thickened and wrinkled as a result of constant scratching (‘lizard’ skin – Fig. 11.32C).
• Subcutaneous nodules (onchocercomas) consisting of encapsulated worms develop nodules over bony prominences (Fig. 11.32D) and the head.
• Occasionally the lymph nodes become grossly enlarged resulting in chronic lymphatic obstruction and lymphoedema.
2 Treatment is with ivermectin given as an annual single dose. Although it acts rapidly to reduce the number of skin microfilariae it depletes them for only a few months after which they reappear at levels of 20% or more of pre-treatment numbers within 1 year, which is sufficient for transmission to continue. Therapies targeting Wolbachia show great promise, including a 6-week course of doxycycline.
image

Fig. 11.32 Onchocerciasis. (A) Maculopapular rash; (B) ‘leopard’ skin; (C) ‘lizard’ skin; (D) subcutaneous nodule (onchocercoma)

(Courtesy of C Gilbert)

Ocular features

1 Anterior segment involvement includes sclerosing keratitis and anterior uveitis that may result in pear-shaped pupillary dilatation. Live floating microfilariae may be seen after the patient has bent face down for a few minutes and then immediately been examined on the slit-lamp.
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2 Chorioretinitis is usually bilateral and predominantly involves the posterior fundus. The severity varies from atrophy and clumping of the RPE which may resemble choroidal ‘sclerosis’ (Fig. 11.33A) to widespread chorioretinal atrophy (Fig. 11.33B).
3 Treatment is aimed at eradicating the source of the microfilariae with ivermectin. Anterior uveitis responds to steroids but the chorioretinal lesions are irreversible.
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Fig. 11.33 Ocular onchocerciasis. (A) Choroidal ‘sclerosis’ and pigmentary changes; (B) severe chorioretinal atrophy

Cysticercosis

1 Pathogenesis. Cysticercosis refers to a parasitic infestation by Cysticercus cellulosae, the larval form of the pork tapeworm Taenia solium. Pigs are the intermediate hosts and humans are the definitive hosts, acquiring the disease by ingesting cysts of T. solium from contaminated pork, vegetables or water.
2 Systemic disease often involves the lungs, muscles and brain.
3 Investigations involve radiology of the chest (Fig. 11.34) and muscles to detect calcified cysts.
4 Ocular features
• Cysts involving conjunctiva, and occasionally the orbit and eyelids.
• The anterior chamber may show a free-floating cyst (Fig. 11.35A).
• The larvae may enter the subretinal space and cause retinal detachment (Fig. 11.35B).
• The larvae can also pass into the vitreous where released toxins incite an intense inflammatory reaction which may ultimately lead to blindness.
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5 Treatment involves systemic steroids to control inflammation together with surgical removal of the larvae from the anterior chamber, vitreous or subretinal space.
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Fig. 11.34 Chest radiograph shows calcified cysticercus cysts

(Courtesy of CA Hart and P Shears, from Color Atlas of Medical Microbiology, Mosby 2004)

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Fig. 11.35 Ocular cysticercosis. (A) Anterior chamber cyst; (B) subretinal cyst with overlying retinal detachment

(Courtesy of A Pearson)

Diffuse unilateral subacute neuroretinitis

1 Pathogenesis. Diffuse unilateral subacute neuroretinitis (DUSN) is characterized by a motile subretinal nematode that typically causes monocular visual loss in an otherwise healthy individual. Baylisascaris procyonis, the raccoon roundworm, as well as Ancylostoma caninum, the dog hookworm, has been implicated but it is possible that different worms are capable of producing the same clinical picture.
2 Presentation is with insidious loss of peripheral and central vision that may be associated with transient visual obscurations.
3 Signs
• Crops of evanescent grey-white outer retinal lesions that tend to resolve within 10 days (Fig. 11.36A) whilst fresh crops appear.
• Papillitis, retinal vasculitis and mild vitritis.
• Optic atrophy, retinal vascular attenuation and diffuse RPE degeneration in end-stage disease (Fig. 11.36B).
• Subretinal scarring.
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4 ERG is subnormal, even in early disease.
5 Treatment involves direct laser photocoagulation of the subretinal nematode by first surrounding it with a ring of burns, which restrict its movement, and then applying heavy burns to the entire area. Systemic albendazole may also be beneficial.
6 Differential diagnosis includes papillitis and multiple evanescent white dot syndrome.
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Fig. 11.36 Diffuse unilateral subacute neuroretinitis. (A) Active lesions; (B) optic atrophy, vascular attenuation and diffuse RPE degeneration

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. A; C de A Garcia – fig. B).

Choroidal pneumocystosis

1 Pathogenesis. Pneumocystis jirovecii, a fungus, is a major cause of morbidity and mortality in AIDS. The presence of choroidal involvement can be an important sign of extrapulmonary systemic dissemination. Most patients with choroiditis have received inhaled pentamidine as prophylaxis against pneumocystis pneumonia. In contrast with systemic prophylaxis this protects only the lungs, allowing the organisms to disseminate throughout the body.
2 Signs
• Flat, yellow, round, choroidal lesions, scattered throughout the posterior pole, which are frequently bilateral and not associated with vitritis (Fig. 11.37A).
• The lesions may coalesce and produce large geographic patches (Fig. 11.37B).
• Even when the fovea is involved there is little visual impairment.
3 Treatment involves intravenous trimethoprim and sulfamethoxazole, or parenteral pentamidine.
image

Fig. 11.37 Choroidal pneumocystosis. (A) Multifocal choroidal lesions; (B) large coalescent lesion

(Courtesy of S Mitchell – fig. A)

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Uveitis in acquired immunodeficiency syndrome

Introduction

Pathogenesis

Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV). On a worldwide basis, heterosexual intercourse is the predominant mode of transmission; in the western world, however, AIDS is commonly transmitted by male homosexual contact. Transmission may also occur by contaminated blood or needles, transplacentally or via breast milk. HIV targets CD4+ T cells, which are vital to the initiation of the immune response to pathogens. A steady decline in the absolute number of CD4+ T cells therefore occurs, resulting in progressive immune deficiency, particularly of cell mediated immunity. Regular estimation of the CD4+ T cell count is therefore a useful measure of disease progression.

Systemic features

1 Progression of HIV infection
a Acute seroconversion illness. HIV infection is sometimes followed a few weeks later by constitutional symptoms such as fever, headache, malaise, and a maculopapular rash associated with generalized lymphadenopathy, soon after which anti-HIV antibodies appear.
b An asymptomatic phase, often lasting many years follows, during which there is a steady depletion of CD4+ T cells.
c Symptomatic HIV infection (AIDS) then follows, characterized by immunosuppression with opportunistic infections, neoplasms and tissue damage directly due to HIV infection.
2 Opportunistic infections with protozoa (e.g. Toxoplasma gandii and Cryptosporidium spp.), viruses (e.g. CMV, HSV) fungi (e.g. Pneumocystis jirovecii (Fig. 11.38A), Cryptococcus neoformans and Candida albicans (Fig. 11.38B), and bacteria (e.g. M. avium-intracellulare and Bartonella henselae).
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3 Tumours include Kaposi sarcoma (Fig. 11.38C), non-Hodgkin B-cell lymphoma and squamous cell carcinoma of the conjunctiva (in Africa), cervix and anus.
4 Other manifestations include HIV wasting syndrome (Fig. 11.38D), HIV encephalopathy and progressive multifocal leucoencephalopathy.
image

Fig. 11.38 Acquired immunodeficiency syndrome. (A) Pneumocystis pneumonia; (B) oral candidiasis; (C) Kaposi sarcoma; (D) HIV wasting syndrome

Serology

• Serological testing for HIV infection should be performed only with informed consent after proper counselling, due to the profound implications of a positive result. HIV is confirmed most commonly by the demonstration of anti-HIV antibodies in the serum, by using the ELISA and Western blot tests.
• ‘Seroconversion’ may take 3 months or longer to occur following exposure to the virus, sometimes necessitating serial testing in individuals at high risk.
• Subsequent to the establishment of HIV positivity, CD4+ T cell counts are measured every 3 months. A count <200/mm3 implies a high risk of HIV related disease; AIDS is diagnosed when an HIV positive subject develops one or more of a defined list of indicator diseases and/or this CD4+ cell level.

Treatment

Although there is no cure for AIDS, the progression of disease can be radically slowed by a number of drugs. The aim of treatment is to reduce the plasma viral load. Ideally therapy should be commenced before the development of irreversible damage to the immune system.

1 Indications for commencement of anti-HIV therapy include:
• Symptomatic HIV disease.
• CD4+ T lymphocyte count <300/mm3.
• Rapidly falling CD4+ T lymphocyte count.
• Viral load >10 000/mL of plasma.
2 Drug treatment is with ‘highly active antiretroviral therapy’ (HAART), which involves 2 nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or 1 or 2 protease inhibitors.
a Nucleoside reverse transcriptase inhibitors include zidovudine, lamivudine and zalcitabine.
b Protease inhibitors include amprenavir, indinavir and neltinavir.
c Non-nucleoside reverse transcriptase inhibitors include efavirenz and nevirapine.

Ocular features

1 Eyelid. Blepharitis, Kaposi sarcoma, multiple molluscum lesions and herpes zoster ophthalmicus.
2 Orbital. Cellulitis, usually from contiguous sinus infection, and B-cell lymphoma.
3 Anterior segment
• Conjunctival Kaposi sarcoma, squamous cell carcinoma and microangiopathy.
• Keratitis due to microsporidia, herpes simplex and herpes zoster.
• Keratoconjunctivitis sicca.
• Anterior uveitis (usually secondary to systemic drug toxicity: rifabutin, cidofovir).
4 Posterior segment
• HIV microangiopathy (see below).
• HlV retinitis (see below).
• Cytomegalovirus retinitis (see below).
• Progressive outer retinal necrosis (see below).
• Choroidal pneumocystosis (see parasitic uveitis).
• Toxoplasmosis, frequently atypical.
• Choroidal cryptococcosis.
• B-cell intraocular lymphoma.

HIV microangiopathy

Retinal microangiopathy is the most frequent retinopathy in patients with AIDS, developing in up to 70% of patients and is associated with a declining CD4+ count. Postulated causes include immune complex deposition, HIV infection of the retinal vascular endothelium, haemorheological abnormalities and abnormal retinal haemodynamics.

1 Signs. Cotton wool spots which may be associated with retinal haemorrhages and capillary abnormalities (Fig. 11.39).
2 Differential diagnosis. The lesions may be mistaken for early CMV retinitis. However, in contrast to CMV, lesions are usually asymptomatic and almost invariably disappear spontaneously after several weeks.
image

Fig. 11.39 HIV microangiopathy

Cytomegalovirus retinitis

Cytomegalovirus (CMV) retinitis is the most common opportunistic ocular infection among patients with AIDS. Since the advent of HAART its incidence has declined and its rate of progression reduced, even in patients with low CD4+ T cell counts. It also appears that the rates of second eye involvement and retinal detachment are less than in the pre-HAART era.

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Clinical features

1 Indolent retinitis frequently starts in the periphery and progresses slowly. It is characterized by a mild granular opacification which may be associated with a few punctate haemorrhages, but vasculitis is absent (Fig. 11.40A).
2 Fulminating retinitis.
• Mild vitritis.
• Vasculitis with perivascular sheathing and retinal opacification.
• Dense, white, well-demarcated, geographical areas of confluent opacification often associated with retinal haemorrhages (Fig. 11.40B).
• Slow but relentless ‘brushfire-like’ extension along the course of the retinal vascular arcades that may involve the optic nerve head (Fig. 11.40C).
• Retinal detachment associated with large posterior breaks may occur in uncontrolled disease (Fig. 11.40D) and require vitreoretinal surgery and the use of silicone oil tamponade.
image

Fig. 11.40 Cytomegalovirus retinitis. (A) Indolent retinitis; (B) fulminating disease; (C) advanced disease involving the optic nerve head; (D) large posterior retinal tear with shallow localized detachment

(Courtesy of C Barry – fig. D)

Systemic treatment

1 Valganciclovir is a pro-drug of ganciclovir that has better gastrointestinal absorption and is as effective as intravenous ganciclovir itself for treatment and prophylaxis. The induction dose is 900 mg b.d. and the daily maintenance dose is 900 mg.
2 Ganciclovir is initially given intravenously (induction) 5 mg/kg every 12 hours for 2–3 weeks, then every 24 hours. Ganciclovir is effective in 80% of patients but 50% subsequently relapse and require reinduction of therapy. The drug carries a high risk of bone marrow suppression which often forces interruption of treatment.
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3 Intravenous foscarnet. The initial dose is 60 mg/kg every 8 hours for 2–3 weeks and then 90–120 mg every 24 hours. Side-effects include nephrotoxicity, electrolyte disturbances and seizures. Foscarnet can also be given intravitreally (2.4 mg in 0.1 mL).
4 Intravenous cidofovir, 5 mg/kg once weekly for 2 weeks and then every 2 weeks may be used where other agents are unsuitable. It must be administered in combination with probenecid. Side-effects include nephrotoxicity, neutropenia and anterior uveitis.

Intravitreal treatment

1 Ganciclovir slow-release device (Vitrasert®) is as effective as intravenous therapy (Fig. 11.41A). The duration of efficacy is 8 months, which is superior to intravenous therapy with either ganciclovir or foscarnet (average 60 days). However, it does not prevent involvement of the fellow eye. Complications include cataract, vitreous haemorrhage, retinal detachment and endophthalmitis.
2 Injection
a Ganciclovir (2.0–2.5 mg in 0.1 mL) may be performed prior to implantation of a slow-release implant to determine the likely response to the drug.
b Fomivirsen has a different mechanism of action from other agents. Adverse effects include anterior uveitis, vitritis, cataract and rarely retinopathy.
c Cidofovir (15–20 µg in 0.1 mL) may occasionally cause severe inflammation leading to hypotony and even phthisis bulbi.
image

Fig. 11.41 Treatment of cytomegalovirus retinitis. (A) Slow-release implant containing ganciclovir that has caused localized lens opacity; (B) regressing retinitis after treatment

(Courtesy of S Milewski – fig. A; L Merin – fig. B)

Prognosis

Initially 95% of cases respond to treatment. Regression is characterized by fewer haemorrhages and less opacification, followed by diffuse atrophy and mild pigmentary changes (Fig. 11.41B). Since the introduction of HAART therapy the incidence of CNV retinitis has decreased and many patients have had their treatment of retinitis stopped after immune recovery (CD4 > 100–150). Many patients with HAART-induced immune recovery develop intraocular inflammation which may cause macular oedema and epiretinal membrane formation, requiring aggressive treatment.

Progressive retinal necrosis

1 Pathogenesis. Although progressive retinal necrosis (PRN) (formerly progressive outer retinal necrosis – PORN) occurs predominantly in AIDS, it may also occur in patients with drug-induced immunosuppression. It is a rare but devastating necrotizing retinitis caused by varicella zoster virus, which behaves aggressively probably as a consequence of the profound immunosuppression of the host.
2 Presentation is with rapidly progressive visual loss which is initially unilateral in 75% of cases.
3 Signs in chronological order:
• Minimal anterior uveitis and vitritis.
• Yellow-white retinal infiltrates (Fig. 11.42A).
• Rapid confluence and full-thickness retinal necrosis with early involvement of the macula (Fig. 11.42B).
• Vitreous inflammation is usually late and reflects extensive retinal necrosis.
4 Investigations. Specific PCR-based diagnostic assay for varicella zoster virus DNA performed on vitreous samples.
5 Treatment involves intravenous and intravitreal ganciclovir, and foscarnet. Even when instituted early the results are often disappointing. Vitreoretinal surgery for retinal detachment often also yields poor results.
image

Fig. 11.42 Progressive retinal necrosis. (A) Early; (B) late

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. A)

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Miscellaneous viral uveitis

Acute retinal necrosis

1 Pathogenesis. Acute retinal necrosis (ARN) is a rare but devastating necrotizing retinitis. It typically affects otherwise healthy individuals of all ages. Males are more frequently affected than females by a 2 : 1 ratio. ARN is a biphasic disease which tends to be caused by herpes simplex virus (HSV) in younger patients and VZV in older individuals. Some patients have a past history of HSV encephalitis, many years before developing ARN, and occasionally encephalitis and ARN develop simultaneously.
2 Presentation is initially unilateral and varies according to severity. Some patients develop severe visual impairment over a few days associated with pain whereas others have an insidious onset with mild visual symptoms such as floaters.
3 Signs
• Vitritis and granulomatous anterior uveitis are universal.
• Peripheral retinal periarteritis associated with multifocal, deep, yellow-white, retinal infiltrates (Fig. 11.43A).
• Gradual coalescence of infiltrates with full-thickness necrosis and circumferential progression (Fig. 11.43B).
• The posterior pole is usually spared until late (Fig. 11.43C).
• The acute lesions resolve within 6–12 weeks, leaving behind transparent necrotic retina with hyperpigmented borders.
• Unless the patient receives appropriate treatment the second eye becomes involved in 30%, usually within 2 months, although in some patients the interval may be much longer.
4 Investigations. PCR on vitreous samples.
5 Treatment is with aciclovir, initially intravenously (10 mg/kg every 8 hours) for 10–14 days and then orally 800 mg five times daily for 6–12 weeks. This may hasten resolution of the acute retinal lesions and reduce the risk of second eye involvement, but it does not prevent retinal detachment. Oral valaciclovir or famciclovir may also be used with similar outcomes. Intravitreal ganciclovir or foscarnet may also be used in very severe cases. Recurrences may occur in some patients and long-term therapy may be required. Systemic steroids may be started 24 hours after initiation of antiviral therapy and are usually indicated in severe cases, especially those with optic nerve involvement.
6 Prognosis is relatively poor, particularly where VZV is the causative agent, with 60% of patients having a final visual acuity of less than 6/60 as a result of the retinal detachment, ischaemic optic neuropathy and occlusive periphlebitis.
image

Fig. 11.43 Acute retinal necrosis. (A) Peripheral infiltrates; (B) full-thickness necrosis; (C) advanced involvement

Herpes simplex anterior uveitis

1 Anterior uveitis, which may be associated with trabeculitis and high IOP (hypertensive uveitis), may occur with or without active corneal disease. Iris atrophy, which is often patchy and occasionally sectoral, is common and may occasionally be associated with spontaneous hyphaema (Fig. 11.44A).
2 Treatment involves topical steroids (in the absence of active epithelial disease), cycloplegic agents and topical or oral aciclovir (400 mg five times a day).
image

Fig. 11.44 (A) Iris atrophy and hyphaema in herpes simplex anterior uveitis; (B) sectoral iris atrophy in herpes zoster anterior uveitis

Varicella zoster anterior uveitis

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1 Anterior uveitis affects nearly 50% of the patients with herpes zoster ophthalmicus (HZO), particularly when the rash involves the side of the nose (Hutchinson sign). The inflammation is often mild and asymptomatic although rarely it may be severe. Residual sectoral iris atrophy (Fig. 11.44B) is seen in 25% of cases and is thought to be due to occlusive vasculitis. All patients with HZO must be examined regularly for 6 weeks from the onset of the rash to detect anterior uveitis because it is often asymptomatic.
2 Treatment is with topical steroids and mydriatics.

Congenital rubella

Rubella (German measles) is usually a benign febrile exanthema. Congenital rubella results from transplacental transmission of virus to the fetus from an infected mother, usually during the first trimester of pregnancy.

1 Anterior uveitis may result in iris atrophy.
2 Retinopathy is a common manifestation, but the exact incidence is unknown because cataracts frequently impair visualization of the fundus.
• ‘Salt and pepper’ pigmentary disturbance involving the periphery and posterior pole (Fig. 11.45).
• Prognosis is usually good although a small percentage of eyes may later develop choroidal neovascularization.
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3 Other manifestations include cataract, microphthalmos, glaucoma, keratitis and extreme refractive errors.
image

Fig. 11.45 Rubella retinopathy

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis is a chronic, progressive neurodegenerative and usually fatal disease of childhood caused by the measles virus.
1 Systemic features include insidious personality change followed by progressive psychomotor deterioration, myoclonus and seizures. Death ensues within years.
2 Posterior uveitis is characterized by papillitis, macular oedema, whitish retinal infiltrates and choroiditis (Fig. 11.46).
image

Fig. 11.46 Retinal involvement in subacute sclerosing panencephalitis

(Courtesy of Z Bashshur)

Fungal uveitis

Presumed ocular histoplasmosis syndrome

Pathogenesis

Histoplasmosis is caused by Histoplasma capsulatum acquired by inhalation of infective mycelia fragments and/or spores with dust particles. The organisms then pass via the bloodstream to the spleen, liver and, on occasion, the choroid, setting up multiple foci of granulomatous inflammation. Although ocular histoplasmosis has never been reported in patients with active systemic histoplasmosis, eye disease has an increased prevalence in areas where histoplasmosis is endemic, such as the Mississippi–Missouri river valley and is speculated that presumed ocular histoplasmosis syndrome (POHS) represents an immune-mediated response in individuals previously exposed to the fungus. Patients with POHS show an increased prevalence of HLA-B7 and HLA-DR2. POHS is asymptomatic unless it causes a maculopathy.

General signs

• Absence of intraocular inflammation.
• The acute stage may manifest with localized swelling of the choroid which may also lead to changes in the overlying RPE.
• Atrophic ‘histo’ spots consist of roundish, slightly irregular, yellowish-white lesions about 200 µm in diameter, often associated with pigment clumps within or at the margins of the scars. The lesions are scattered in the mid-retinal periphery (Fig. 11.47A) and posterior fundus.
• Peripapillary atrophy may be diffuse (Fig. 11.47B) or focal, or a combination of both.
• Linear streaks in the midperiphery (Fig. 11.47C) are found in 5% of cases.
image

Fig. 11.47 Presumed ocular histoplasmosis syndrome; (A) Peripheral ‘histo’ spots; (B) circumferential peripapillary atrophy and histo spots; (C) linear streaks

Exudative maculopathy

Choroidal neovascularization (CNV) is a late manifestation which usually develops between the ages of 20 and 45 years in about 5% of eyes. In most cases, CNV is associated with an old macular ‘histo spot’, although occasionally it develops within a peripapillary lesion.

1 The course may show the following patterns:
• Leakage from CNV causes serous macular elevation which may be associated with an underlying focal yellow-white or grey lesion. In 12% of eyes the subretinal fluid absorbs spontaneously and visual symptoms regress.
• A dark green-black ring frequently develops on the surface of the yellow-white lesion and bleeding occurs into the subretinal space (Fig. 11.48) causing a marked drop in visual acuity. In a few eyes, the subretinal haemorrhage resolves and visual acuity improves.
• The initial CNV may remain active for about 2 years giving rise to recurrent haemorrhages and subsequently disciform scarring with permanent loss of central vision.
• Patients with maculopathy in one eye and an asymptomatic atrophic macular scar in the other are likely to develop a disciform lesion in the second eye. They should therefore test themselves every day with an Amsler grid to detect early metamorphopsia because without treatment 60% of eyes with CNV have a final visual acuity of less than 6/60.
2 Treatment of CNV may involve argon laser photocoagulation for extrafoveal CNV and photodynamic therapy (PDT) for subfoveal membranes. Intravitreal triamcinolone acetonide and VEGF inhibitors may be effective for both extrafoveal and subfoveal CNV. Surgical removal may be considered in selected cases.
image

Fig. 11.48 Choroidal neovascularization in presumed ocular histoplasmosis. (A) The fovea shows a focal area of oedema and a few small haemorrhages, and a small histo spot temporally; (B) FA arterial phase shows a choroidal neovascular membrane just above the fovea

(Courtesy of S Milewski)

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Cryptococcosis

Pathogenesis

Soil contaminated with pigeon droppings containing encapsulated dimorphic yeast, Cryptococcus neoformans, enters the body through inhalation. Infection primarily affects patients with cell-mediated immune deficiency and occurs in 5–10% of patients with AIDS. Other predisposing factors include lymphoma, active hepatitis, alcoholism, uraemia, systemic lupus erythematosus, organ transplantation with immunosuppression and close exposure to pigeons.

Systemic features

1 Signs
• CNS involvement (meningitis, meningoencephalitis and cryptococcoma) is the most important.
• Occasionally pneumonia, mucocutaneous lesions, pyelonephritis, endocarditis and hepatitis.
2 Investigations involve culture or recognition of spores in cerebrospinal fluid, and serological detection of antigen.
3 Treatment is with intravenous amphotericin B and oral flucytosine.

Ocular features

Ocular involvement is present in approximately 6% of patients with cryptococcal meningitis. The most likely route of infection is via direct extension from the optic nerve or by haematogenous spread to the choroid and retina.

1 Signs
• Meningitis-associated manifestations are the most common and include papilloedema, ophthalmoplegia, ptosis, optic neuropathy and sixth nerve palsy.
• Multifocal choroiditis (Fig. 11.49).
• Iris infiltration, keratitis and conjunctival granuloma have been reported.
2 Treatment of sight-threatening lesions is with intravenous amphotericin, oral fluconazole and itraconazole.
image

Fig. 11.49 Multifocal cryptococcal choroiditis

(Courtesy of A Curi)

Endogenous fungal endophthalmitis

1 Pathogenesis. The major source of fungal infection within the eye is metastatic spread from a septic focus associated with catheters, intravenous drug abuse, parenteral nutrition and chronic lung disease such as cystic fibrosis. Neutropenia following immunosuppression and AIDS are also major risk factors. Approximately 75% of isolates are Candida spp.; other pathogens include Cryptococcus spp., Sporothrix schenckii and Blastomyces spp.
2 Presentation is dependent on the location and intensity of the inflammatory focus. Peripheral lesions may cause few or no visual disturbance while central lesions or those resulting in severe vitritis will manifest earlier. The progression is, however, much slower than in bacterial endophthalmitis and bilateral involvement is common.
3 Signs
• Anterior uveitis is uncommon in the early stages but may become prominent later.
• One or several creamy white chorioretinal lesions with overlying vitritis (Fig. 11.50A).
• Floating ‘cotton ball’ colonies in the vitreous (Fig. 11.50B).
• Chronic endophthalmitis characterized by severe vitreous infiltration and abscess formation (Fig. 11.50C).
4 Course is relatively chronic and may result in retinal necrosis (Fig. 11.50D) and retinal detachment associated with severe proliferative vitreoretinopathy.
5 Investigations involving vitreous biopsy and smears and cultures may be required to confirm the diagnosis and test the sensitivity of the organisms to antifungal agents.
6 Medical treatment is indicated for systemic disease and ocular disease without vitreous involvement.
• Oral fluconazole 100–200 mg/day (400–800 mg for disseminated disease) for 3–6 weeks. It can be used in conjunction with flucytosine (100 mg/kg/day) and has good ocular penetration.
• Oral, intravenous or intravitreal voriconazole to treat cases resistant to fluconazole. Good intraocular levels are achieved.
• Intravenous amphotericin has relatively poor ocular penetration.
7 Pars plana vitrectomy combined with intravitreal injection of amphotericin 5–10 µg in 0.1 mL is indicated in the presence of vitreous involvement.
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image

Fig. 11.50 Fungal endophthalmitis. (A) Focal chorioretinitis; (B) cottonball colonies; (C) severe vitritis; (D) retinal necrosis

Coccidioidomycosis

1 Systemic features. Coccidioides immitis acquired by inhalation resulting in pulmonary infection and cavitation, erythema nodosum, arthropathy and meningitis.
2 Ocular features include Parinaud oculoglandular syndrome, phlyctenulosis, multifocal choroiditis and anterior uveitis.

Bacterial uveitis

Tuberculosis

Pathogenesis

Tuberculosis (TB) is a chronic granulomatous infection caused by the tubercle bacillus which is of the genus Mycobacterium, which are non-motile, non-sporing, strictly aerobic acid-fast rods. The two species responsible for TB in humans are the human strain M. tuberculosis, which is acquired by inhaling infected airborne droplets, and the bovine strain M. bovis, which is acquired by drinking unpasteurized milk from infected cattle. TB is primarily a pulmonary disease but it may spread by the bloodstream to other sites to form a generalized (miliary) infection. Human immunodeficiency virus increases the risk of developing TB. In addition infection with atypical mycobacteria such as M. avium complex may cause disease in immunocompromised individuals.

Anterior segment involvement

• Eyelid involvement may manifest as reddish-brown nodules (lupus vulgaris) or a ‘cold abscess’.
• Tuberculous conjunctivitis is uncommon and may be associated with lymphadenopathy as in Parinaud syndrome.
• Corneal involvement most commonly manifests as phlyctenular keratoconjunctivitis or interstitial keratitis.
• Scleritis is rare.

Tuberculous uveitis

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Tuberculous uveitis may be difficult to diagnose because it may occur in patients without systemic manifestations of TB. The diagnosis is therefore often presumptive, based on indirect evidence such as intractable uveitis unresponsive to steroid therapy, a positive history of contact, a positive skin test and negative findings for other causes of uveitis.

1 Anterior uveitis, usually granulomatous, is the most frequent feature.
2 Choroiditis is caused by direct infection.
• Unilateral focal or (less frequently) multifocal.
• Extensive diffuse choroiditis may occur in patients with AIDS (Fig. 11.51A).
• Large solitary choroidal granulomas (Fig. 11.51B) are uncommon.
• Choroiditis may occasionally resemble serpiginous choroidopathy (Fig. 11.52).
4 Periphlebitis is often bilateral and represents a manifestation of hypersensitivity to the bacillus. It may be mild and innocuous or occlusive resulting in severe retinal ischaemia (Fig. 11.53) and secondary retinal neovascularization.
5 Treatment is initially with at least three drugs (isoniazid, rifampicin and pyrazinamide) and then with isoniazid and rifampicin. Quadruple therapy with the addition of ethambutol is necessary in pulmonary TB and in resistant cases. Concomitant systemic steroid therapy is also frequently necessary. The steroid dose needs to be adjusted when given with rifampicin.
image

Fig. 11.51 Tuberculous choroiditis (A) Diffuse involvement in a patient with AIDS; (B) choroidal granuloma

(Courtesy of C de A Garcia – fig. A)

image

Fig. 11.52 (A) Tuberculous choroiditis resembling serpiginous choroidopathy; (B) FA shows corresponding areas of hyper- and hypofluorescence

(Courtesy of C Pavésio)

image

Fig. 11.53 Occlusive tuberculous periphlebitis. (A) Superior retinal branch occlusion; (B) FA shows extensive hypofluorescence due to capillary non-perfusion

(Courtesy of C Pavésio)

Syphilis

Pathogenesis

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Syphilis is caused by the spirochaete bacterium Treponema pallidum. The organism is thin and has a spiral shape resulting in corkscrew movements. It is very fragile, does not live in culture and dies quickly on drying or heat. In adults the disease is usually sexually acquired when the treponemes enter through an abrasion of skin or mucous membrane. Transmission by kissing, blood transfusion and percutaneous injury are rare. Transplacental infection of the fetus can also occur from a mother who has become infected during or shortly before pregnancy. Although the infection is systemic from onset, in some cases clinical manifestations may be minimal or absent. The natural history of untreated syphilis is variable and may remain latent throughout, although overt disease may develop at any time.

Stages

1 Primary syphilis occurs after an incubation period commonly lasting 2–4 weeks and is characterized by a painless ulcer (chancre) at the site of infection. The most common site in males is the penis (Fig. 11.54A) and in females the vulva. In homosexual men the anus is a major site. The chancre is associated with discrete, mobile, rubbery enlargement of inguinal lymph nodes. Without treatment the chancre resolves within 2–6 weeks leaving an atrophic scar.
2 Secondary syphilis usually develops 6–8 weeks after the chancre and is characterized by:
• Generalized lymphadenopathy with mild or absent constitutional symptoms.
• Symmetrical maculopapular rash on the trunk (Fig. 11.54B), palms and soles.
• Condylomata lata on the vulva, scrotum or the anal region.
• Mucous patches in the mouth, pharynx and genitalia consisting of painless greyish-white circular erosions (‘snail-track ulcers’).
• Meningitis, nephritis and hepatitis may occur.
3 Latent syphilis follows resolution of secondary syphilis, may last for years and can be detected only by serological tests.
4 Tertiary syphilis occurs in about 40% of untreated cases and is characterized by the following.
• Cardiovascular manifestations: aortitis with aneurysm formation and aortic regurgitation.
• Neurosyphilis is characterized by tabes dorsalis, Charcot joints and general paresis of the insane.
• Gummatous infiltration of bone and viscera. Gummatous infiltration of the tongue (Fig. 11.54C) may lead to leukoplakia and an increased risk of carcinoma.
image

Fig. 11.54 Acquired syphilis. (A) Chancre in primary disease; (B) maculopapular rash in secondary disease; (C) gummatous infiltration of the tongue in tertiary disease

(Courtesy of RT Emond, PD Welsby and HA Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003)

Syphilitic uveitis

1 AAU occurs in about 4% of patients with secondary syphilis and is bilateral in 50%. In some cases, iritis is first associated with dilated iris capillaries (roseolae – Fig. 11.55A) which may develop into more localized papules and subsequently into larger yellowish nodules. Various types of post-inflammatory iris atrophy may ensue.
2 Posterior uveitis
• Chorioretinitis is often multifocal (Fig. 11.55B) and bilateral.
• Acute posterior placoid chorioretinitis is characterized by bilateral, large, solitary, placoid, pale-yellowish subretinal lesions (Fig. 11.55C).
• Untreated neuroretinitis gives rise to secondary optic atrophy and replacement of retinal vessels by white strands (Fig. 11.55D).
• Retinal vasculitis may be occlusive and involves both arteries and veins.
3 Treatment is the same as for neurosyphilis (which should be ruled out by lumbar puncture). One of the following regimens may be used:
a Intravenous aqueous penicillin G 12–24 million units daily for 10–15 days.
b Intramuscular procaine penicillin 2.4 million units daily, supplemented with oral probenecid (2 g daily), for 10–15 days.
image

Fig. 11.55 Ocular syphilis. (A) Roseolae; (B) old multifocal chorioretinitis; (C) acute posterior placoid chorioretinitis; (D) end-stage disease

(Courtesy of J Salmon – fig. B; C de A Garcia – fig. C)

Penicillin-allergic patients can be treated with oral tetracycline or erythromycin 500 mg q.i.d. for 30 days.

Lyme disease

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1 Pathogenesis. Lyme disease (borreliosis) is an infection caused by a flagellated spirochaete bacterium Borrelia burgdorferi, transmitted through the bite of a hard-shelled tick (Fig. 11.56A) of the genus Ixodes (Fig. 11.56B) which feeds on a variety of large mammals, particularly deer. The disease is endemic in temperate regions of North America, Europe and Asia. It is the commonest vector-borne disease in many areas. Systemic manifestations are complex and are best conceptualized as early and late.
2 Early stage presents several days after the bite with a pathognomonic annular expanding skin lesion at the site – erythema chronicum migrans (Fig. 11.56C), which may be accompanied by constitutional symptoms and lymphadenopathy. This may last for several weeks and resolve even without treatment. Complications, both neurological (cranial nerve palsies, meningitis) and cardiac (conduction defects, myocarditis), may follow within 3–4 weeks of the initial manifestations.
3 Late complications include chronic arthritis of large joints, polyneuropathy and encephalopathy. Some patients develop a doughy, patchy, skin discoloration most evident on the limbs which eventually results in shiny atrophy (acrodermatitis chronica atrophicans).
4 Investigations include PCR and ELISA.
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5 Treatment of acute disease involves oral doxycycline or amoxicillin. Patients with ocular, cardiac, joint or neurological disease may require intravenous ceftriaxone. Prophylaxis with doxycycline should be given within 72 hours of the tick bite.
6 Uveitis is uncommon and may take the following forms: anterior, intermediate, peripheral multifocal choroiditis, retinal periphlebitis and neuroretinitis.
7 Other ocular manifestations include follicular conjunctivitis, episcleritis, keratitis, scleritis, orbital myositis, optic neuritis, ocular motor nerve palsies and reversible Horner syndrome.
image

Fig. 11.56 Lyme disease. (A) Transmission; (B) engorged tick; (C) erythema chronica migrans

(Courtesy of RT Emond, PD Welsby and HA Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003 – figs B and C)

Brucellosis

1 Pathogenesis. Brucellosis is caused by the Gram-negative bacteria Brucella melitensis or Brucella abortus. It is transmitted from animals to man through the ingestion of unpasteurized milk products, or uncooked meat.
2 Systemic features include fever, arthralgia, myalgia, anorexia, sweating, headache and malaise. The onset of symptoms may be acute or insidious, generally beginning 2–4 weeks after inoculation.
3 Treatment involves tetracycline for 6 weeks with streptomycin or gentamicin for 2 weeks. Doxycycline with rifampicin for 6 weeks is an alternative.
4 Uveitis usually develops after the acute phase and may be characterized by chronic anterior uveitis, multifocal choroiditis, and rarely, endogenous endophthalmitis.
5 Other ocular manifestations include dacryoadenitis, episcleritis, nummular keratitis and optic neuritis.

Endogenous bacterial endophthalmitis

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1 Pathogenesis. Endogenous (metastatic) endophthalmitis occurs when organisms enter the eye through the blood–eye barrier. However, no ocular infection occurs in the vast majority of cases of bacteraemia, although Roth spots develop in about 1% of cases. The most common pathogen is Klebsiella spp. although a wide variety of organisms may be responsible. Both eyes are involved in about 12% of cases.
2 Predisposing factors include diabetes, cardiac disease and malignancy. Other risks include indwelling catheters, intravenous drug abuse, liver abscess, pneumonia, endocarditis, cellulitis, urinary tract infection (E. coli), meningitis, septic arthritis and abdominal surgery.
3 Presentation is with pain, blurred vision, floaters, photophobia and headache. The patient is usually systemically unwell with fever and rigors.
4 Anterior segment
• Chemosis, swollen lids and corneal oedema.
• Discrete iris nodules or plaques, fibrinous anterior uveitis (Fig. 11.57A) and hypopyon in severe cases.
5 Posterior segment
• Retinal infiltrates (Fig. 11.57B).
• Vitreous haze or abscess.
• Retinal necrosis in severe cases.
6 Investigations
• Search for septic foci (skin, joints); collaboration with a physician or intensive care specialist is essential.
• Blood and urine cultures in all patients.
• Appropriate cultures from other sites depending on the clinical features (e.g. catheter tips, cerebrospinal fluid, skin wounds, abscesses and joints).
• Investigations for endocarditis (chest X-ray, ECG and echocardiography).
• Abdominal ultrasound.
• Aqueous and vitreous samples should be taken (see above).
7 Treatment
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a Systemic infection is treated with intravenous antibiotics. The choice is based on culture and sensitivity results and should continue for 2–3 weeks, or longer if there is endocarditis. Patients without an evident source of infection should be treated with a combination of ceftazidime 1 g every 12 hours and vancomycin 1 g every 12 hours.
b Endophthalmitis is treated with oral ciprofloxacin and intravitreal antibiotics.
8 Prognosis is poor, probably as a result of delay in presentation and the virulence of the organism. Phthisis or evisceration occurs in 25%. There is also a mortality of 5–10% from associated systemic disease.
image

Fig. 11.57 Endogenous bacterial endophthalmitis. (A) Fibrinous anterior uveitis; (B) retinal infiltrates

Table 11.6 Comparison of exogenous and endogenous endophthalmitis

  Postoperative Metastatic
Ocular cultures Yes Yes
Blood culture No Yes
Systemic investigation No Yes
Topical antibiotic Yes Yes
Systemic antibiotic Oral fluoroquinolone Intravenous (various)
Intravitreal antibiotics Yes Yes
Corticosteroid Yes Uncertain value
Visual outcome 70% > 6/60 70% < count fingers
Mortality None 10%

Cat-scratch disease

1 Pathogenesis. Cat-scratch disease (benign lymphoreticulosis) is a subacute infection caused by Bartonella henselae, a Gram-negative rod. The infection is transmitted by the scratch or bite of an apparently healthy cat. Ocular involvement occurs in about 6% of cases.
2 Presentation is with a red papule or pustule at the site of inoculation followed by fever, malaise and regional lymphadenopathy (Fig. 11.58). However, general symptoms are frequently absent or unremarkable and a history of contact with a cat not always present.
3 Disseminated disease is rare but may affect immunocompromised individuals in the form of endocarditis, encephalopathy, meningitis, splenomegaly, splenic abscess formation and osteomyelitis.
4 Investigations include serology for B. henselae and PCR.
5 Treatment is with oral doxycycline or erythromycin, with or without rifampicin; the organism is also sensitive to ciprofloxacin and cotrimoxazole.
6 Uveitis may take the following forms: intermediate, focal choroiditis and panuveitis.
7 Other ocular manifestations include neuroretinitis (most common), Parinaud oculoglandular syndrome, exudative maculopathy and retinal vascular occlusion.
image

Fig. 11.58 Cat-scratch disease. (A) Ulcerated papule on the cheek caused by a cat scratch 2 weeks previously, and enlargement of submandibular lymph nodes; (B) line of papules on the forearm of another patient at the site of a cat scratch; (C) marked enlargement of the ipsilateral axillary lymph nodes

(Courtesy of BJ Zitelli and HW Davis, from Atlas of Pediatric Physical Diagnosis, Mosby 2002)

Leprosy

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1 Pathogenesis. Leprosy (Hansen disease) is a chronic granulomatous infection caused by the intracellular acid-fast bacillus Mycobacterium leprae which has an affinity for skin, peripheral nerves and the anterior segment of the eye. The exact mode of infection is unknown although the upper respiratory tract appears the most likely portal of entry.
2 Lepromatous leprosy is a generalized multisystem infection with widespread lesions of skin, peripheral nerves, upper respiratory tract, reticuloendothelial system, eyes, bones and testes.
• Leonine facies characterized by cutaneous thickening and ridging, nasal widening and thickening of ear lobes (Fig. 11.59A).
• Peripheral cutaneous plaques and nodules.
• Mucosal thickening and saddle-shaped nasal deformity.
• Motor neuropathy is exemplified by the ‘claw hand’ deformity due to ulnar nerve palsy (Fig. 11.59B).
• Sensory peripheral neuropathy facilitates trauma which may result in shortening and loss of digits (Fig. 11.59C).
3 Tuberculoid leprosy is restricted to the skin and peripheral nerves.
• Annular, anaesthetic, hypopigmented lesions with raised edges.
• Thickening of cutaneous sensory nerves.
4 Lepromin test is strongly positive in tuberculoid leprosy and negative in lepromatous disease.
5 CAU may occur in lepromatous leprosy as the result of direct invasion of the iris by bacilli. The signs are:
• Low-grade inflammation associated with the formation of synechiae.
• A pathognomonic sign is the presence of iris pearls formed from dead bacteria (Fig. 11.60A). They slowly enlarge and coalesce, become pedunculated and drop into the anterior chamber, from which they eventually disappear.
• Eventually, the pupil becomes miosed (Fig. 11.60B) and the iris atrophic (Fig. 11.60C) as a result of damage to the sympathetic innervation to the dilator pupillae.
image

Fig. 11.59 Lepromatous leprosy. (A) Leonine facies; (B) ‘claw hand’ due to motor neuropathy; (C) loss of digits due to sensory neuropathy

(Courtesy of RT Emond, PD Welsby and HA Rowland, from Colour Atlas of Infectious Diseases, Mosby 2003 – figs A and B; CD Forbes and WF Jackson, from Color Atlas and Text of Clinical Medicine, Mosby 2003 – fig. C)

image

Fig. 11.60 Lepromatous chronic anterior uveitis. (A) Iris pearls; (B) miosis; (C) iris atrophy

White Dot Syndromes

White dot syndromes are caused by inflammation at the level of the choriocapillaris resulting in non-perfusion and secondary changes involving the choroid and outer retina.

Multiple evanescent white dot syndrome

Multiple evanescent white dot syndrome (MEWDS) is an uncommon, idiopathic, usually unilateral, self-limiting disease with a female preponderance. About one-third of patients have a preceding viral-like illness.

Although uncommon, it is important to be aware of MEWDS because the subtle signs may be overlooked and a misdiagnosis made of a more serious disorder such as retrobulbar neuritis.

1 Presentation is in the 3rd–4th decades with sudden onset of decreased central vision and photopsia.
2 Signs
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• Mild vitritis.
• Numerous very small deep ill-defined, grey-white dots at the posterior pole and mid-periphery (Fig. 11.61A).
• The macula is spared but has a characteristic granular orange appearance which renders the foveal reflex abnormal or absent.
• The physiological blind spot is enlarged.
• Over several weeks the dots fade and central vision recovers.
• Foveal granularity may remain (Fig. 11.61B) and the enlarged blind spot may take much longer to diminish in size.
3 FA shows subtle early hyperfluorescence of the dots with late staining (Fig. 11.61C) but is of limited diagnostic value because in some cases the findings may be minimal or absent.
4 ICGA shows more numerous hypofluorescent spots than are apparent clinically or on FA (Fig. 11.61D). Peripapillary non-perfusion as demonstrated by FA and ICGA explains the enlarged blind spot.
5 ERG shows a decrease in a-wave amplitude which returns to a normal pattern within a few weeks.
6 Treatment is not required.
image

Fig. 11.61 Multiple evanescent white dot syndrome. (A) Active lesions; (B) FA arteriovenous phase shows subtle hyperfluorescent spots; (C) ICGA shows hypofluorescent spots which are more numerous than on FA

(Courtesy of Moorfields Eye Hospital)

Acute idiopathic blind spot enlargement syndrome

Acute idiopathic blind spot enlargement syndrome is a rare, self-limiting, condition which seems to exclusively affect women.

1 Presentation is in the 3rd–6th decade with photopsia and decreased vision which may be misdiagnosed as migraine or optic neuritis. Occasionally photopsia may precede visual loss by several weeks.
2 Signs
• A relative afferent pupillary defect may be present.
• Blind spot enlargement with steep margins but variable size is universal.
• Mild disc swelling or hyperaemia with peripapillary subretinal pigmentary changes in 50% of cases.
• Vision improves after a few weeks but the blind spot may remain permanently enlarged.
• Recurrences may occur in the same or fellow eye.
3 FA may show late staining of the optic nerve head.
4 Treatment is not required.

Acute posterior multifocal placoid pigment epitheliopathy

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an uncommon, idiopathic, usually bilateral condition. It affects both sexes equally and is associated with HLA-B7 and HLA-DR2. In about one-third of patients it follows a flu-like illness.

1 Presentation is in the 3rd–4th decade with subacute visual impairment, central and paracentral scotomas and often photopsia. Within a few days to several weeks the fellow eye becomes affected.
2 Signs
• Very mild anterior uveitis and vitritis.
• Multiple, large, deep, yellow-white, placoid lesions which typically begin at the posterior pole and then extend to the post-equatorial fundus (Fig. 11.62A).
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• After a few days the lesions begin to fade centrally and within two weeks the majority are replaced by RPE disturbances of varying severity.
• New lesions may appear, so that different stages of evolution may be seen.
• Within several months visual acuity usually recovers to normal or near-normal; occasionally paracentral scotomas persist.
3 FA of active lesions shows early dense hypofluorescence associated with non-perfusion of the choriocapillaris (Fig. 11.62B) and late hyperfluorescence due to staining (Fig. 11.62C).
4 ICGA is superior to FA in demonstrating non-perfusion of the choriocapillaris (Fig. 11.62D).
5 EOG may be subnormal.
6 Treatment is controversial because of the absence of controlled studies. Some authorities do not advocate treatment whilst others believe that systemic steroid therapy is appropriate, particularly in severe cases.
image

Fig. 11.62 (A) Active posterior multifocal placoid pigment epitheliopathy; (B) FA early venous phase shows dense foci of hypofluorescence; (C) late phase shows hyperfluorescence; (D) ICGA shows focal hypofluorescence

(Courtesy of C Barry)

Multifocal choroiditis and panuveitis

Multifocal choroiditis and panuveitis is an uncommon, usually bilateral, chronic/recurrent, frequently asymmetrical disease that predominantly affects myopic females.

1 Presentation is in the 3rd–4th decade with blurring of central vision which may be associated with floaters and photopsia.
2 Signs
• Vitritis is universal and anterior uveitis is present in 50% of cases.
• Active disease is characterized by bilateral, multiple, discrete, ovoid, yellowish-grey lesions.
• The lesions involve the posterior pole and/or periphery and may be arranged in clumps or linear streaks (Schlagel lines).
• Mild disc oedema and blind spot enlargement may be present.
• Inactive lesions have sharp ‘punched-out’ margins and pigmented borders resembling POHS (Fig. 11.63A).
• Peripapillary fibrosis simulating a napkin holder may develop.
• The course is prolonged with the development of new lesions and recurrent inflammatory episodes.
• Complications include CNV (Fig. 11.63B and C), CMO and occasionally subretinal fibrosis.
3 FA of active lesions shows early hypofluorescence due to blockage and late hyperfluorescence due to staining. Old inactive lesions show RPE window defects.
4 ICGA shows hypofluorescent acute lesions which may not be clinically apparent. Old lesions remain hypofluorescent throughout and correspond to the atrophic chorioretinal scars seen on fundus examination.
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5 ERG remains normal until there is advanced retinal atrophy and substantial mid-peripheral field loss, at which time visual loss may be irreversible. Multifocal ERG shows moderate to severe depression of retinal function.
6 Large visual field defects may appear acutely and are not explained on the basis of fundus abnormalities.
7 Treatment with systemic and periocular steroids is effective when administered early. Steroid-resistant patients require immunosuppressive therapy.
8 Prognosis is variable because the disease has a wide spectrum varying between those with few lesions and short periods of activity to patients with progressive scarring and visual loss due to maculopathy or diffuse subretinal fibrosis.
image

Fig. 11.63 Choroidal neovascularization in multifocal choroiditis with uveitis. (A) Inactive lesions; (B) early venous phase fluorescein angiogram shows variable hypo- and hyperfluorescence of the lesions and lacy hyperfluorescence at the fovea associated with choroidal neovascularization; (C) late phase shows hyperfluorescence at the fovea due to leakage from choroidal neovascularization

(Courtesy of Moorfields Eye Hospital)

Punctate inner choroidopathy

Punctate inner choroidopathy (PIC) is an uncommon, idiopathic disease which typically affects young myopic women. Both eyes are frequently involved but not simultaneously.
1 Presentation is in the 3rd–4th decade with blurring of central vision or paracentral scotomas which may be associated with photopsia.
2 Signs
• Absent or minimal intraocular inflammation.
• Multiple small yellow-white spots with fuzzy borders at the level of the inner choroid and retina.
• The lesions are all of the same age and principally involve the posterior pole (Fig. 11.64A).
• Plentiful lesions occasionally may be associated with an overlying serous sensory retinal detachment.
• After a few weeks the acute lesions resolve leaving sharply demarcated atrophic scars which may subsequently become pigmented (Fig. 11.64B).
• CNV develops in up to 40% of patients, usually within a year of presentation.
• After a variable period of time the fellow eye frequently becomes involved.
3 FA of PIC lesions shows early hyperfluorescence and late staining. It is of particular value in detecting CNV (Fig. 11.64C and D).
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4 ERG is normal.
5 Prognosis is guarded because central vision may become compromised either due to foveal involvement by a lesion or to CNV.
6 Treatment is reserved for CNV.
image

Fig. 11.64 Punctate inner choroidopathy. (A) Active stage; (B) inactive disease; (C) FA arterial phase shows several hyperfluorescent spots with hypofluorescent edges inferior to the fovea and mild lacy hyperfluorescence at the fovea due to choroidal neovascularization; (D) late phase shows more hyperfluorescent spots and intense hyperfluorescence at the fovea due to leakage from choroidal neovascularization

(Courtesy of M Westcott – figs C and D)

Serpiginous choroidopathy

Serpiginous choroidopathy is an uncommon chronic/recurrent disease which is usually bilateral, although the extent of involvement is frequently asymmetrical. It is associated with HLA-B7 and affects men more frequently than women.

1 Presentation is in the 5th–6th decade with unilateral blurring of central vision, scotoma or metamorphopsia. After a variable period of time the fellow eye is also affected although it is not uncommon to find evidence of inactive asymptomatic disease in the other eye at presentation.
2 Signs
• Mild anterior uveitis and vitritis are common.
• The disease typically starts around the optic disc and then gradually spreads in a serpentine manner towards the macula and peripheral fundus.
• Active lesions are grey-white (Fig. 11.65A) and may remain active for several months.
• Inactive lesions are characterized by scalloped, atrophic areas of choroidal and RPE atrophy (Fig. 11.65B and C).
• Recurrences are characterized by yellow-grey extensions, contiguous or as satellites to existing areas of chorioretinal atrophy.
• The course lasts many years in an episodic and recurrent fashion and activity may recur after several months of remission, eventually resulting in extensive chorioretinal atrophy (Fig. 11.65D).
• Complications CNV and occasionally subretinal fibrosis.
3 FA of active lesions shows early hypofluorescence and late hyperfluorescence, similar to APMPPE; inactive lesions show window defects.
4 ICGA of active lesions reveals marked hypofluorescence throughout all phases of the angiogram.
5 ERG may be abnormal in eyes with extensive retinal damage.
6 Treatment is difficult and frequently unsatisfactory. Acute exacerbations may respond to periocular or systemic steroids but this does not prevent recurrences. Chronic disease requires long-term immunosuppression with systemic steroids, azathioprine and ciclosporin.
7 Prognosis is poor and 50–75% of patients will eventually develop visual loss in one or both eyes despite treatment, as a result of macular involvement by the disease or CNV.
image

Fig. 11.65 Serpiginous choroidopathy. (A) Active stage; (B) inactive disease; (C) severe involvement; (D) end-stage disease

Progressive subretinal fibrosis and uveitis syndrome

Progressive subretinal fibrosis and uveitis syndrome is a rare, idiopathic, chronic bilateral condition which typically affects healthy women who are frequently myopic.

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1 Presentation is in the 3rd decade with gradual onset of unilateral blurring of vision, although both eyes are usually eventually involved.
2 Signs
• Mild anterior uveitis and vitritis.
• Yellow, indistinct subretinal lesions which coalesce into dirty-yellow mounds at the posterior pole and midperiphery (Fig. 11.66A).
• Eventually large areas of subretinal fibrosis develop (Fig. 11.66B).
• CMO and CNV may develop.
3 FA reveals normal retinal and choroidal filling, early mottled hyperfluorescence and window defects with late hyperfluorescence along the edges of the lesions.
4 ERG may be decreased.
5 Treatment with systemic steroids and other immunosuppressive agents may be tried to treat recurrences but is not effective once the fibrotic process is established.
6 Prognosis is poor.
image

Fig. 11.66 Progressive subretinal fibrosis and uveitis syndrome. (A) Early involvement; (B) advanced disease

Acute macular neuroretinopathy

Acute macular neuroretinopathy is a rare, self-limiting condition that typically affects healthy females. The disease may affect one or both eyes and may be preceded by a flu-like illness.

1 Presentation is in the 2nd–4th decade with sudden decrease of visual acuity and paracentral scotomas.
2 Signs
• Absence of intraocular inflammation.
• Brown-red wedge-shaped lesions in a flower petal arrangement around the centre of the macula (Fig. 11.67).
• Amsler grid and perimetry reveal remarkable correspondence of the lesions with the shape and location of the scotoma.
• Within several months visual symptoms gradually improve and the lesions fade, although do not completely resolve for many years.
• Recurrences are uncommon.
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3 FA is normal or shows faint hypofluorescence.
4 ERG is normal.
5 Treatment is not available.
image

Fig. 11.67 Acute macular neuroretinopathy

(Courtesy of J Donald Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997)

Acute zonal occult outer retinopathy

The acute zonal outer retinopathies (AZOR) are a group of very rare, idiopathic syndromes characterized by acute onset of loss of one or more zones of visual field. Acute zonal occult outer retinopathy (AZOOR) is the most common of the AZOR syndromes. The entity shares clinical similarities with other conditions in this group in that it typically affects young myopic females, some of whom have an antecedent viral-like illness.

1 Presentation is with acute loss affecting one or more zones of the visual field, frequently associated with photopsia. The temporal field is commonly involved but the central field is usually spared; bilateral involvement occurs in 50% of patients.
2 Signs in chronological order:
• Normal fundus.
• After several weeks there may be mild vitritis, attenuation of retinal vessels in the affected zone and occasionally periphlebitis, particularly in patients with large visual field defects.
• The zones may enlarge, or less frequently they remain the same or improve.
• In 50% of cases visual field loss stabilizes within 4–6 months.
• Late findings are characterized by RPE clumping (Fig. 11.68) and arteriolar narrowing in the involved area, although if the retinal cells survive the fundus remains normal.
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3 Perimetry should include both peripheral and central fields otherwise large peripheral zones of visual field loss may go undetected. Visual field loss does not correlate with retinal findings.
4 ERG characteristically shows a-wave and b-wave amplitude reduction and delayed 30 Hz flicker.
5 EOG shows absence or severe reduction of the light rise.
6 Prognosis is reasonable with a final visual acuity of 6/12 in at least one eye in 85% of cases. A recurrence rate of 25% in the affected eye and delayed involvement of the fellow eye may occur.
image

Fig. 11.68 Retinal pigment epithelial changes in acute zonal occult outer retinopathy

(Courtesy of C Pavésio).

Primary stromal choroiditis

In primary stromal choroiditis the inflammatory focus, which is usually granulomatous, develops at the level of the stroma and is associated with inflammation of the larger non-fenestrated stromal vessels.

Vogt–Koyanagi–Harada syndrome

Pathogenesis

Vogt–Koyanagi–Harada (VKH) syndrome is an idiopathic multisystem autoimmune disease featuring inflammation of melanocyte-containing tissues such as the uvea, ear and meninges.

VKH predominantly affects Hispanics, Japanese and pigmented individuals. In different racial groups the disease is associated with HLA-DR1 and HLA-DR4, suggesting a common immunogenic predisposition.

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In practice, VKH can be subdivided into Vogt–Koyanagi disease, characterized mainly by skin changes and anterior uveitis, and Harada disease, in which neurological features and exudative retinal detachments predominate. Possible trigger factors include cutaneous injury or a viral infection which may lead to sensitization of melanocytes. CSF analysis shows pleocytosis with predominant small lymphocytes in about 80% of patients within 1 week and 97% within 3 weeks of disease onset.

Phases

1 Prodromal phase lasting a few days is characterized by neurological and auditory manifestations.
• Meningitis causing headache and neck stiffness.
• Encephalopathy is less frequent and may manifest with convulsions, paresis and cranial nerve palsies.
• Auditory features include tinnitus, vertigo and deafness.
2 Acute uveitic phase follows soon thereafter and is characterized by bilateral granulomatous anterior or multifocal posterior uveitis and exudative retinal detachments.
3 Convalescent phase follows several weeks later and is characterized by:
• Localized alopecia, poliosis and vitiligo (Fig. 11.69).
• Focal depigmented fundus lesions (sunset glow fundus) and depigmented limbal lesions (Sugiura sign).
4 Chronic-recurrent phase is characterized by smouldering anterior uveitis with exacerbations.
image

Fig. 11.69 Vitiligo and poliosis in Vogt–Koyanagi–Harada syndrome

(Courtesy of U Raina)

Table 11.7 Modified diagnostic criteria for VKH syndrome

1 Absence of a history of penetrating ocular trauma
2 Absence of other ocular disease entities
3 Bilateral uveitis
4 Neurological and auditory manifestations
5 Integumentary findings, not preceding onset of central nervous system or ocular disease, such as alopecia, poliosis and vitiligo

In complete VKH, criteria 1–5 must be present.

In incomplete VKH, criteria 1–3 and either 4 or 5 must be present.

In probable VKH (isolated ocular disease), criteria 1–3 must be present.

Uveitis

1 Anterior uveitis is usually non-granulomatous during the acute phase but shows granulomatous features during recurrences which involve only the anterior segment.
2 Posterior uveitis occurs in patients with Harada disease and is frequently bilateral. In chronological order the findings are as follows:
• Diffuse choroidal infiltration and papillitis.
• Multifocal detachments of the sensory retina and disc oedema (Fig. 11.70A).
• The chronic phase shows diffuse RPE atrophy (sunset glow fundus) which may be associated with small peripheral atrophic spots (Fig. 11.71).
• Complications include CNV and subretinal fibrosis.
3 FA of the acute phase shows multifocal hyperfluorescent dots at the level of the RPE (see Fig. 11.70B) and then accumulation of dye in the subretinal space (see Fig. 11.70C). The chronic phase shows areas of hyperfluorescence due to RPE window defects.
4 ICGA during the acute phase of the disease shows regularly-distributed hypofluorescent spots, most of which remain hypofluorescent during the late phase of the angiogram although a few may become isofluorescent. The late phase also shows diffuse hyperfluorescence over the posterior pole. Eyes with retinal detachment show hyperfluorescent areas as seen on FA. ICGA is useful in monitoring the evolution of the choroidal inflammation and the effect of therapy.
5 Treatment involves high-dose oral prednisolone (60–100 mg/day) that may be augmented with 3-day intravenous pulse therapy with methylprednisolone (500–1000 mg/day). Steroid-resistant patients may require ciclosporin.
6 Prognosis depends on early recognition and aggressive control of the early stages of the disease. Late diagnosis or incorrect initial therapy is more likely to be associated with a guarded prognosis with only 50% of patients having a final visual acuity better than 6/12.
7 Differential diagnosis of bilateral exudative retinal detachments
• Carcinoma metastatic to the choroid.
• Uveal effusion syndrome.
• Posterior scleritis.
• Eclampsia.
• Central serous retinopathy.
• Age-related wet macular degeneration.
image

Fig. 11.70 Active Harada disease. (A) Multifocal serous retinal detachments; (B) FA venous shows multiple hyperfluorescent spots; (C) late phase shows extensive areas of hyperfluorescence due to pooling of dye under the serous detachments

(Courtesy of Moorfields Eye Hospital)

image

Fig. 11.71 Sunset glow fundus

Sympathetic ophthalmitis

1 Pathogenesis. Sympathetic ophthalmitis (SO) is a bilateral granulomatous panuveitis occurring after penetrating trauma, often associated with uveal prolapse, or, less frequently, following intraocular surgery, usually multiple vitreoretinal procedures. The traumatized eye is referred to as the exciting eye and the fellow eye, which also develops uveitis, is the sympathizing eye. Since histological proof is frequently lacking, the diagnosis is mostly presumptive.
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2 Histology shows a diffuse and massive lymphocytic infiltration of the choroid, and scattered aggregates of epithelioid cells, many of which contain fine granules of phagocytosed melanin (Fig. 11.72A). Dalen–Fuchs nodules are granulomas located between Bruch membrane and the RPE (Fig. 11.72B).
3 Presentation in 65% of cases is between 2 weeks and 3 months after initial injury and 90% of all cases occur within the first year.
4 Signs in chronological order:
• The exciting eye shows evidence of the initial trauma and is frequently very red and irritable (Fig. 11.73A).
• The sympathizing eye then develops irritation, blurred vision, photophobia and loss of accommodation.
• Both eyes develop anterior uveitis which may be mild or severe and is usually granulomatous. Because the severity of inflammation may be asymmetrical, mild involvement in one eye may be missed.
• Multifocal choroidal infiltrates in the midperiphery (Fig. 11.73B).
• Sub-RPE infiltrates corresponding to Dalen–Fuchs nodules seen on histology.
• Exudative retinal detachment may occur in severe cases.
• Residual chorioretinal scarring may cause visual loss when involving the macula.
• ‘Sunset glow appearance similar to VKH (see Fig. 11.71).
5 FA shows multiple foci of leakage at the level of RPE, with subretinal pooling in the presence of exudative retinal detachment.
6 ICGA shows hypofluorescent spots in active disease which resolve with treatment.
7 Ultrasound may show choroidal thickening and retinal detachment.
8 Systemic manifestations are the same as in VKH but are less common.
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9 Treatment
a Enucleation within first 10 days following trauma should be considered only in eyes with a hopeless visual prognosis because the exciting eye may eventually have better vision than the sympathizing eye. Evisceration does not seem to protect against SO.
b Topical treatment of the anterior uveitis with steroids and cycloplegics is given but the inflammation tends to be resistant to this form of therapy (diagnostic clue).
c Systemic steroids are usually effective although ciclosporin or azathioprine may be required in resistant cases. Treatment is often required for at least a year with gradual tapering of the dose to reduce the risk of relapse. With aggressive therapy 75% of sympathizing eyes retain a visual acuity of better than 6/60. Long-term follow-up is mandatory because relapses occur in 50% of cases, and may be delayed for several years.
image

Fig. 11.72 Histology of sympathetic ophthalmitis. (A) Infiltration of the choroid by lymphocytes and scattered aggregations of epithelioid cells, many of which contain fine granules of melanin; (B) Dalen–Fuchs nodule – a granuloma situated between Bruch membrane and the retinal pigment epithelium

(Courtesy of J Harry)

image

Fig. 11.73 Sympathetic ophthalmitis. (A) The exciting eye; (B) multifocal choroidal infiltrates

(Courtesy of W Wykes – fig. A)

Birdshot retinochoroidopathy

1 Definition. Birdshot retinochoroidopathy is an uncommon idiopathic chronic/recurrent bilateral disease which predominantly affects females. Over 95% of patients are positive for HLA-A29. The disease involves both the choroid and retina independently, in contrast to the other conditions in this group.
2 Presentation is in the 3rd–6th decades with insidious impairment of central vision associated with photopsia and floaters. Nyctalopia and impairment of colour vision occur later.
3 Signs
• Multiple ill-defined cream-coloured choroidal patches, less than one disc diameter in size, in the posterior pole and midperiphery.
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• The lesions often appear to radiate outward from the disc but usually spare the macula itself (Fig. 11.74A).
• Many of the lesions are ovoid although some are elongated or have an irregular shape.
• Over several years new spots may appear and old lesions may enlarge.
• Inactive lesions consist of well-delineated atrophic spots, which show no tendency to become hyperpigmented (Fig. 11.74B).
• Other features include vitritis and vasculitis.
• Complications include CMO, macular pucker and CNV.
4 FA shows disc staining, hyperfluorescence due to leakage and CMO (Fig. 11.74C).
5 ICGA reveals, well-defined oval hypofluorescent spots during the intermediate phase (Fig. 11.74D), most of which become isofluorescent in the late phase. Many more spots can be seen by ICGA than clinically.
6 ERG is normal in early disease but with time the b-wave amplitude and then the oscillatory potentials become decreased. A delay in implicit time of the 30 Hz flicker ERG is the most sensitive change. ERG findings seem to reflect intraretinal oedema and for this reason correlate well with the severity of retinal vasculopathy rather than choroidal involvement.
7 Treatment. Although a good response may be achieved with systemic steroids optimal treatment may involve a steroid-sparing agent, such as ciclosporin or azathioprine. Periocular steroids may be useful for CMO.
8 Prognosis. About 20% of patients have a self-limited course and maintain normal visual acuity at least in one eye. The majority have variable visual impairment in one or both eyes.
image

Fig. 11.74 Birdshot chorioretinopathy. (A) Active stage; (B) inactive lesions; (C) late phase fluorescein angiogram shows disc hyperfluorescence and cystoid macular oedema; (D) early phase indocyanine green angiogram shows numerous hypofluorescent lesions

(Courtesy of C Pavésio – fig. B; P Gili – fig. C)

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Miscellaneous anterior uveitis

Fuchs uveitis syndrome

1 Definition. Fuchs uveitis syndrome (FUS) or Fuchs heterochromic iridocyclitis is a chronic non-granulomatous specific uveitis entity which is usually unilateral. It has an insidious onset, occurs mostly in the 3rd–4th decades and affects both sexes equally. Although FUS accounts for about 4% of all cases of uveitis, it is frequently misdiagnosed and over-treated. The heterochromia (difference in iris colour between the two eyes) may be absent or difficult to detect, particularly in brown-eyed individuals. The diagnosis is based mainly on ocular signs, which in early cases may be subtle and easily overlooked.
2 Presentation
• Chronic, annoying vitreous floaters are often the presenting symptom.
• Gradual blurring of vision secondary to cataract formation is common.
• Colour difference between the two eyes.
• Incidental detection.
3 General signs
• Absence of posterior synechiae, except following cataract surgery.
• KP are characteristically small, round or stellate and grey-white in colour. They are scattered throughout the corneal endothelium and are frequently associated with feathery fibrin filaments (Fig. 11.75A).
• Small nodules on the pupillary border and stroma (Fig. 11.75B) are seen in 30% of cases.
• Aqueous humour shows faint flare and mild cellular reaction.
• Vitritis and stringy opacities may be dense enough to reduce vision.
4 Diffuse iris atrophy
• The earliest finding is loss of iris crypts.
• Advanced stromal atrophy makes the affected iris appear dull with loss of detail particularly in the pupillary zone where the sphincter pupillae becomes prominent (Fig. 11.75C). The normal radial iris blood vessels appear prominent due to lack of stromal support.
• Posterior pigment layer iris atrophy is best detected by retroillumination (Fig. 11.75D).
5 Heterochromia iridis is an important and common sign; it is demonstrated most effectively in daylight.
• The nature of heterochromia is determined by the relative degrees of atrophy of the stroma and posterior pigment epithelium, as well as the patient’s natural iris colour.
• It is easily seen in green eyes, but if the iris is blue or deep brown, heterochromia may be more difficult to detect.
• Most frequently the affected eye is hypochromic (Fig. 11.75E).
• In blue eyes, predominant stromal atrophy allows the posterior pigmented layer to show through and become the dominant pigmentation, so that the eye may become hyperchromic (reverse heterochromia).
6 Gonioscopy may be normal or may show one of the following:
• Fine radial twig-like vessels in the angle (Fig. 11.75F) which are responsible for the filiform haemorrhages which develop on anterior chamber paracentesis (Amsler sign).
• Small, non-confluent, irregular peripheral anterior synechiae.
7 Systemic association. Parry–Romberg syndrome (hemifacial atrophy) is present in a small minority of cases.
8 Complications
a Cataract is extremely common and is often the presenting feature (see Fig. 11.75E). It does not differ from that associated with other types of anterior uveitis. The results of surgery with posterior chamber intraocular lens implantation are good.
b Glaucoma is a late manifestation which typically develops only after several years of follow-up. It is usually well-controlled on topical therapy, but some patients may require surgery.
9 Treatment is only indicated in patients with troublesome vitreous opacities.
a Posterior sub-Tenon injections of a long-acting steroid preparation such as triamcinolone acetonide may be beneficial although improvement is usually temporary.
b Vitrectomy may be considered for severe vitreous opacification that is reducing vision or is very disturbing.
image

Fig. 11.75 Fuchs uveitis syndrome. (A) Keratic precipitates; (B) small nodules at the pupil border and in the stroma; (C) stromal iris atrophy rendering the sphincter pupillae prominent, and small pupil border nodules; (D) posterior pigment layer atrophy seen on retroillumination; (E) heterochromia and left cataract; (F) angle vessels and small peripheral anterior synechiae

(Courtesy of C Pavésio – fig. A)

Topical steroids are generally ineffective and mydriatics unnecessary because of lack of posterior synechiae.

Table 11.8 Other causes of heterochromia iridis

1 Hypochromic
• Idiopathic congenital
• Horner syndrome, particularly if congenital
• Waardenburg syndrome
2 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

Lens-induced uveitis

Lens-induced uveitis is triggered by an immune response to lens proteins following rupture of the lens capsule, which may be due to trauma or incomplete cataract extraction (Fig. 11.76).

image

Fig. 11.76 Lens-induced uveitis. (A) Escaping lens material producing an inflammatory reaction; (B) giant cells in relation to extracapsular material

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

Phacoanaphylactic endophthalmitis

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1 Presentation is with abrupt reduction in visual acuity and pain, which is less severe than in bacterial endophthalmitis, days to weeks after rupture of the lens capsule.
2 Signs
• Anterior uveitis is granulomatous and of variable severity.
• The IOP is frequently high.
• The posterior segment is not involved.
3 Differential diagnosis is from bacterial endophthalmitis; in doubtful cases vitreous tap may be required.
4 Treatment involves removal of all lens material in conjunction with intensive steroid therapy.

Phacogenic non-granulomatous uveitis

1 Signs. Anterior uveitis is less severe and more chronic than in phacoanaphylactic endophthalmitis, and develops within 2–3 weeks of lens capsule rupture.
2 Differential diagnosis includes low-grade bacterial and fungal endophthalmitis, SO and IOL-induced inflammation.
3 Treatment of mild cases is with topical steroids but periocular and systemic therapy will be necessary for more intense inflammation. Removal of remaining lens material may also be necessary.

Miscellaneous posterior uveitis

Acute retinal pigment epitheliitis

Acute retinal pigment epitheliitis (Krill disease) is a rare, idiopathic, self-limiting condition of the RPE that is unilateral in 75% of cases.

1 Presentation is in the 3rd decade with sudden mild disturbance of central vision.
2 Signs
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• The macula shows 2–4 discrete clusters of subtle small grey spots at the level of the RPE surrounded by hypopigmented yellow halos (Fig. 11.77A).
• These lesions tend to appear 1–2 weeks after the onset of symptoms.
• After 6–12 weeks the lesions resolve and vision returns to normal.
• Recurrences are uncommon.
3 FA may be normal or the halos may show hyperfluorescence without leakage (Fig. 11.77B).
4 EOG is subnormal.
5 Treatment is not required.
image

Fig. 11.77 (A) Acute retinal pigment epitheliitis; (B) FA venous phase shows corresponding focal hyperfluorescence

(Courtesy of M Prost)

Acute idiopathic maculopathy

Acute idiopathic maculopathy is a very rare, self-limiting condition which is most frequently unilateral and may be preceded by a flu-like illness.

1 Presentation is in the 2nd–4th decades with a unilateral sudden and severe loss of central vision.
2 Signs
• Detachment of the sensory retina at the macula with an irregular outline (Fig. 11.78A); intraretinal haemorrhages may be seen in the detached area.
• Smaller, greyish subretinal thickening at the level of the RPE beneath the detachment is frequently present.
• Iritis, papillitis and mild vitritis may be present.
• Within a few weeks the exudative changes resolve.
• A bull’s eye appearance may develop following resolution and may be associated with visual loss.
3 FA
• Early phase shows irregular mild hyperfluorescence beneath the sensory retinal detachment (Fig. 11.78B).
• Mid-venous (Fig. 11.78C) and late venous (Fig. 11.78D) phases show intense staining of the subretinal fluid.
4 Treatment is not required.
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image

Fig. 11.78 Acute idiopathic maculopathy. (A) Detachment of the sensory retina at the macula with an irregular outline; (B) FA early phase shows mild irregular subretinal hyperfluorescence; (C) mid-venous phase shows extensive hyperfluorescence due to staining of the subretinal fluid; (D) late venous phase shows further staining of subretinal fluid

(Courtesy of S Milewski)

Acute multifocal retinitis

Acute multifocal retinitis is a very rare, frequently bilateral, self-limiting condition that typically affects healthy individuals. It may be preceded by a flu-like illness, usually 1–2 weeks before the onset of the visual symptoms. It has been postulated by some that acute multifocal retinitis may be an unusual presentation of cat-scratch disease.

1 Presentation is in the 3rd–4th decades with sudden onset of mild visual loss.
2 Signs
• Multiple areas of retinitis posterior to the equator (Fig. 11.79) in both eyes.
• Mild vitritis and disc oedema are frequent.
• A macular star is present in a few cases.
• Small retinal branch artery occlusions occur in a minority.
• After 2–4 months the fundus lesions resolve and vision recovers.
3 Treatment is not required.
image

Fig. 11.79 Acute multifocal retinitis

(Courtesy of S Milewski)

Solitary idiopathic choroiditis

Solitary idiopathic choroiditis is a distinct clinical entity that may give rise to diagnostic problems as it can simulate other pathology.

1 Presentation is with mild visual loss and floaters.
2 Signs
• Vitritis is present during active disease.
• Discrete, post-equatorial, dull-yellow choroidal elevation with ill-defined margins.
• Associated findings include adjacent subretinal fluid and a macular star away from the main lesion.
• As the inflammation resolves the lesion develops a better-defined margin with resolution of subretinal fluid and exudation.
3 Treatment of active, vision-threatening lesions is with systemic steroids. Most inactive lesions either remain stable or resolve without treatment.
4 Differential diagnosis includes inflammatory lesions such as sarcoidosis, tuberculosis (see Fig. 11.51B), nodular posterior scleritis and syphilis, and amelanotic tumours such as amelanotic melanoma and metastasis.

Frosted branch angiitis

Frosted branch angiitis (FBA) describes a characteristic fundus picture, usually bilateral, which may represent a specific syndrome (primary form) or a common immune pathway in response to multiple infective agents. Secondary FBA may be associated with infectious retinitis, most notably cytomegalovirus retinitis, but it may also occur in association with other conditions such as glomerulonephritis and central retinal vein occlusion. Primary FBA is rare and typically affects children and young adults.

1 Presentation is with subacute bilateral visual loss, floaters and/or photopsia.
2 Signs
• Visual acuity is usually very poor.
• Florid translucent retinal perivascular sheathing of both arterioles and venules (Fig. 11.80A).
• Anterior uveitis, vitritis and retinal oedema are common.
• Uncommon findings include papillitis, hard exudates, retinal haemorrhages and venous occlusion (Fig. 11.80B).
3 Treatment is with systemic and topical steroids, but the optimal regimen has not been established. The primary form has a good visual prognosis but significant visual loss may result in secondary forms.
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image

Fig. 11.80 Frosted branch angiitis. (A) Perivascular sheathing; (B) secondary venous occlusion

(Courtesy of J Donald Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. A; C Barry – fig. B)

Idiopathic retinal vasculitis, aneurysms and neuroretinitis syndrome

Idiopathic retinal vasculitis, aneurysms and neuroretinitis syndrome is a rare entity that typically affects one or both eyes of healthy young women.

1 Signs
• Anterior uveitis and vitritis.
• Multiple, leaking, tied-knot-like aneurysmal dilatations along the retinal arteriolar tree and optic nerve head that give rise to marked circumpapillary intraretinal lipid deposition (Fig. 11.81A).
• The aneurysms may increase in number although some may spontaneously regress.
• Disc oedema and a macular star.
• Irregular venous dilatation and vascular sheathing.
2 FA shows multiple aneurysms at arterial bifurcations and marked variation of arteriolar calibre (Fig. 11.81B). Extensive peripheral capillary non-perfusion is also seen.
3 Treatment by laser photocoagulation may be beneficial in eyes with extensive peripheral ischaemia and retinal neovascularization.
image

Fig. 11.81 Idiopathic retinal vasculitis, aneurysms and neuroretinitis syndrome. (A) Circinate pattern of hard exudates surrounding the disc. There is also venous irregularity and obscuration of the optic nerve head; (B) FA shows multiple aneurysms at arteriolar bifurcations and marked variation in arteriolar calibre

(Courtesy of J Donald Gass, from Stereoscopic Atlas of Macular Diseases, Mosby 1997 – fig. A; RF Spaide, from Diseases of the Retina and Vitreous, WB Saunders 1999 – fig. B)