Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison.
This month the Archives of Ophthalmology joins with JAMA in focusing on tuberculosis for their theme issue. Tuberculosis remains the world’s leading infectious cause of death and can also cause a variety of diseases throughout the body and the eye.1 Worldwide there are approximately 8 million new cases and 3 million deaths from tuberculosis each year.2,3 Approximately one third of the world’s population has been infected.3 The demographics of infection vary widely, with developing countries bearing the heaviest burden of disease.
In the United States in 1953, the annual risk of being infected with tuberculosis was 53 per 100 000 members of the population. This decreased to 9.4 per 100 000 by 1984, and the World Health Organization set a goal of eliminating tuberculosis worldwide. There was a resurgence in the United States to a peak of 10.5 per 100 000 by 19924,5; the reported incidence then declined to 5.1 per 100 000 in 2003.6
Ocular tuberculosis has always been considered rare, yet its incidence has varied widely across time, patient populations, and geography. In 1967, Donahue7 reported an incidence of ocular tuberculosis of 1.46% in 10 524 patients from a tuberculosis sanitarium. A prospective study from Spain, reported in 1997, examined 100 randomly chosen patients with proven systemic tuberculosis and found ocular involvement in 18 patients (18%).8 In Malawi, Africa, a 2.8% incidence of choroidal granuloma in 109 patients with fever and tuberculosis was reported in a prospective study in 2002.9 In India, in a study conducted from January 1992 to December 1994, 0.6% of uveitis cases were believed to be caused by tuberculosis.10 In Japan, a prospective case series from April 1998 to August 2000 reported that 20.6% of 126 patients with uveitis had a positive purified protein derivative (PPD) skin test result, and 7.9% were thought to have intraocular tuberculosis.11 In Saudi Arabia, during the period from 1995 to 2000, tuberculosis was the cause in 10.5% of uveitis cases seen in a referral center.12 In Boston, 0.6% of patients with uveitis from 1982 to 1992 were believed to have tuberculosis as an underlying cause.13
Human immunodeficiency virus (HIV) has contributed to the increase in the incidence of tuberculosis worldwide9; HIV increases the risk of development of active tuberculosis in patients infected with Mycobacterium tuberculosis.14 However, rates of ocular tuberculosis in patients with tuberculosis with or without HIV are variable. In a study reported in 1993 of autopsy eyes from 235 patients with AIDS, intraocular tuberculosis was found in only 2 eyes.15 The effect of HIV on the immune system can influence both the diagnosis, by reducing the response to PPD testing, and the success of treatment.
Tuberculosis affecting the eyelid is most often found in children.16 The most common form of cutaneous tuberculosis, lupus vulgaris, is characterized by reddish-brown nodules that blanch to an “apple-jelly” color when pressure is applied and may appear on the skin of the eyelids.17,18 Tuberculosis can also manifest as a “cold abscess,” a soft, fluctuant mass without acute inflammation,19 or simulate a chalazion.20
Primary infection of the conjunctiva is unusual and more commonly affects children.16,21,22 Tuberculous conjunctivitis is often a chronic disease that may lead to scarring of the involved tissue. Patients with tuberculous conjunctivitis have nonspecific complaints such as ocular redness and discomfort. Examination may reveal mucopurulent discharge and lid edema, often with an accompanying marked lymphadenitis such as in Parinaud oculoglandular syndrome, which is absent in most other forms of bacterial and allergic conjunctivitis and less prominent in viral conjunctivitis. In cases of primary conjunctival tuberculosis, M tuberculosis can be detected via traditional acid-fast stains on either a conjunctival smear or a biopsy specimen.23
Corneal involvement most commonly manifests as phlyctenular keratoconjunctivitis or interstitial keratitis. Phlyctenular keratoconjunctivitis is a nonspecific allergic response in the cornea and/or conjunctiva to a foreign protein.24 It has been associated with tuberculosis, staphylococcal blepharitis, and parasite infection. Tuberculosis remains the leading etiology in areas where tuberculosis is common.25 It typically starts with redness, tearing, and foreign-body sensation, the severity of which corresponds to the degree of corneal involvement. Lesions most commonly begin as small nodules at the limbus that may then migrate centrally, dragging superficial vessels along behind. The overlying epithelium is initially intact but often erodes, leading to an epithelial defect. Treatment consists of systemic antituberculous chemotherapy in confirmed tuberculosis cases in conjunction with topical steroids.25 Severe visual loss is uncommon.25
Interstitial keratitis is characteristically unilateral and manifests as a sectoral, peripheral stromal infiltrate with vascularization. It may be more anterior than syphilitic interstitial keratitis and have more frequent recurrences.16 As is the case with phlyctenular keratoconjunctivitis, mycobacterial proteins are postulated as antigens that induce a corneal hypersensitivity reaction.26 Treatment of tuberculous interstitial keratitis consists of systemic as well as topical antituberculous chemotherapy and cycloplegia.
Tuberculosis as a cause of scleritis and episcleritis is rare. Focal necrotizing scleritis is the most common type, appearing as an area of dark red discoloration of the sclera with chronic granulomatous inflammation and caseous necrosis.27- 30 A case of posterior scleritis was also reported in a patient with systemic tuberculosis.31 Scleral perforation can occur.32 In a case series from the United States reported in 1976, only 1 of 217 patients with episcleritis and 4 of 301 patients with scleritis were found to have active tuberculosis.33 Although rare, tuberculous scleritis should be considered in patients with a positive PPD or chest radiograph result or in cases in which scleritis is unresponsive to traditional therapy.
Tuberculous uveitis is classically a chronic granulomatous disease that causes mutton-fat keratic precipitates, iris nodules, posterior synechiae, and secondary glaucoma.17,34,35 Nongranulomatous uveitis may also occur,36 and there may be anterior and/or posterior inflammation. Miliary tuberculosis may cause seeding of the iris.16
During the past 50 years, tuberculosis has been responsible for a progressively smaller percentage of uveitis cases in the United States. The incidence of tuberculous uveitis at the Wilmer Eye Institute (Baltimore, Md) fell from 79% in 1944 to 22% in 1953.37 The incidence of uveitis caused by tuberculosis at the Massachusetts Eye and Ear Infirmary (Boston) from 1982 through 1992 was only 0.6%.13 Uveitis is more likely to be attributed to tuberculosis in parts of the world where the prevalence of tuberculosis is higher. In patients with uveitis at a uveitis clinic in India between January 1992 and December 1994, 0.6% of cases were believed to be caused by tuberculosis.10 In a major referral center in northern India between January 1996 and June 2001, 10% of uveitis cases were caused by tuberculosis, the most common etiology.38 In a prospective case series in Japan from April 1998 to August 2000, 20.6% of 126 patients with uveitis had a positive PPD result, and 7.9% were thought to have intraocular tuberculosis.11 In Saudi Arabia, tuberculosis was the cause of 10.5% of uveitis cases seen in a referral center according to a retrospective review of clinical records that was reported in October 2002.12
Choroidal tubercles can occur in a variety of clinical circumstances, despite claims that they occur only in terminally ill patients with miliary tuberculosis or tuberculous meningitis.39 Choroidal tubercles have been reported in young children with miliary tuberculosis40 and in patients with pulmonary tuberculosis without evidence of systemic disease.41 A case was described in which miliary tubercles were associated with optic neuropathy but not with other systemic lesions.42 Choroidal tubercles may be one of the earliest signs of disseminated disease.
Choroidal tubercles may appear as white, gray, or yellow lesions and may be accompanied by hemorrhages or exudates. They have indistinct borders with surrounding edema, and their size varies from about 0.5 mm to 3.0 mm in diameter. Choroidal tubercles are usually multiple and are probably the most common form of ocular tuberculosis.42 Other manifestations of tuberculous infection of the choroid include multifocal choroiditis43 and serpiginouslike choroiditis.44
Tuberculous choroiditis has been reported in patients with AIDS and systemic tuberculosis.45,46 Choroidal tubercles in 3 patients with AIDS in a hospital in Madrid, Spain, were discovered after the initiation of systemic antituberculous chemotherapy, when the patients were considered to be in a healing stage.45 The condition of one patient with AIDS who had central nervous system tuberculosis and tuberculosis choroiditis improved dramatically after the initiation of a triple antituberculous therapy. The cerebrospinal fluid findings returned to normal, and visual acuity improved from 20/200 to 20/20 OU.46
The prognosis for patients with choroidal tubercles has greatly improved with the use of systemic antituberculous agents. No specific local therapy is needed. Many lesions regress completely with minimal residual damage, whereas others heal with focal chorioretinal scars.41,47,48 In the setting of AIDS, however, tuberculous choroiditis may progress despite effective antituberculous chemotherapy.49 Increasing resistance of M tuberculosis to antibiotics may also result in unresponsiveness to therapy.50
Tuberculosis of the retina most commonly results from choroidal extension but may also be caused by hematogenous spread. Retinal lesions may be either focal tubercles or diffuse retinitis. There may be vitreous opacification, gray-white retinal lesions,26 or retinal vasculitis.51 Neovascularization and peripheral capillary occlusion have been described in cases of choroiditis, chorioretinitis, and retinal vasculitis.17,52,53 A combination of systemic treatment and retinal photocoagulation has been advocated for the treatment of retinal neovascularization related to tuberculosis.17,52 Fountain and Werner54 described a case of central retinal vein occlusion associated with active pulmonary tuberculosis and typical retinal gray-white lesions.
Tuberculosis has also been reported to manifest as retinal vasculitis.52 Eales disease is a form of retinal perivasculitis that predominantly affects the peripheral retina and is most common in young and otherwise healthy adults.37,55,56 The initial event in Eales disease is often a sudden, painless decrease in vision secondary to a vitreous hemorrhage. After the vitreous hemorrhage clears, perivascular exudates and hemorrhages are visible along the retinal vessels. The vasculitis can progress to venous thrombosis, neovascularization, glial tissue proliferation, and eventual tractional retinal detachment. Tuberculosis DNA has reportedly been found via polymerase chain reaction (PCR) of vitreous and epiretinal membrane tissues obtained from patients with Eales disease.56,57 Eales disease may have multiple other causes. Gupta et al58 described 13 patients with retinal vasculitis and a PCR result positive for tuberculosis in the aqueous or vitreous fluid, further strengthening the association between tuberculosis and retinal vasculitis. According to these authors, the association between active or healed patches of choroiditis and retinal vasculitis strengthens the suggestion of tubercular etiology.
Tuberculosis of the orbit is rare, with only 5 cases reported in the Western literature in the past 50 years. In India and in other areas where tuberculosis is endemic, cases of orbital tuberculosis are more common. Patients exhibit a mixture of orbital findings such as pain, proptosis, eyelid swelling, intermittent periorbital swelling, headache, epistaxis, decreased vision, visual field abnormalities, chemosis, Marcus Gunn pupil, epiphora, and increased orbital resistance to retropulsion.59- 61 In one case, proptosis was an incidental finding.59 There was also a case of a woman with dacryoadenitis secondary to tuberculosis.62,63 Diagnosis can be confirmed by orbital tissue biopsy and culture or by orbital fine-needle aspiration. Cases can be followed up with computed tomography. Patients have been treated successfully with systemic antituberculous therapy, although additional surgery is sometimes required.60,61,64- 66
Acute tuberculous panophthalmitis begins with painless, progressive loss of vision, decreased motility of the eye, cloudy cornea, signs of granulomatous ocular inflammation, and low intraocular pressure. Perforation of the globe can occur, usually at a site near the equator. Panophthalmitis usually appears in children or severely ill adults with evidence of systemic tuberculosis and poor nutrition, chronic illness, or intravenous drug use.67,68 There have been reports of tuberculous panophthalmitis and endophthalmitis masquerading as ocular tumors.69,70
Tuberculosis can cause meningitis, and increased intracranial pressure can result in palsy of the sixth cranial nerve.71 A variety of pupillary abnormalities may occur; optic nerve involvement may lead to optic neuritis or optic atrophy.16,71
Diagnosis of tuberculosis infection is difficult. A definitive diagnosis is possible when M tuberculosis can be visualized in, or cultured from, or its DNA amplified from the involved tissue. In cases in which this is not possible, indirect evidence can strongly suggest that tuberculosis is responsible for a patient’s clinical condition, and the diagnosis is best termed presumed ocular tuberculosis.
The diagnosis of tuberculosis begins with a complete physical examination, including a sputum smear and culture, PPD test, and chest radiograph. The presence of a systemic tuberculosis infection strongly indicates but does not prove that tuberculosis is causative of ocular findings. Additionally, an initial workup that yields negative results should not eliminate tuberculosis from the differential diagnosis. Abrams and Schlaegel36 reported that in 18 patients with presumed tuberculosis uveitis, the chest radiograph showed no active or inactive evidence of tuberculosis in 17 cases and that only 9 patients had at least 5 mm of induration when evaluated with an intermediate-strength PPD test (5 TU), with 5 experiencing no reactivity at all. All 18 patients were diagnosed as having presumed tuberculous uveitis based on history, physical examination, tests to rule out other etiologies, the tuberculin skin test, and the isoniazid therapeutic test. (The isoniazid therapeutic test consists of 3 weeks of 300 mg/d of isoniazid. A result is considered positive if there is dramatic improvement in 1 to 3 weeks of therapy. There may be a false-negative result in patients with AIDS or in cases of drug-resistant disease.)
Whereas cultures may easily be obtained in patients with external disease, in most ocular tuberculosis cases, culture and biopsy of the involved tissues is not practical. When performed, aqueous and vitreous paracentesis have generally failed to yield positive bacterial culture results.37
Diagnosis based on detection of mycobacterial DNA through PCR is becoming the method of choice. Advantages of PCR include rapid test results and the ability to test a very small sample. By comparison, cultures may require several weeks for a positive result. Mycobacterial DNA has been detected via PCR in a variety of tissues, including eyelid skin, the conjunctiva, aqueous and vitreous humor, fixed choroidal tissue, subretinal fluid, epiretinal membranes, and several nonocular tissues.56,57,72- 78 There have also been reports of testing for tuberculosis antigens, such as cord factor antigen, via enzyme-linked immunosorbent assay (ELISA).79 Although further investigations are needed to determine the sensitivity and specificity of PCR and ELISA testing for tuberculosis in ocular tissues, these techniques have added a valuable alternative for the diagnosis of intraocular tuberculosis infection.
Systemic treatment with a multidrug regimen is preferred because pulmonary infection and other foci of infection may coexist. Systemic treatment is successful in the vast majority of cases, with subsequent resolution of symptoms, inflammation, and often an improvement in visual acuity to near premorbid levels. Primary treatment should always be systemic. Therapy is frequently continued for several months depending on the patient’s immune status and response and should be administered in conjunction with a physician who is able to monitor for systemic toxic effects of the medication, such as liver damage. There have been reports of systemic therapy failing to check ocular infection, and multidrug-resistant tuberculosis should be kept in mind.80
Ocular penetration of systemic drugs varies, and additional topical treatment may be useful in patients with external disease. Isoniazid given as a topical ointment or subconjunctival injection can achieve adequate intraocular drug levels, especially in the anterior segment. However, parenteral administration results in higher vitreous drug levels and makes this route of administration the method of choice in posterior intraocular tuberculosis.81 Streptomycin sulfate administered topically penetrates the aqueous humor at high levels only in the presence of an epithelial defect. Intravitreal injection is more successful in generating therapeutic intraocular levels but may lead to retinal damage with high doses.82 Parenteral administration of high doses can achieve detectable levels in all ocular tissues.83 Rifampin administered orally was shown to attain an aqueous concentration of 2% to 9% of its serum level, which may be a therapeutic level against some organisms.84 Studies regarding the ocular penetration of pyrazinamide have not yet been published.
There may be a role for laser treatment as an adjuvant therapy for ocular tuberculosis. Balashevich85 has reported that argon laser photocoagulation of tuberculous chorioretinitis lesions near the fovea results in better visual acuity than conventional treatment. In contrast, Jabbour et al68 reported a subretinal granulomatous lesion that grew outside previously placed photocoagulation scars. There have been 2 reports of the successful use of sector photocoagulation for the treatment of subretinal neovascularization in cases of chorioretinitis.17,52 Laser therapy should never be considered a primary treatment without systemic antituberculous chemotherapy. It is wise to delay laser treatment until the diagnosis is established and the response to chemotherapy is confirmed to avoid further confusion of the clinical picture and course.
Ethambutol hydrochloride has significant ocular toxic effects, including optic neuritis, photophobia, and extraocular muscle paresis.86 Symptoms of optic neuritis are most often abrupt in onset and typically begin 3 to 6 months after the start of ethambutol therapy. Toxic effects are dose related; they occur in 1% to 2% of patients receiving a daily dose of 25 mg/kg and are rare with a daily dose not exceeding 15 mg/kg.
Patients should undergo ophthalmic examination, including visual field and color plate tests at baseline and every 4 weeks when doses greater than 15 mg/kg per day are used and every 3 to 6 months for lower doses. The patient should be given a vision card and instructed to stop the ethambutol and seek an ophthalmic examination immediately if there is a decrease in visual acuity.
Most symptoms resolve during a period of 3 to 12 months, but cases of permanent vision loss have been reported. If the vision does not improve after 10 to 15 weeks of drug discontinuation, treatment with parenteral hydroxocobalamin, 40 mg/d during a 10- to 28-week period, should be considered.
Correspondence: Matthew J. Thompson, MD, 2870 University Ave, Room 206, Madison, WI 53705 (email@example.com).
Submitted for Publication: January 24, 2005; final revision received March 14, 2005; accepted March 17, 2005.
Financial Disclosure: None.
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