This document provides an overview of uveitis including its definition, epidemiology, differential diagnosis, classification, clinical assessment, workup, and treatment approach. Some key points: - Uveitis refers to inflammation within the eye and can be caused by over 30 disease entities. It is the third leading cause of blindness worldwide. - Differential diagnosis considers factors like anatomic location, presentation/course, lesion morphology, and presence of systemic disease. Common etiologies include infectious, autoimmune, and masquerade syndromes. - Workup aims to exclude infections, identify underlying systemic diseases, provide prognostic information, and guide treatment. Testing may include labs for infectious diseases, systemic illnesses, and imaging

1. INTRODUCTION
TO UVEITIS
P R E S E N T E R : D R . I D D I N D YA B AW E
M O D U L ATO R : D R . L U S O BYA R E B E C C A

2. LECTURE OUTLINE
• Definition
• Epidemiology
• Approach To Uveitis Patient
• Differential Diagnosis
• “SUN”
• Anatomical Classification
• Expanded Anatomical Classification
• Classification Of Uveitis: Non-granulomatous
• Classification Of Uveitis: Granulomatous
• Choroidal Spots Descriptors
• Clinical Assessment Of Uveitis
• Labs
• Imaging
• Therapeutic Approach

3. UVEITIS DEFINITION
• “Uva” Latin for grapes
• >30 separate disease entities: Clinical features, course, prognosis; Disease specific
treatment indications
• Infectious Vs. non-infectious
• Autoimmune/autoinflammatory
• Neoplastic masquarades
• Etiologic diagnosis: Infectious and Mendelian genetic diseases

4. EPIDEMIOLOGY
• Third leading cause of blindness worldwide
• 10-15% total blindness USA
-Incidence:17 to 52.4/100,000/ year
-Estimated 1% - 3% lifetime risk
-30,000 new cases blindness USA/yr
-Prevalence: 114 to 203/100,000 USA/yr
• 5th to 6th cause of visual loss after DM, AMD
• Peak onset: 30-0 yr
• Personal and economic impact of potential vision lost may be greater than age-related
disease.

5. APPROACH TO THE UVEITIS PATIENT
• History:
-Ophthalmic;
-medical;
-ROS, questionnaire.
-“Listen to the patient he is telling you the diagnosis!”
• Ocular exam:
-Anatomic location, grade/stage severity of inflammation
-Assess for structural complications (CME, CNVM)
General medical exam
• Differential diagnosis

6. DIFFERENTIAL DIAGNOSIS
• Characterize along several dimensions
• Anatomic location of the inflammation:
-Anterior/intermediate, posterior, panuveitis
• Presentation, course, laterality
-Acute, monophasic vs. recurrent acute vs chronic
-Unilateral vs bilateral vs alternating
• Lesion morphology, location, number, descriptors
-Retinitis vs choroiditis, pacuifocal vs multifocal
-Posterior vs peripheral retina, pattern
-Granulomatous vs non-granulomatous

7. DIFFERENTIAL DIAGNOSIS
• Host factors: systemic vs purely ocular disease
-Non-infectious: sarcoid MS, Behcet, spondylitis, VKH
-Infection: Syphilis, Lyme, WNV, Toxoplasmosis, Herpes
-Immunocompetence: AIDS, iatrogenic
• Demographics
• Associated symptoms
• Associated signs

8. APPROACH TO THE UVEITIS PATIENT
• Directed laboratory investigation:
-Exclude infection
-Identify systemic disease impacting health
-Prognostic information
• Treatment plan
-Antimicrobial therapy
-Step-ladder algorithm: IMT as first line vs. steroid sparing
-Assess treatment
-Monitor side effects, toxicity

9. STANDARDIZATION OF UVEITIS
NOMENCLATURE (SUN)

10. ANATOMIC CLASSIFICATION: EXAMPLES

11. EXPANDED ANATOMICAL CLASSIFICATION
• Keratouveitis:
-Herpetic until proven otherwise
• Sclerouveitis:
-Systemic vasculitis: RA, GPA, PAN, SLE.
• Retinal Vasculitis:
-Primary or secondary
-Predominant vessels involved: arteritis, phlebitis, both
-Systemic vasculitis (1.4%): BD, GPA, PAN
-Non-vasculitis systemic disease: sarcoid
-Purely ocular: pars planitis, infectious disease

12. SUN WORKING GROUP.
ONSET, DURATION, COURSE

13. CLASSIFICATION OF UVEITIS:
NON-GRANULOMATOUS

14. CLASSIFICATION OF UVEITIS:
GRANULOMATOUS

15. DIFFERENTIAL DX GRANULOMATOUS
UVEITIS
• Sarcoid
• Sympathetic
• Lens induced
• IOFB
• VKH
• TB
• MS associated uveitis
• Herpes
• Syphilis

16. MAJOR DISEASES: ANTERIOR
• Infectious
-HSV anterior uveitis
-VZV anterior uveitis
-CMV anterior uveitis
-Syphilis
• Systemic disease
-HLA-B27 –associated uveitis
-JIA-associated uveitis
-Sarcoidosis
-Behcet’s disease
• No systemic disease
-Fuch’s uveitis syndrome

17. MAJOR UVEITIDES: INTERMEDIATE
• Infectious
-HSV anterior uveitis
-VZV anterior uveitis
-CMV anterior uveitis
-Syphilis
• Systemic disease
-HLA-B27 –associated uveitis
-JIA-associated uveitis
-Sarcoidosis
-Behcet’s disease
• No systemic disease
-Fuch’s uveitis syndrome

18. MAJOR UVEITIDES: INTERMEDIATE

19. MAJOR UVEITIDES: INTERMEDIATE

20. MAJOR UVEITIDES: INTERMEDIATE

21. MAJOR DISEASES: INTERMEDIATE
• Infectious
-Syphilis
-Lyme disease
• Systemic disease
-MS associated disease
-Sarcoidosis
• No systemic disease
-Pars planitis

22. MAJOR DISEASES: INTERMEDIATE

23. MAJOR DISEASES: INTERMEDIATE

24. MAJOR DISEASES: INTERMEDIATE

25. MAJOR DISEASES: INTERMEDIATE

26. POSTERIOR UVEITIS MORPHOLOGY:
SUN
• Primary level inflammation
-Primary retinitis
-Primary choroiditis
• Lesion #, location, descriptors
-Pauicifocal vs multifocal
-Posterior vs. peripheral
-Colour, size, shape

27. CHOROIDAL SPOTS DESCRIPTORS
Descriptor Disease
Ameboid Serpiginous
Placoid APMPPE
Yellow-orange ovoid BSCR
Punched-out MFCPU
Punctate PIC
Evanescent white MEWDS

28. CHOROIDAL SPOTS DESCRIPTORS

29. CHOROIDAL SPOTS DESCRIPTORS

30. CHOROIDAL SPOTS DESCRIPTORS

31. CHOROIDAL SPOTS DESCRIPTORS

32. MAJOR DISEASE: POSTERIOR
• Infectious
-Toxoplasmic retinitis
-CMV retinitis
-Acute retinal necrosis
-DUSN
-Lyme disease
-Syphilis
-Tuberculosis
Systemic disease
-Sarcoidosis
• No systemic disease:
-Serpiginous choroiditis
-APMPEE
-MEWDS
-Birdshot choroiditis
-MFCPU
-PIC
-Relentless placoid

33. MAJOR DISEASE: POSTERIOR

34. MAJOR DISEASE: POSTERIOR

35. MAJOR DISEASE: POSTERIOR

36. MAJOR DISEASES: PANUVEITIS
• Infectious
-Syphilis
-Lyme disease
• Systemic disease
-Vogt-Koyanagi-Harada
-Behcet’s disease
-Sarcoidosis
• No systemic disease
-Sympathetic ophthalmia

37. MAJOR DISEASE: POSTERIOR

38. MAJOR DISEASE: POSTERIOR

39. MAJOR DISEASE: POSTERIOR

40. UVEITIS CHARACTERIZATION

41. CLINICAL ASSESSMENT OF UVEITIS
• BCVA
• IOP
• Standardization grading scale for grading and reporting uveitis activity: anterior
chamber cells and vitreous haze

42. CLINICAL ASSESSMENT OF UVEITIS:
ANTERIOR CHAMBER CELLS

43. ANTERIOR CHAMBER FLARE

44. FLARE IN REAL LIFE!!!

45. CLINICAL ASSESSMENT OF UVEITIS:
VITREOUS HAZE

46. VITREOUS CELL
NEI SCORING SYSTEM

47. IMPORTANCE OF UVEITIS WORKUP
• Exclude infectious etiologies
• Identify systemic disease impacting health
• Guide appropriate treatment
• Provide prognostic information for patient

48. GENERAL PRINCIPLES:
WORK UP
• Selective workup
-History, ROS, signs/symptoms. Ocular/medical exam
-Working differential diagnosis
• Stage workup
-Proceed from more common to rare
• Always consider syphilis (Lyme), sarcoid, or TB
• Consider masquerade syndromes in the differential

49. INFECTIOUS DISEASE
• Syphilis
-Screen with FTA-Abs, MHA-TP
, or TP-PA
-Specific for prior exposure and remain + for life
-2% false positive, CTD, IVDA, other spirochetes (Lyme, Bejel)
• RPR/VDRL
-Non-specific: vary with disease duration, prior treatment
-1/3 syphilitic uveitis and untreated late latent/ tertiary syphilis negative
-False positive: CTD, IVDA, pregnancy, age hypergammaglobulinemia
• Lyme
-Endemic areas, hx exposure
-ELISA screen for IgM/G with confirmatory WB

50. INFECTIOUS DISEASES: TB
TEST Sensitivity Specificity PPV
PPD 75% 85% 1.0%
Quanti-FERON 76% 97% 11%

51. .
• Specific uveitis entity associated with TB
• CAU/iris nodules, granulomatous
disease, miliary TB
• Choroidal tuberculoma
• Eales’ disease
• Serpiginous-like choroiditis
• Multifocal choroiditis in ISS
• Patient factor
• Immigrant/elderly
• Significant exposure risk
• Pre IMT/anti-TNF

52. INFECTIOUS DISEASES: OTHER
• Targeted screening valuable
• Bartonella hensleae/Quintana
-Neuroretinitis
• WNV
-MFC, targetoid features, encephalitis
• PCR of aqueous and/or vitreous
-Necrotizing retinitis
-HSV, VZV, CMV, toxoplasmosis
• Routine screening limited value
• VZV. HSV (70% seropositive)
• Toxoplasmosis (25% seropositive)
• High prevalence general population

53. IDENTIFICATION OF SYSTEMIC DISEASE
• HLA-B27
-Unilateral, alternating, recurrent AAU
-50% are HLA-B27 positive
-37%-88% undiagnosed spondyloarthropathy
• ANA
-Identify risk of bilateral CAU child with JIA
-Not as routine screen for uveitis unless additional features of SLE
-Sensitivity 95%, Specificity 85%
-PPV 0.6% for frequency SLE 0.1% among uveitis patients
• B-2 macroglobulin and serum creatinine
-Screen for TINU, young women with bilateral CAU
• ANCA/RF/CCP
• Scleritis associated with systemic disease 50%
• Not as routine screen for uveitis

54. SYSTEMIC DISEASE: SARCOID
• Any type of uveitis (5-10%)
-25% sarcoidosis may have uveitis
-85% both ocular and systemic dz at onset
• Organs affected
-Lungs (90%), skin (20%);
-Reticuloendothelial (25-33%)
• ACE (60%), lysozyme (76%) bx proven dz
-PPV 18% routine screening vs. proven dz
-Non-specific (TB, leprosy. Osteoarthritis, PI)
-Sensitivity/specificity/PPV better for lysozyme
-ACE: Increased in children, decreased in pts on ACE
inhibitors
• Abnormal liver enzyme tests:
Two of the following:
-Alkaline phosphatase
-ALT/AST
-LDH/ Gamma-GT

55. IMAGING: SARCOID
• Chest X-ray
-Useful screening exam
-Abnormal 90% patients with active dz
• Chest CT: thin cut, spiral
-Sensitive for detection of hilar
adenopathy pts with negative CXR

56. TISSUE DIAGNOSIS: SARCOID
• Tissue diagnosis definitive:
• Lung, lymph nodes
• Skin, conjunctival nodules, lacrimal
gland
• Nondirected conjunctival biopsy of
limited value

57. ANCILLARY IMAGING
• CXR, Sacroiliac, sinus films
-TB, Sarcoid, HLA-B27, Wegener’s
• CT, MRI
-Sarcoid, TB, Lymphoma, Toxo, MS
• B scan
-Media opacity: chorioretinal pathology
• UBM:
• Hypotony
-Cyclitic membrane
-CB detachment
-Atrophic ciliary processes

58. MULTIMODAL OCULAR IMAGING
• Fluorescein angiography
-CME
-Disc leakage
-Retinal, choroidal NV
-Vasculitis
-Non-perfusion
-RPE-derangement
• ICG angiography
-RPE/PR, choroidal dz

59. MULTIMODAL OCULAR IMAGING
• SD-OCT, EDI
-CME
-VRT
-CNVM
-SRF
-OS/EZ/RPE
-Choroid

60. MULTIMODAL OCULAR IMAGING:
FUNDUS AUTOFLUORESCENCE (FAF)
• Hypoautofluorescence
-RPE death, atrophy
• Hyperautofluorescence
-Increased lipofuscin
-Halo surrounding active lesions
• Utility
-White Dot Syndromes
-Choroid/RPE/outer retina independently affected
-Disease progression/modifiable with treatment?
• FLIO
• Emerging modality

61. ANCILLARY TESTING
• FFERG
• mfERG
• VF
-Humphrey: 10-2, 24-2, 30-2
-GVF

62. DIAGNOSIS OF UVEITIS: SUMMARY
• Collection of >30 different diseases
-Intraocular inflammation
-Infectious, non-infectious, masquerade syndromes
• Diagnosis
-Anatomic location, course, laterality, lesion morphology
• Laboratory testing
-Infectious diseases
-Systemic diseases impacting health
• Mutlimodal imaging
• No specific diagnostic entity
-Diagnose “undifferentiated”
-Anatomic location, course, laterality, lesion morphology

63. THERAPEUTIC APPROACH
• Establish a diagnosis
-Rule out infection/malignancy
• Appropriate antimicrobial therapy
• Disease specific indications for treatment
• Stepladder algorithm
• Reconsider diagnosis
-Atypical response to treatment
-New findings emerge

64. TREATMENT OF UVEITIS: GOALS
• Elimination of inflammation
-Prompt control of acute activity
-Suppress chronic/recurrent dz
-Induction of remission
• Treat/reduce/prevent ocular structural complications
• Improve visual function, prevent visual loss
• Avoid/minimize potential systemic complications

65. THERAPEUTIC APPROACH
• Stepladder algorithm
• Frequent topical steroids, cycloplegic
• Oral NSAIDs in selected patients (naproxen, meloxicam)
• Periocular/intravitreal steroid
• Triamcinolone acetonide (40mg/ml)/(4mg/ml)
• Dexamethasone
• Fluocinolone implants/inserts
• Brief (3 months) systemic steroid therapy
• 1mg/kg/day, taper
• Steroid sparing immunomodulatory therapy (IMT)
• Conventional
• Biologic agents
• Diagnostic and therapeutic PPV

66. TREATMENT OF UVEITIS
• Route and choice of medication determined by location and laterality of inflammation,
ocular complications, and systemic health of patient
• Topical steroids usually sufficient for anterior uveitis (except in children)
• Periocular/intravitreal or systemic corticosteroids (+/- IMT) for intermediate, posterior,
or panuveitis

67. TREATMENT: ANATOMIC SITE

68. TOPICAL THERAPY
• Topical steroids ideal for isolated anterior uveitis AC “spillover” in intermediate, and
panuveitis
• High dosage delivered directly to the eye
• Minimal systemic side effects
• Limited delivery to posterior segment for treatment intermediate, posterior, panuveitis
• Vitrectomized, pseudophakic eye
• Difluprednate 0.05% better penetration: more side effects
• NSAID drops for post-op macular edema: frequently in combination with topical steroids

69. TOPICAL STEROIDS: TREATMENT
APPROACH
• Frequency:
• Prednisolone acetate 1%/rimexolone 1%: q 1-2hr wa
• Difluprednate 0.05%: 4-8 x/day
• Ointment at bedtime in severe cases
• Taper over 6-8 weeks after control of inflammation
• Discontinue and confirm remission by follow-up exam
• Identify suppressive threshold if known to be chronic: Target <3 x day
• Cycloplegia:
• Atropine 1% or scopolamine ¼ % 1-2 x/day
• Cyclopentolate 1% 1-4 x/day
• DC when AC grade 0

70. PERIOCULAR CORTICOSTEROIDS
• Local sustained drug delivery 3-4 months
• Minimal systemic adverse effects
• Indications
• Acute remitting non-infectious IU, PU, panuveitis>chronic
• Primary or adjunctive
• Unilateral>bilateral intermediate/posterior/panuveitis
• Uveitic macular edema
• Contraindications
• Infectious uveitis (toxoplasmosis)
• Scleritis (relative)
• Corticosteroid – IOP responders (relative)

71. PERIOCULAR CORTICOSTEROIDS
• Preparations
• Triamcinolone acetate (TA), 40mg/ml
• Methylprenisolone (MP) 20-40mg/ml
• Delivery method
• Posterior sub-Tenon’s (PST)
• Orbital floor injection (OF)
• Cannula method (CM)
• Efficacy (PSF=OF=CM)
• Resolution of inflammation (30%)
• Visual improvement 50% at 6 months
• Additional benefit of repeated injection
• Lower relapse rate in conjunction with systemic
rx

72. INTRAVITREAL CORTICOSTEROID
• Triamcinolone acetonide (2-4mg/0.05-
0.1cc)
• Efficacy
• CME decreased
• Improved VA
• Decreased vitritis
• Duration:3-6 months
• No tachyphylaxis repeated injections

73. REGIONAL CORTICOSTEROID
INJECTIONS FOR MACULAR EDEMA

74. REGIONAL CORTICOSTEROIDS
• Relatively short acting
• Less effective for chronic inflammation
• Tx for relapse
• Subtle structural damage with each relapse
• Saw-toothed decline with long term administration
• VF/ERG loss BSCR with intermittent rx
• Cumulative risk steroid exposure
• Cataract
• IOP/glaucoma

75. SYSTEMIC CORTICOSTEROIDS
• Prednisolone
• Acute therapy: 1mg/kg/day (maximum 60mg/day)< one month, then taper
• Chronic therapy: grade 0 inflammation, < 7.5mg/day
• Steroid sparing IMT as needed
• IV Pulsed Methylprednisolone 1gm/day over 1-2 hrs for 3 days
• Calcium supplement: 500mg TID
• Vitamin D: 400-800 IU daily
• Antiresorptive agents
• Alendronate 35mg/week: osteopenia
• Alendronate 70mg/week: osteoporosis
• Monitor
• BP. Weight, serum glucose baseline, every 3 months
• Fasting lipids annually
• Bone densitometry annually

76. GUIDELINES FOR USE OF IMT IN
UVEITIS
• Failure on systemic steroids
• Unacceptable side effects of corticosteroids
• Disease known to be poorly responsive to steroids
• Requirement for chronic systemic corticosteroids
• >3 months at doses> 7.5mg/day
• Likely to produce serious side effects

77. ABSOLUTE AND RELATIVE
INDICATIONS FOR IMT
• IMT typically commenced at onset of
treatment with corticosteroids:
• Adamantiades – Behcet’s dz
• Severe ocular mucus membrane
pemphigoid
• Serpiginous choroidopathy
• Necrotising scleritis
• Sympathetic ophthalmia
• Corticosteroids first-line treatment
with IMT often added for long-term
management:
• Birdshot retinochoroidopathy
• Multifocal choroiditis panuveitis
• VKH
• Intermediate uveitis
• JIA-associated iritis

78. CONVENTIONAL IMT
• Modify specific immune sensitization
of lymphoid cells
• Interfere with DNA/protein synthesis
• Specific receptor/ligand antagonism
• Interference with signal transduction
• Receptor blockade
• Precise mechanisms not yet elucidated

79. CONVENTIONAL IMT
• Antimetabolites
• Methotrazate (15-25mg/week) PO, SC
• Mycophenolate mofetil (1-1.5gm bid) PO
• Azathioprine (2-3mg/kg/day) PO
• T cell transduction/calcineurin inhibitors
• Cyclosporine (2.5-5mg/kg/day) PO
• Tacrolimus (1-3mg bid) PO
• Alkylating agents
• Chlorambucil (0.1mg/kg/day) PO
• Cyclophosphamide
• PO (1-2.0mg/kg/day, maximal dose 250mg/day)
• IV pulse (500mg-kg/m2 once monthly)
• Therapeutic dose adjustment (WBC 3K off prednisolone)

80. TREATMENT PRINCIPLES
• Acute care with steroids
• Use large enough doses, soon enough initially, all routes
• Taper based on clinical response
• Steroid bridge
• Know response time
• Start with low dose IMT and then titrate up

81. TREATMENT PRINCIPLES
• Close monitoring of patient for potential toxicity
• Laboratory evaluations at baseline and at regular intervals (weekly to every 6-8 weeks)
depending on the agent
• CBC (differential and platelet counts)
• Avoid suppressing Leucocytes <3500cells/ul
• Neutrophils <1500 cells/ul
• Liver function tests
• Bun, Creatinine
• UA

82. MULTICENTER UVEITIS STEROID
TREATMENT TRIAL (MUST)
• RCCT fluocinolone implant v standard RX (oral corticosteroids +/- immunosuppression)
intermediate, posterior, or panuveitis
• Primary outcome: visual acuity 2 years
• Other outcomes: uveitis control, complications
• 24 clinical centres
• … 7yr follow-up
• Conclusions:
• Long term VA results favour systemic vs implant: chorioretinal structural damage from
relapses with implant
• Initial superior control of inflammation with implant
• Expected greater OHT, cataract, glaucoma tx and glaucoma sx with implant
• No increased risk of systemic side effects with systemic tx at 7 yrs

83. MUST – FUS, 7 YEARS: RX
IMPLICATIONS
• Systemic therapy may be preferred initial treatment
• Implant excellent alternative to systemic therapy:
• Uncontrolled inflammation
• Intolerance to medications
• Individual patient factors

84. TNF-ALPHA INHIBITORS
• Etanercept
• Infliximab
• Adalimumab
• Infliximab and adalimumab: first line agents for Behcet’s dz
• Concerns:
• Increased risk of infection; TB, histoplasmosis. All patients must be screened with PPD, Quantiferon gold,
ELISA spot
• Increased risk of lymphoma
• Increased risk: demyelination, optic neuropathy. CI in MRI findings showing MS
• Psych: depression, anorexia nervosa

85. BIOLOGIC RESPONSE MODIFIERS
• Therapeutic proteins bioengineered as antagonists to immunoactive molecules
• Recombinant antibodies and antibody-derived proteins
• Block cytokines, cytokine receptors, cell surface proteins, or other bioactive proteins
• More specific, targeted, effective therapies
• Decrease in side effects

86. SUMMARY OF BIOLOGIC AGENTS