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Tuberculous uveitis is a rare condition caused by Mycobacterium tuberculosis. Involvement of the uveal tract is the most common manifestation of the disease, and findings of granulomatous anterior uveitis, disseminated choroiditis with vitritis, and cystoid macular edema are common. Diagnosis requires a high level of suspicion for the disease as systemic signs and symptoms of infection may not be present and is made by exclusion of other causes of uveitis. Treatment involves multidrug antimicrobial therapy in combination with topical and oral corticosteroids.

Disease Entity

Tuberculous Uveitis ICD9 364.11

Disease

Currently, ocular involvement of tuberculosis (TB) is a rare condition in the United States, diagnosed in only 1-2% of patients. In the developing world, the incidence of systemic disease is much higher, with over 8 million new cases each year, and the incidence of TB uveitis mirrors this rate. At major referral centers in India, the incidence of tuberculous uveitis ranged from 0.6% to 10%; similarly, in Japan and Saudi Arabia, rates were 7.9% to 10.5%. This contrasts with an incidence rate of 0.6% at a large tertiary care facility in the United States. However, while overall rates are still low in the US, the incidence of tuberculosis has increased simultaneously with the commencement of the AIDS epidemic. In the immunocompromised population, rates of extrapulmonary TB have increased. In addition, foreign-born individuals represent nearly half of the cases in the US and are another emerging population of new patients with this disease entity.

Most commonly, the infection is limited to pulmonary involvement, with only 20% having extrapulmonary disease. Extrapulmonary disease is often seen in severely immunocompromised patients or those with HIV/AIDS. A small minority of infected patients develop symptomatic disease generally in the first 1-2 years.

Etiology

Mycobacterium tuberculosis is the acid-fast-staining obligate aerobe responsible for the disease, which is characterized by granuloma formation. It is transmitted most commonly via aerosolized droplets. Organisms are commonly found in lung apices because they have an affinity for highly oxygenated tissue. This is the same reason organisms infect the choroid, as this tissue has the highest blood flow rate in the body.

Risk Factors

Recent exposure can cause primary systemic infection, and more commonly, reactivation of latent disease causes secondary infection. Patients who are immunocompromised from chronic disease, HIV/AIDS, or medication, health care workers, and recent immigrants from endemic areas are high-risk populations.

General Pathology

Bacilli invade tissue, and a delayed-type hypersensitivity reaction develops, causing caseous necrosis and tubercle. Infection spreads throughout the body when bacteria-laden macrophages carry the organism to different sites. Ziehl-Neelsen acid-fast stain can be used to visualize bacteria within granulomas.

Pathophysiology

Tuberculosis can affect the eye either primarily with active infection or secondarily due to an immune reaction to the mycobacterium. The conjunctiva, cornea, and sclera are sites of primary ocular involvement. The hematogenous spread of the disease or its spread from neighboring structures is responsible for uveitis, the most common manifestation of secondary ocular TB. Ocular manifestations of TB are varied and include scleritis, phlyctenulosis, interstitial keratitis, corneal infiltrates, anterior chamber cells, iris nodules, and granulomatous anterior uveitis. These can occur without signs of systemic involvement.

Primary prevention

Primary prevention for tuberculous uveitis involves avoiding exposure to actively infected individuals in order to prevent systemic infection.

Diagnosis

Diagnosis of tuberculous uveitis is often one of exclusion, as identification of the mycobacteria in ocular tissue or aqueous humor is not always possible. Laboratory and diagnostic testing pointing to systemic TB infection aids in diagnosing presumptive TB uveitis. Serologic testing should be done to rule out other causes of uveitis.

History

The time of onset, duration of symptoms, and a thorough review of systems are necessary. Patients should be questioned regarding fevers, night sweats, chronic pulmonary infection, and weight loss to assess for systemic involvement because extrapulmonary infection can present with these classic symptoms as well. A history of travel to endemic areas or prior exposure to an acutely infected individual should also be elicited. Immunosuppressive medications taken for another process need to be documented and addressed.

Symptoms

Blurry vision and light sensitivity may be the only symptoms that are reported. Other complaints may include headache, redness of the eye, floaters, or flashes. Patients may also be asymptomatic.

Physical examination

Anterior segment examination should be done to evaluate for granulomatous anterior uveitis. Mutton-fat keratic precipitates, iris or angle granulomas, posterior synechiae, hypopyon, and secondary glaucoma may be present. Panuveitis and intermediate uveitis are possible. Posterior uveitis with disseminated choroiditis is the most common manifestation of tuberculous uveitis and is often bilateral. Multiple, discrete, yellow lesions uni- or bilaterally may be seen in the posterior pole ranging from pinpoint to several disc diameters in size. As lesions progress, their borders may become more distinct with a rim of surrounding black pigment, and the center becomes paler or turns yellow, leading to an atrophic scar. Subretinal neovascularization can later develop. Disc edema, periphlebitis, vasculitis, and vitritis can be present. Single large choroidal tuberculomas may be found with or without associated retinal detachment and macular star formation. Infection can also present as multifocal choroiditis or serpiginous-like choroiditis, and caseous liquefaction of choroidal granulomas can lead to subretinal abscesses.

Clinical diagnosis

Diagnosing tuberculosis uveitis requires a combination of patient history, clinical examination, and adjunct testing.

Usually, the diagnosis of IOTB (intraocular tuberculosis) is presumptive after excluding other possible uveitis entities. As suggested by Guta et al. the definite (confirmed) diagnosis of intraocular T.B. requires the following :

One or more clinical signs that are suggestive of TB
One of the following ocular investigations needs to be positive
- Demonstration of AFB (acid-fast bacilli) by microscope or culture of M. tuberculosis from the ocular fluids.
- Positive polymerase chain reaction from ocular fluids.

Because that is always difficult to obtain, the diagnosis of IOTB is almost always presumptive. For presumed intraocular TB, Abu El-Asrar et al. and Gupta et al., in their reviews of intraocular TB, have defined presumed intraocular TB as the following :

Ocular findings consistent with possible intraocular TB with no other cause of uveitis suggested by history or symptoms or ancillary testing.
Strongly positive tuberculin skin test results (≥15 mm area of induration/necrosis), radiological evidence of healed or active tubercular lesion in the chest, or evidence of confirmed active extrapulmonary TB either by microscopic examination or by culture from affected tissue.
Response to antitubercular therapy with the absence of recurrences.

Diagnostic procedures

Fluorescein angiography reveals early hypofluorescence of active choroiditis and late leakage. Cicatricial lesions show early blocked hyperfluorescence with late staining. Indocyanine green angiography shows early and late-stage hypofluorescence of the lesions, and subclinical lesions may be seen.

Ultrasonography reveals moderate to low internal reflectivity of large tuberculomas and can distinguish them from intraocular malignancy.

Laboratory test

Laboratory workup includes testing to rule out other causes of uveitis and PPD (purified protein derivative or tuberculin) skin testing, chest x-ray, and/or chest computed tomography (CT). A positive PPD skin test indicates prior exposure and not necessarily active infection. Half of patients with extrapulmonary involvement can have a negative chest x-ray, and 20% can have a negative purified protein derivative skin test. Also, false negative PPD results occur 25% of the time in those with immunocompromise. Prior history of Bacille Calmette-Guerin (BCG) vaccination causes false positives.

The Quantiferon-Gold test, an interferon-gamma release assay, was developed in 2007 to aid in the diagnosis of tuberculosis and is recommended for use as an alternative to tuberculin skin testing by the United States Centers for Disease Control and Prevention. Because diagnosis of tuberculosis-related uveitis is often difficult because of complicating factors such as prior BCG vaccination, immunosuppression, and low yield of aqueous fluid cultures in diagnosis, the use of Quantiferton-Gold testing has been found to be useful in increasing the confidence in a diagnosis when skin test results are indeterminate or inconsistent with clinical findings. However, negative Quantiferon-Gold testing does not necessarily rule out a diagnosis of tuberculous uveitis and repeat testing may be necessary.

Negative testing for systemic disease still does not rule out ocular involvement. Intraocular fluid analysis or tissue biopsy would make a definitive diagnosis in these cases; however, this is not always available. Diagnosis can be made with nucleic acid amplification by either transcription-mediated amplification of 16S RNA or PCR amplification of DNA sequences of the mycobacteria. Chorioretinal biopsy has also been used to make the diagnosis and can be used with nucleic acid amplification techniques.

Differential diagnosis

Differential diagnosis includes other etiologies for uveitis, including histoplasmosis, toxocariasis, sarcoidosis, syphilis, toxoplasmosis, and acute retinal necrosis. Tuberculomas may resemble melanoma or retinoblastoma.

Management

General treatment

Treating tuberculous uveitis involves treating the underlying infection, whether it manifests as pulmonary or disseminated systemic disease. Ocular therapy alone is not curative and may mask the expression of the disease symptoms; however, it may be used with systemic therapy to treat the ocular manifestations and prevent the ocular sequelae of chronic uveitis.

Medical therapy

For patients with suspected tuberculous uveitis, systemic multi-drug antibiotic therapy is necessary due to the prevalence of multidrug-resistant tuberculosis, and they should be managed in conjunction with an infectious disease specialist. In addition to antimicrobial therapy, topical and oral corticosteroids are frequently used. The use of steroids necessitates the use of antituberculous therapy concurrently, as ocular disease will worsen on steroids alone.

Medical follow up

There are no exact guidelines for the duration of treatment of ocular TB. Generally, at least nine months of therapy are required. CDC recommendations include prolonged therapy for any unresponsive sites.

Surgery

Surgical intervention is often limited to diagnostic procedures such as diagnostic vitrectomy or chorioretinal biopsy.

Complications

Persistent inflammation may lead to secondary glaucoma, cataract formation, and cystoid macular edema, the most common cause of visual loss in uveitis. Anti-tuberculous treatments themselves may contribute to ocular complications. Ethambutol can lead to dose-related optic neuritis, color vision deficiencies, central scotomas, retinal edema, and foveal pigmentary changes. These effects are usually present after 3-6 months of treatment and necessitate frequent examinations, especially for those patients on more than 15 mg/kg/day. Isoniazid has less commonly been reported to cause optic neuritis as well. Rifabutin's side effects include severe acute anterior uveitis with hypopyon.

Prognosis

Without treatment, there is a waxing and waning course of disease, with eventual degradation of the blood-aqueous barrier, increased vitreous opacities, and cystoid macular edema. It is possible to have scleral necrosis and perforation if the disease process involves the sclera. With the initiation of anti-tuberculous therapy, the prognosis is good, and choroidal lesions can resolve completely. Serpiginous-like choroiditis has a poorer prognosis with little response to antituberculous therapy or corticosteroids.

Additional Resources

References

Intraocular Inflammation and Uveitis, Section 9. Basic and Clinical Science Course, AAO, 2006.
Gupta V, Gupta A, and Rao N. Intraocular tuberculosis – an update. Surv Ophthalmol 2007; 52: 561-587.
Albini T, Karakousis, and Rao N. Interferon-gamma release assays in the diagnosis of tuberculous uveitis. Am J Ophthalmol 2008; 146(4): 486-488.
Ang M, Htoon H, and Chee S. Diagnosis of tuberculous uveitis: clinical application of an interferon-gamma release assay. Opthalmol 2009; 116: 1391-1396.
Abu El-Asrar AM, Abouammoh M, Al-Mezaine HS. Tuberculous uveitis. Middle East Afr J Ophthalmol 2009;16:188-201
Neuhouser AJ, Sallam A. Ocular Tuberculosis. [Updated 2023 Jan 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559303/

Tuberculosis Uveitis

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