WENDY M SMITH, MDSENIOR STAFF FELLOW,

UVEITIS AND OCULAR IMMUNOLOGYNATIONAL EYE INSTITUTE

NATIONAL INSTITUTES OF HEALTH

Uveitis

a generic term for intraocular inflammation.does not indicate site of inflammationdoes not indicate the cause: autoimmune or infectious

Uveitis: Definition

How Common is Uveitis?

10-­15% of severe visual handicap in the U.S.

3rd leading cause of blindness in the world

U.S. Incidence 52.4/100,000U.S. Prevalence 115.3/100,0003 times higher than previous estimatePrevalence higher in women (1:1.4)Common in older patients

Gritz and Wong. Ophthalmology 2004

Worldwide prevalence ~2.4 million

~5-­10% of cases in children <16 yrsMean age of onset is 37.2 yearsRange 20-­50 years

151,200322,000

2,400,000

U.S. Prevalence WorldwideU.S. Incidence

IUSG Classification of Uveitis

Anterior uveitisiris and pars plicata (CB)

Intermediate uveitispars plana and vitreous

Posterior uveitisretina + choroid

Panuveitis

Cells per high-­power field in 1x1 mm slit beam0 = < 1 cell/hpf0.5+ = 1 -­ 5 cells1+ = 6 -­ 152+ = 16 -­ 253+ = 26 -­ 504+ = > 50

Flare0 = none1+ = faint2+ = moderate, (iris/lens details clear)3+ = marked(iris/lens hazy)4+ = intense (fibrin or plastic aqueous)

SUN Grading system for AC cell and flare

Number of Cells* Description Grade0-­1 clear 02-­20 few opacities trace21-­50 scattered opacities 1+51-­100 moderate opacities 2+101-­250 many opacities 3+>250 dense opacities 4+*cells are counted using a Hruby, 90 or 78 diopter lens

National Eye Institute Grading System for Vitreous Cell(No SUN Working Group Consensus)

0 = Clear

0.5+/trace = Trace

1+ = Few opacities,mild blurring

2+ = Significantblurring but stillvisible

3+ = Optic nervevisible, no vessels seen

4+ = Dense opacityobscures opticnerve head

National Eye Institute Grading System for Vitreous Haze (adopted by SUN Working Group)

Developing a Differential Diagnosis

Is the disease acute or chronic?

Where is the inflammation located in the eye?

Unilateral or bilateral?

Granulomatous or non-­granulomatous?

What are the demographics of the patient?

Associated symptoms?

Associated signs on physical exam?

How did the disease respond to previous therapy?

Anterior Uveitis: ~60% of all uveitis

Idiopathic

HLA-­B27 associatedInflammatory bowel disease

Ankylosing spondylitis

Psoriatic arthritis

JIA (Juvenile Idiopathic Arthritis) associated

Sarcoidosis

Syphilis

Glaucomatocyclitic crisis

Masquerade syndromes

Anterior uveitisprevalence: 81/100,000 (Gritz et al)

Differential Diagnosis of Stellate Keratic Precipitates:Fuchs heterochromia (rubella, herpes, toxoplasmosis)

Viral

Toxoplasmosis

Differential Diagnosis of hypopyon:HLA-­B27 associated

Low back pain, ethnicity, GI symptoms, ulcers, joints

JIA-­associated uveitis

<16yo,>6mo disease

Pauci-­articular: 25%Type 1=Ana+ young girls

Type 2=Older boys B27+

Poly-­articular: ~15%

Systemic onset: 1-­5%

Most at risk:ANA+, RF-­, pauciarticular girls

Uveitis develops within 5-­7 yrsNo correlation betw joint and eye

Frequently asymptomaticUveitis before joint disease poor pxBK/PS/cataract/ON hyperemia/CME common

Complications Treatment

Posterior synechiaeCataract Inflammation-­relatedSteroid-­induced

Secondary glaucomaSteroid responseAngle closure

Cystoid macular edemaBand keratopathymore common in children

Topical corticosteroidsCycloplegicsGlaucoma gttsNSAIDs (gtt or PO)

Periocular steroids

Systemic steroidsSystemic immunosuppression

Anterior Uveitis

Intermediate Uveitis: ~15% of all uveitis

Most common causes:Sarcoidosis

Pars planitis syndrome (idiopathic)

Multiple sclerosis

Masquerade Syndromes

Infection Toxoplasma, Lyme, Toxocara, Syphilis, TB

Intermediate Uveitis

Vitritis +/-­ periphlebitis

Snowballs, snowbanking (more severe disease process)

Pars planitis: PP exudates (HLA-­DR15)~15% of patients with pars planitis will develop MS

CME is the main vision threatening complication

Posterior & Panuveitis: 10-­15% of all uveitis

Focal choroiditis/retinitis: Toxocariasis

Tuberculosis

Nocardiosis

Masquerade syndrome

Multifocal Retinitis:SyphilisHerpes simplex virus, CMVSarcoidosisMasquerade syndromesCandidiasisMeningococcus

Multifocal Choroiditis:SOVKHSarcoidosisSerpiginousBirdshot

Histoplasmosis/TBMasquerade syndrome

PANuveitis:SyphilisSarcoidosisVKH

disease Sympathetic OphthalmiaInfectious endophthalmitis

Posterior (Pan) Uveitis

Inflammation involving retina/choroid

Optic nerve:ON Edema, papillitis, granulomaFA features hot?

Retinal vasculature:Staining, leakage, capillary dropoutInvolves mainly veins vs arteriesPeripheral vs central

Chorioretinal lesions:Dalen-­fuchs nodulesSize, age of lesion (old atrophic vs new elevated with substance to it)

Sarcoidosis

Sarcoidosis is a multisystem granulomatous disorder lungs (90-­95%), lymph nodes, skin, eyes, CNSTypically affects young adults

More commonly seen in African Americans and Caucasians of Northern European descentIn US 8-­10x more common in AA AA: 35 to 82/100,000 Caucasians: 8 to 11/100,000

Etiology unknown but believed to be immune mediated: genetic predisposition (familial aggregation, monozygotic twins, HLAB8, HLADRB1) and environmental factors (environmental allergens and infectious agents) have been suggested.

Ocular disease most common extra-­pulmonary presentationUveitis occurs in 25-­50% of pts20-­50 yrs, typically bilateral (98%)

Sarcoidosis: Dalen-­

30 yo AAM: Referred for endogenous candida endophthalmitisAlso has recent onset of headache, mood changes, gait abnormalities

Slit-like third ventricle

Enlarged lateral ventricles

Transependymal CSF flow

Diagnosis: Biopsy-­Proven Neurosarcoidosis

75 yo WF with recent onset blurry visionCarried dx of SLE for >20 yrs

CBC: slightly elevated WBCNeg or wnl: Lyme, RPR, FTA ABS, PPD HLA B27 neg, UA & Chem 20 wnl

Diagnostic vitrectomy:Nests of macrophages & giant cellsSmall and reactive lymphocytesFurther work-up: hilar LAD on CT and PET scan

Diagnosis: Presumed Ocular Sarcoidosis

Modified Japanese Criteria:Major criteria (skin, oral, genital, eye)Minor criteria (arthritis, GI, epididymitis, neuropsychiatric etc)

ClassificationComplete (4 major), Incomplete (3 major OR ocular disease+1 major), Suspect (2 major nonocular), Possible (1 major)

International Study Group for BD recurrent oral ulcers is a must (+2 other criteria)

retinitis

VKH: Common in pigmented ethnic groupsBilateral panuveitisVitiligo, alopecia, poliosis, (10-­60%)Dysacusia, tinnitus (75% auditory problems)Meningitis (80% have CSF lymphocytic pleocytosis)

ON edema & hyperemia, Serous RDDalen-­Fuchs nodulesSunset-­glow fundusSigiura sign (perilimbal vitiligo)HLA DR4 (esp Japanese), DR1

24 yo Latino male with VKH:

Sudden onset blurred visionHeadacheTinnitus & hearing loss

One month after presentation

Ten months after presentation

End-­stage VKH with diffuse RPE loss and subretinal fibrosis

Systemic Lupus ErythematosusRetinopathy is an important marker of systemic activity esp CNS vasculitis-­75%

Polyarteritis Nodosa (PAN)

Untreated: 90% mortalityWegener granulomatosis Necrotizing granulomatosis of upper & lower resp tract -­esp paranasal sinusesGlomerulonephritis (85%), peripheral neuropathy Untreated: 80% mortality

Retinal Vasculitis

52 yo MAcute onset of blurred vision & photophobia OS

Non-­granulomatous anterior uveitis OS > OD

Vitritis OS > OD

BRAO and retinitis OD

HIV+ not on HAARTRPR+ 1:2048, Syphilis IgG+

Syphilis-­related panuveitisResponded to IV Penicillin x 4 wks

Serpiginous choroidopathyRelationship w/TB?Treated with immunosuppressivesHLA-­B07>30% VA <20/200

APMPPE: Acute posterior multifocal placoid pigment epitheliopathy

Bitten by a lab animalPreceding flu-­like symptoms

Early hypo, late hyper on FA(White Dot Syndromes)

Hypofluorescent spots on ICGCNS vasculitisBenign course20% Visual Sequelae

Posterior/Panuveitis complications

Cataract

Epiretinal membrane

Secondary glaucoma

Hypotony

Chronic cystoid macular edema

Subretinal fibrosis

Atrophy of retina/RPE

Choroidal neovascularization

Retinal ischemia

Retinal neovascularization

Optic nerve atrophy

Retinal detachment

Phthisis bulbi

Work-­up

CBC with diff,Chem 20, UA, ESR, CRPTB (PPD+anergy panel)+Chest X-­raySyphilis (both RPR and Sy IgM, IgG)HIVAdditional:ACE, lysozyme, Ca sarcoidosisUA-­> TINU, Wegener, SLEANA, anti-­DNA, RF, anti-­CCP, ENA panel connective tissue disordersANCAs (c-­ANCA=PR3;; p-­ANCA=MPO) Wegener, PANHypercoagulability panel (ACA, LAC, Factor V Leiden mut) occlusive vasculitis

High Resolution Chest CT TB, sarcoidosisPFT/pulm consult sarcoidosisHearing test VKH, sarcoidosisLP MS, VKH, PIOL/CNSLHLA panel Birdshot, HLA-­B27, Behçet, MS, sarcoidSinus CT WLumbosacral XR/MRI HLAB27 associated uveitidesColonoscopy IBD, Behçet, malignancy work-­up

Anterior chamber and/or vitreous tap for PCR, cultures, cytokines

Despite a million dollar work-­up-­> 40% still idiopathic

Treatment:Corticosteroids have been the mainstay since 1970s

Neutrophils Inhibit neutrophil migration

neutrophil adherence to vascular endothelium bactericidal activity of neutrophils

Local effects on the endothel ium

Mononuclear phagocytes Chemotaxis Clearance of antibody coated particles Production of Il-1 and TNF

Lymphocytes Redistribution of T lymphocytes(CD4 > CD8) Inhibit T lymphocyte activation proliferation and lymphokine production Inhibit Ig production by B cells (high dose)

Immunosuppressive Therapy

Antimetabolites:Methotrexate (anti-­folate), Azathioprine (purine inhibitor), Mycophenolate Mofetil (pu) (Cellcept), Leflunomide (pyrim inh)T-­cell Inhibitors:Cyclosporine, Tacrolimus (cacineurin), Sirolimus(mtor)Alkylating agents:Cyclophosphamide, ChlorambucilBiologics:Anti-­TNF( *infliximab, etanercept, adalimumab, golimumab, certolizumab)Anti-­IL2R (*daclizumab, basiliximab)Anti-­IL1 (anakinra)Anti-­B cell (*Rituximab, Ocralizumab)

million dollar treatment ?effect on outcome

Summary

Diagnosis: what, where, when, who

Differential: use to guide testing rule out etiologies that must be treated before immunosuppression (infections!)

corticosteroid treatments (Please refer!)If not responding to treatment, consider another diagnosis

Goals: Prevent complications, minimize side effects of treatment, PRESERVE VISION

Thank you!