Ординатура / Офтальмология / Английские материалы / Clinical Ophthalmology A Systematic Approach 7th Edition_Kanski, Bowling_2011

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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).

1Presentation 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.

2Retinitis 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.

3Choroiditis 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).

4Vasculitis 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.

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

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Special investigations

Indications

1Not 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.

2Indications

•Granulomatous inflammation.

•Recurrent uveitis.

•Bilateral disease.

•Systemic manifestations without a specific diagnosis.

•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).

bNegative result usually excludes TB, but may also occur in patients with advanced consumptive disease.

cWeakly 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.

dStrongly 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).

2Pathergy 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).

3Lepromin 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.

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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.

1Non-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.

2Treponemal 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).

3Dark-ground microscopy of exudate from a mucocutaneous lesion is reliable if positive.

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

1Dye 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.

2Immunofluorescent 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).

3Haemagglutination 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).

4Enzyme-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.

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

Enzyme assay

1Serum 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.

2Lysozyme assay has good sensitivity but less specificity than ACE in the diagnosis of sarcoidosis but performing both tests seems to increase sensitivity and specificity.

HLAtissue typing

Table 11.3 -- HLA type and systemic disease

Imaging

1Fluorescein 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).

•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).

2Indocyanine 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

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provide information regarding inflammation affecting the choroidal stroma.

3Optical 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

1Chest X-ray is frequently requested to exclude tuberculosis and sarcoidosis.

2Sacroiliac joint X-ray is helpful in the diagnosis of a spondyloarthropathy in the presence of symptoms of low back pain and uveitis.

3CT 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.

1Conjunctival and lacrimal gland biopsy may useful for the diagnosis of sarcoidosis but only in the presence of clinically apparent disease.

2Aqueous samples for polymerase chain reaction (PCR) may occasionally be useful in the diagnosis of viral retinitis.

3Vitreous 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.

4Retinal 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.

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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

1Short-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.

2Long-acting

aHomatropine 2%has a duration of up to 2 days.

bAtropine 1%is the most powerful cycloplegic and mydriatic with a duration of up to 2 weeks.

Indications

1To 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 shortacting preparation can be used.

2To 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.

3To 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

1Treatment 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.

2Treatment 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

1Elevation of IOP is common in susceptible individuals (‘steroid responders’), but long-term exposure to topical steroids may

eventually result in glaucoma in many patients.

2Cataract can be induced by both systemic and, less frequently, topical steroid administration. The risk increases with dose and

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duration of therapy.

3Corneal 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.

4Systemic side-effects are rare, but may occasionally occur following prolonged administration, particularly in children.

Periocular steroid injection

1Advantages 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).

2Indications

•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.

3Complications

•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.

4Technique

aA topical anaesthetic such as tetracaine is instilled.

bA small cotton pledget impregnated with amethocaine (or equivalent) is placed into the superior fornix at the site of injection for 2 minutes.

cThe vial containing the steroid is shaken.

d1.5 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).

eThe patient is asked to look away from the site of injection; most frequently inferiorly when the injection is being given superotemporally.

fThe bulbar conjunctiva is penetrated with the tip of the needle, bevel towards the globe, slightly on the bulbar side of the fornix.

gThe 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!

hWhen 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.

iAlternatively, some practitioners prefer orbital floor injection via the skin or conjunctiva, due to a perceived lower risk of ocular perforation.

Fig. 11.10 Technique of posterior sub-Tenon steroid injection

(Courtesy of C Pavésio)

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Intraocular steroids

1Injection

•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.

•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.

2Slow-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

1Preparations

aOral prednisolone 5 or 25 mg tablets are the main preparations.

bIntravenous infusion of methylprednisolone 1 g/day, repeated for 2 to 3 days is an option in severe disease.

2Indications

•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.

•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.

5Side-effects depend on the duration and dose of administration.

aShort-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.

bLong-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

1Sight-threatening uveitis, which is usually bilateral, non-infectious, reversible and has failed to respond to adequate steroid therapy.

2Steroid-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.

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Azathioprine

1Indications 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.

2Dose 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.

3Side-effects include bone marrow suppression, hepatotoxicity and nausea.

4Monitoring involves a complete blood count, initially weekly and then every 4–6 weeks, and liver function tests every 12 weeks.

Methotrexate

1Indications 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.

2Dose 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.

3Side-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.

4Monitoring 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.

2Dose and route is 1–2 g daily orally.

3Side-effects include gastrointestinal disturbance and bone marrow suppression.

4Monitoring involves a full blood count initially weekly for 4 weeks and then monthly.

Calcineurin inhibitors

Ciclosporin

1Indications. 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.

2Dose and route is 2.5–7 mg/kg daily orally.

3Side-effects include nephrotoxicity, hyperlipidaemia, hepatotoxicity, hypertension, hirsutism and gingival hyperplasia. Poorly controlled hypertension and renal disease are relative contraindications.

4Monitoring involves blood pressure, and renal and liver function tests every 6 weeks.

Tacrolimus

1 Indications. An alternative to ciclosporin in intolerant or unresponsive patients.

2Dose and route is 1–0.25 mg/kg daily orally.

3Side-effects include hyperglycaemia, neurotoxicity and nephrotoxicity; these are more common than with ciclosporin.

4Monitoring 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.

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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

1Presentation 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.

2Anterior 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.

3Vitreous

•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).

4Posterior 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

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