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Uveitis Update

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.

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Uveitis Update

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  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 Behcet’s 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%

  6. 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

  8. 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 !

  9. Seropositivity(%) by Stage

  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

  11. 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 !

  12. 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

  13. 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)

  14. 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

  15. 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

  16. 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 Tuberculosis Fanning A. CMAJ. 1999;160:1597-1603.

  17. 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

  18. 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.

  19. 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

  20. 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.

  21. Tuberculosis and PPD Routine PPD: Rarely helpful False-positive: Atypical mycobacterium; BCG False-negative: Sarcoidosis, aging,uremia, lymphoma, corticosteroid use

  22. 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.

  23. Quantiferon T B test was not more sensitive than TST

  24. Management after TST and IGRA testingCDC 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

  25. 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

  26. 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 - PCR

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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.

  32. 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.

  37. 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)

  41. 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

  42. 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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