Uveitis

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8 Uveitis

Pathophysiology

Retinal S-antigen

Protein found in human retinal photoreceptors and pineal gland

Most potent uveitic antigen; thought to be an enzyme located in rod outer segments

In animal model: produces uveitis when injected into nonocular sites (experimental autoimmune uveitis [EAU]; type 4 hypersensitivity); removal of thymus prevents EAU (supports T cell-mediated basis of inflammatory response)

Human diseases that resemble EAU: VKH, sympathetic ophthalmia, birdshot retinochoroidopathy; lymphocytes from these patients develop an in vitro proliferative response to retinal S-antigen, suggesting an autoimmune basis for these diseases

Classification

Pathology

nongranulomatous, granulomatous

Etiology

infection, immune response, malignancy, trauma, chemical, idiopathic

Location

sclerouveitis, keratouveitis, anterior uveitis (iritis), iridocyclitis, lens-induced uveitis, intermediate uveitis, endophthalmitis (infection or inflammation of the vitreous, anterior chamber, ciliary body, and choroid), posterior uveitis (retinitis, choroiditis, vasculitis), panuveitis (endophthalmitis and involvement of the sclera)

Anterior uveitis

Inflammation of iris (iritis) and ciliary body (cyclitis)

Most common cause of anterior uveitis in adults is idiopathic (followed by HLA-B27 associated)

Most common cause of acute, noninfectious, hypopyon iritis is HLA-B27-associated iritis

Etiology

Children: JRA, ankylosing spondylitis, psoriatic arthritis, acute interstitial nephritis, Fuchs’ heterochromic iridocyclitis, sarcoidosis, postviral, HSV, Lyme disease, trauma, Kawasaki’s disease

50% have posterior component (toxoplasmosis in 50% with posterior component)

Young adults: HLA-B27 associated, sarcoidosis, syphilis, Fuchs’, Behçet’s disease, spillover from intermediate or posterior uveitis

Older adults: idiopathic, sarcoidosis, HZO, masquerade syndromes (peripheral RD, intraocular foreign body, JXG, multiple sclerosis, malignancies [retinoblastoma, leukemia, large cell lymphoma, malignant melanoma])

Classification

Nongranulomatous:

ACUTE: idiopathic, HLA-B27 associated (5% of general population; associated with acute, recurrent uveitis; usually starts unilaterally; associated with the following 4 disorders: ankylosing spondylitis, Reiter’s syndrome, psoriatic arthritis, inflammatory bowel disease), Behçet’s disease, glaucomatocyclitic crisis (Posner-Schlossman syndrome), HSV, Kawasaki’s disease, Lyme disease, traumatic, postoperative, other autoimmune diseases (lupus, relapsing polychondritis, Wegener’s granulomatosis, interstitial nephritis)

CHRONIC (duration >6 weeks): JRA, Fuchs’ heterochromic iridocyclitis

Granulomatous:

INFECTIOUS: syphilis, TB, leprosy, brucellosis, toxoplasmosis, P. acnes, fungal (Cryptococcus, Aspergillus), HIV

IMMUNE-MEDIATED: sarcoidosis, VKH syndrome, sympathetic ophthalmia, phacoanaphylactic

Symptoms

pain, photophobia, decreased vision, redness

Findings

conjunctival and episcleral injection, ciliary injection (circumcorneal flush from branches of anterior ciliary arteries), miosis (iris sphincter spasm), AC reaction; may have hypopyon, keratic precipitates, iris nodules, dilated iris vessels (occasionally, rubeosis), synechiae (posterior [iris adhesions to lens; seclusio pupillae is a complete adhesion that can result in iris bombe] or anterior [iris adhesions to cornea and angle]) (Figure 8-1)

Keratitic precipitates (KP): aggregates of white blood cells on corneal endothelium; typically located inferiorly and centrally (Figure 8-2)

May occur with any intraocular inflammation, most commonly with uveitis

May be white or pigmented, small or large, nongranulomatous (fine) or granulomatous (mutton fat), diffuse or focal

NONGRANULOMATOUS: composed of lymphocytes and PMNs

GRANULOMATOUS: composed of macrophages, lymphocytes, epithelioid cells, and multinucleated giant cells

DDX OF DIFFUSE KP: Fuchs’ heterochromic iridocyclitis, sarcoidosis, syphilis, keratouveitis, toxoplasmosis (rarely)

Iris nodules:

KOEPPE: located at pupil margin; occur in granulomatous and nongranulomatous uveitis

BUSACCA: located on anterior iris surface; occur only in granulomatous uveitis (Figure 8-3)

BERLIN: located in anterior chamber angle; occur in granulomatous uveitis

Figure 8-1 Severe idiopathic anterior uveitis with fibrinoid reaction.

(From Hooper PL: Idiopathic and other anterior uveitis. In Yanoff M, Duker JS [eds]: Ophthalmology, London, Mosby, 1999.)

Figure 8-2 Keratic precipitates in anterior uveitis.

(From Forster DJ: General approach to the uveitis patient and treatment strategies. In Yanoff M, Duker JS [eds]: Ophthalmology, London, Mosby, 1999.)

Figure 8-3 Chronic granulomatous uveitis demonstrating Busacca nodules.

(From Forster DJ: General approach to the uveitis patient and treatment strategies. In Yanoff M, Duker JS [eds]: Ophthalmology, London, Mosby, 1999.)

DDx of hypopyon

HLA-B27 associated, infection (keratitis, endophthalmitis), foreign body, Behçet’s disease, VKH syndrome, malignancy (leukemia, retinoblastoma), toxic (rifabutin)

DDx of uveitic glaucoma

HSV, HZV, Posner-Schlossman syndrome, Fuchs’ heterochromic iridocyclitis, sarcoidosis; rarely toxoplasmosis, syphilis, sympathetic ophthalmia

Diagnosis

Minimum: CBC with differential, urinalysis, VDRL and FTA-ABS

Expanded (for recurrent anterior [3 or more attacks], granulomatous, positive review of systems, or posterior involvement): ESR, ACE, ANA, ANCA, IL-10, PPD plus anergy panel, CXR or chest CT; consider Lyme test in endemic areas, HLA typing (25% with HLA-B27 develop sacroiliac disease, so obtain sacroiliac X-ray), HIV Ab test

Targeted approach:

RECURRENT UVEITIS, WITH BACK STIFFNESS UPON AWAKENING: rule out ankylosing spondylitis

Lumbosacral spine imaging (CT)

GRANULOMATOUS UVEITIS: rule out TB and sarcoidosis

Upper body gallium scan

Angiotensin-converting enzyme ([ACE]; elevated in 60% with sarcoidosis; also in Gaucher’s disease, miliary tuberculosis, silicosis)

Liver function tests and bilirubin

CHILD WITH RECURRENT OR CHRONIC IRIDOCYCLITIS: rule out JRA (usually ANA-positive, RF-negative)

RETINAL VASCULITIS, RECURRENT APHTHOUS ULCERS, PRETIBIAL SKIN LESIONS: rule out Behçet’s disease

Skin lesion biopsy

HLA-B51 and -B27

PARS PLANITIS AND EPISODIC PARESTHESIAS: rule out multiple sclerosis (MS)

Lumbar puncture

RETINOCHOROIDITIS ADJACENT TO PIGMENTED CR SCAR: rule out toxoplasmosis

Toxoplasma IgM and IgG titers

RETINAL VASCULITIS AND SINUSITIS: rule out Wegener’s granulomatosis

RECURRENT UVEITIS AND DIARRHEA: rule out inflammatory bowel disease (IBD)

Endoscopy with biopsy

CHOROIDITIS, EXUDATIVE RD, EPISODIC TINNITUS: rule out Harada’s disease/VKH syndrome

Lumbar puncture

ELDERLY FEMALE WITH VITRITIS: rule out intraocular lymphoma or infection

Vitreal biopsy for culture or cytology

UNILATERAL IRIDOCYCLITIS, FINE WHITE KP, LIGHTER IRIS IN AFFECTED EYE: rule out Fuchs’ heterochromic iridocyclitis

Gonioscopy (fine-angle vessels)

Treatment

topical steroids, cycloplegic; may require systemic steroids, immunosuppressive agents, antibiotics

Poor response to steroids: Fuchs’, syphilis, toxoplasmosis, keratouveitis, Lyme disease, chronic postoperative endophthalmitis, ARN, CMV

Complications

iris atrophy, band keratopathy, cataract, glaucoma, cystoid macular edema

Psoriatic Arthritis

Associated with HLA-B17 and HLA-B27

Uveitis does not occur in psoriasis without arthritis

Findings

conjunctivitis, dry eyes, anterior uveitis

Other findings

arthritis (hands, feet, sacroiliac joints), psoriatic skin and nail changes

Inflammatory Bowel Disease (IBD)

Uveitis occurs in ulcerative colitis (10%) and Crohn’s disease (3%)

Findings

conjunctivitis, keratoconjunctivitis sicca, episcleritis, scleritis, anterior uveitis, orbital cellulitis, optic neuritis

Other findings

arthritis, erythema nodosum, pyoderma gangrenosum, hepatitis, sclerosing cholangitis

Fuchs’ Heterochromic Iridocyclitis

Occurs in young adults; unilateral

Associated with chorioretinal scars (toxo)

Symptoms

Findings

diffuse small white stellate KP, minimal AC reaction, no posterior synechiae, iris heterochromia (diffuse atrophy of stroma, loss of iris crypts; involved iris is paler; 15% bilateral), fine-angle vessels (may bleed during gonioscopy, cataract surgery, or paracentesis) (Figure 8-4)

Figure 8-4 Fuchs’ uveitis

(From Hooper PL: Idiopathic and other anterior uveitis. In Yanoff M, Duker JS [eds]: Ophthalmology, London, Mosby, 1999.)

DDx of iris heterochromia

trauma (intraocular metallic foreign body), inflammation, congenital Horner’s syndrome, iris melanoma, Waardenburg’s syndrome (iris heterochromia, telecanthus, white forelock, congenital deafness), Parry-Romberg syndrome (iris heterochromia, Horner’s syndrome, ocular motor palsies, nystagmus, facial hemiatrophy), glaucomatocyclitic crisis, medication (topical prostaglandin analogues [Xalatan, Lumigan, Travatan]), nevus of Ota

Pathology

plasma cells in ciliary body

Treatment

poor response to steroids

Complications

glaucoma (60%), cataract (PSC; 50%)

Juvenile Rheumatoid Arthritis (JRA)

(See Ch. 5, Pediatrics/Strabismus)

Kawasaki’s Disease

(See Ch. 5, Pediatrics/Strabismus)

Lyme Disease

Due to Borrelia burgdorferi (spirochete)

Ocular involvement is usually bilateral

Affected organ systems: skin, CNS, cardiovascular, musculoskeletal

Findings (in stage 2 and 3 disease)

cranial nerve palsies (CN 7 most common), orbital myositis, follicular conjunctivitis, symblepharon, episcleritis, keratitis (multiple nummular stromal infiltrates), chronic granulomatous iridocyclitis with posterior synechiae and vitreous cells, intermediate or posterior uveitis, pars planitis, chorioretinitis, exudative RD, CME, BRAO, retinal vasculitis, papilledema, pseudotumor cerebri, optic neuritis, optic atrophy

Posner-Schlossman Syndrome (Glaucomatocyclitic Crisis)

Recurrent anterior uveitis and increased IOP; episodes are typically self-limited

Symptoms

unilateral pain

Findings

mild AC reaction, few or no KP, elevated IOP

Treatment

may require topical glaucoma medications to control IOP, steroids to control inflammation

Phacoanaphylactic Endophthalmitis

Immune complex disease (type 3 hypersensitivity reaction) when normal tolerance to lens protein is lost

Previous rupture of lens capsule in same or fellow eye, followed by latent period; with re-exposure to lens protein during surgery, zonal granulomatous uveitis occurs

Associated with trauma (80%)

May develop severe uveitis with hypotony, secondary open-angle glaucoma

Pathology

zonal pattern (PMNs infiltrate central lens material; epithelioid histiocytes and mononuclear cells around nidus)

Treatment

Interstitial Nephritis

Rare; can be idiopathic or triggered by allergic reaction to medicines (antibiotics, NSAIDs)

Associated with acute anterior uveitis

Pathology

interstitial edema with mononuclear inflammatory cells; eosinophils can be present

Intermediate uveitis

Etiology

pars planitis, multiple sclerosis (5–25% have periphlebitis and intermediate uveitis), Lyme disease, sarcoidosis, Fuchs’ heterochromic iridocyclitis

Pars Planitis

Most common cause of intermediate uveitis (85–90%)

Usually young adults; females > males; 75% bilateral

Accounts for 25% of uveitis in children

Associated with HLA-DR15 and MS

Etiology

unknown; diagnosis of exclusion

Symptoms

floaters, decreased vision

Findings

light flare with a few KP, anterior vitritis, snowballs (white vitreous cellular aggregates near ora serrata; may coalesce to form peripheral fibrovascular accumulation [snowbank] over inferior pars plana and vitreous base), peripheral retinal periphlebitis, hyperemic disc, no chorioretinitis, no synechiae (Figure 8-5)

Figure 8-5 Inferior pars plana snowbank with attached snowballs.

(From Zimmerman PL: Pars planitis and other intermediate uveitis. In Yanoff M, Duker JS [eds]: Ophthalmology, London, Mosby, 1999.)

Pathology

Snowballs: epithelioid cells and multinucleated giant cells

Snowbank: preretinal membrane of fibroglial and vascular elements

Peripheral retinal veins: often have perivascular cuff of lymphocytes

DDx

sarcoidosis, toxoplasmosis, toxocariasis, syphilis, Lyme disease, MS

Multiple sclerosis: bilateral pars planitis can occur (80% bilateral, 20% unilateral); may present with band keratopathy, mild AC reaction, vitreous cells in a young patient; can also have cataract (PSC), epiretinal membrane, CME, retinal phlebitis

Treatment

(main indication is CME with reduced vision): periocular and oral steroids; consider immunosuppressive agents, vitrectomy, cryotherapy to areas of peripheral NV (controversial; can decrease leakage and macular edema, but can lead to retinal tears)

Prognosis

10% self-limited, 90% chronic ( with exacerbations)

Complications

cataract, retrolenticular cyclitic membrane, VH (from peripheral retinal neovascularization), tractional RD, CME (primary cause of vision loss, followed by cataract), band keratopathy

Posterior uveitis

Most common cause of posterior uveitis in adults is toxoplasmosis (followed by retinal vasculitis)

Signs

vitreous cells, membranes, opacities, inflammatory exudates (’snowballs’), vasculitis (opacification around vessels [sheathing {whole vessel}, cuffing {segment of vessel}]), exudates (candlewax drippings), retinitis, pigmentary changes (due to RPE inflammation), choroiditis (focal, multifocal, or diffuse), choroidal detachment

Complications

NV, CME, ON swelling and atrophy

CME: common cause of vision loss in pars planitis, birdshot retinochoroidopathy, retinal vasculitis, and any iridocyclitis (especially chronic, recurrent cases); CME does not occur in VKH

Indications for cytotoxic therapy

Behçet’s disease, sympathetic ophthalmia, VKH, pars planitis, Eales disease, retinal vasculitis, serpiginous choroidopathy, OCP, necrotizing scleritis, inflammations unresponsive to maximum steroid therapy

Infections

Toxoplasmosis

(See Ch. 5, Pediatrics/Strabismus)

Toxocariasis

(See Ch. 5, Pediatrics/Strabismus)

Presumed Ocular Histoplasmosis Syndrome (POHS)

(See Ch. 11, Posterior Segment)

Cytomegalovirus (CMV)

Progressive hemorrhagic necrotizing retinitis involving all retinal layers

Occurs in 15–46% of AIDS patients; usually when CD4 count <50 cells/mm³

40% bilateral at presentation

Rare syndrome of neonatal cytomegalic inclusion disease

Symptoms

often asymptomatic; may have floaters, scotoma

Findings

well-circumscribed necrotizing retinitis (2 appearances), mild AC and vitreous reaction

Brushfire: indolent, granular, yellow-white advancing edge with peripheral atrophic ‘burned out’ region

Pizza-pie fundus: thick, yellow-white necrosis; hemorrhage, vascular sheathing (Figure 8-6)

Figure 8-6 Cytomegalovirus retinitis.

(From Hudson HL, Boyer DS, Martin DF, et al: Viral posterior uveitis. In Yanoff M, Duker JS [eds]: Ophthalmology, London, Mosby, 1999.)

Pathology

infected retinal cells are markedly enlarged, then necrotic, finally atrophic; large owl’s eye intranuclear inclusions

Treatment

antiviral therapy (induction during first 2 weeks)

Ganciclovir (Cytovene): virostatic

TOXICITY: neutropenia and thrombocytopenia

INDUCTION: 5–7.5 mg/kg IV bid × 2–4 weeks

MAINTENANCE: 5–10 mg/kg IV qd

INTRAVITREAL INJECTION: 200–2000 µg/0.1 mL 2–3 times a week × 2–3 weeks

Foscarnet: virostatic

TOXICITY: renal

INDUCTION: 90 mg/kg IV bid or 60 mg/kg IV tid × 2 weeks

MAINTENANCE: 90–120 mg/kg IV qd

INTRAVITREAL INJECTION: 2.4 mg/0.1 mL 2–3 times a week × 2-3 weeks, then 1–2 times a week

Ganciclovir (Vitrasert):

Median time to progression = 194 days (vs 72 days with IV ganciclovir and 15 days with no treatment)

May be increased risk of RD with implantation

Oral ganciclovir: poor bioavailability; only 6% absorbed with food, 9% absorption without food

Surgery: vitrectomy with long-acting tamponade for RD repair

Complications

rhegmatogenous RD

Acute Retinal Necrosis (ARN)

Acute self-limited confluent peripheral necrotizing retinitis due to infection with VZV, HSV, or rarely CMV

Usually occurs in immunocompetent individuals; 33% bilateral (BARN), commonly in immunosuppressed

Association with HLA-DQw7 (50%)

Symptoms

rapid onset of ocular/periocular pain, pain on eye movement, redness, photophobia, floaters, decreased vision, constriction of visual field

Findings

diffuse episcleral injection, mild iritis with granulomatous KP, vitritis; ‘thumbprint’ nummular infiltrates posterior to equator with isolated peripheral patches of necrotizing retinitis that becomes confluent; sawtooth demarcation line between necrotic and healthy retina, generalized obliterative retinal arteritis (with peripheral vaso-occlusion), pale disc edema (Figure 8-7); within 2 months, retinitis gradually resolves and necrotic retina sloughs; coarse salt and pepper pigmentation

Figure 8-7 Acute retinal necrosis.

(From Kaiser PK, Friedman NJ, Pineda II, R: Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology, 2nd edn. Philadelphia, WB Saunders, 2004.)

Pathology

necrosis occurs from virally induced cytolysis, arteriolar and choriocapillaris occlusion; necrotic cells slough into vitreous, leaving large areas devoid of retina

FA

focal areas of choroidal hypoperfusion early; late staining

Treatment

acyclovir (IV × 5–10 days, then oral × 6 weeks; decreases risk of development of ARN in fellow eye by approximately 50%; ganciclovir is an alternative); oral steroids; aspirin to inhibit vascular thrombosis

Prognosis

watch fellow eye closely (usually develops ARN within 4 weeks)

65–90% develop rhegmatogenous RD (usually within 3 months)

Progressive Outer Retinal Necrosis (PORN)

Variant of ARN in AIDS but painless with minimal intraocular inflammation

Often have history of cutaneous zoster

74% unilateral at presentation, 70% become bilateral

Findings: multiple discrete peripheral or central areas of retinal opacification/infiltrates (deep with very rapid progression), ‘cracked mud’ appearance after resolution; vasculitis is not prominent (Figure 8-8)

Figure 8-8 Progressive outer retinal necrosis, early stage.

(From Hudson HL, Boyer DS, Martin DF, et al: Viral posterior uveitis. In Yanoff M, Duker JS [eds]: Ophthalmology, London, Mosby, 1999.)

Treatment: combination of foscarnet and ganciclovir; poor response to antivirals

Prognosis: 67% become NLP within 4 weeks; RD in 90%

Herpes Zoster

Uveitis typically develops during convalescence from acute Varicella infection

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