Terminology
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Uveitis: inflammation of the uveal tract.
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Anterior uveitis: iritis and iridocyclitis (iris and ciliary body).
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Intermediate uveitis: inflammation of the pars plana, the peripheral retina and the vitreous.
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Posterior uveitis: inflammation posterior to the vitreous base.
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Retinitis: primary retinal focus of inflammation.
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Choroiditis: primary choroidal focus.
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Vasculitis: inflammation of veins, arteries or both.
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Panuveitis: involvement of the entire uveal tract.
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Endophthalmitis: involves all intraocular tissues except the sclera.
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Panophthalmitis: involves the entire globe.
Clinical Features
Acute anterior uveitis
Acute anterior uveitis (AAU) is the most common form of uveitis.
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Presentation: rapid onset of unilateral pain, photophobia and redness.
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Signs: (a) ciliary injection ( Fig. 12.1A ), (b) miosis, (c) endothelial dusting by inflammatory cells progresses to fine/medium keratic precipitates (KP) after a few days, (d) hypopyon in intense inflammation ( Fig. 12.1B ), (e) anterior vitreous cells in iridocyclitis, (f) aqueous flare, (g) fibrinous exudate in severe AAU ( Fig. 12.2A ).
Fig. 12.1
Acute anterior uveitis: (A) ciliary injection, (B) hypopyon.
(From Salmon JF, Kanski’s Clinical Ophthalmology: A Systematic Approach , 9th edition. Oxford, UK: Elsevier; 2020.)
Fig. 12.2
Chronic anterior uveitis: (A) fibrinous exudate (arrow), (B) ‘mutton fat’ keratic precipitates, (C) Busacca nodule (iris stroma) and Koeppe nodule (pupil margin), (D) posterior synechiae after dilatation showing pigment on lens.
( Figure 12.2C courtesy of C. Pavesio.)
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Duration: most episodes completely resolve within 5–6 weeks.
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Prognosis: good with adequate treatment.
Chronic anterior uveitis
Chronic anterior uveitis (CAU) is less common than the acute type and it is more frequently bilateral. Inflammation may be granulomatous or non-granulomatous.
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Presentation: often insidious and may be asymptomatic until complications such as cataract or band keratopathy develop.
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Signs: (a) eye may be mildly injected or white, depending on the cause, (b) aqueous cells vary in number according to activity, (c) aqueous flare may be more marked than cells, in eyes with prolonged activity, (d) large KP with a greasy ‘mutton-fat’ appearance ( Fig. 12.2B ) and iris nodules (Busacca in the iris stroma, Koeppe on the pupil margin) in granulomatous disease ( Fig. 12.2C ), (e) posterior synechiae ( Fig. 12.2D ).
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Duration: prolonged; may last for months or even years with remissions and exacerbations.
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Prognosis: influenced by complications such as cataract, glaucoma, hypotony and phthisis bulbi. Oral immunotherapy has improved the prognosis in recent years.
Posterior uveitis
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Presentation : varies according to the location of the inflammatory focus and the presence of vitritis.
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Cause: the clinical features and special investigations will usually allow a definitive diagnosis to be made. To determine the cause of a persistent and severe posterior uveitis of unknown aetiology for which all workup is negative, consider undertaking a vitreous and/or retinochoroidal biopsy.
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Retinitis: whitish retinal opacities with indistinct borders ( Fig. 12.3A ) and overlying vitritis.
Fig. 12.3
Posterior uveitis: (A) retinitis, (B) choroiditis, (C) vasculitis, (D) posterior sub-Tenon steroid injection.
( Figure 12.3D courtesy of C. Pavesio.)
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Choroiditis: deep, round, yellow nodules ( Fig. 12.3B ).
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Vasculitis: (periphlebitis, periarteritis) may be primary or secondary to retinitis; yellowish or grey-white patchy perivascular cuffing which may be associated with haemorrhages ( Fig. 12.3C ).
Principles of Treatment
Mydriatics
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Indications: (a) to relieve pain caused by iridociliary spasm, (b) prevent (or break recently formed) posterior synechiae.
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Topical short-acting: (a) cyclopentolate (0.5%, 1%) acts for approximately 24 hours, (b) tropicamide and phenylephrine are shorter-acting.
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Topical long-acting: (a) homatropine 2% (approximately 2 days), (b) atropine 1% (up to 2 weeks).
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Subconjunctival: Mydricaine (adrenaline, atropine and procaine) if no response to drops.
Topical steroids
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Indications: anterior uveitis.
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Preparations: dexamethasone, prednisolone (range of concentrations available), betamethasone, loteprednol, fluorometholone and rimexolone.
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Complications: glaucoma, cataract and corneal infection.
Periocular steroid injection
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Advantages over topical administration: (a) higher posterior segment concentrations may be achieved, (b) water-soluble drugs, incapable of penetrating topically, but can enter across the sclera, (c) prolonged effect can be achieved with ‘depot’ preparations.
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Indications: (a) primary treatment of intermediate and certain types of posterior uveitis, (b) to supplement systemic therapy or when it is contraindicated, (c) poor compliance with topical or systemic medication, (d) perioperatively in uveitic eyes.
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Complications: (a) globe penetration, (b) elevation of IOP (may be refractory with depot preparations), (c) ptosis, (d) subdermal fat atrophy, (e) ocular motility paresis, (f) optic nerve injury, (g) retinal and choroidal vascular occlusion, (h) cutaneous hypopigmentation.
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Technique: via the superotemporal conjunctiva (posterior sub-Tenon; Fig. 12.3D ), or to the orbital floor via skin or conjunctiva.
Intraocular steroids
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Intravitreal injection: triamcinolone acetonide can be used for some forms of posterior uveitis unresponsive to other modalities and for refractory cystoid macular oedema (CMO).
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Complications: (a) elevation of IOP, (b) cataract, (c) endophthalmitis (sterile or infectious), (d) haemorrhage, (e) retinal detachment.
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Slow-release implants: biodegradable insert or a slow-release reservoir (fluocinolone acetonide, dexamethasone) offer the benefits of intravitreal steroid injection but over an extended period of up to 3 years; complications are similar to those of intravitreal triamcinolone injection.
Systemic steroids
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Indications: (a) intermediate uveitis unresponsive to periocular injection, (b) sight-threatening posterior uveitis, particularly if bilateral.
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Contraindications: (a) poorly-controlled diabetes (relative contraindication), (b) peptic ulceration, (c) osteoporosis, (d) active systemic infection, (e) psychosis on previous exposure to steroids.
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Preparations: oral prednisolone and intravenous methylprednisolone.
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Common cause of failure: inadequate dosage; a large dose should be used initially and subsequently tapered.
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Side effects with short-term use: (a) dyspepsia, (b) mental changes, (c) electrolyte imbalance, (d) aseptic necrosis of the head of the femur, (e) destabilization of diabetic control.
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Side effects with long-term use: (a) Cushing syndrome, (b) osteoporosis, (c) limitation of growth in children, (d) reactivation of infections such as TB, (e) cataract, (f) elevation of IOP.
Antimetabolites
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Indications: (a) sight-threatening uveitis, typically bilateral, noninfectious and reversible, after failure to respond to adequate steroid therapy, (b) steroid-sparing therapy in patients with intolerable side effects from systemic steroids, (c) chronic relapsing disease requiring a daily dose of prednisolone above approximately 10 mg.
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Preparations: azathioprine, methotrexate and mycophenolate mofetil.
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Side effects: (a) gastrointestinal disturbance, (b) bone marrow suppression, (c) hepatotoxicity.
Alkylating agents
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Indications: retinal vasculitis (not commonly used, as safer medication is available).
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Preparations: cyclophosphamide, chlorambucil
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Side effects: (a) gastrointestinal disturbance, (b) infection, (c) bone marrow suppression, (d) infertility, (e) allergic reactions, (f) cancer.
Other drugs
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Ciclosporin: particularly useful in Behçet disease; side effects include nephrotoxicity and hepatotoxicity.
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Tacrolimus: alternative to ciclosporin; for severe refractory uveitis.
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Biopharmacologicals: interleukin receptor antagonists (daclizumab, anakinra) and tumour necrosis factor-alpha antagonists (infliximab, adalimumab, etanercept, golimumab, certolizumab). These agents take time to suppress inflammation (2 weeks to 3 months). Topical and systemic steroids may be needed initially to control acute inflammation.
Intermediate Uveitis
Definition:
intermediate uveitis (IU) is a chronic/relapsing condition that may be idiopathic or associated with systemic disease. It is typically bilateral but asymmetrical. Systemic associations include: (a) multiple sclerosis (MS), (b) sarcoidosis, (c) Lyme disease, (d) tuberculosis. The course and prognosis are very variable.
Diagnosis
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Presentation: in childhood or early adult life with insidious onset of blurred vision and floaters.
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Signs: (a) mild anterior uveitis, (b) vitreous cells with anterior predominance ( Fig. 12.4A ), (c) inferior vitreous ‘snowballs’, (d) peripheral phlebitis, (e) inferior ‘snowbanking’ ( Fig. 12.4B ), (f) neovascularization on the snowbank or the optic nerve head.
Fig. 12.4
Intermediate uveitis: (A) severe vitreous activity showing haze and condensation visible in the slit beam (arrow), (B) inferior snowbanking and snowballs.
(From Salmon JF, Kanski’s Clinical Ophthalmology: A Systematic Approach , 9th edition. Oxford, UK: Elsevier; 2020.)
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Complications: (a) CMO in 30% is the major cause of visual impairment, (b) epimacular membranes and occasionally (c) retinal detachment (tractional, rhegmatogenous, or exudative).
Treatment
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Medical: (a) initially topical and/or periocular steroids, (b) systemic steroids and immunosuppressive agents may be required, (c) interferon beta for IU in MS.
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Vitrectomy: following failure of systemic steroids to control CMO; other indications include retinal detachment, vitreous haemorrhage and epiretinal membranes.
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Photocoagulation: to peripheral retina for neovascularization at the vitreous base.
Uveitis In Spondyloarthropathies
Ankylosing spondylitis
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Definition : an inflammatory disease leading to ossification of joints with bony ankylosis of the axial skeleton. It typically affects adult males, of whom 90% are HLA-B27 positive. Radiology of the sacroiliac joints and spine reveals characteristic changes.
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Ocular features: AAU occurs in approximately 25% of patients with ankylosing spondylitis; conversely, 25% of males with AAU will have ankylosing spondylitis.
Reiter syndrome
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Definition : Reiter syndrome comprises the triad of: (a) nonspecific urethritis, (b) conjunctivitis, (c) arthritis. Those affected are commonly men in the 3rd and 4th decades, of whom 85% are positive for HLA-B27.
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Ocular features: (a) conjunctivitis is common and usually precedes the arthritis, with spontaneous resolution occurring within 7–10 days, (b) AAU occurs in up to 12% of patients but is higher in carriers of HLA-B27.
Psoriatic arthritis
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Definition: arthritis developing in patients with psoriasis.
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Ocular features: (a) AAU occurs in approximately 7%, (b) other uncommon manifestations include conjunctivitis, marginal corneal infiltrates and secondary Sjögren syndrome.
Juvenile idiopathic arthritis
Definition:
idiopathic arthritis of at least 6 weeks’ duration occurring before the age of 16 years. Juvenile idiopathic arthritis (JIA) is by far the most common disease associated with childhood anterior uveitis. Girls are affected more commonly than boys. Positivity for antinuclear antibodies (ANA) is associated with a higher risk of uveitis.
Diagnosis
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Pauci-articular onset (60% of cases): four or fewer joints, most commonly the knees ( Fig. 12.5A ), are involved during the first 6 months with a peak age of onset around 2 years; approximately 75% of children are ANA-positive and uveitis affects approximately 20%.
Fig. 12.5
JIA: (A) arthritis of the knee, (B) posterior synechiae and cataract.
(From Salmon JF, Kanski’s Clinical Ophthalmology: A Systematic Approach , 9th edition. Oxford, UK: Elsevier; 2020.)
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Poly-articular onset (20%): five or more joints are involved; may commence throughout childhood; 40% ANA-positive and uveitis affects 5%.
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Systemic onset (Still’s disease; 20%): presents with fever, maculopapular rash, generalized lymphadenopathy, hepatosplenomegaly, and serositis; arthritis may be absent or minimal; most are ANA-negative and uveitis does not occur.
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Features of anterior uveitis in JIA: (a) onset is usually asymptomatic with a white eye, (b) chronic non-granulomatous inflammation, (c) 70% bilateral, (d) other complications include band keratopathy, cataract ( Fig. 12.5B ), glaucoma and hypotony.
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Differential diagnosis: (a) idiopathic juvenile chronic iridocyclitis, (b) other types of juvenile arthritis and uveitis (e.g. juvenile spondyloarthropathies, sarcoidosis, Lyme disease, IU), and (c) masquerade syndromes (e.g. anterior segment involvement by retinoblastoma).
Treatment
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Screening: regular slit lamp examinations at intervals ranging from (a) 9-monthly in low-risk ANA-negative polyarticular-onset patients, (b) 2-monthly in high-risk ANA-positive pauciarticular-onset children, (c) not required in systemic-onset disease.
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Treatment: topical steroids are initially effective. Immunomodulatory treatment, including biological medication, should be used early in the course of the disease.
Uveitis in Bowel Disease
Ulcerative colitis
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Definition: idiopathic chronic inflammatory disease presenting in the 2nd and 3rd decades, affecting principally the large intestine and rectum. Extra-intestinal manifestations include mucocutaneous lesions, arthritis and hepatic disease.
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Ocular features: AAU occurs in approximately 5%.
Crohn disease
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Definition: an idiopathic chronic granulomatous inflammatory disease of the intestinal wall, most frequently involving the ileocaecal region. Presentation is in the 2nd and 3rd decades with fever, weight loss, diarrhoea and abdominal pain. Extra-intestinal manifestations include mucocutaneous lesions and skeletal features.
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Ocular features: AAU occurs in approximately 3%. Episcleritis and acute bowel inflammation often occur together. Rarely, scleritis and corneal infiltration.
Sarcoidosis
Pathogenesis:
T-lymphocyte-mediated granulomatous inflammatory disorder of unknown cause. The prevalence is highest in young adults of both genders and the disease is most common in Northern European and African countries. A wide range of tissues can be involved, particularly lung disease. Severity varies from mild single-organ involvement to potentially fatal multisystem disease.
Diagnosis
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Presentation: (a) acute with fever, erythema nodosum, arthralgia and cranial nerve palsy or (b) insidious with symptomatic pulmonary involvement.
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Pulmonary lesions: vary from symptomatic hilar lymphadenopathy to severe fibrosis.
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Skin lesions: (a) erythema nodosum, (b) granulomas, (c) lupus pernio.
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Neurological disease: (a) facial palsy, (b) seizures, (c) meningitis, (d) peripheral neuropathy, (e) psychiatric symptoms.
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Other: (a) arthropathy, (b) bone cysts, (c) renal disease, (d) lymphadenopathy, (e) liver disease.
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Investigations: (a) chest X-ray (abnormal in 90%), (b) biopsy (lung, lymph node, skin, conjunctiva, lacrimal gland), (c) serum angiotensin-converting enzyme and lysozyme, (d) bronchoalveolar lavage, (e) pulmonary function tests, (f) Mantoux test is negative in most patients.
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Ocular features: (a) AAU typically occurs in patients with acute-onset sarcoid, (b) CAU, typically granulomatous ( Fig. 12.6A ), tends to affect older patients with chronic disease, (c) intermediate uveitis, (d) periphlebitis with ‘candle wax drippings’ ( Fig. 12.6B ), (e) choroidal infiltrates, (f) multifocal choroiditis ( Fig. 12.6C ), (g) retinal granulomas, (h) peripheral retinal neovascularization, (i) optic nerve granulomas, (j) disc oedema, (k) lid granulomas ( Fig. 12.6D ).
Fig. 12.6
Sarcoidosis: (A) granulomatous KP, (B) periphlebitis, (C) multiple granulomas, (D) lower lid granulomas.
(From Salmon JF, Kanski’s Clinical Ophthalmology: A Systematic Approach , 9th edition. Oxford, UK: Elsevier; 2020.)
Treatment:
anterior uveitis is treated with topical and/or periocular steroids. Posterior uveitis often requires systemic steroids and occasionally other immunosuppressive agents.
Behçet Syndrome
Definition:
idiopathic multisystem disease characterized by recurrent episodes of orogenital ulceration and vasculitis. It typically affects Eastern Mediterranean and Japanese individuals and is strongly associated with HLA-B51. The peak age of onset is in the 3rd decade; males are affected more frequently than females.
Diagnosis
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Recurrent oral ulceration: plus at least two of the following: (a) recurrent genital ulceration, (b) ocular inflammation, (c) skin lesions, (d) positive pathergy test (pustule at needle prick site).
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Other systemic features: (a) vascular (aneurysms, coronary artery disease, venous thrombosis), (b) arthritis, (c) skin hypersensitivity, (d) gastrointestinal ulceration, (e) occasionally neurological manifestations.
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Ocular features: common and often bilateral; (a) AAU (transient mobile hypopyon in a relatively white eye; Fig. 12.7A ), (b) persistent vitritis, (c) transient superficial white retinal infiltrates, (d) diffuse retinitis, (e) retinal vasculitis (veins and arteries, often occlusive; Fig. 12.7B ), (f) CMO, disc oedema and optic atrophy in end-stage disease.
Fig. 12.7
Behçet disease: (A) hypopyon in a white eye, (B) retinal vasculitis.
(From Salmon JF, Kanski’s Clinical Ophthalmology: A Systematic Approach , 9th edition. Oxford, UK: Elsevier; 2020.)
Treatment:
anterior uveitis responds well to topical steroids. Posterior uveitis requires systemic steroids, azathioprine, ciclosporin and biological blockers (e.g. infliximab). Interferon-alpha is an alternative option in severe disease.
Toxoplasmosis
Pathogenesis
Toxoplasmosis is caused by the obligate intracellular protozoan Toxoplasma gondii .
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Hosts: the cat is the definitive host; intermediate hosts include mice, livestock and humans ( Fig. 12.8 ).
Fig. 12.8
Life cycle of Toxoplasma gondii .
(From Salmon JF, Kanski’s Clinical Ophthalmology: A Systematic Approach , 9th edition. Oxford, UK: Elsevier; 2020.)
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Sporozoites: excreted in the faeces of the cat and spread to intermediate hosts.
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Bradyzoites: contained within cysts in the brain, eye, skeletal muscles and other tissues and may lie dormant for many years.
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Tachyzoites: proliferating active form responsible for tissue destruction.
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Modes of human infection: (a) ingestion of undercooked meat from an intermediate host containing bradyzoites, (b) ingestion of sporocysts following inadvertent contamination of hands (e.g. cat litter tray), (c) transplacental tachyzoite transfer.
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Congenital toxoplasmosis: follows maternal infection during pregnancy. Manifestations range from stillbirth earlier in pregnancy through hydrocephalus, convulsions, paralysis, and visceral involvement to subclinical disease (may still cause intracranial calcification and chorioretinal scars).
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Acquired toxoplasmosis: commonly subclinical in the immunocompetent, although a lymphadenopathic syndrome and rarely meningoencephalitis or an exanthematous form, can occur. In immunocompromised patients, infection is much more commonly life-threatening (e.g. intracerebral space-occupying lesion in AIDS).
Toxoplasma retinitis
Pathogenesis:
reactivation at previously inactive cyst-containing scars. Inflammatory episodes (average age 25 years) occur when cysts rupture and release hundreds of tachyzoites into normal retina.
Diagnosis
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Presentation: subacute onset of floaters and blurring.
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Signs: (a) ‘spillover’ anterior uveitis may be granulomatous or resemble Fuchs syndrome, (b) solitary focal retinitis near an old pigmented scar (‘satellite lesion’) is typical ( Fig. 12.9A ), (c) vitritis ( Fig. 12.9B ).
