UVEITIS AND OCULAR IMMUNOLOGY by Wendy Smith MD COPE ID 31562-SD Lecture Series 12th Visionary Ophthalmology

1. Uveitis
W E N D Y M S M I T H , M D
S E N I O R S T A F F F E L L O W ,
U V E I T I S A N D O C U L A R I M M U N O L O G Y
N A T I O N A L E Y E I N S T I T U T E
N A T I O N A L I N S T I T U T E S O F H E A L T H

2. Uveitis: Definition
a generic term for intraocular inflammation.
does not indicate site of inflammation
does not indicate the cause: autoi mmune or infectious

3. 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 2,400,000
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 322,000
151,200
Mean age of onset is 37.2 years
Range 20-­50 years
U.S. Incidence U.S. Prevalence Worldwide

4. IUSG Classification of Uveitis
Anterior uveitis
iris and pars plicata (CB)
Intermediate uveitis
pars plana and vitreous
Posterior uveitis
retina + choroid
Panuveitis

5. SUN Grading system for AC cell and flare
Cells per high-­power field in 1x1 mm slit beam
0 = < 1 cell/hpf
0.5+ = 1 -­ 5 cells
1+ = 6 -­ 15
2+ = 16 -­ 25
3+ = 26 -­ 50
4+ = > 50
Flare
0 = none
1+ = faint
2+ = moderate,
(iris/lens details clear)
3+ = marked
(iris/lens hazy)
4+ = intense (fibrin or plastic aqueous)

6. National Eye Institute Grading System for Vitreous Cell
(No SUN Working Group Consensus)
Number of Cells* Description Grade
0-­1 clear 0
2-­20 few opacities trace
21-­50 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

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

8. 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?

9. Anterior Uveitis: ~60% of all uveitis
Idiopathic
HLA-­B27 associated
Inflammatory bowel Sarcoidosis
disease Syphilis
Ankylosing spondylitis
Glaucomatocyclitic crisis
Masquerade syndromes
Psoriatic arthritis
JIA (Juvenile Idiopathic
Arthritis) associated

10. Anterior uveitis
prevalence: 81/100,000 (Gritz et al)

11. Differential Diagnosis of Stellate Keratic Precipitates:
Fuchs heterochromia (rubella, herpes, toxoplasmosis)
Viral
Toxoplasmosis

12. Differential Diagnosis of hypopyon:
HLA-­B27 associated
Low back pain, ethnicity, GI symptoms,
ulcers, joints

13. 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 yrs
No correlation betw joint and eye
Frequently asymptomatic
Uveitis before joint disease poor px
BK/PS/cataract/ON hyperemia/CME common

14. Anterior Uveitis
Complications Treatment
Posterior synechiae Topical corticosteroids
Cataract Cycloplegics
Inflammation-­related Glaucoma gtts
Steroid-­induced NSAIDs (gtt or PO)
Secondary glaucoma
Steroid response Periocular steroids
Angle closure
Cystoid macular edema Systemic steroids
Band keratopathy Systemic
more common in children immunosuppression

15. Intermediate Uveitis: ~15% of all uveitis
Most common causes:
Sarcoidosis
Pars planitis syndrome (idiopathic)
Multiple sclerosis
Masquerade Syndromes
Infection
Toxoplasma, Lyme, Toxocara, Syphilis, TB

16. 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

17. Posterior & Panuveitis: 10-­15% of all uveitis
Focal choroiditis/retinitis: Multifocal Retinitis:
Toxocariasis Syphilis
Herpes simplex virus, CMV
Tuberculosis
Sarcoidosis
Nocardiosis Masquerade syndromes
Masquerade syndrome Candidiasis
Meningococcus
Multifocal Choroiditis:
SO PANuveitis:
VKH Syphilis
Sarcoidosis Sarcoidosis
Serpiginous
VKH
Birdshot
disease
Sympathetic Ophthalmia
Histoplasmosis/TB
Infectious endophthalmitis
Masquerade syndrome

18. 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)

19. 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, HLAB8,
HLADRB1) 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%)

21. Sarcoidosis: Dalen-­

22. Slit-like third ventricle
Transependymal CSF flow
Diagnosis: Biopsy-­Proven Neurosarcoidosis
30 yo AAM: Referred for endogenous candida endophthalmitis
Also has recent onset of headache, mood changes, gait abnormalities
Enlarged lateral ventricles

23. 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
75 yo WF with recent onset blurry vision
Carried dx of SLE for >20 yrs
CBC: slightly elevated WBC
Neg or wnl: Lyme, RPR, FTA ABS, PPD
HLA B27 neg, UA & Chem 20 wnl

24. 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)

25. retinitis

26. 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

27. 24 yo Latino male with VKH:
Sudden onset blurred vision
Headache
Tinnitus & hearing loss
One month after presentation
Ten months after presentation

28. End-­stage VKH with diffuse RPE loss and subretinal fibrosis

29. Retinal Vasculitis
Systemic Lupus Erythematosus
Retinopathy is an important marker of systemic activity esp CNS vasculitis-­75%
Polyarteritis Nodosa (PAN)
Untreated: 90% mortality
Wegener granulomatosis
Necrotizing granulomatosis of upper & lower resp tract -­esp paranasal sinuses
Glomerulonephritis (85%), peripheral neuropathy
Untreated: 80% mortality

30. HIV+ not on HAART
52 yo M RPR+ 1:2048, Syphilis IgG+
Acute onset of blurred
vision & photophobia OS
Non-­granulomatous
anterior uveitis OS > OD
Vitritis OS > OD
Syphilis-­related panuveitis
BRAO and retinitis OD Responded to IV Penicillin x 4 wks

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

32. 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

33. Posterior/Panuveitis complications
Cataract Choroidal
Epiretinal membrane neovascularization
Secondary glaucoma Retinal ischemia
Hypotony Retinal
neovascularization
Chronic cystoid macular
edema Optic nerve atrophy
Subretinal fibrosis
Atrophy of retina/RPE Retinal detachment
Phthisis bulbi

34. 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
Despite a million dollar work-­up-­>
ANCAs (c-­ANCA=PR3;; p-­ANCA=MPO) Wegener, PAN
Hypercoagulability panel (ACA, LAC, Factor V Leiden mut) occlusive vasculitis
40% still idiopathic
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 W
Lumbosacral XR/MRI HLAB27 associated uveitides
Colonoscopy IBD, Behçet, malignancy work-­up
Anterior chamber and/or vitreous tap for PCR, cultures, cytokines

35. 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
Mononuclea r phagocytes Chemotaxis
Clearance of antibody coated particles
Production of Il-1 and TNF
L ymphocytes Redistribution of T lymphocytes(CD4 > CD8)
Inhibit T lymphocyte activation
proliferation and lymphokine production
Inhibit Ig production by B cells (high dose)

36. 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

37. 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

38. Thank you!