Tuberculous Uveitis - Cybersight · – Ocular manifestations of tuberculosis are due to: •...

Tuberculous UveitisRamana S. Moorthy, MD FACS

Associate Clinical Professor of Ophthalmology

Indiana University Medical Center: Eskenazi Hospital

Founding Partner

Associated Vitreoretinal and Uveitis Consultants

Indianapolis, Indiana

Polling Question 1The global tuberculosis disease burden is greatest in which

part of the globe?

A. North America

B. South America

C. Sub-Saharan Africa

D. Southeast Asia

Tuberculosis : Epidemiology• Global: WHO Global Tuberculosis Report 2015

– 9.6 Million new cases in 2014

– 1.5 million deaths in 2014 (0.4M with TB+HIV)

• Disease Burden – Incidence – total number of cases in 2014

– North and South America – 0.280M

– South East Asia – 4.0M

– Africa – 2.7M

– Middle East -0.740M

– Europe – 0.320M

– Western Pacific – 1.6M

Tuberculosis – Global Incidence

WHO Global Tuberculosis Report 2015

Tuberculosis – Global Distribution


Tuberculosis • Latent TB infection (LTBI)

• TB Disease

– Pulmonary

– Extrapulmonary

• Uveitis

– Prevalence 0.7%-10%

• Renal Disease

– Prevalence

Tuberculosis

• Concomitant HIV infection

– Increased risk of developing TB disease

• 7-10%/year risk if HIV + compared to 10% lifetime risk

for those with just LTBI without HIV

• 25% of HIV deaths are caused by TB disease

Tuberculosis and HIV


Tuberculosis• Drug resistant TB

– Multidrug resistant TB (MDR-TB)

• Resistant to rifampin and/or INH

– Extensively drug resistant TB (XDR-TB)

– Disease burden is highest in the poorest countries

• Treatment failures

– Lack of proper drug availability

– Non-compliance

– Increased prevalence of drug-resistance

– Higher HIV rates

TB Disease• General symptoms

– Fevers

– Chills

– Night Sweats

– Weight Loss

– Appetite Loss

– Malaise

• Pulmonary TB Symptoms

– Cough lasting >3 weeks

• Sputum and/or hemoptysis

– Pleuritic pain with breathing and coughing

• Extrapulmonary TB

– Renal – Hematuria

– Spine – Back pain

Tuberculous Uveitis• Etiology

– Intraocular inflammation resulting from Mycobacterium tuberculosis infection

– Transmitted by aerosolized respiratory droplets with the primary site of infection being

the lung

– High affinity for highly oxygenated tissues – Apex of lung and choroid

– Ocular manifestations of tuberculosis are due to:

• Active infection involving ocular tissue

– Primary inoculation of eye from adjacent sites – very rare

» May cause eyelid tubercle, conjunctivitis, dacryocystitis…

– Hematogenous dissemination

• Immunologic reaction to paucibacillary systemic or ocular disease

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Tuberculous Uveitis– Ocular Symptoms

• Waxing and waning course

• Progressive increase in floaters

• Worsening of vision due to progressive intraocular

inflammation, choroidal and retinal involvement or cystoid

macular edema

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Polling Question 2Tuberculosis can cause which of the following :

A. Scleritis

B. Anterior Uveitis

C. Intermediate Uveitis

D. Panuveitis

E. All of the Above

Tuberculous Uveitis

– Ocular Signs

• Scleritis

– Nodular anterior scleritis

– Posterior scleritis with acute angle closure glaucoma

» Rare - TB should be considered in such cases

• Anterior uveitis: Mutton-fat keratic precipitates; Iris nodules; Posterior synechiae; Secondary

glaucoma; Rarely nongranulomatous

• Intermediate uveitis

– Vitreous cells and opacity

– Cystoid macular edema

» Retinal periphlebitis

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Tuberculous Uveitis– Posterior uveitis or panuveitis

» Vitreous opacities

» Disseminated choroiditis -most common presentation: Choroidal tubercles

» Deep, multiple, discrete, yellowish lesions

» Single, large elevated choroidal mass (tuberculoma)

» Serpiginous-like choroiditis

» Retinal periphlebitis-Eales disease

» Subretinal abscess in immunocompromised host

» Optic neuritis

» Acute panophthalmitis

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Tuberculous Uveitis• Testing

– Definitive diagnosis requires demonstration of mycobacteria from bodily fluids or affected

tissues

• Not accomplished in most cases of ocular TB, but...

– Acid fast staining should be performed in all cases of chorioretinal biopsy performed for uveitis unresponsive to

therapy

– Diagnosis - presumptive in most cases

• Indirect evidence

– Positive PPD or IGRAs

– Therapeutic response to anti-TB agents

– A positive PPD is indicative of prior exposure to TB but not necessarily of active systemic infection

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Tuberculous Uveitis : Testing– Positive Tuberculin Skin Test (TST)

• Interpretation depends on the size of induration and the

person’s risk factors for TB (5mm, 10mm, >15mm)

• Booster effect – Two step testing can help differentiate

or IGRA

Tuberculous Uveitis : Testing– In the United States, PPD is considered positive requiring

intervention if:• Induration of > 5 mm in

– HIV– contact with active TB– Radiographs consistent with healed tuberculous lesions

• Induration of > 10 mm in– Diabetes– Renal failure– Immunosuppressive agents– Health care workers– Recent immigrants from high prevalence countries

• Induration is > 15 mm with no known risk factors

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Tuberculous Uveitis : Testing– False-negative skin testing occurs at a rate of 25%

• Profound acute illness

• Immunosuppression

• Corticosteroid use

• Advanced age

• Poor nutrition

• Sarcoidosis

– False positives skin tests

• Individuals infected with atypical mycobacteria

• Immunized with BCG (Bacillus Calmette-Guerin)

• Treated with intra-luminal BCG injections for bladder carcinoma

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Tuberculosis : Testing – IGRA

• Used in place of TST

• Cannot reliably differentiate LTBI from TB disease

• QuantiFERON® TB-Gold In Tube – measures concentration of interferon γ produced – against ESAT-

6, CFP-10, TB7.7 antigens

• T-SPOT®-TB - measures number of interferon γ producing cells (spots) against ESAT-6 and CFP-10

antigens

Tuberculous Uveitis : Testing– Definitive diagnosis may require intraocular fluid analysis or tissue biopsy

• Nucleic acid amplification techniques

– PCR

– X-Pert MTB/RIF assay - Multiplex PCR – can determine if TB present in sputum and if Rifampin

resistant in 2 hours

» Not evaluated for ocular fluids yet

• Biopsy of affected ocular tissue

• Culture and Sensitivity testing - Important in sputum evaluation

– Slow growth

– Mycobacteriology laboratory required

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Tuberculous Iris Ganuloma

Photographs Courtesy of Prof. S. Rathinam

Tuberculous Choroiditis


Multifocal Tuberculous SerpiginoidChoroiditis

Photographs Courtesy of Dr. Narsing A. Rao

Tuberculous ScleritisTuberculousScleritis

Photographs courtesy of Debra A. Goldstein, MD

Tuberculous Sclerokeratitis


Tuberculous Scleritis and Choroiditis


Tuberculous Choroiditis


Tuberculous Multifocal Choroiditis

Tuberculous Retinal Vasculitis with NVD

Pediatric Tuberculous Anterior Uveitis


Anterior Chamber Tuberculous Granuloma

Photograph Courtesy of Prof. S. Rathinam

Anterior Chamber Tuberculous Granuloma


Tuberculous Scleritis in HIV


Tuberculous Scleritis in HIV After Immune Reconsttitution

SR Rathinam and P Lalitha. Eye (2007) 21, 667–668.

Tuberculous Uveitis • Differential Diagnosis

– Sarcoid uveitis

– Syphilitic uveitis

– Retinal Vasculitis

– Vogt-Koyanagi-Harada disease

– Sympathetic ophthalmia

– Serpiginous choroiditis,

– Herpes simplex or varicella zoster infection,

– Lepromatous uevitis

– choroidal granulomas from Toxoplasmosis, Toxocariasis, and Cryptococcus.

Tuberculosis Therapy• Therapy for LTBI

– 9 months INH – definitive

• 6 months is acceptable

– Alternative – 12 dose (Weekly ) DOT of INH+Rifapentine

– Alternative – 4 months Rifampin (if INH resistance)

Tuberculosis Therapy

– Prophylactic treatment: single agent

• Positive PPD or abnormal chest film

– If systemic treatment with corticosteroids is being considered or

– If received corticosteroids for longer than 2 weeks at doses greater than 15 mg per day

– Prophylactic treatment with INH for 6 months to a year

• If anti-TNF therapy is being considered in patients with latent TB (positive

PPD or IGRA)

– INH prophylaxis beginning at least 3 weeks prior to the first infusion

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Isoniazid Rifampin Pyrazinamide Ethambutol

Tuberculosis Therapy• Therapy for TB disease

– Multi-drug regimen for 6 months – to ensure death of bacilli and reduce drug resistance

• Isoniazid (INH)

• Rifampin (RIF)

• Pyrazinamide (PZA)

• Ethambutol (EMB)

– 6+ Months of therapy

• 2 months with all 4 drugs

• 4-6 months with 2 or more drugs tailored to susceptibility test results (if available)

Tuberculosis Therapy• Complications

– Side effects of therapeutic agents

• INH

– Hepatotoxicity

– Neurotoxicity – due to pyridoxine deficiency

» Peripheral neuropathies, seizures, agitation, insomnia

» Treated with pyridoxine

• Pyrazinamide

– Hepatotoxicity

• Rifampin

– Thrombocytopenia

– Nephritis

– Hepatotoxicity

• Ethambutol

– Optic neuropathy

» Can improve with drug cessation

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• Multi-drug-resistant tuberculosis (MDRTB)

– Risk Factors for MDRTB development

» Noncompliant patients on single-agent therapy

» Migrant or indigent populations

» Immunocompromised patients – e.g. HIV

» Recent immigrants from countries where INH and rifampin are

available over the counter

• Direct observed therapy (DOT) ideal

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Tuberculosis Therapy : MDR and XDR-TB

(GROUP 2) Fluoroquinolones

1

Always use in MDR andor

XDR tuberculosis

(GROUP 3) Injectable drugs

2

Always use in MDR and d

XDR tuberculosis

(GROUP 4)

Nearly always use:

Ethionamide/prothionamide

(GROUP 5)

Used in MDR and XDR-TB

but - clinical data are sparse3

Ofloxacin

Streptomycin Ethionamide/Prothionamide Clofazimine

Levofloxacin Kanamycin Cycloserine/Terizidone

Amoxicillin with clavulanate

Moxifl oxacin Amikacin

P-aminosalicylic acid (acid salt) Linezolid

Capreomycin Imipenem

Clarithromycin

Thioacetazone

Tuberculous Uveitis

– Corticosteroids

• Topical and systemic corticosteroids

– Should be used only with appropriate anti-tuberculosis coverage

– Intensive steroid treatment administered without appropriate

anti-tuberculosis cover leads to progressive worsening of ocular

disease

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TB – Future Directions

• New Anti-tuberculosis

drugs under

investigation

• TB vaccine

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