AAO READING

INFECTION AND IMMUNOLOGY SUBDIVISION

INFECTIOUS
UVEITIS

-TUBERCULOSIS-
Ocular involvement caused by tuberculosis (TB) is uncommon in the United States.

In the last 6 decades, its incidence rate in the US has decreased from 52.6 cases per
100,000 persons in 1953 to 2.9 cases per 100,000 in 2016.

Worldwide, however, TB remains an important systemic infectious disease, with

more than 10.4 million new cases and 1.7 million deaths reported annually.

Nearly one-third of the world’s population is infected, and 95% of cases occur in
resource-limited countries.

Mycobacterium tuberculosis  acid-fast–staining, obligate aerobe most commonly

transmitted by aerosolized droplets has an affinity for highly oxygenated tissues.

Tuberculous lesions are commonly found in the apices of the lungs, in the choroid,
highest blood flow rate in the body.

Systemic infection may occur primarily, due to recent exposure; in 90% of patients,
however, it occurs secondarily from reactivation of the disease with immune compromise

Widespread hematogenous dissemination of TB, known as miliary disease most often in

immunocompromised persons.

Pulmonary TB  +/- 80% of patients, whereas
extrapulmonary about 20% one-half of them with a
normal-appearing chest radiograph up to 20%
having a negative result on the purified protein
derivative (PPD) skin test
Patients coinfected with HIV present more often
with extrapulmonary disease, the frequency of
which increases with deteriorating immune
function only 10% of infected individuals develop
symptomatic disease; one-half of these manifest
illness within the first 1–2 years. Most, remain
infected but asymptomatic

• The classic presentation of symptomatic disease

fever, night sweats, and weight loss
occurs in both pulmonary and extrapulmonary infection
• This fact is important to keep in mind when conducting a review of systems in patients suspected of
tuberculous uveitis because histologically proven intraocular TB has been found in asymptomatic patients
as well as in patients with extrapulmonary disease
 External ocular and anterior segment findings
• scleritis, phlyctenulosis, interstitial keratitis,
• corneal infiltrates, anterior chamber and iris nodules,
May result from either active infection or an
• and isolated granulomatous anterior uveitis (Fig 10-9);
immunologic reaction to the organism. • the last is exceedingly uncommon in the absence of
• posterior segment disease.

A, Slitlamp photograph revealing diffuse hyperemic sclera.

B, Photograph of the same eye 6 months after initiation of antituberculosis therapy, showing a marked
decrease in inflammation but thinning of the sclera.
A. Limbally located phlycten.
B. Elevated eye demonstrating extent of surrounding blood vessel injection.
C. Slit beam illustrating raised nature of phlycten.
Ferdi, A., Kopsachilis, N. and Parmar, D. (2017), Phlyctenulosis: a systemic diagnosis made or missed in the blink of an eye. Clin Exp Optom, 100: 285-287. 
https://doi.org/10.1111/cxo.12474

Figure 10-9 Severe fibrinous inflammation and large iris nodules OS: Sectoral and peripheral interstitial keratitis
in a patient with ocular tuberculosis.
Polymerase chain reaction testing was positive from aqueous.
(Courtesy of H. Nida Sen,MD, National Eye Institute.)

Belghmaidi Sarah, Mouafik Sara Batoul, Hajji Ibtissam, Hocar Ouafa, Amal Said, Moutaouakil Abdeljalil. Corneal Manifestations of Tuberculosis: About 2
Cases. American Journal of Medical Case Reports. Vol. 4, No. 5, 2016, pp 160-164. http://pubs.sciepub.com/ajmcr/4/5/4
Tuberculous uveitis is classically a chronic granulomatous disease that may ffect the
anterior and/or posterior segments. It may be replete with mutton-fat keratic precipitates,
iris nodules, posterior synechiae, and secondary glaucoma, although nongranulomatous
uveitis may also occur. Patients typically experience a waxing and waning course, with
accumulation of vitreous opacities and macular edema

Figure 10-10 Chronic tuberculous uveitis. A, Fluorescein angiogram of chronic tuberculous uveitis with disc edema,
periphlebitis, and macular edema. B, Spectral-domain optical coherence tomography confirms macular edema.
(Courtesy of Daniel V. Vasconcelos-Santos, MD, PhD.)
 Disseminated choroiditis is the most These lesions, or tubercles, are located
common presentation and is characterized predominantly in the posterior pole and
by multiple deep, discrete, yellowish lesions may be accompanied by disc edema, nerve
between 0.5 mm and 3.0 mm in diameter fiber layer hemorrhages, and varying
and numbering from 5 to several degrees of vitritis and granulomatous
hundred(Fig 10-11). anterior uveitis.

Figure 10-11 Tubercular multifocal choroiditis with serous retinal detachment. Fundus photography shows multiple pockets of subretinal fluid overlying
choroidal tubercles (top left). Fluorescein angiography reveals multifocal leakage (top middle), and indocyanine green angiography delineates
hypocyanescence (top right), presumably corresponding to areas of choroidaln inflammatory infiltration. Choroidal nodules (tubercles) are revealed by
spectral-domain OCT
A, Left eye fundus photograph (montage) showing mild vitreous hemorrhage (inferiorly),
focal retinal vasculitis (arrowheads) in all quadrants, retinal neovascularization (asterisk),
along superotemporal arcade, and 2 bright, yellowish-white chorioretinal lesions (arrows),
located near blood vessels. Two more chorioretinal lesions were noted in inferior periphery, 1
of which was
included in tissue excised for biopsy. 

B, Periodic acid-Schiff (PAS) staining of retinal tissue (10×) showing a large intraretinal
granuloma (arrow) and a smaller granuloma (black arrowhead) located in close proximity of
a vessel wall (yellow arrowhead). 

C, Hematoxylin-eosin staining of retinal tissue section (40×) showing discrete granuloma

(arrow) composed of epithelioid cells and occasional lymphocytes. 

D, Immunostaining with anti-goat human leucocyte antigen-DR antibodies showing positive

staining (arrow) of the granuloma. Several elongated cells, suggestive of activated microglia
(arrowheads), are seen in close proximity of the granuloma.
 Alternatively, they may present as a single, focal, large, elevated choroidal mass (tuberculoma) that varies
in size from 4 mm to 14 mm and may be accompanied by neurosensory retinal detachment and macular star
formation (Fig 10-12).

Choroidal tubercles  one of the earliest signs of disseminated disease and more commonly in
immunocompromised hosts.

On FA, active choroidal lesions display early hypo-hyperfluorescence with late leakage, and cicatricial
lesions show early blocked fluorescence with late staining.

ICG angiography reveals early- and late-stage hypofluorescence corresponding to the choroidal lesions

Other manifestations :
multifocal choroiditis,
frequently with a serpiginoid pattern (multifocal serpiginoid choroiditis, also called
serpiginouslike choroiditis; Fig 10-13).

In patients with HIV/AIDS, tuberculous

choroiditis may progress despite effective antituberculous therapy.

Figure 10-13 Fundus photograph showing tuberculous choroiditis masquerading as atypical serpiginous-like choroiditis. The patient showed progression and recurrence while receiving immunomodulatory drugs; however, after antituberculous treatment
was begun, the patient showed improvement in vision and resolution of the vitritis without recurrences. (Courtesy of Narsing A. Rao, MD.)
Retinal involvement in TB is usually secondary to extension of the choroidal
disease or an immunologic response to mycobacteria and should be
differentiated from Eales disease, a peripheral retinal perivasculitis that
presents in otherwise healthy young men aged 20–40 years with recurrent,
unilateral retinal and vitreous hemorrhage and subsequent involvement of the
fellow eye.

The disease may be associated, at least in part, to some degree of tuberculin

hypersensitivity. Interestingly a few studies employing PCR-based assays have
detected M tuberculosis DNA from aqueous, vitreous, and epiretinal membranes
of some patients with Eales disease.
Periphlebitis is commonly observed in this setting, and may be accompanied by venous occlusion, peripheral
nonperfusion, neovascularization (Fig 10-14), and eventual development of tractional retinal detachment in some cases.
Other posterior segment findings of TB include subretinal abscess, CNV, optic neuritis, and panophthalmitis.

Figure 10-14 Eales disease.

A, Wide-angle fundus photograph of Eales disease.
B, Angiographic image shows peripheral retinal nonperfusion and neovascularization (temporally), in addition to perivenular
hyperfluorescence (periphlebitis). (Courtesy of Emilio Dodds, MD.)
a. A massive subretinal abscess was seen in the left eye of a patient recently diagnosed with pulmonary tuberculosis. The patient had a history of vision
loss in the left eye. The disc was hyperemic.
b. B-mode ultrasonogram of the left eye showed retinochoroidal thickening and serous retinal detachment.
c. After completion of antitubercular treatment, the lesion healed completely, with macula scarring, but focal subretinal hemorrhage remained
d. Optical coherence tomography was suggestive of choroidal neovascular membranes. Vision improved from light perception to 20/40 in the left eye.

https://www.aao.org/image/pre-post-treatment-subretinal-tubercular-abscess
 Diagnosis
Definitive diagnosis of TB  mycobacteria in bodily fluids or tissues In
many cases of ocular TB, this confirmation is not possible  the
diagnosis is instead presumptive, based on indirect evidence.
A positive result on a tuberculin skin test using PPD (purified protein
derivative of Mycobacterium bovis) test or an interferon-gamma release
assay is indicative of prior exposure to TB but not necessarily of active
systemic or ocular infection.

In the United States, an induration of 5 mm or more, read 48–72 hours after intradermal injection of the standard 5-tuberculin-unit (5-TU), or intermediate-
strength, test dose is considered a positive result in individuals with HIV infection, those exposed to active TB, or those whose radiographs are
consistent with healed tuberculous lesions. An induration of 10 mm or more is considered indicative of a positive result for other high-risk individuals
(DM or renal failure, those on immunomodulatory therapy (IMT), health care workers, and recent immigrants from high-prevalence countries.

Patients with no known risks for tuberculosis are considered to have a positive test result if induration is 15 mm or more.
False-negative skin testing results  up to 25% because of patients with profound acute illness or immune
compromise, which can stem from corticosteroid use, advanced age, poor nutrition, and sarcoidosis.

False-positive results  patients infected with atypical mycobacteria, immunized with BCG vaccine, and
treated with intraluminal BCG injections for bladder carcinoma.

Individuals recently immunized with BCG vaccine  induration around 10 mm at presentation, but the
reaction is usually not sustained and tends to decrease with time compared with the reaction following the
skin test after more recent systemic TB exposure.
 • A Bayesian analysis predicts that routine screening of uveitis patients for TB has a
low probability of detecting disease in settings where the prevalence of TB is low.

• It is recommended, therefore, that testing be selectively used for patients in whom the
index of suspicion has been heightened by a careful history, review of systems, and
clinical examination.

• Testing for TB is required in patients being considered for treatment with tumor
necrosis factor inhibitors or other biologic agents.

A history of recent exposure to TB or a positive TB test result warrants a concerted search for systemic infection,
using chest imaging (radiography, computer-assisted tomography and positron emission tomography scanning),
and/or microbiologic analysis of sputum, urine, or gastric aspirates, or a cervical lymph node biopsy for acid-fast
bacilli.

Failure to demonstrate systemic disease does not, however, exclude the possibility of intraocular infection.
For cases of suspected ocular TB in which the results of the above-mentioned testing for systemic infection are negative, the patient is
asymptomatic, or the infection is thought to be extrapulmonary, definitive diagnosis may require intraocular fluid analysis or tissue biopsy.
Nucleic acid amplification techniques, with either transcription-mediated amplification of 16S ribosomal RNA or PCR amplification of
unique DNA sequences of M tuberculosis, have been successfully used in some cases to diagnose intraocular TB, though the yield may be
low because of a thick cell wall and possibly low bacterial load in the vitreous.

Chorioretinal biopsy used in conjunction with PCR testing and routine histologic examination
may be necessary in atypical cases where the differential diagnosis and therapeutic options are
widely divergent.
Recently, antibodies against purified cord factor, the most antigenic and abundant cell wall
component of tubercle bacilli, have been detected by ELISA and may be useful for rapid
serodiagnosis of pulmonary TB, in addition to providing supportive data for the diagnosis of
ocular infection.
 Treatment
• Systemic antitubercular therapy is clearly indicated for patients with uveitis
whose TB test results have recently converted to positive, patients with an
abnormal-appearing chest radiograph suggestive of tuberculosis, or persons
with positive mycobacterial culture or PCR results to M tuberculosis.
• Multidrug therapy is recommended because of the increasing incidence of
resistance to isoniazid as well as adherence problems associated with long-
term therapy. .

• These problems, together with the extremely slow growth rate of TB, contribute to the acquisition of
multidrug-resistant tuberculosis (MDRTB).
• Patients at risk for MDRTB include nonadherent patients receiving single-drug therapy; migrant or
indigent populations; immunocompromised patients, including those with HIV infection; and recent
immigrants from countries where isoniazid and rifampin are available over the counter
 • More difficult is the treatment approach to patients with uveitis consistent
with TB, normal chest radiograph appearance, and positive TB test result.
• In this situation, a diagnosis of extrapulmonary TB may be entertained and
treatment initiated, particularly in cases with medically unresponsive
uveitis or other findings supportive of the diagnosis, such as recent
exposure to or inadequate treatment of the disease, a large area of
induration, or skin test result recently converted to positive.

• Topical and even systemic corticosteroids may be used in conjunction with antimicrobial therapy to
treat the inflammatory component of the disease.
• Because intensive corticosteroid treatment administered without appropriate coverage with
antituberculosis treatment may lead to progressive worsening of ocular disease, any patient suspected
of harboring TB should undergo appropriate testing before beginning such therapy.
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