Uveitis Update

1
Uveitis Update

• Narsing A. Rao, MD
• Doheny Eye Institute
• Los Angles

2
Uveitis

• 1. Prevalence of Uveitis
• 2. Uveitis and related entities one should not
  miss
• 3. Investigations in supporting the clinical
  diagnosis
• 4. Treatment of uveitis and its complications

3
Prevalence of Uveitis in adults

• Migration and its affect on prevalence of uveitis
• Behcets disease
• Intraocular Tuberculosis
• Geographic and ethnic variations
• Ocular Histoplasmosis
• Birdshot choroiditis
• Vogt-Koyanagi Harada disease

4
Uveitis Entities one should not miss

• Infectious Uveitis
• Treponema pallidum
  (Syphilis)
• Tuberculosis
• Toxoplasmosis
• Herpetic
  infection (ARN)
• Masquerade syndromes
• Primary intraocular
  lymphoma

5
Syphilitic uveitis

• 1 - 2 of all uveitis cases
• Uveitis is the common ophthalmic manifestation
• Acquired disease
• a. primary 3 weeks of
  incubation painless chancre
• b. secondary 6 to 8 weeks
  later lymphadenopathy, skin rash,
• palms
  and soles uveitis in 5 cases
• c. Latent/ tertiary gumma,
  cardiovascular and CNS involvement
• uveitis
  in 2.5

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Syphilitic uveitis clinical features

• Sudden or insidious onset blurred vision or
  floaters
• Variable severity Variable pain, redness and
  photophobia
• Anterior Intermediate Posterior or Pan uveitis
  
• granulomatous or non-granulomatous uveitis
• Retinitis focal or diffuse necrotizing
• Exudative retinal detachment
• Retinal vasculitis or perivasculitis
• Neuroretinitis or isolated papillitis
• Chorio-retinitis focal or multifocal

7
Syphilitic Uveitis Bilateral in
50 of the cases
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Serology

• Nontreponemal tests VDRL, RPR (false negative in
  30)
• Clumping of cardiolipin ( lecithin and
  cholesterol).
• False positive
• SLE and other autoimmune disorders.
• Tissue damage, liver diseases, pregnancy
• Other Treponema- Lyme disease, Leptospirosis
• Treponemal tests (High sensitivity /specificity)
• FTA-ABS (Fluorescent Treponemal Antibody
  absorption test)
• Detects antibody to T. pallidum after serum
  treated with nonpathogenic treponemal antigen
• Hemagglutination tests MHA-TP
• 15 in SLE and can be in Lyme disease.
• ELISA, DNA-PCR, direct antigen
• HIV TEST !

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Seropositivity() by Stage
Syphilis VDRL FTA-ABS
Primary 70 80
Secondary 100 100
Latent
Tertiary 70 98
Post-treatment -
10
Syphilis

• Syphilis is the great masquerader
• Treatable uveitis
• Routine RPR or VDRL and FTA-ABS or MHA-TP
• Lumbar puncture
• Ocular Inflammation secondary to syphilis should
  be treated as neurosyphilis (AAO)
• HIV
• Chao JR, Khurana RN and Rao NA. Syphilis
  reemergence of an old adversary.
• 
  Ophthalmology 2006 113 2074-2079

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Serology

• Nontreponemal tests VDRL, RPR
• Clumping of cardiolipin (non-treponemal Abs) in
  presence of lecithin and cholesterol.
• False
• SLE/autoimmune.
• Tissue destruction, liver disease, pregnancy
• Other treponemal infection
• Treponemal tests (High sensitivity/specificity)
• FTA-ABS (Fluorescent Treponemal Antibody
  absorption test)
• Detects Antibody to T. pallidum after serum
  treated with nonpathogenic treponemal antigen
• Hemaglutination tests MHA-TP, HATTS, TPHA
• 15 in SLE and can be in Lyme.
• ELISA, DNA-PCR, direct antigen
• HIV TEST !

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Indications for LP

• Latent syphilis gt 1 yr
• Suspected neurosyphilis
• Treatment failure
• HIV co-infection
• High RPR titers ( gt 132)
• Late manifestations (gumma, cardiac)
• CSF Pleocytosis, Elevated protein, VDRL
  (specific but not sensitive), FTA

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Treatment

• Exquisitely sensitive to Benzathine Penicillin
  G
• Primary, Secondary and Early Latent (lt1 yr)
• Penicillin G 2.4 million U IM x 1
• Late Latent (gt1 yr) or Duration Unknown
• Penicillin G 2.4 million U IM q week x 3
• Neurosyphilis
• Penicillin G 3-4 million U IV q4hr x 10-14 d
• Alternatives Doxycycline, Tetracycline, CTX,
  Azithromycin
• Consider treatment with topical, regional, oral
  corticosteroids
• Consider treat sexual partner (Pen G/Azithromycin
  x 1 dose)

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Tuberculous Uveitis
Two billion people are latently infected with
M.tuberculosis worldwide 9
million new cases and 3 million deaths per year
3 million uveitis patients
WHO, 2009
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Latent TB infection

• Clinical syndrome
• Positive PPD
• No clinical symptoms, negative chest X-ray
• Likely consists of a small number of viable
  bacilli maintained in a
• non-replicating state by host immunity

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Tuberculosis

• Pulmonary TB 80
• Extra-pulmonary TB 20
• 25 have history of TB
• 50 have normal chest x-ray film and no
  evidence
• of pulmonary TB
• Up to 20 have negative PPD

Fanning A. CMAJ. 19991601597-1603.
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Tuberculous Intraocular Inflammation

• 1. Endemic versus Non-endemic areas
• a. Clinical presentation
• b. Pathogenesis
• c. Diagnosis
• d. Limited to the eye
• 2. Limitations of current diagnostic approach
• PPD and Interferon release
  assays X-ray chest
• PCR and therapeutic trial
• 3. Serpiginous choroiditis Serpiginous-like and
• Multifocal Serpiginoid
  choroiditis
• 4. Suggested approach to Diagnosis in Non-endemic
  region

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Tuberculosis endemic and non-endemic

• Non-endemic areas - USA and Canada
• high rates of TB have been documented
  among
• HIV-infected
  individuals
• Immigrants, migrants
• Elderly population
• Endemic areas no such predilection except in HIV

Chan J, Flynn J. Clin Immunol. 20041102-12.
Munsiff SS, et al. J Acquir Immune Defic Syndr
Hum Retrovirol. 199819361-366.
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Intraocular Tuberculosis
Endemic vs. Non-endemic

• Endemic regions reactivation and re-infection
• incomplete
  treatment and drug resistance
• Non-endemic regions reactivation
• Endemic regions Initial approach is to rule out
  tuberculosis
• Non-endemic Initial approach is to rule
  out other infections

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Tuberculous Uveitis Diagnostic criteria

• Intraocular tuberculosis can mimic several
  uveitis entities
• Diagnosis requires laboratory support
• 1. Definite
• Histological examination and culture of
  affected tissue.
• Polymerase chain reaction (PCR)
• Evidence of active systemic infection
• 2. Presumed
• Clinical history and ophthalmic
  findings
• PPD or Gamma interferon release assay
  
• Chest x-ray findings and
• Response to anti-TB agents
• Gupta V, Gupta A and Rao NA. Tuberculosis in the
  eye. Survey Ophthalmol. 52 561-587, 2007.

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Tuberculosis and PPD

• Routine PPD Rarely helpful
• False-positive Atypical mycobacterium BCG
• False-negative Sarcoidosis, aging,uremia,
  lymphoma, corticosteroid use

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PPD

• Bayes theorem allows a mathematical approach to
  the assessment of the utility of a laboratory
  test based on the sensitivity, specificity of the
  test, and the pretest likelihood that the disease
  the test is intended to identify is present
• a patient with uveitis and a positive PPD has a
  1 likelihood of having tuberculosis
• The low probability means that the test is not
  useful in the routine evaluation of patients with
  uveitis
• Indiscriminate use may lead to improper diagnosis
  and occasionally, inappropriate therapy.
• Rosenbaum JT, Wernick R. Arch
  Ophthalmol. 19901081291-3.

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TST QFT QFT -TST QFT TST
Sensitivity 95.5 90.9 72.7 93.3
Specificity 72.7 81.8 90.9 82.4
Positive predictive value 87.5 90.9 62.5 82.4
Negative predictive value 88.9 81.8 62.5 93.3
ROC curve (AUC) 0.84 0.86 0.82 0.88
Quantiferon T B test was not more sensitive than
TST
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Management after TST and IGRA testing CDC
guidelines. CDC MMWR weekly report. June 25, 2010

• Diagnosis of TB infection and decision to treat
  should not be based on TST or IGRA results alone
• Diagnostic approach should include
  consideration of
• a. Epidemiologic
• b. Medical history
• c. Other clinical information
• Neither TST nor IGRA can distinguish LTBI from
  active TB
• Negative TST or IGRA results are NOT sufficient
  to exclude TB

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Nucleic acid amplification tests - PCR

• High specificity Better sensitivity than
  microscopy.
• Fast results Allows identification and
  investigation of genetic resistance patterns.
• False negative results are known to occur
• In a clinical case positive results are helpful
  and negative results cannot rule out ocular TB

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Nucleic acid amplification tests - PCR

• Main disadvantages
• Higher cost and limited availability
• Variable sensitivity
• Inferior sensitivity for non-respiratory
  specimens (not established for ocular samples)
• Does not allow ruling out tuberculous etiology
• Detects only DNA (prone to contamination and
  microorganisms may not be viable or may be
  dormant)

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Serpiginous vs. Multifocal Serpiginous like
Choroiditis

• Serpiginous choroiditis (US and Canada)
• Older age group
• Vitritis absent or insignificant
• Contiguous amoeboid extension, mainly
• Predominantly extending from juxta
  papillary choroid
• Insignificant pigmentation of the
  lesions except at borders
• relative slow progression
• Multifocal Serpiginoid choroiditis TB endemic
• Younger age group
• Vitritis present
• Combined contiguous and
  non-contiguous lesions of varying
• geographic shape
• Juxtapapillary choroid may be spared
• Significant pigmentation of the
  lesions
• rapid progression

Vasconcelos-Santos, PK Rao, Davies JB, Sohn EH
and Rao NA. Clinical features of Tuberculous
Serpiginous-like choroiditis in contrast to
Classic Serpiginous Choroiditis. Arch. Ophthalmol
2010
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Serpiginous choroiditis

• Serpiginous choroiditis
• Serpiginous-like choroiditis
• Multifocal serpiginoid choroiditis
• A. Idiopathic
• B. Tuberculous
• C. Herpes
• D. Others
• Priya K, Madhavan HN, Reiser BJ, Biswas J,
  Saptagirish R, Narayana and Rao NA Association of
  herpes virus with serpiginous choroiditis a
  polymerase chain reaction based study. Ocular
  immunol Inflamm. 2002 4253-261

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Tuberculosis Treatment

• Combination of isoniazid, rifampin, and
  pyrazinamide with or
• without a fourth drug such as ethambutol or
  streptomycin
• Fourth drug ethambutol or streptomycinis
  used in
• suspected drug-resistant TB
• For intraocular TB recommend treatment for
  9-12 months
• similar to Tuberculous meningitis
• Most clinicians prefer treatment with four
  drugs combination of
• isoniazid, rifampin, pyrazinamide and
  ethambutol for TWO
• months followed by Isoniazid and rifampin for
  9- 12 months

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Summary

• Pathogenesis of Intraocular Tuberculosis may
  differ in Endemic vs. Non-endemic
• Chest X-ray is not reliable
• Interferon release assays may not
  differentiate latent from active disease and in
  most cases the diagnosis remains
• presumed
  tuberculosis
• PCR is helpful if positive and negative
  results are not helpful
• Multifocal Serpiginoid choroiditis is a feature
  of intraocular TB in endemic region
• Clinically Serpiginous choroiditis can be
  differentiated from tuberculous Serpiginous-like
  choroiditis and such differentiation is important
  to avoid un-necessary TB treatment side effects
  

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Ocular Toxoplasmosis Clinical
features

• Unilateral focal chorio-retinitis adjacent to
  healed
• chorioretinal scar
• a. Healed scars may be multiple, but usually
  only
• one reactivates at a time.
• b. Atypical forms of extensive
  chorio-retinitis can
• occur in immunocompromised
  individuals.
• c. Active chorio-retinitis is yellow-white,
  slightly
• elevated, with a relatively
  well-defined border.

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Clinical features Intraocular inflammation

• a. Iritis. Often granulomatous may be
  associated with
• ocular hypertension
• b. Vitritis. Often intensified over the
  lesion
• c. Vasculitis. Variably present Often
  arteritis, but
• also periphlebitis and the
  vasculitis can be remote from
• the chorio-retinitis
• d. Optic neuritis or neuro-retinitis.

33
Appropriate Laboratory Testing

• 1. Conformation of exposure to toxoplasmosis by
  serum ab. titer high sensitivity and low
  specificity because of high prevalence of
  positive antibody titers in general population
• 2. Determination of toxoplasmosis IgG or IgA
  titers in aqueous
• humor useful in cases with atypical features
• 3. PCR of aqueous humor for toxoplasmosis DNA
  useful in older
• patients with large lesions or in
  immunocompromised patients

34

• Risk of congenital infection
• Acquired toxoplasmosis infection in a pregnant
  woman
• a. Most severe effects on fetus if acquired
  during first trimester
• b. Risk of transmission greatest if acquired
  during third trimester
• Seroconversion treated with antibiotic therapy
• Prenatal treatment reduces fetal effects.

35
Differential Diagnosis

• 1. Toxocariasis
• 2. Cytomegalovirus retinitis
• 3. Necrotizing herpetic retinitis
• 4. Syphilis
• 5. Focal fungal or bacterial infections
• 6. Intraocular lymphoma

36
Treatment

• Decision to treat based on proximity to macula
  and optic nerve, amount of inflammation, and
  vision
• 1. Sight-threatening infections almost always
  treated.
• 2. Small, peripheral lesions often observed.
• 3. Infection is self-limited in most cases in
  healthy patients.

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Treatment

• 1. Pyrimethamine is most common agent combined
  with sulfadiazine or triple-sulfa, azithromycin,
  or clindamycin
• Usually given with leukovorin to mitigate
  hematologic toxicity
• 2. Trimethoprim-sulfamethoxazole increasing in
  use combined with clindamycin for increased
  efficacy
• 3. Monotherapy-generally reserved for non-sight-
• threatening disease Doxycycline or
  minocycline

38
Anti-inflammatory Treatment

• Topical corticosteroids
• Oral corticosteroids
• Indicated for vision threatening inflammation
• Low to moderate doses for 2 to 3 weeks
• Not given alone because of risk of worsened
  infection
• without antibiotic coverage
• Periocular steroids felt to be contraindicated
• because of reports of uncontrolled
  infection after injection
• Generally not used in immunocompromised patients

39
ARN

• Posterior Segment findings - Clinical Triad
• Vitritis
• Peripheral Retinal Necrosis
• Retinal vasculitis Arteritis
• Optic disk may be swollen
• Viral Etiology VZV HSV and rarely CMV

40
ARN Treatment

• Initial 10mg/kg q8 hrs or 1500mg per meter
  square/day, Intravenous for 5-10 days. Followed
  by oral acyclovir 800mg 5 times a day for 6
  weeks good to continue 6-12 mon.
• Oral Val acyclovir 1000mg qd or tid
• Oral Corticosteroids (prednisone
  40-60mg/day)
• Aspirin
• Prophylactic photocoagulation ( 35 with
  treatment versus 80 without treatment)
• Prophylactic vitrectomy ( may be some benefit
  in preventing RD)

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ARN complications

• Retinal detachment 50-70 usually within 1-2
  months. It is managed usually by vitrectomy,
  silicone oil injection and scleral buckling.
• Contra lateral eye involvement is seen in over
  30 of the cases and this may occur usually
  within 2- 4 months

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Summary ARN (Herpetic Retinitis)

• Posterior or Pan uveitis, retinal arteritis and
  peripheral retinal necrosis
• In doubt start anti-viral first while waiting for
  laboratory results in support of clinical
  diagnosis
• A tailored treatment approach is ideal
• Follow-up is important for contra lateral eye
  involvement and retinal detachment.

43
Investigations in support of Diagnosis

• Imaging
• Fundus photography wide field
• OCT Autofluorescence
• Fluorescein angiography
• Classical investigations
• CBC RPR and FTA-ABS Chest X-ray
  PPD or
• Quantiferon TB test
• Polymerase chain reaction
• HSV, VZV, CMV, Toxoplasma
  M.tuberculosis

44
Treatment

• Systemic
• Corticosteroids
• Immunomodulatory agents
• Biologicals
• Local
• Intravitreal injections
  Corticosteroids Anti-VEGF and
• 
  Methotrexate and anti-Microbials
• Dexamethosone intravitreal implant
  (Posudex)
• Fluociolone implant (Retisert)

45
Local Intervention

• Local Intravitreal injections
• Rapid therapeutic concentration in
  the retinal tissue
• Potential complications
• Corticosteroids Anti-VEGF for refractory
  non-infectious uveitis CME
• Triamcinolone acetonide (kenacort) 4 mg for
  CME usually effective numerous side effects
• Anti-VEGF 2.5 mg lower therapeutic
  activity compared to the
• corticosteroids
• Ocular Immunology and Inflammation 2009
  17 423-30
• 
  

46
Local Treatment

• Primary Intraocular lymphoma and Intravitreal
  Methotrexate
• Injection of 400 microg / 0.1 ml
  methotrexate twice weekly for 4 weeks
• 
  once a week for 8 weeks
• 
  once a month for 9 months
• 
  a total of 25 injections
• most common side effect was corneal
  epitheliopathy, usually after third
• injection subsides when the intervals
  between injections are increased
• Other Potential complications cataract
  vitreous hemorrhage,
• retinal detachment

47
Local Treatment

• Methotrexate
• Therapeutic activity could be similar to
  corticosteroid
• 400micrograms in 0.1 ml
• 15 patients with CME 4 lines
  improvement at 3 m.
• 5 patients relapsed at 4 m.
  similar improvement
• with reinjection
• Potential complications cataract vitreous
  hemorrhage,
• retinal detachment and
  corneal epitheliopathy
• Intravitreal methotrexate cumulative dose up
  to 1,200 micrograms is safe in silicone-filled
  eyes

48
Dexamethosone intravitreal implant (Posudex)

• Dexamethosone drug delivery in patients with
  persistent CME
• of diverse causes including uveitis CME
• 315 patients with chronic CME at 90 day
  primary end point, improvement in BCVA
• 10 or more letters
  15 or more letters
• 350 micrograms--- 24
  6
• 700 micrograms---- 35
  18
• 700 microg potentially useful in treatment of
  persistent CME
• 11 developed ocular hypertension
  and 2 controls
• Kupperman et al. Arch Ophthalmology. 2007 125
  309-17

49
Dexamethosone intravitreal implant (Posudex)

• In uveitis
• The benefit of improved uveitis ( vitreous
  haze) and
• 15 or more letters from baseline was
  persistent for 26 weeks
• 350 micrograms--- elevated IOP in 8.7
  cataract 12
• 700 micrograms---
  7.1 15
• Lowder C et al. Arch Ophthalmol, 2011 129
  543-53

50
Fluociolone implant (Retisert)

• In uveitis Improvement in intraocular
  inflammation
• Complications cataract 93 (controls 20)
  and
• elevated IOP requiring topical medication
  in 75 trabeculectomy in 37
• Randomized comparison of systemic therapy
  (includes corticosteroid sparing
  immunosuppressive agents) versus the implant (255
  patients 479 eyes with uveitis)
• 1. Visual acuity improved over 24 mon in
  both groups neither
• approach was superior
• 2. Elevated IOP and cataracts were
  significantly high in implant
• 3. Systemic treatment was well tolerated
  and safe but require monitoring
• for any systemic infections

Kempen et al. Ophthalmology 2011 118 1916-26
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Uveitis Entities one should not miss

• Infectious Uveitis
• Treponema pallidum
  (Syphilis)
• Tuberculosis
• Toxoplasmosis
• Herpetic
  infection (ARN)
• Masquerade syndromes
• Primary intraocular
  lymphoma