Fritz Allen, MDVisionary Eye Doctors

Review of Uveitis

• A generic term for intraocular inflammation.• Does not indicate site of inflammation• Does 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 52.4/100,000 U.S. Prevalence 115.3/100,000 3 times higher than previous estimate

Prevalence 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 yrs Mean age of onset is 37.2 years Range 20-50 years

151,200322,000

2,400,000

U.S. Prevalence WorldwideU.S. Incidence

IUSG Classification of Uveitis

Anterior uveitis iris and pars plicata (CB)

Intermediate uveitis pars plana and vitreous

Posterior uveitis retina + choroid

Panuveitis

“front”

“back”

Cells per high-power field in 1x1 mm slit beam

0 = < 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+ = Significant blurring but still visible

3+ = Optic nerve visible, no vessels seen

4+ = Dense opacity obscures optic nerve 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

IdiopathicHLA-B27 associated

Inflammatory bowel disease

Ankylosing spondylitis Reiter’s syndrome Psoriatic arthritis

JIA (Juvenile Idiopathic Arthritis) associated

Behçet’s diseaseFuchs’ heterochromiaSarcoidosisSyphilis Glaucomatocyclitic

crisisMasquerade

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 Behçet’s disease

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

JIA-associated uveitis <16 yo,>6 mo 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-, pauci-articular girls

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

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

Complications Treatment

Posterior synechiaeCataract

Inflammation-related Steroid-induced

Secondary glaucoma Steroid response Angle closure

Cystoid macular edemaBand keratopathy

more 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:SarcoidosisPars planitis syndrome (idiopathic)Multiple sclerosisMasquerade SyndromesInfection

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: ToxocariasisTuberculosisNocardiosisMasquerade syndrome

Multifocal Retinitis:SyphilisHerpes simplex virus, CMVSarcoidosisMasquerade syndromesCandidiasisMeningococcusMultifocal Choroiditis:

SOVKH SarcoidosisSerpiginousBirdshotWegener’s, SLEHistoplasmosis/TBMasquerade syndrome

PANuveitis:SyphilisSarcoidosisVKHBehçet’s disease Sympathetic OphthalmiaInfectious endophthalmitis

Posterior (Pan) Uveitis

Inflammation involving retina/choroid

Optic nerve: ON Edema, papillitis, granuloma FA features—hot?

Retinal vasculature: Staining, leakage, capillary dropout Involves mainly veins vs arteries Peripheral vs central

Chorioretinal lesions: Dalen-fuchs nodules Size, 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, CNS Typically affects young adults

More commonly seen in African Americans and Caucasians of Northern European descent In 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,

HLA-B8, HLA-DRB1) and environmental factors (environmental allergens and infectious agents) have been suggested.

Ocular disease most common extra-pulmonary presentation Uveitis occurs in 25-50% of pts 20-50 yrs, typically bilateral (98%)

Sarcoidosis: Dalen-Fuch’s Nodules

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 cells• Small and reactive lymphocytes• Further work-up: hilar LAD on CT and PET scan

Diagnosis: Presumed Ocular Sarcoidosis

Behçet’s Disease Modified Japanese Criteria:

Major criteria (skin, oral, genital, eye) Minor criteria (arthritis, GI, epididymitis,

neuropsychiatric etc) Classification

Complete (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)

Behçet’s retinitis

VKH: Common in pigmented ethnic groups•Bilateral panuveitis•Vitiligo, alopecia, poliosis, (10-60%)•Dysacusia, tinnitus (75% auditory problems)•Meningitis (80% have CSF lymphocytic pleocytosis)

•ON edema & hyperemia, Serous RD•Dalen-Fuchs nodules•Sunset-glow fundus•Sigiura sign (perilimbal vitiligo)•HLA DR4 (esp Japanese), DR1

24 yo Latino male with VKH:•Sudden onset blurred vision•Headache•Tinnitus & hearing loss

One month after presentation

Ten months after presentation

End-stage VKH with diffuse RPE loss and subretinal fibrosis

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

Polyarteritis Nodosa (PAN) M>F; HBs+, polyneuropathy, Raynaud’s, coronary arteritis Untreated: 90% mortality

Wegener granulomatosis Necrotizing granulomatosis of upper & lower resp tract -esp paranasal sinuses Glomerulonephritis (85%), peripheral neuropathy Untreated: 80% mortality

Behçet’s Disease

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 choroidopathy Relationship w/TB? Treated with immunosuppressives HLA-B07 >30%VA <20/200

APMPPE: Acute posterior multifocal placoid pigment epitheliopathy

•Bitten by a lab animal•Preceding flu-like symptoms

•Early hypo, late hyper on FA (White Dot Syndromes)•Hypofluorescent spots on ICG•CNS vasculitis•Benign course•20% Visual Sequelae

24 yo WM with “flashes of light” and blurry vision that developed overnight

Posterior/Panuveitis complications

CataractEpiretinal membraneSecondary glaucomaHypotony

Chronic cystoid macular edema

Subretinal fibrosisAtrophy of retina/RPE

Choroidal neovascularization

Retinal ischemiaRetinal

neovascularization

Optic nerve atrophy

Retinal detachmentPhthisis bulbi

Work-up

CBC with diff,Chem 20, UA, ESR, CRP TB (PPD+anergy panel)+Chest X-ray Syphilis (both RPR and Sy IgM, IgG) HIV Additional:

ACE, lysozyme, Ca sarcoidosis UA-> TINU, Wegener, SLE ANA, anti-DNA, RF, anti-CCP, ENA panel connective tissue disorders ANCAs (c-ANCA=PR3; p-ANCA=MPO) Wegener, PAN Hypercoagulability panel (ACA, LAC, Factor V Leiden mut) occlusive vasculitis

High Resolution Chest CT TB, sarcoidosis PFT/pulm consult sarcoidosis Hearing test VKH, sarcoidosis LP MS, VKH, PIOL/CNSL HLA panel Birdshot, HLA-B27, Behçet, MS, sarcoid Sinus CT Wegener’s Lumbosacral XR/MRIHLAB27 associated uveitides Colonoscopy 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 endothelium 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, Chlorambucil

Biologics: 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, whoDifferential: use to guide testing

Rule out etiologies that must be treated before immunosuppression (infections!)

Treatment: don’t wait too long to move beyond corticosteroid treatments (Please refer!) If not responding to treatment, consider another

diagnosis

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

Thank you!