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
Ocular Involvement
May result from either active infection or an immunologic
reaction to the organism.
External ocular and anterior segment findings
scleritis, phlyctenulosis, interstitial keratitis,
corneal infiltrates, anterior chamber and iris nodules,
and isolated granulomatous anterior uveitis (Fig 10, 9);
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.

Taki W, Keino H, Watanabe T, Nakashima C, Okada AA. Interferon-γ Release Assay in Tuberculous
Scleritis. Arch Ophthalmol. 2011;129(3):360–371. doi:10.1001/archophthalmol.2011.27
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 OS: Sectoral and peripheral interstitial keratitis
large iris nodules
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
affect 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.)
Choroidal Involvement
Disseminated choroiditis is the most
common presentation and is characterized
by multiple deep, discrete, yellowish
lesions between 0.5 mm and 3.0 mm in
diameter
and numbering from 5 to several hundred
(Fig 10-11).

These lesions, or tubercles, are located

predominantly in the posterior pole and
may
be accompanied by disc edema, nerve fiber
layer hemorrhages, and varying degrees of
vitritis and granulomatous 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 choroidal
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). 

Basu et. al, Ophthalmology, 119, 10, 10 2012

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
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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