Uveitis Update Uveitis Update
Narsing A. Rao, MDDoheny Eye Institute
Los Angles
UveitisUveitis
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 adultsPrevalence of Uveitis in adultsMigration 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 Uveitis Entities one should not missone should not miss
Infectious Uveitis: Treponema pallidum (Syphilis) Tuberculosis Toxoplasmosis Herpetic infection (ARN)
Masquerade syndromes: Primary intraocular lymphoma
Syphilitic uveitisSyphilitic 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 featuresSyphilitic 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
SerologySerology
• 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 StageSeropositivity(%) by Stage
Syphilis VDRL+ FTA-ABS+
Primary 70* 80
Secondary 100 100
Latent + +
Tertiary 70* 98
Post-treatment - +
SyphilisSyphilis
• 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
SerologySerology
• 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 LPIndications 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
TreatmentTreatment 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)
WHO, 2009
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
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
Latent TB infection
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.
Tuberculosis
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
Tuberculous Intraocular Inflammation
Tuberculosis: Tuberculosis: endemic and non-endemicendemic 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 Intraocular Tuberculosis Endemic vs. Non-endemicEndemic 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 tuberculosisNon-endemic : Initial approach is to rule out other infections
Tuberculous Uveitis: Diagnostic criteriaTuberculous Uveitis: Diagnostic criteriaIntraocular tuberculosis can mimic several uveitis entitiesDiagnosis 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 PPDTuberculosis and PPD
Routine PPD: Rarely helpful
False-positive: Atypical mycobacterium; BCG
False-negative: Sarcoidosis, aging,uremia, lymphoma, corticosteroid use
PPDPPD
• 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%
ROC curve (AUC) 0.84 0.86 0.82 0.88
Quantiferon T B test was not more sensitive than TST
Management Management after TST and IGRA testingafter TST and IGRA testing CDC guidelines. CDC MMWR weekly report. June 25, 2010 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 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
Main disadvantages: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)
Nucleic acid amplification tests - PCRNucleic acid amplification tests - PCR
Serpiginous Serpiginous vs. vs. Multifocal Serpiginous like ChoroiditisMultifocal 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 choroiditisSerpiginous 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 TreatmentTuberculosis 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
• 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
Summary
Ocular Toxoplasmosis Ocular Toxoplasmosis
Clinical featuresClinical 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: Clinical features: Intraocular inflammationIntraocular 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 TestingAppropriate 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 therapyPrenatal treatment reduces fetal effects.
Differential DiagnosisDifferential Diagnosis
1. Toxocariasis 2. Cytomegalovirus retinitis 3. Necrotizing herpetic retinitis 4. Syphilis 5. Focal fungal or bacterial infections 6. Intraocular lymphoma
TreatmentTreatment
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.
TreatmentTreatment
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
Anti-inflammatory TreatmentAnti-inflammatory Treatment
Topical corticosteroids
Oral corticosteroidsIndicated for vision threatening inflammationLow to moderate doses for 2 to 3 weeksNot given alone because of risk of worsened infection
without antibiotic coveragePeriocular steroids felt to be contraindicated
because of reports of uncontrolled infection after injection Generally not used in immunocompromised patients
ARNARN
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: ARN: TreatmentTreatment
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: complicationsARN: 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:Summary: ARN ARN (Herpetic Retinitis)(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 DiagnosisInvestigations 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
TreatmentTreatment
• Systemic Corticosteroids Immunomodulatory agents Biologicals
• Local Intravitreal injections: Corticosteroids; Anti-VEGF and Methotrexate and anti-Microbials
Dexamethosone intravitreal implant (Posudex) Fluociolone implant (Retisert)
Local InterventionLocal InterventionLocal: 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 TreatmentLocal 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 TreatmentLocal 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 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)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 Fluociolone implant (Retisert)(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 Uveitis Entities one should not missone should not miss
Infectious Uveitis: Treponema pallidum (Syphilis) Tuberculosis Toxoplasmosis Herpetic infection (ARN)
Masquerade syndromes: Primary intraocular lymphoma