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Uveitis Update
Narsing A. Rao, MD
Doheny Eye Institute
Los Angles
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
Prevalence of Uveitis in adults
Migration and its affect on prevalence of uveitis
Behcet’s disease
Intraocular Tuberculosis
Geographic and ethnic variations
Ocular Histoplasmosis
Birdshot choroiditis
Vogt-Koyanagi Harada disease
Uveitis Entities one should not miss
Infectious Uveitis:
Treponema pallidum (Syphilis)
Tuberculosis
Toxoplasmosis
Herpetic infection (ARN)
Masquerade syndromes:
Primary intraocular lymphoma
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%
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
Syphilitic Uveitis
Bilateral in 50% of the cases
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 !
Seropositivity(%) by Stage
Syphilis
VDRL+
FTA-ABS+
Primary
70*
80
Secondary
100
100
Latent
+
+
Tertiary
70*
98
-
+
Post-treatment
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
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 !
Indications for LP
•
•
•
•
•
•
Latent syphilis > 1 yr
Suspected neurosyphilis
Treatment failure
HIV co-infection
High RPR titers ( > 1:32)
Late manifestations (gumma, cardiac)
CSF: Pleocytosis, Elevated protein, VDRL (specific but not sensitive), FTA
Treatment
Exquisitely sensitive to Benzathine Penicillin G
•
•
•
•
Primary, Secondary and Early Latent (<1 yr)
Penicillin G 2.4 million U IM x 1
•
Late Latent (>1 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)
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
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
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. 1999;160:1597-1603.
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
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. 2004;110:2-12.
Munsiff SS, et al. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;19:361-366.
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
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.
Tuberculosis and PPD
Routine PPD: Rarely helpful
False-positive: Atypical mycobacterium; BCG
False-negative: Sarcoidosis, aging,uremia, lymphoma,
corticosteroid use
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. 1990;108:1291-3.
+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%
0.84
0.86
0.82
0.88
ROC curve (AUC)
Quantiferon T B test was not more sensitive than TST
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
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
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)
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
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; 4:253-261
Tuberculosis Treatment
Combination of isoniazid, rifampin, and pyrazinamide with or
without a fourth drug such as ethambutol or streptomycin
Fourth drug; ethambutol or streptomycin—is 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
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
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.
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.
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
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.
Differential Diagnosis
1.
2.
3.
4.
5.
6.
Toxocariasis
Cytomegalovirus retinitis
Necrotizing herpetic retinitis
Syphilis
Focal fungal or bacterial infections
Intraocular lymphoma
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.
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-sightthreatening disease; Doxycycline or minocycline
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
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
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)
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
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.
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
Treatment
• Systemic
Corticosteroids
Immunomodulatory agents
Biologicals
• Local
Intravitreal injections: Corticosteroids; Anti-VEGF and
Methotrexate and anti-Microbials
Dexamethosone intravitreal implant (Posudex)
Fluociolone implant (Retisert)
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
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
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
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
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
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
Uveitis Entities one should not miss
Infectious Uveitis:
Treponema pallidum (Syphilis)
Tuberculosis
Toxoplasmosis
Herpetic infection (ARN)
Masquerade syndromes:
Primary intraocular lymphoma